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{ "abstract": "Inappropriate verbal and physical sexual behaviour is not common among individuals with dementia, but when it does occur, it can have profound consequences. We report a case of 79-year-old woman with dementia of the Alzheimer's type who complained of increased libido after an increased dose of donepezil, which was being used along with tianeptine. Donepezil withdrawal led to the resolution of increased libido, but when it was reintroduced, increased libido reappeared once again (Naranjo score: 7). Increased libido was not reported by the patient during the 6-year follow-up period after donepezil withdrawal. A potential mechanism of acetylcholinesterase inhibitor-induced increased libido and the current literature on hypersexuality as a side-effect of donepezil treatment are discussed.", "affiliations": "University Psychiatric Hospital Ljubljana, Ljubljana, Slovenia.;Department of Psychiatry, University of Cambridge, Cambridge, UK.;University Psychiatric Hospital Ljubljana, Ljubljana, Slovenia.", "authors": "Segrec|Nusa|N|;Zaman|Rashid|R|;Pregelj|Peter|P|", "chemical_list": "D000929:Antidepressive Agents, Tricyclic; D002800:Cholinesterase Inhibitors; D007189:Indans; D010880:Piperidines; D013841:Thiazepines; C050504:tianeptine; D000077265:Donepezil", "country": "England", "delete": false, "doi": "10.1111/psyg.12113", "fulltext": null, "fulltext_license": null, "issn_linking": "1346-3500", "issue": "16(1)", "journal": "Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society", "keywords": "adverse effects; dementia; dementia of the Alzheimer's type; donepezil; increased libido", "medline_ta": "Psychogeriatrics", "mesh_terms": "D000544:Alzheimer Disease; D000929:Antidepressive Agents, Tricyclic; D002800:Cholinesterase Inhibitors; D000077265:Donepezil; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007189:Indans; D007989:Libido; D010880:Piperidines; D007319:Sleep Initiation and Maintenance Disorders; D013841:Thiazepines; D016896:Treatment Outcome", "nlm_unique_id": "101230058", "other_id": null, "pages": "70-2", "pmc": null, "pmid": "25735193", "pubdate": "2016-01", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Increased libido associated with donepezil treatment: a case report.", "title_normalized": "increased libido associated with donepezil treatment a case report" }

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}, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DEPRESSION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "6.25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TIANEPTINE" }, { "actiondrug": "3", "activesubstance": { "activesubstancename": "DONEPEZIL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, 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"drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TIANEPTINE" } ], "patientagegroup": null, "patientonsetage": "79", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Decreased appetite", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Libido increased", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "SEGREC N, ZAMAN R, PREGELJ P. INCREASED LIBIDO ASSOCIATED WITH DONEPEZIL TREATMENT: A CASE REPORT. 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HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNCONFIRMED", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNK", "drugdosagetext": "5 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DONEPEZIL HYDROCHLORIDE (UNKNOWN)" } ], "patientagegroup": null, "patientonsetage": "79", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pain", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dysgeusia", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dizziness", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Libido increased", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anxiety", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Parosmia", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Decreased appetite", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SEGREC N, ZAMAN R, PREGELJ P. INCREASED LIBIDO ASSOCIATED WITH DONEPEZIL TREATMENT: A CASE REPORT. PSYCHOGERIATRICS. 2016?16(1):70-2", "literaturereference_normalized": "increased libido associated with donepezil treatment a case report", "qualification": "1", "reportercountry": "SI" }, "primarysourcecountry": "SI", "receiptdate": "20160226", "receivedate": "20160226", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12118590, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160526" }, { "companynumb": "SI-LUPIN PHARMACEUTICALS INC.-2016-00816", "fulfillexpeditecriteria": "2", "occurcountry": "SI", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "DONEPEZIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "202782", "drugbatchnumb": "UNKNOWN", "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": "DONEPEZIL." } ], "patientagegroup": "6", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Libido increased", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypersexuality", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PREGELJ P, ZAMAN R, SEGREC N, CHEMALI Z. INCREASED LIBIDO ASSOCIATED WITH DONEPEZIL TREATMENT: A CASE REPORT. PSYCHOGERIATRICS. 2016;16:70-72.", "literaturereference_normalized": "increased libido associated with donepezil treatment a case report", "qualification": "1", "reportercountry": "SI" }, "primarysourcecountry": "SI", "receiptdate": "20160509", "receivedate": "20160509", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 12345551, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160815" }, { "companynumb": "SI-LUPIN PHARMACEUTICALS INC.-2016-00786", "fulfillexpeditecriteria": "2", "occurcountry": "SI", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "DULOXETINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "090694", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DEPRESSIVE SYMPTOM", "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": "DONEPEZIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "202782", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, 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"drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DONEPEZIL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TIANEPTINE" }, "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": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "12.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TIANEPTINE" }, { "actiondrug": null, 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"UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "30 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANXIETY", "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": "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." } ], "patientagegroup": null, "patientonsetage": "79", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pain", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dizziness", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Decreased appetite", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anxiety", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { 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INCREASED LIBIDO ASSOCIATED WITH DONEPEZIL TREATMENT: A CASE REPORT. 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INCREASED LIBIDO ASSOCIATED WITH DONEPEZIL TREATMENT: A CASE REPORT. PSYCHOGERIATRICS. 2015?MAR 3", "literaturereference_normalized": "increased libido associated with donepezil treatment a case report", "qualification": "1", "reportercountry": "SI" }, "primarysourcecountry": "SI", "receiptdate": "20160301", "receivedate": "20160301", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12134133, "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": "SI-LUPIN PHARMACEUTICALS INC.-2016-00817", "fulfillexpeditecriteria": "2", "occurcountry": "SI", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "DONEPEZIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "202782", "drugbatchnumb": "UNKNOWN", "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": "DONEPEZIL." } ], "patientagegroup": "6", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypersexuality", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Libido increased", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PREGELJ P, ZAMAN R, SEGREC N, CHEMALI Z. INCREASED LIBIDO ASSOCIATED WITH DONEPEZIL TREATMENT: A CASE REPORT. PSYCHOGERIATRICS. 2016;16:70-72.", "literaturereference_normalized": "increased libido associated with donepezil treatment a case report", "qualification": "1", "reportercountry": "SI" }, "primarysourcecountry": "SI", "receiptdate": "20160509", "receivedate": "20160509", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 12345553, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160815" } ]

{ "abstract": "Cardiotoxicity, including heart failure, thromboembolic events, and myocardial ischemia, is a concern for cardiologists and oncologists. The most frequently involved drugs are anthracyclines. We report an episode of coronary spasm due to vincristine, a vinca alkaloid, in a 49-year-old man treated for a diffuse undifferentiated carcinoma. The patient suffered recurrent episodes of typical chest pain with ST-elevation in the inferior area. Coronary spasm was confirmed by an angiogram, which showed normal coronary arteries. No recurrence occurred with the medical management. Coronary spasm induced by vincristine is a newly described facet of chemotherapy-related cardiotoxicity.", "affiliations": "Intensive Care Unit, Centre Hospitalier Métropole-Savoie, Chambéry, France.", "authors": "Gros|Rosine|R|;Hugon|Vincent|V|;Thouret|Jean-Marc|JM|;Peigne|Vincent|V|", "chemical_list": "D000972:Antineoplastic Agents, Phytogenic; D019210:Troponin I; D014750:Vincristine", "country": "Switzerland", "delete": false, "doi": "10.1159/000455224", "fulltext": null, "fulltext_license": null, "issn_linking": "0009-3157", "issue": "62(3)", "journal": "Chemotherapy", "keywords": null, "medline_ta": "Chemotherapy", "mesh_terms": "D000972:Antineoplastic Agents, Phytogenic; D002277:Carcinoma; D017023:Coronary Angiography; D003329:Coronary Vasospasm; D004562:Electrocardiography; D006801:Humans; D008297:Male; D008875:Middle Aged; D009378:Neoplasms, Multiple Primary; D014057:Tomography, X-Ray Computed; D019210:Troponin I; D014750:Vincristine", "nlm_unique_id": "0144731", "other_id": null, "pages": "169-171", "pmc": null, "pmid": "28142134", "pubdate": "2017", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Coronary Spasm after an Injection of Vincristine.", "title_normalized": "coronary spasm after an injection of vincristine" }

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{ "abstract": "BACKGROUND\nVancomycin has recently gained popularity as an empiric therapy for late onset sepsis in the NICU. Changes in resistance patterns in common organisms has resulted in targeting higher trough concentrations of vancomycin. Consequently, an increase in vancomycin associated nephrotoxicity has been speculated. The objective of this study is to compare the incidence of acute kidney injury (AKI) in neonates with serum vancomycin trough concentrations less than 10 mg/L, 10-15 mg/L, or greater than 15 mg/L.\n\n\nMETHODS\nA retrospective chart review of patients in the neonatal intensive care unit (NICU) was conducted to determine the incidence of AKI in neonates receiving vancomycin.\n\n\nRESULTS\nThe overall incidence of AKI was 2.7%. Comparison of the incidence of AKI in the three groups using Mantel-Haenszel Chi-Square test showed a statistically significant association between increasing vancomycin trough concentration and incidence of AKI.\n\n\nCONCLUSIONS\nThere is a low incidence of AKI in neonates receiving vancomycin. However, there is a positive correlation between increasing vancomycin trough concentrations and an increasing serum creatinine.", "affiliations": "Department of Pediatrics, University of Texas Medical Branch, 301 UNIVERSITY BLVD, GALVESTON, 77555, TEXAS, USA. vibharga@utmb.edu.;Department of Pediatrics, Division of Neonatology, University of Texas Medical Branch, 301 UNIVERSITY BLVD, GALVESTON, 77555, TEXAS, USA.;Department of Pediatrics, Division of Neonatology, University of Texas Medical Branch, 301 UNIVERSITY BLVD, GALVESTON, 77555, TEXAS, USA.", "authors": "Bhargava|Vidit|V|;Malloy|Michael|M|;Fonseca|Rafael|R|", "chemical_list": "D000900:Anti-Bacterial Agents; D014640:Vancomycin", "country": "England", "delete": false, "doi": "10.1186/s12887-017-0777-0", "fulltext": "\n==== Front\nBMC PediatrBMC PediatrBMC Pediatrics1471-2431BioMed Central London 77710.1186/s12887-017-0777-0Research ArticleThe association between vancomycin trough concentrations and acute kidney injury in the neonatal intensive care unit Bhargava Vidit +1 409-789-2359vibharga@utmb.edu 1Malloy Michael 2Fonseca Rafael 21 0000 0001 1547 9964grid.176731.5Department of Pediatrics, University of Texas Medical Branch, 301 UNIVERSITY BLVD, GALVESTON, 77555 TEXAS USA 2 0000 0001 1547 9964grid.176731.5Department of Pediatrics, Division of Neonatology, University of Texas Medical Branch, 301 UNIVERSITY BLVD, GALVESTON, 77555 TEXAS USA 11 2 2017 11 2 2017 2017 17 506 8 2016 3 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\nVancomycin has recently gained popularity as an empiric therapy for late onset sepsis in the NICU. Changes in resistance patterns in common organisms has resulted in targeting higher trough concentrations of vancomycin. Consequently, an increase in vancomycin associated nephrotoxicity has been speculated. The objective of this study is to compare the incidence of acute kidney injury (AKI) in neonates with serum vancomycin trough concentrations less than 10 mg/L, 10–15 mg/L, or greater than 15 mg/L.\n\nMethods\nA retrospective chart review of patients in the neonatal intensive care unit (NICU) was conducted to determine the incidence of AKI in neonates receiving vancomycin.\n\nResults\nThe overall incidence of AKI was 2.7%. Comparison of the incidence of AKI in the three groups using Mantel-Haenszel Chi-Square test showed a statistically significant association between increasing vancomycin trough concentration and incidence of AKI.\n\nConclusion\nThere is a low incidence of AKI in neonates receiving vancomycin. However, there is a positive correlation between increasing vancomycin trough concentrations and an increasing serum creatinine.\n\nElectronic supplementary material\nThe online version of this article (doi:10.1186/s12887-017-0777-0) contains supplementary material, which is available to authorized users.\n\nKeywords\nAKI, NephrotoxicityPrematurityVancomycinissue-copyright-statement© The Author(s) 2017\n==== Body\nBackground\nVancomycin is a glycopeptide antibiotic which gained popularity in 1980’s for treatment of coagulase negative Staphylococcus (CONS) and Methicillin resistant staphylococcus aureus (MRSA). Late onset sepsis is a common concern in premature infants in neonatal intensive care unit (NICU). Vancomycin is widely used as an empiric therapy for late onset sepsis, and in confirmed infections with CONS and MRSA. [1, 2] Consequently, vancomycin is used in the NICU even though limited information is available concerning the dosing, monitoring, and adverse effects of this medication in neonates. Additionally, increasing antibiotic resistance among familiar pathogens in the NICU, as evidenced by higher minimum inhibitory concentrations (MICs), has resulted in targeting higher vancomycin trough concentrations. [3, 4] Vancomycin associated nephrotoxicity has not been well studied in the neonatal population and limited data exists on the association between higher vancomycin trough and incidence of acute kidney injury (AKI).\n\nThis study aims to measure the association between increasing trough concentrations and AKI in neonates receiving vancomycin therapy. We also look at the effect of co-administration of other nephrotoxic agents on the incidence of AKI.\n\nMethods\nA retrospective chart review was performed for patients in NICU at University of Texas Medical Branch (UTMB) at Galveston. The electronic medical record was reviewed between January 2008 and December 2012 to determine the incidence of AKI in neonates receiving vancomycin. The patient population consisted of premature neonates admitted to NICU at UTMB and received at least one course of vancomycin. Each patient may have received several courses of vancomycin during this period. Courses of vancomycin were included in the study group if they met the following inclusion criteria: a) Duration of treatment at least 5 days b) Availability of serum creatinine (SCr) values both prior to and after completing the vancomycin therapy and c) at least one vancomycin trough collected during the duration of treatment. Courses of vancomycin therapy were excluded if: a) evidence of pre-existing renal insufficiency or congenital anomalies including renal agenesis, renal hypoplasia, polycystic kidney disease, or renal dysplasia were present b) extracorporeal membrane oxygenation was required or c) there was incomplete data in the UTMB electronic medical record, Epic. Baseline serum creatinine was defined as the serum creatinine obtained prior to starting vancomycin therapy. Post vancomycin creatinine was defined as the serum creatinine value obtained at the end of vancomycin therapy or after a suspected episode of AKI.\n\nCourses of vancomycin therapy were divided into three groups based on highest achieved vancomycin trough concentrations; less than 10 mg/L, 10–15 mg/L, or greater than 15 mg/L. Standardized vancomycin dosage proposed by Capparelli et al., based on gestational age was used for each patient.[5] The trough was obtained prior to the fourth dose. If the trough was found sub-therapeutic or toxic, changes in dose or frequency of vancomycin administration were accordingly made. The change in dose was subsequently followed by a repeat trough measurement prior to the 4th dose. For each course of vancomycin therapy, multiple vancomycin trough concentrations may have been measured, but the highest achieved trough concentration was used to classify courses of vancomycin therapy into the three study groups. The incidence of AKI was determined in each group. AKI was defined as an increase in SCr of at least 0.5 mg/L or an increase of at least 100% from lowest trough previously available. This definition is based on pRIFLE criteria for renal injury proposed by Akcan-Arikan et al. and the increase in serum creatinine proposed by moghal et al. [6–8] A decrease in urine output was not used as a defining criteria due to lack of this being a universal finding.\n\nData collected included gestational age; postnatal age; gender; birth weight; APGAR scores; vancomycin dose, frequency, duration, and trough concentrations; date and time of vancomycin doses and trough concentrations; concurrent nephrotoxic medications administered including amphotericin B, acyclovir, amikacin, captopril, dobutamine, dopamine, enalapril, epinephrine, ganciclovir, gentamicin, indomethacin, ibuprofen, naficillin, and tobramycin; blood culture results; type of infection; presence of a patent ductus arteriosus; and final discharge status. Maternal history was also collected and included the presence of pregnancy-induced hypertension, chorioamnionitis, diabetes, renal dysfunction, or urinary tract infection.\n\nMantel-Haenszel Chi-Square test was used to compare the incidence of AKI between the three groups. A p-value of < 0.05 was considered to be statistically significant. Regression analysis was used to examine the relationship between vancomycin trough concentrations and serum creatinine. All statistical analyses were done using SAS 9.3©. The study was approved by the institutional review board (IRB) at UTMB, Galveston.\n\nResults\nNine hundred and sixty-two patients receiving vancomycin therapy administered between January 2008 and December 2012 were evaluated for study inclusion. Eight hundred and fifty-two patients were excluded due to inability to meet one or more inclusion criteria. The majority of patients were excluded due to vancomycin being administered for less than five days. The second most common reason for exclusion was incomplete data in the electronic medical record. Therefore, 110 patients were included in the analysis. The majority of patients were male. The mean birth weight was 1200 g, and the mean gestational age was 29 weeks. (Table 1) Central line associated blood stream infection (CLABSI), sepsis and necrotizing enterocolitis (NEC) were the most common suspected diagnoses for which patients were started on vancomycin therapy. The most common organism was Coagulase Negative Staphylococcus aureus (32 patients) followed by Enterococcus faecalis (5 patients) and Staphylococcus aureus.Table 1 Baseline characteristics of patients\n\n\nN = 110\t\nMale/Female\t58/52\t\nBirth weight (grams) ± SD\t1200 ± 734\t\nGestational age (weeks) ± SD\t29 ± 5\t\nPostnatal age at time of first vancomycin course (days) ± SD\t23 ± 27\t\n\n\n\nOne hundred ten patients were further studied to determine an association with AKI. There were 72 patients with a highest vancomycin trough concentration less than 10 mg/L, 27 patients with a highest vancomycin trough concentration of 10–15 mg/L, and 11 patients with a highest vancomycin trough concentration greater than 15 mg/L. The incidence of AKI was 1.39% (1/72 patients) in the group achieving vancomycin trough concentrations less than 10 mg/L, 0% (0/27 patients) in the group achieving vancomycin trough concentrations between 10–15 mg/L, and 18.18% (2/11 patients) in the group achieving vancomycin trough concentrations greater than 15 mg/L (Table 2). There was a statistically significant association between AKI and vancomycin trough groups (p = 0.04). Regression analysis between increasing vancomycin trough concentrations and post vancomycin serum creatinine values demonstrated a positive correlation value of 0.32 (p < 0.05) (Fig.1).Table 2 Incidence of acute kidney injury\n\nGroup\tTotal number of patients\tPatients with AKI\tIncidence of AKI\t\nVancomycin trough < 10 mg/L\t72\t1\t1.38%\t\nVancomycin trough 10–15 mg/L\t27\t0\t0%\t\nVancomycin trough > 15 mg/L\t11\t2\t18.18%\t\nTOTAL\t110\t3\t2.7%\t\n\nFig. 1 Showing a Fit plot between vancomycin trough concentrations and post vancomycin creatinine. The plot depicts a positive co-relation between the two parameters\n\n\n\n\nEach of the patients with AKI were also receiving at least one concurrent nephrotoxic medication including dobutamine, dopamine, and/or gentamicin (Table 3). Gentamicin was the only nephrotoxic drug that a large percentage of the 87 patients received during vancomycin therapy (79%). There was no significant correlation between post vancomycin creatinine values and the total number of days’ gentamicin was received (p = 0.10) or of a change in creatinine of greater than or equal to 0.5 mg/dl from pre- to post-vancomycin administration (p = 0.13). In an ANOVA regression equation with gentamicin days run as a covariate with vancomycin trough group, however, gentamicin days were significantly associated with post vancomycin creatinine values (p = 0.04). The vancomycin trough groups remained significantly associated with post vancomycin creatinine values independent of gentamicin days (p < 0.01).Table 3 Cases of acute kidney injury\n\nCase\tTrough (mg/L)\tTiming of trough\tDose of vancomycin\tFrequency\tDuration of treatment\tTotal vancomycin days\t\n1\t<5.0\tPrior to 4th dose\t20 mg/kg\n20 mg/kg\tQ18H\nQ12H\t4 days\n5 days\t9 days\t\n2\t18.8\tPrior to 4th dose\t20 mg/kg\tQ24H\t6 days\t6 days\t\n3\t27.2\tPrior to 4th dose\t20 mg/kg\n15 mg/kg\tQ24H\nQ24H\t5 days\n6 days\t11 days\t\n\n\n\nDiscussion\nThere has been an on-going debate on the dosage, frequency of administration and the most appropriate monitoring of vancomycin therapy. This is the result of multiple factors responsible for clearance of vancomycin including gestational age, post-natal age, weight, renal tubular function and creatinine levels. [9] Historically, area-under-the-curve concentration versus time to the minimum inhibitory concentration (AUC:MIC), was accepted as the pharmacokinetic and pharmacodynamic predictor of adequate treatment with vancomycin. AUC: MIC > 400 has been recommended to achieve desired anti-microbial effect in both adult and pediatric populations. [10] A consensus statement released by the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists in 2009 recommended vancomycin as the first choice drug for MRSA with MIC < 2. [10] The consensus statement also recommends assessment of vancomycin clinical effectiveness through serum vancomycin trough concentrations at steady state. Studies have demonstrated that trough between 7–10 mg/L corresponds to AUC:MIC > 400 if the MIC of MRSA is < 1. [11] However, with increasing MIC’s higher trough concentrations are recommended. In serious clinical infections such as endocarditis, meningitis, hospital-acquired pneumonia, bacteremia, and osteomyelitis trough concentrations between 15–20 are recommended.[12] These higher troughs allow for greater vancomycin exposure, a higher AUC and the ability to reach the goal AUC:MIC ≥ 400, or a trough concentration approximately four to five times the MIC of the infecting organism. [12] Concerns for increased nephrotoxicity, an adverse effect traditionally associated with vancomycin, has accompanied the recommendation for more aggressive dosing.\n\nIn adults, increasing serum vancomycin trough concentrations have been associated with increasing incidence of AKI. In a study done to evaluate vancomycin-associated nephrotoxicity incidence in adults with MRSA infections with serum trough concentrations of 15–20 mg/L and receiving concomitant nephrotoxic medications, a significantly higher incidence of AKI was noted.[3] A 2011 prospective study also showed similar results. Adults with MRSA infections had a greater risk of AKI with serum vancomycin trough concentration greater than 15 mg/L.[13] Similarly, adults with MRSA pneumonia were shown to be at a 3–5 times greater risk for developing AKI with vancomycin serum trough concentrations of 15 mg/L.[14] On the other hand, there are other studies in adults which did not show increased risk of AKI with elevated serum vancomycin trough > 15 mg/L. In study done by Prabaker et al., an overall incidence of 2.1% was noticed with vancomycin serum trough concentration between 15–20 mg/L [15].\n\nNephrotoxicity in the neonatal population is poorly defined. Several definitions of acute kidney injury (AKI) exist in the literature; however, there are no standard criteria for diagnosing AKI in neonates. Commonly used definitions of AKI in neonates include oliguria of less than 1 mL/kg/h of urine output that develops 24 h after birth and persists for at least 24 h, an increase in serum creatinine (SCr) to greater than 1.5 mg/L 72 h after birth, or an increase in SCr between 0.5 and 1 mg/L per day.[8, 16] Nephrotoxicity attributed to vancomycin use is not clearly defined in neonates; however, the mechanism of injury to the kidney is believed to be the result of proximal tubule damage. [17, 18] Although causality has not been proven, a higher risk of vancomycin-induced nephrotoxicity in the pediatric population with higher vancomycin trough concentrations has been speculated.\n\nDue to pharmacokinetic differences between adults and neonates, and since neonates have immature renal function compared to adults, the applicability and adverse effects of increased target troughs in premature neonates remain unknown. Lastly, it has been documented in adult populations that concurrent treatment using other known nephrotoxic agents, such as aminoglycosides, is associated with an increased risk for nephrotoxicity with vancomycin. [19] Again, it is unclear whether this is true in the neonatal population.\n\nPreviously done studies in children receiving vancomycin alone have reported incidence of AKI from 9%–14%. Linder et al. and Nahata et al. found the incidence of AKI in neonatal population to be low. Their studies did not show statistically significant difference in the incidence of AKI with concomitant administration of gentamicin.[20, 21] However, McKamy and Knoderer et al. reported slightly higher overall incidence of AKI at 14% in children between the ages 1 month and 17 years.[17, 22] Both the studies also reported significantly higher incidence of AKI with vancomycin trough > 15 mg/L at 28% and 18% respectively.\n\nIn our study, the overall incidence of AKI was low at 2.71%. A statistically significant association between AKI and vancomycin trough groups was found (p = 0.04). There was also a positive correlation between vancomycin trough concentrations and post vancomycin creatinine values, indicating that vancomycin may have some role in AKI in predisposed individuals. It also indicates that higher vancomycin troughs are associated with rising creatinine values post treatment. Additionally, we looked at several covariates using a linear regression model to assess whether these were significantly associated with higher post vancomycin creatinine values. Highest vancomycin trough value (p < 0.001), total vancomycin days (p ~ 0.0021) and gestational age (p value < 0.001) were found to have an independent association. Gender and APGAR scores were also looked at and were not found to be significantly associated with vancomycin trough and rising creatinine values. Even after controlling for these independent variables, the highest trough value and post vancomycin creatinine values showed a significant association.\n\nAlso of interest is the observation that vancomycin trough groups continued to be positively associated with increasing post vancomycin creatinine values independent of the number of days of gentamicin the infants had received. In addition, independent of vancomycin trough groups there was a positive association between the number of days that gentamicin was received and post vancomycin creatinine values. Thus, gentamicin, another potentially nephrotoxic had its effect on post vancomycin creatinine values obscured by the effect of vancomycin. Only after having the effect of vancomycin controlled for in the regression equation was gentamicin’s effect revealed. Because of the small number of courses associated with our definition of acute kidney failure whether or not vancomycin and gentamicin were additive in their nephrotoxic effects cannot be determined in this analysis. Larger studies are needed to confirm these findings.\n\nOur study has limitations. The study was retrospective in nature and had a small sample size. Due to the lack of a standardized definition a hybrid definition of AKI was used in this study. Another limitation is that patients may have received multiple courses of vancomycin therapy during the same admission. However, courses of vancomycin therapy were often separated by weeks. Further, for each course of vancomycin therapy, multiple vancomycin trough concentrations may have been measured, but the highest achieved trough concentration was used to divide the vancomycin courses into the three study groups. Finally, despite the fact that patients were often on concurrent nephrotoxic medications, only three cases of AKI were identified in this study which is different from the previously reported studies.\n\nConclusion\nBased on our study, vancomycin troughs greater than 20 mg/dl may be associated with increased incidence of AKI. We recommend close monitoring of vancomycin trough concentrations during therapy and appropriate alteration in dosage/frequency should be made based on serum trough concentrations. However, this was a single-center retrospective study, and larger prospective studies are required to validate this finding.\n\nAdditional files\n\nAdditional file 1: The file contains raw data used for analysis during the study. This includes patient gender, prenatal history, birth history, vancomycin start and end dates for each course of vancomycin administered. It also contains information regarding vancomycin trough and serum creatinine values obtained during each vancomycin course. (XLSX 55 kb)\n\n\n\n\nAbbreviations\nAKIAcute kidney injury\n\nAUC: MICArea-under-the-curve concentration versus time to the minimum inhibitory concentration\n\nCONSCoagulase negative staphylococcus aureus\n\nMRSAMethicillin resistant staphylococcus aureus\n\nNICUNeonatal intensive care unit\n\nSCrSerum creatinine\n\nUTMBUniversity of Texas Medical Branch\n\nAcknowledgements\nNot applicable\n\nFunding\nNot applicable.\n\nAvailability of data and materials\nAll data generated or analysed during this study are included in this published article and its supplementary information files. A separate file containing all the raw data is also provided along with the manuscript (Additional file 1). Permission was obtained from IRB to access electronic medical records and conduct a chart review.\n\nAuthors’ contributions\nVB was involved in writing the manuscript and collection of data. MM was involved in data interpretation and statistical analysis of the data. He was also involved in critical review of the article and multiple corrections prior to submission. RF is the chief investigator in the study. He was involved in designing the study, reviewing the results and reviewing the manuscript and the whole project at each stage. All authors read and approved the final manuscript.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nConsent for publication\nNot applicable.\n\nEthics approval and consent to participate\nThe study was approved by the ethics committee of Institutional Review Board (IRB) at UTMB. Consent required to participate in the study was waived by the IRB at UTMB.\n==== Refs\nReferences\n1. Klingenberg C Aarag E Ronnestad A Sollid JE Abrahamsen TG Kjeldsen G Flaegstad T Coagulase-negative staphylococcal sepsis in neonates. Association between antibiotic resistance, biofilm formation and the host inflammatory response Pediatr Infect Dis J 2005 24 9 817 822 10.1097/01.inf.0000176735.20008.cd 16148849 \n2. Healy CM Palazzi DL Edwards MS Campbell JR Baker CJ Features of invasive staphylococcal disease in neonates Pediatrics 2004 114 4 953 961 10.1542/peds.2004-0043 15466090 \n3. Hidayat LK Hsu DI Quist R Shriner KA Wong-Beringer A High-dose vancomycin therapy for methicillin-resistant Staphylococcus aureus infections: efficacy and toxicity Arch Intern Med 2006 166 19 2138 2144 10.1001/archinte.166.19.2138 17060545 \n4. Sakoulas G Moise-Broder PA Schentag J Forrest A Moellering RC Jr Eliopoulos GM Relationship of MIC and bactericidal activity to efficacy of vancomycin for treatment of methicillin-resistant Staphylococcus aureus bacteremia J Clin Microbiol 2004 42 6 2398 2402 10.1128/JCM.42.6.2398-2402.2004 15184410 \n5. Capparelli EV Lane JR Romanowski GL McFeely EJ Murray W Sousa P Kildoo C Connor JD The influences of renal function and maturation on vancomycin elimination in newborns and infants J Clin Pharmacol 2001 41 9 927 934 10.1177/00912700122010898 11549096 \n6. Akcan-Arikan A Zappitelli M Loftis LL Washburn KK Jefferson LS Goldstein SL Modified RIFLE criteria in critically ill children with acute kidney injury Kidney Int 2007 71 10 1028 1035 10.1038/sj.ki.5002231 17396113 \n7. Moghal NE Brocklebank JT Meadow SR A review of acute renal failure in children: incidence, etiology and outcome Clin Nephrol 1998 49 2 91 95 9524778 \n8. Viswanathan S Manyam B Azhibekov T Mhanna MJ Risk factors associated with acute kidney injury in extremely low birth weight (ELBW) infants Pediatr Nephrol 2012 27 2 303 311 10.1007/s00467-011-1977-8 21809002 \n9. Pacifici GM Allegaert K Clinical pharmacokinetics of vancomycin in the neonate: a review Clinics (Sao Paulo) 2012 67 831 837 \n10. Rybak MJ Lomaestro BM Rotschafer JC Moellering RC Jr Craig WA Billeter M Dalovisio JR Levine DP Therapeutic monitoring of vancomycin in adults summary of consensus recommendations from the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists Pharmacotherapy 2009 29 11 1275 1279 10.1592/phco.29.11.1275 19873687 \n11. Frymoyer A Guglielmo BJ Hersh AL Desired vancomycin trough serum concentration for treating invasive methicillin-resistant Staphylococcal infections Pediatr Infect Dis J 2013 32 10 1077 1079 10.1097/INF.0b013e318299f75c 23652479 \n12. Liu C Bayer A Cosgrove SE Daum RS Fridkin SK Gorwitz RJ Kaplan SL Karchmer AW Levine DP Murray BE Clinical practice guidelines by the infectious diseases society of america for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children Clin Infect Dis 2011 52 3 e18 55 10.1093/cid/ciq146 21208910 \n13. Bosso JA Nappi J Rudisill C Wellein M Bookstaver PB Swindler J Mauldin PD Relationship between vancomycin trough concentrations and nephrotoxicity: a prospective multicenter trial Antimicrob Agents Chemother 2011 55 12 5475 5479 10.1128/AAC.00168-11 21947388 \n14. Jeffres MN Isakow W Doherty JA Micek ST Kollef MH A retrospective analysis of possible renal toxicity associated with vancomycin in patients with health care-associated methicillin-resistant Staphylococcus aureus pneumonia Clin Ther 2007 29 6 1107 1115 10.1016/j.clinthera.2007.06.014 17692725 \n15. Prabaker KK Tran TP Pratummas T Goetz MB Graber CJ Elevated vancomycin trough is not associated with nephrotoxicity among inpatient veterans J Hosp Med 2012 7 2 91 97 10.1002/jhm.946 22086511 \n16. Ringer SA Acute Renal Failure in the Neonate 2010 \n17. McKamy S Hernandez E Jahng M Moriwaki T Deveikis A Le J Incidence and risk factors influencing the development of vancomycin nephrotoxicity in children J Pediatr 2011 158 3 422 426 10.1016/j.jpeds.2010.08.019 20888013 \n18. Zappitelli M Selewski DT Askenazi DJ Nephrotoxic Medication Exposure and Acute Kidney Injury in Neonates 2012 \n19. Fauconneau B Favreliere S Pariat C Genevrier A Courtois P Piriou A Bouquet S Nephrotoxicity of gentamicin and vancomycin given alone and in combination as determined by enzymuria and cortical antibiotic levels in rats Ren Fail 1997 19 1 15 22 10.3109/08860229709026256 9044448 \n20. Linder N Edwards R MeClead R Mortensen ME Walson P Koren G Safety of vancomycin with or without gentamicin in neonates Neonatal Netw 1993 12 8 27 30 8121352 \n21. Nahata MC Lack of nephrotoxicity in pediatric patients receiving concurrent vancomycin and aminoglycoside therapy Chemotherapy 1987 33 4 302 304 10.1159/000238512 3608631 \n22. Knoderer CA Nichols KR Lyon KC Veverka MM Wilson AC Are Elevated Vancomycin Serum Trough Concentrations Achieved Within the First 7 Days of Therapy Associated With Acute Kidney Injury in Children? J Pediatric Infect Dis Soc 2014 3 2 127 131 10.1093/jpids/pit076 26625365\n\n", "fulltext_license": "CC BY", "issn_linking": "1471-2431", "issue": "17(1)", "journal": "BMC pediatrics", "keywords": "AKI, Nephrotoxicity; Prematurity; Vancomycin", "medline_ta": "BMC Pediatr", "mesh_terms": "D058186:Acute Kidney Injury; D000900:Anti-Bacterial Agents; D005260:Female; D006801:Humans; D015994:Incidence; D007231:Infant, Newborn; D007363:Intensive Care Units, Neonatal; D015931:Intensive Care, Neonatal; D008297:Male; D012189:Retrospective Studies; D018805:Sepsis; D016896:Treatment Outcome; D014640:Vancomycin", "nlm_unique_id": "100967804", "other_id": null, "pages": "50", "pmc": null, "pmid": "28187757", "pubdate": "2017-02-11", "publication_types": "D016428:Journal Article", "references": "16148849;9524778;15184410;22086511;11549096;21809002;15466090;23652479;9044448;17396113;8121352;21208910;22892931;19873687;26625365;21947388;17060545;20888013;3608631;17692725", "title": "The association between vancomycin trough concentrations and acute kidney injury in the neonatal intensive care unit.", "title_normalized": "the association between vancomycin trough concentrations and acute kidney injury in the neonatal intensive care unit" }

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THE ASSOCIATION BETWEEN VANCOMYCIN TROUGH CONCENTRATIONS AND ACUTE KIDNEY INJURY IN THE NEONATAL INTENSIVE CARE UNIT.. 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THE ASSOCIATION BETWEEN VANCOMYCIN TROUGH CONCENTRATIONS AND ACUTE KIDNEY INJURY IN THE NEONATAL INTENSIVE CARE UNIT. 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BMC-PEDIATR. 2017?17(1):50", "literaturereference_normalized": "the association between vancomycin trough concentrations and acute kidney injury in the neonatal intensive care unit", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20180514", "receivedate": "20180514", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14890115, "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-STRIDES ARCOLAB LIMITED-2017SP007464", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "VANCOMYCIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "65490", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MG/KG, QD", "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": "20", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VANCOMYCIN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BHARGAVA V, MALLOY M, FONSECA R. THE ASSOCIATION BETWEEN VANCOMYCIN TROUGH CONCENTRATIONS AND ACUTE KIDNEY INJURY IN THE NEONATAL INTENSIVE CARE UNIT. BMC-PEDIATR. 2017?17(1):50", "literaturereference_normalized": "the association between vancomycin trough concentrations and acute kidney injury in the neonatal intensive care unit", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20180514", "receivedate": "20180514", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14890113, "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" } ]

{ "abstract": "We report a 4-year-old female who presented with severe hypereosinophilia (215.7 K/μl) and end-organ dysfunction. Extensive evaluation including whole exome sequencing was performed, revealing no causative mutation. Initial treatment with corticosteroids, leukapheresis, and hydroxyurea decreased her absolute eosinophil count (AEC), although it remained elevated. Despite the absence of a PDGFRA mutation, an imatinib trial resulted in normalization of her AEC. Imatinib was discontinued after sustained normal counts for 1 month. AECs have remained normal for more than 1 year off therapy. This provides support for consideration of imatinib in the treatment of hypereosinophilia even in the absence of a known tyrosine kinase mutation.", "affiliations": "Division of Pediatric Hematology and Oncology, Department of Pediatrics and Communicable Diseases, University of Michigan Medical Center, Ann Arbor, Michigan.;Division of Pediatric Hematology and Oncology, Department of Pediatrics and Communicable Diseases, University of Michigan Medical Center, Ann Arbor, Michigan.;Department of Pathology, University of Michigan Medical Center, Ann Arbor, Michigan.;Michigan Center of Translational Pathology (MCTP), University of Michigan Medical Center, Ann Arbor, Michigan.;Division of Pediatric Hematology and Oncology, Department of Pediatrics and Communicable Diseases, University of Michigan Medical Center, Ann Arbor, Michigan.;Division of Pediatric Hematology and Oncology, Department of Pediatrics and Communicable Diseases, University of Michigan Medical Center, Ann Arbor, Michigan.", "authors": "Weyand|Angela C|AC|;Yanik|Gregory A|GA|;Bailey|Nathanael G|NG|;Wu|Yi-Mi|YM|;Mody|Rajen J|RJ|;Castle|Valerie P|VP|", "chemical_list": "D047428:Protein Kinase Inhibitors; D000068877:Imatinib Mesylate; D020796:Receptor, Platelet-Derived Growth Factor alpha", "country": "United States", "delete": false, "doi": "10.1002/pbc.25702", "fulltext": null, "fulltext_license": null, "issn_linking": "1545-5009", "issue": "63(1)", "journal": "Pediatric blood & cancer", "keywords": "PDGFRA; hypereosinophilia; imatinib; pediatric", "medline_ta": "Pediatr Blood Cancer", "mesh_terms": "D002675:Child, Preschool; D005260:Female; D006801:Humans; D017681:Hypereosinophilic Syndrome; D000068877:Imatinib Mesylate; D047428:Protein Kinase Inhibitors; D020796:Receptor, Platelet-Derived Growth Factor alpha; D017422:Sequence Analysis, DNA", "nlm_unique_id": "101186624", "other_id": null, "pages": "164-7", "pmc": null, "pmid": "26257279", "pubdate": "2016-01", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Imatinib Treatment in PDGFRA-Negative Childhood Hypereosinophilic Syndrome.", "title_normalized": "imatinib treatment in pdgfra negative childhood hypereosinophilic syndrome" }

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{ "abstract": "Romosozumab is an effective treatment for spine osteoporosis because it reduces the incidence of new fractures and significantly increases the percent change in the spine BMD at 12 months. The percent change in the spine BMD is higher in patients not previously treated with other anti-osteoporosis medications.\n\n\nBACKGROUND\nRomosozumab appeared as a new osteoporosis medication in Japan in 2019. It is an anti-sclerostin antibody, which increases bone formation and suppresses bone resorption. The aim of our study was to elucidate the clinical effects, safety, and predictors of the effects of one-year romosozumab treatment.\n\n\nMETHODS\nThis study was an observational study designed as a pre-post study in 262 patients. Romosozumab (210 mg) was administered subcutaneously once every 4 weeks during 12 months. We focused on incidence of new fractures, safety, bone mineral density (BMD) at the spine and total hip, and bone metabolism markers.\n\n\nRESULTS\nThere were five cases of new fractures during one-year romosozumab treatment. There were no fatal adverse events. Percent changes from baseline in the spine and total hip BMD after 12 months of romosozumab treatment were 10.67% and 2.04%, respectively. Romosozumab had better effects in cases of severe osteoporosis with low spine BMD, high TRACP-5b, and high iP1NP at the start of romosozumab treatment. The percent change in the spine BMD at 12 months was significantly lower in the group transitioning from bisphosphonates than in the group not previously treated with other anti-osteoporosis medications.\n\n\nCONCLUSIONS\nRomosozumab is an effective treatment for spine osteoporosis because it significantly increases the percent change in the spine BMD at 12 months. The percent change in the spine BMD is higher in patients not previously treated with other anti-osteoporosis medications.", "affiliations": "Department of Orthopedic Surgery, Tokyo Women's Medical University, 8-1 Kawadacho Shinjuku-ku, Tokyo, Japan.;Department of Orthopedic Surgery, Tokyo Women's Medical University, 8-1 Kawadacho Shinjuku-ku, Tokyo, Japan. keijiwadajp@yahoo.co.jp.;Department of Orthopedic Surgery, Tokyo Women's Medical University, 8-1 Kawadacho Shinjuku-ku, Tokyo, Japan.;Hasuda Hospital, 1662-1 Negane Hasudashi, Saitama, Japan.;Hasuda Hospital, 1662-1 Negane Hasudashi, Saitama, Japan.;Kita Shinagawa 3rd Hospital, 3-3-7 Kitashinagawa Shinagawa-ku, Tokyo, Japan.", "authors": "Tominaga|A|A|;Wada|K|K|;Okazaki|K|K|;Nishi|H|H|;Terayama|Y|Y|;Kato|Y|Y|", "chemical_list": "D000911:Antibodies, Monoclonal; D050071:Bone Density Conservation Agents; C557282:romosozumab", "country": "England", "delete": false, "doi": "10.1007/s00198-021-05925-3", "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": "Anti-osteoporosis drug; Anti-sclerostin antibody; BMD; Bone metabolism markers; Osteoporosis; Romosozumab", "medline_ta": "Osteoporos Int", "mesh_terms": "D000911:Antibodies, Monoclonal; D015519:Bone Density; D050071:Bone Density Conservation Agents; D005260:Female; D006801:Humans; D010024:Osteoporosis; D015663:Osteoporosis, Postmenopausal", "nlm_unique_id": "9100105", "other_id": null, "pages": "1999-2009", "pmc": null, "pmid": "33770201", "pubdate": "2021-10", "publication_types": "D016428:Journal Article; D064888:Observational Study", "references": "19749026;19568689;32777516;17395698;24382002;20200929;28064540;31168657;28892457;9685512;24743048;16393431;11138687;31425674;27641143;32195618;26859106;28755782", "title": "Early clinical effects, safety, and predictors of the effects of romosozumab treatment in osteoporosis patients: one-year study.", "title_normalized": "early clinical effects safety and predictors of the effects of romosozumab treatment in osteoporosis patients one year study" }

[ { "companynumb": "JP-AMGEN-JPNSP2021048933", "fulfillexpeditecriteria": "2", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ROMOSOZUMAB-AQQG" }, "drugadditional": null, "drugadministrationroute": "058", "drugauthorizationnumb": "761062", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "210 MILLIGRAM, Q4WK", "drugenddate": null, "drugenddateformat": null, "drugindication": "OSTEOPOROSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "210", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EVENITY" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Serum procollagen type I N-terminal propeptide decreased", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Blood alkaline phosphatase decreased", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Fracture", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Blood calcium decreased", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pancreatic enzymes increased", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Blood parathyroid hormone increased", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Adverse event", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dental care", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pyrexia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Unevaluable event", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hepatic enzyme increased", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Injection site pain", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "OKAZAKI K. EARLY CLINICAL EFFECTS, SAFETY, AND PREDICTORS OF THE EFFECTS OF ROMOSOZUMAB TREATMENT IN OSTEOPOROSIS PATIENTS: ONE?YEAR STUDY. OSTEOPOROSIS INTERNATIONAL. 2021", "literaturereference_normalized": "early clinical effects safety and predictors of the effects of romosozumab treatment in osteoporosis patients one year study", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20210603", "receivedate": "20210405", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19092521, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210717" } ]

{ "abstract": "Addressing \"total pain\" is a concept commonly practiced in palliative care. Spiritual healing in a Navy Veteran led to a significant improvement in pain allowing a voluntary taper of opioid medication. The Veteran was able to reconcile his faith in God and participated in several spiritual practices daily. The palliative care pharmacist assisted the team in developing an opioid taper process per Veteran's request as he had a strong conviction that he was spiritually healed. A reduction in opioid morphine equivalent daily doses (MEDD) were 87.5% without any symptoms from the clinical opioid withdrawal scale (COWS). The Veteran died peacefully during an opioid taper in hospice care.", "affiliations": "Sandra L. DiScala, PharmD, BCPS, Brittany Faley, PharmD, Vanessa Lewis, MD, Christine M. Vartan, PharmD, BCPS, and Michael Silverman, MD, CMD are with the West Palm Beach (WPB) Veterans Affairs Medical Center, West Palm Beach, Florida, USA.;Sandra L. DiScala, PharmD, BCPS, Brittany Faley, PharmD, Vanessa Lewis, MD, Christine M. Vartan, PharmD, BCPS, and Michael Silverman, MD, CMD are with the West Palm Beach (WPB) Veterans Affairs Medical Center, West Palm Beach, Florida, USA.;Sandra L. DiScala, PharmD, BCPS, Brittany Faley, PharmD, Vanessa Lewis, MD, Christine M. Vartan, PharmD, BCPS, and Michael Silverman, MD, CMD are with the West Palm Beach (WPB) Veterans Affairs Medical Center, West Palm Beach, Florida, USA.;Sandra L. DiScala, PharmD, BCPS, Brittany Faley, PharmD, Vanessa Lewis, MD, Christine M. Vartan, PharmD, BCPS, and Michael Silverman, MD, CMD are with the West Palm Beach (WPB) Veterans Affairs Medical Center, West Palm Beach, Florida, USA.;Sandra L. DiScala, PharmD, BCPS, Brittany Faley, PharmD, Vanessa Lewis, MD, Christine M. Vartan, PharmD, BCPS, and Michael Silverman, MD, CMD are with the West Palm Beach (WPB) Veterans Affairs Medical Center, West Palm Beach, Florida, USA.", "authors": "DiScala|Sandra L|SL|https://orcid.org/0000-0002-8264-2431;Faley|Brittany|B|;Lewis|Vanessa|V|;Vartan|Christine M|CM|;Silverman|Michael|M|", "chemical_list": "D000701:Analgesics, Opioid", "country": "England", "delete": false, "doi": "10.1080/15360288.2021.1914281", "fulltext": null, "fulltext_license": null, "issn_linking": "1536-0288", "issue": "35(2)", "journal": "Journal of pain & palliative care pharmacotherapy", "keywords": "Veterans; analgesics; hospice care; opioid; pain; palliative care; spiritual therapies", "medline_ta": "J Pain Palliat Care Pharmacother", "mesh_terms": "D000701:Analgesics, Opioid; D017051:Hospice Care; D006738:Hospices; D006801:Humans; D008297:Male; D010166:Palliative Care; D026443:Spiritual Therapies; D014728:Veterans", "nlm_unique_id": "101125608", "other_id": null, "pages": "117-122", "pmc": null, "pmid": "33955813", "pubdate": "2021-06", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Spiritual Healing in a Hospice Veteran Led to a Successful Opioid Taper: A Case Report.", "title_normalized": "spiritual healing in a hospice veteran led to a successful opioid taper a case report" }

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Spiritual Healing in a Hospice Veteran Led to a Successful Opioid Taper: A Case Report. J-Pain-Pall-Care-Pharmacother 2021;35(2):117-122.", "literaturereference_normalized": "spiritual healing in a hospice veteran led to a successful opioid taper a case report", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20211223", "receivedate": "20211223", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20222299, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220303" }, { "companynumb": "US-BAYER-2021A233876", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "SORAFENIB" }, "drugadditional": "4", "drugadministrationroute": null, 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"drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "15", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MORPHINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MORPHINE" }, "drugadditional": null, "drugadministrationroute": "058", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 MG, Q1HR", "drugenddate": null, "drugenddateformat": null, "drugindication": "Pain", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MORPHINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MORPHINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "160 MG, TID", "drugenddate": null, "drugenddateformat": null, "drugindication": "Pain", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "3", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "160", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MORPHINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MORPHINE" }, "drugadditional": null, "drugadministrationroute": "058", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, Q1HR", "drugenddate": null, "drugenddateformat": null, "drugindication": "Pain", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MORPHINE" } ], "patientagegroup": "6", "patientonsetage": "65", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hepatocellular carcinoma", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Treatment failure", "reactionmeddraversionpt": "24.1", "reactionoutcome": null }, { "reactionmeddrapt": "Abdominal pain upper", "reactionmeddraversionpt": "24.1", "reactionoutcome": null }, { "reactionmeddrapt": "Impaired self-care", "reactionmeddraversionpt": "24.1", "reactionoutcome": null }, { "reactionmeddrapt": "Anxiety", "reactionmeddraversionpt": "24.1", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "DiScala SL, Faley B, Lewis V, Vartan CM, Silverman M. 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"drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SPIRONOLACTONE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "RIFAXIMIN" }, "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": "RIFAXIMIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PROPRANOLOL HYDROCHLORIDE" }, "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": "PROPRANOLOL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LACTULOSE" }, "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": "LACTULOSE" } ], "patientagegroup": null, "patientonsetage": "65", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "DiScala SL, Faley B, Lewis V, Vartan CM, Silverman M. Spiritual healing in a hospice veteran led to a successful opioid taper: a case report. Journal of Pain and Palliative Care Pharmacotherapy. 2021;35(2):117-122", "literaturereference_normalized": "spiritual healing in a hospice veteran led to a successful opioid taper a case report", "qualification": "2", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20211229", "receivedate": "20211229", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20246013, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220303" } ]

{ "abstract": "We present the case report of a 66-year-old woman who was attended at our gynaecology department at a tertiary university hospital in Barcelona, Spain for a high-risk pregnancy and comment on the obstetric implications and bioethical issues. We retrospectively analysed clinical data about the case and bibliographic references related to the issue. The woman underwent in vitro fertilisation of donated embryos in a private centre and came to our unit at 27 weeks of gestation for pregnancy care. At 33 weeks, she presented pre-eclampsia and a caesarean section was performed. She gave birth to healthy twin boys. Four months later, she returned to our centre with the diagnosis of ovarian cancer and died 30 months after delivery. We present the clinical course and management of this pregnancy and comment on the obstetric implications, the impact on maternal and neonatal health, and bioethical issues related to assisted reproduction techniques in pregnancies beyond the natural reproductive age.", "affiliations": "a Department of Obstetrics and Gynecology , Hospital de la Santa Creu i Sant Pau, Universitat Autonoma , Barcelona , Spain.;a Department of Obstetrics and Gynecology , Hospital de la Santa Creu i Sant Pau, Universitat Autonoma , Barcelona , Spain.;b Grifols Foundation of Bioethics, Universitat de Vic - Central de Catalunya , Barcelona , Spain.;a Department of Obstetrics and Gynecology , Hospital de la Santa Creu i Sant Pau, Universitat Autonoma , Barcelona , Spain.;b Grifols Foundation of Bioethics, Universitat de Vic - Central de Catalunya , Barcelona , Spain.;a Department of Obstetrics and Gynecology , Hospital de la Santa Creu i Sant Pau, Universitat Autonoma , Barcelona , Spain.", "authors": "Simó González|Marta|M|;Calaf Alsina|Joaquim|J|;Terribas Sala|Núria|N|;Luqui Scarcelli|Nerea|N|;Plana Borrás|Juliana|J|;Polo Ramos|Ana|A|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1080/13625187.2016.1234599", "fulltext": null, "fulltext_license": null, "issn_linking": "1362-5187", "issue": "21(6)", "journal": "The European journal of contraception & reproductive health care : the official journal of the European Society of Contraception", "keywords": "Fertility; assisted reproduction; bioethical connotations; older women; pregnancy", "medline_ta": "Eur J Contracept Reprod Health Care", "mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D002585:Cesarean Section; D005260:Female; D005307:Fertilization in Vitro; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008423:Maternal Age; D009367:Neoplasm Staging; D018587:Oocyte Donation; D010051:Ovarian Neoplasms; D017698:Postmenopause; D011225:Pre-Eclampsia; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome; D011264:Pregnancy Trimesters; D027724:Reproductive Techniques, Assisted; D013030:Spain; D062606:Tertiary Care Centers; D014427:Twins", "nlm_unique_id": "9712127", "other_id": null, "pages": "496-498", "pmc": null, "pmid": "27666894", "pubdate": "2016-12", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Pregnancy beyond 65: report of a unique case and discussion of a controversial issue.", "title_normalized": "pregnancy beyond 65 report of a unique case and discussion of a controversial issue" }

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PREGNANCY BEYOND 65: REPORT OF A UNIQUE CASE AND DISCUSSION OF A CONTROVERSIAL ISSUE. 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PREGNANCY BEYOND 65: REPORT OF A UNIQUE CASE AND DISCUSSION OF A CONTROVERSIAL ISSUE. 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PREGNANCY BEYOND 65: REPORT OF A UNIQUE CASE AND DISCUSSION OF A CONTROVERSIAL ISSUE. EUR-J-CONTRACEPT-REPROD-HEALTH-CARE 2016;21(6):496-498.", "literaturereference_normalized": "pregnancy beyond 65 report of a unique case and discussion of a controversial issue", "qualification": "3", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20161223", "receivedate": "20161223", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13059335, "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": "OBJECTIVE\nIn this study, we aimed to detect the incidences of ototoxicity in patients with hemoglobinopathies taking deferoxamine (DFO), deferiprone, and deferasirox using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) scale to obtain more objective data.\n\n\nMETHODS\nFifty-five transfusion-dependent patients were evaluated in this study. The NCI CTCAE scale was used to assess ototoxicity levels. The average ferritin and hemoglobin levels, the type of iron chelator, and the duration of therapy of all the patients were recorded.\n\n\nRESULTS\nOtotoxicity was observed in 15 patients (31.9 %), all of whom were taking DFO. The median age was 19.5 (6-43) in patients without ototoxicity and 29 (16-50) in those with ototoxicity; this difference was statistically significant (p<0.05). The median ferritin and pre-tx Hb levels were 1391 ng/mL and 9.06 mg/dL, respectively, in patients with ototoxicity and 986.7 ng/mL and 9.24 mg/dL, respectively, in those without ototoxicity; these differences were not significant (p>0.05). Ototoxicity was not observed in the eight patients who used only deferasirox and deferiprone.\n\n\nCONCLUSIONS\nThe ototoxicity incidence with DFO at doses below 50 mg/kg/day was 27.3%. Deferiprone and deferasirox were not associated with ototoxic effects in patients taking these drugs.", "affiliations": "Muğla Sıtkı Koçman University School of Medicine, Department of Otolaryngology, Muğla, Turkey. serhanderin@yahoo.com.tr.", "authors": "Derin|Serhan|S|;Azık|Fatih Mehmet|FM|;Topal|Yaşar|Y|;Topal|Hatice|H|;Karakuş|Volkan|V|;Çetinkaya|Petek Uzay|PU|;Şahan|Murat|M|;Azık|Tansel Erdem|TE|;Kocabaş|Can Naci|CN|", "chemical_list": "D007502:Iron Chelating Agents", "country": "Turkey", "delete": false, "doi": "10.5152/iao.2016.1852", "fulltext": null, "fulltext_license": null, "issn_linking": "1308-7649", "issue": "13(1)", "journal": "The journal of international advanced otology", "keywords": null, "medline_ta": "J Int Adv Otol", "mesh_terms": "D000293:Adolescent; D000328:Adult; D015913:Chelation Therapy; D002648:Child; D003430:Cross-Sectional Studies; D004427:Ear Diseases; D005260:Female; D006801:Humans; D015994:Incidence; D007502:Iron Chelating Agents; D008297:Male; D008875:Middle Aged; D013789:Thalassemia; D014421:Turkey", "nlm_unique_id": "101522982", "other_id": null, "pages": "136-139", "pmc": null, "pmid": "27879229", "pubdate": "2017-04", "publication_types": "D016428:Journal Article", "references": null, "title": "The Incidence of Ototoxicity in Patients Using Iron Chelators.", "title_normalized": "the incidence of ototoxicity in patients using iron chelators" }

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{ "abstract": "Pembrolizumab is a novel immune checkpoint inhibitor approved for use in non-small cell lung carcinoma. There have been a few cases that have associated adverse renal outcomes with pembrolizumab. We present a case of acute kidney injury in a patient on pembrolizumab who was noted to have acute tubulointerstitial nephritis on renal biopsy. Pembrolizumab was discontinued and the patient was started on long-term corticosteroids with a taper. Her renal function improved partially with treatment.", "affiliations": "Department of Internal Medicine, Reading Hospital, 420 S Fifth Avenue, West Reading, PA 19611, USA. sijan.basnet@towerhealth.org.;Department of Internal Medicine, Reading Hospital, 420 S Fifth Avenue, West Reading, PA 19611, USA. rashmi.dhital@outlook.com.;Department of Internal Medicine, Trumbull Regional Medical Center, 1350 E Market St, Warren, OH 44483, USA. biswaraj.tharu@gmail.com.", "authors": "Basnet|Sijan|S|0000-0002-8324-2827;Dhital|Rashmi|R|;Tharu|Biswaraj|B|0000-0003-4594-741X", "chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D003404:Creatinine; C582435:pembrolizumab", "country": "Switzerland", "delete": false, "doi": "10.3390/medicina55050176", "fulltext": "\n==== Front\nMedicina (Kaunas)medicinaMedicina1010-660X1648-9144MDPI 10.3390/medicina55050176medicina-55-00176Case ReportAcute Tubulointerstitial Nephritis: A Case Report on Rare Adverse Effect of Pembrolizumab https://orcid.org/0000-0002-8324-2827Basnet Sijan 1*Dhital Rashmi 1https://orcid.org/0000-0003-4594-741XTharu Biswaraj 21 Department of Internal Medicine, Reading Hospital, 420 S Fifth Avenue, West Reading, PA 19611, USA; rashmi.dhital@outlook.com2 Department of Internal Medicine, Trumbull Regional Medical Center, 1350 E Market St, Warren, OH 44483, USA; biswaraj.tharu@gmail.com* Correspondence: sijan.basnet@towerhealth.org; Tel.: +4846288255; Fax: 484628900321 5 2019 5 2019 55 5 17615 1 2019 14 5 2019 © 2019 by the authors.2019Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).Pembrolizumab is a novel immune checkpoint inhibitor approved for use in non-small cell lung carcinoma. There have been a few cases that have associated adverse renal outcomes with pembrolizumab. We present a case of acute kidney injury in a patient on pembrolizumab who was noted to have acute tubulointerstitial nephritis on renal biopsy. Pembrolizumab was discontinued and the patient was started on long-term corticosteroids with a taper. Her renal function improved partially with treatment.\n\npembrolizumabacute kidney injuryprogrammed cell death 1 inhibitornon-small cell lung cancer\n==== Body\n1. Introduction\nPembrolizumab is an immune checkpoint inhibitor (CPI) approved by the United States Food and Drug Administration for use in non-small cell lung carcinoma (NSCLC) [1,2,3]. It prevents the suppression of T-cell activation by inhibiting binding of programmed cell death ligand (PD-L1) produced by tumor cells to the inhibitory programmed cell death (PD-1) receptor expressed on the surface of T-cells [1,2,4]. By doing this, T-cells can mediate an antitumor response. Pembrolizumab has been associated with side effects like fatigue, pruritus, and decreased appetite. Renal toxicity was not seen in initial reports [5]. Since then, renal adverse effects in association with CPIs have been described [2,4]. We present a case of NSCLC on pembrolizumab found to have acute kidney injury during hospitalization for chest and abdominal pain. Informed consent was obtained from the patient for submission of the case.\n\n2. Case Description\nThe patient is a 62-year-old woman who was brought to the emergency department (ED) with 2 episodes of sudden onset substernal chest pain, each episode lasting for 30 min. Her chest pain had resolved at the time of arrival. Prior to that, she had felt nauseous which was usual for her after her chemotherapy. Chest pain was followed by right-sided, sharp diffuse abdominal pain which lasted for 10 min and resolved spontaneously. She had received her last chemotherapy infusion 2 days prior to the episode. She denied any fever, chills, cough or shortness of breath. She was diagnosed of NSCLC with bone metastases (epidermal growth factor receptor negative and PD-L1-80%) a year ago for which she underwent radiation therapy of left hip and right upper ribs, completed palliative chemotherapy with 6 cycles of pemetrexed 500 mg/m2/dose, carboplatin 550 mg, and pembrolizumab 200 mg followed by same doses of pemetrexed and pembrolizumab maintenance every 3 weeks with last dose 2 days prior to presentation. The patient had been on pembrolizumab for 6 months prior to the decline in renal function. Other past medical history included stage IA right breast cancer (estrogen receptor+ (90%), progesterone receptor+ (3–5%), and human epidermal growth factor receptor 2-negative invasive ductal carcinoma) for which she underwent a bilateral mastectomy, 6 cycles of cyclophosphamide, methotrexate, and fluorouracil, and tamoxifen for 5 years 20 years ago, hypothyroidism, and hyperlipidemia. Her home medications included levothyroxine 75 µg daily, folic acid 1 mg daily, pantoprazole 40 mg daily, rosuvastatin 5 mg nightly, dexamethasone 8 mg two doses before and after chemotherapy, olanzapine 10 mg nightly, lorazepam 0.5 mg as needed, ondansetron 8 mg as needed, prochlorperazine 10 mg as needed, and promethazine 25 mg as needed. She had smoked a pack a day for 15 years before quitting 27 years ago.\n\nOn examination, vitals were stable with a temperature of 36.7 °C (98.1 °F), blood pressure 139/82 mm Hg, pulse 79 beats per minute, respiratory rate 18 breaths per minute, and she was maintaining saturation on room air. Chest, cardiac, and abdominal examinations were unremarkable. Her hemoglobin was 9.1 g/dL (reference range: 12.0–16.0 g/dL), platelet count was 556,000/µL (reference range: 13,000–400,000/µL), and white count was 10,700/µL (reference range: 4800–10,800/µL) with neutrophil count of 9800/µL (reference range: 2000–8000/µL), monocyte count of 400 (reference range: 100–1300/µL), and immature granulocyte count of 260/µL (reference range: 0–30/µL). Serial troponins and electrocardiograms were non-suggestive of an acute coronary syndrome. Her creatinine was 1.69 mg/dL (reference range: 0.6–1.3 mg/dL). It was 1.72 two days prior above her baseline of 0.6–0.9. Although d-dimer was 1.02 (reference range: <0.53 µg/mL), computed tomography (CT) pulmonary embolism protocol was not done as ultrasound lower extremity vein bilateral was negative and there was low clinical suspicion for pulmonary embolism. CT without contrast of chest/abdomen/pelvis showed decreasing right upper lobe mass and surrounding consolidation. She had bilateral enlarging metastatic lung nodules. Hepatic metastases were not identified but contrast was not used. Bone metastases were unchanged. Her kidneys and urinary tract on CT and urinalysis were unremarkable. Her acute kidney injury (AKI) was thought to be related to poor oral intake and vomiting related volume depletion. The patient was discharged home and was recommended hydration and repeat labs in a few days. Her creatinine on the day of discharge was 1.83 mg/dL. \n\nTwo days post discharge, the patient called her oncologist and told that she had started feeling sick on the same day after she was discharged. She complained of fever with maximum recorded temperature was 102.7 °F along with chills and rigors. She had multiple episodes of vomiting and poor intake. She was directly admitted to the hospital. At presentation, her vitals were stable with a temperature of 37.0 °C (98.6 °F), blood pressure 140/71 mm Hg, pulse 84 beats per minute, and respiratory rate 20 breaths per minute. Chest, cardiac, and abdominal examinations were unremarkable. Her mucous membranes were moist. Her hemoglobin was 8.2 g/dL (reference range: 12.0–16.0 g/dL), platelet count was 257,000/µL (reference range: 13,000–400,000/µL), white count was 2600/µL (reference range: 4800–10,800/µL) with neutrophil count of 1500/µL (reference range: 2000–8000/µL), monocyte count of 0/µL (reference range: 100–1300/µL), and immature granulocyte count of 50/µL (reference range: 0–30/µL). Her low cell counts were thought to be related to her chemotherapy. No eosinophilia was noted in complete blood count during hospitalization or prior to presentation. Her urinalysis was negative for infection but showed 30 mg /dL (1+) proteinuria. Her blood and urine cultures showed no growth. Her creatinine was elevated at 3.70 mg/dL and this was again thought to be related to volume depletion. The patient was started on intravenous fluids. Her renal ultrasound was unremarkable. With suspicion for pembrolizumab as a potential cause for acute kidney injury, future infusions were held. The patient was given a dose of IV methylprednisone 80 mg (1 mg/kg) and planned to be started on prednisone 80 mg daily next day. She was planned for a renal biopsy to rule out medication-related injury. Her creatinine progressively improved during her 5-day-stay and was 2.10 on discharge. We think this was with discontinuation of pembrolizumab. Her renal biopsy showed evidence of acute tubular injury, focal interstitial inflammation (lymphocytes, plasma cells, few eosinophils, few neutrophils) with focal mild tubulitis, 14% globally sclerotic glomeruli, mild arterial thickening, and mild interstitial fibrosis (Figure 1). This was thought to be secondary to pembrolizumab which was permanently discontinued. She was started on docetaxel 125 mg every 3 weeks. She has received 3 cycles so far. With non-improvement in kidney function, prednisone dose was increased to 1 mg/kg/day (70 mg) for a course of 3 months. Sulfamethoxazole-trimethoprim and pantoprazole were started for prophylaxis. Her creatinine even after 5 months is still elevated. Her new creatinine baseline is around 1.8–2.0. Pertinent case details are summarized in Table 1. \n\n3. Discussion\nRenal adverse effects are rare with CPIs [6]. The overall incidence of acute kidney injury was reported to be 2.2% among 3695 patients on a CPI by Cortazar et al. [4] and 1.77% among 676 pembrolizumab by Izzedine et al. [6]. Acute kidney injury can occur at any time, from 6 to 10.5 weeks up to 24 months after treatment initiation [4,6]. It may take 3–6 weeks for resolution [6]. No gender predisposition has been noted [2]. Two different patterns of renal parenchymal damage have been noted on renal biopsy, acute (granulomatous) tubulointerstitial nephritis (ATIN) and immune complex glomerulonephritis [6]. ATIN was reported in 4 out of 12 [6], 12 out of 13 [4], and 14 out of 16 [7] with AKI. ATIN is thought to result from loss of tolerance of self-reactive T-cells against renal antigens by inhibition of inhibitory the PD-1/PD-L1 signaling pathway [2,4,6]. This triggers an inflammatory response against renal parenchymal tissue manifesting as ATIN [2,6]. Shirali et al. report 6 cases of acute interstitial nephritis in association with CPIs. Out of them, 3 were on proton pump inhibitors (PPIs) like our patient. They theorize that initiation of PD-1 inhibitor therapy may have disrupted tolerance to PPIs and precipitated ATIN [8]. Our patient was on pantoprazole for years for subjective acid reflux which was continued during and after pembrolizumab was stopped. It might have contributed to the worsened renal injury. It was continued for gastrointestinal protection as the patient was placed on long term prednisone. \n\nRenal biopsy is recommended in cases where AKI from pembrolizumab is suspected. Discontinuation of pembrolizumab and initiation of corticosteroids is the mainstay of treatment [2,6,8]. Prognosis is excellent with corticosteroids [4,6]. Among the 12 patients with ATIN, 10 patients who received glucocorticoids had partial or complete recovery of the renal function while 2 had non-improvement in the absence of glucocorticoids [4]. Similar outcome was noted in 6 alive pembrolizumab-treated patients who had a recovery of ~50% of their renal function [6]. Similarly, Shirali et al. reported 6 biopsy-proven cases of interstitial nephritis with checkpoint inhibitors that improved with discontinuation of the medication and course of corticosteroids [8]. Izzedine et al. recommend careful corticosteroid taper over a month [6]. Mamlouk et al. used prednisone at doses ranging between 0.5–4 mg/kg/day which was tapered off 4–24 months based on the pathology and recurrence of renal disease [7]. Longer courses and additional immunosuppressive medications may be needed in patients with poor response [6]. Infliximab has been tried to improve renal function [7]. Re-challenge with PD-1 inhibitor therapy can be considered with improvement in renal function and withdrawal of any other possible offending agents [6,8]. Recurrence of severe ATIN resulted with reintroduction of pembrolizumab. Our patient’s renal function never recovered and she progressed to chronic kidney disease stage IV from stage II. Hence, further treatment with pembrolizumab was aborted.\n\n4. Conclusion\nClinicians should be aware of the potential renal complications of pembrolizumab which can lead to a break in the treatment of the underlying condition. Early identification of an increase in creatinine with regular monitoring may help with prevention and early institution of effective treatment. \n\nAcknowledgments\nAccepted for poster presentation at South Central PA Chapter, Society of Hospital Medicine Academic Day and Poster Competition 2018. \n\nAuthor Contributions\nWriting—Original Draft Preparation, S.B.; Writing—Review & Editing, R.D., B.T.\n\nFunding\nThis research received no external funding.\n\nConflicts of Interest\nThe authors declare no conflicts of interest. \n\nFigure 1 Renal biopsy with focal interstitial inflammation, mostly lymphocytes (arrow) and focal tubulitis.\n\nmedicina-55-00176-t001_Table 1Table 1 Summary of case details.\n\nS.N.\tHeadings\tPrior to Hospitalization\tFirst Hospitalization\tIndex Hospitalization\t\n1.\tSerum creatinine (reference range: 0.6–1.3 mg/dL)\t<1 mg/dL\tDay 1: 1.69 mg/dL\nDischarge: 1.83 mg/dL\tDay 1: 3.70 mg/dL (also peak)\nDischarge: 2.10 mg/dL\t\n2.\tEstimated GFR (mL/min/1.73 m2)\t>70 mL/min/1.73 m2\tDay1: 30.66 mL/min/1.73 m2\nDischarge: 27.97 mL/min/1.73 m2\tDay 1: 12.41 mL/min/1.73 m2\nDischarge: 23.86 mL/min/1.73 m2\t\n3.\tPresentation\t\n\tSubsternal chest pain, diffuse abdominal pain\tFever and vomiting\t\n4.\tWorkup\t\n\tNormal kidneys and urinary tract on computed tomography\nNormal urinalysis \tNormal renal ultrasound and urinalysis\t\n5.\tTreatment\t\n\tIntravenous hydration\tIntravenous hydration\nPembrolizumab permanently discontinued\nIntravenous methylprednisone 80 mg (1 mg/kg) followed by prednisone for 3 months and 3 cycles of docetaxel 125 mg every 3 weeks. \nSulfamethoxazole-trimethoprim and pantoprazole for prophylaxis.\n==== Refs\nReferences\n1. Khoja L. Butler M.O. Kang S.P. Ebbinghaus S. Joshua A.M. Pembrolizumab J. Immunother. Cancer 2015 3 36 10.1186/s40425-015-0078-9 26288737 \n2. Wanchoo R. Karam S. Uppal N.N. Barta V.S. Deray G. Devoe C. Launay-Vacher V. Jhaveri K.D. Cancer and Kidney International Network Workgroup on Immune Checkpoint Inhibitors. Adverse renal effects of immune checkpoint inhibitors: A narrative review Am. J. Nephrol. 2017 45 160 169 10.1159/000455014 28076863 \n3. Research C for DE and. Approved Drugs-FDA Grants Regular Approval for Pembrolizumab in Combination with Chemotherapy for First-Line Treatment of Metastatic Nonsquamous NSCLC Available online: https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm617471.htm (accessed on 3 November 2018) \n4. Cortazar F.B. Marrone K.A. Troxell M.L. Ralto K.M. Hoenig M.P. Brahmer J.R. Le D.T. Lipson E.J. Glezerman I.G. Wolchok J. Clinicopathological features of acute kidney injury associated with immune checkpoint inhibitors Kidney Int. 2016 90 638 647 10.1016/j.kint.2016.04.008 27282937 \n5. Garon E.B. Rizvi N.A. Hui R. Leighl N. Balmanoukian A.S. Eder J.P. Patnaik A. Aggarwal C. Gubens M. Horn L. Pembrolizumab for the treatment of non-small-cell lung cancer N. Engl. J. Med. 2015 372 2018 2028 10.1056/NEJMoa1501824 25891174 \n6. Izzedine H. Mateus C. Boutros C. Robert C. Rouvier P. Amoura Z. Mathian A. Renal effects of immune checkpoint inhibitors Nephrol. Dial. Transplant. 2017 32 936 942 10.1093/ndt/gfw382 28025384 \n7. Mamlouk O. Selamet U. Machado S. Abdelrahim M. Glass W.F. Tchakarov A. Gaber L. Lahoti A. Workeneh B. Chen S. Nephrotoxicity of immune checkpoint inhibitors beyond tubulointerstitial nephritis: Single-center experience J. Immunother. Cancer 2019 7 2 10.1186/s40425-018-0478-8 30612580 \n8. Shirali A.C. Perazella M.A. Gettinger S. Association of acute interstitial nephritis with programmed cell death 1 inhibitor therapy in lung cancer patients Am. J. Kidney Dis. 2016 68 287 291 10.1053/j.ajkd.2016.02.057 27113507\n\n", "fulltext_license": "CC BY", "issn_linking": "1010-660X", "issue": "55(5)", "journal": "Medicina (Kaunas, Lithuania)", "keywords": "acute kidney injury; non-small cell lung cancer; pembrolizumab; programmed cell death 1 inhibitor", "medline_ta": "Medicina (Kaunas)", "mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D002289:Carcinoma, Non-Small-Cell Lung; D002637:Chest Pain; D003404:Creatinine; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D008875:Middle Aged; D009395:Nephritis, Interstitial", "nlm_unique_id": "9425208", "other_id": null, "pages": null, "pmc": null, "pmid": "31117208", "pubdate": "2019-05-21", "publication_types": "D002363:Case Reports", "references": "25891174;26288737;27113507;27282937;28025384;28076863;30612580", "title": "Acute Tubulointerstitial Nephritis: A Case Report on Rare Adverse Effect of Pembrolizumab.", "title_normalized": "acute tubulointerstitial nephritis a case report on rare adverse effect of pembrolizumab" }

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"reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "White blood cell count decreased", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haemoglobin decreased", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tubulointerstitial nephritis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Neutrophil count decreased", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Monocyte count decreased", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Chronic kidney disease", "reactionmeddraversionpt": "22.1", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "BASNET S, DHITAL R, THARU B. ACUTE TUBULOINTERSTITIAL NEPHRITIS: A CASE REPORT ON RARE ADVERSE EFFECT OF PEMBROLIZUMAB. 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ACUTE TUBULOINTERSTITIAL NEPHRITIS: A CASE REPORT ON RARE ADVERSE EFFECT OF PEMBROLIZUMAB. 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"OLANZAPINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "NIGHTLY", "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": null, "activesubstance": { "activesubstancename": "ONDANSETRON" }, "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": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ONDANSETRON" } ], "patientagegroup": null, "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Monocyte count decreased", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Chronic kidney disease", "reactionmeddraversionpt": "22.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Renal injury", "reactionmeddraversionpt": "22.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "White blood cell count decreased", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neutrophil count decreased", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tubulointerstitial nephritis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Haemoglobin decreased", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BASNET S. ACUTE TUBULOINTERSTITIAL NEPHRITIS: A CASE REPORT ON RARE ADVERSE EFFECT OF PEMBROLIZUMAB.", "literaturereference_normalized": "acute tubulointerstitial nephritis a case report on rare adverse effect of pembrolizumab", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20191219", "receivedate": "20190712", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16568055, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200122" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2019R1-230576", "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": "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": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "80 MILLIGRAM, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "Acute kidney injury", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "80", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 MILLIGRAM/KILOGRAM, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "007", "drugtreatmentduration": "3", "drugtreatmentdurationunit": "802", "medicinalproduct": "PREDNISONE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM" }, "drugadditional": null, "drugadministrationroute": "065", "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": "SULFAMETHOXAZOLE\\TRIMETHOPRIM" } ], "patientagegroup": null, "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Condition aggravated", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Basnet S, Dhital R, Tharu B. Acute Tubulointerstitial Nephritis: A Case Report on Rare Adverse Effect of Pembrolizumab. 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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": "ROSUVASTATIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "8 MG, BID, BEFORE AND AFTER CHEMOTHERAPY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, 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"drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROMETHAZINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ONDANSETRON" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "8 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": "ONDANSETRON" } ], "patientagegroup": null, "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "22.1", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "BASNET S, DHITAL R, THARU B. ACUTE TUBULOINTERSTITIAL NEPHRITIS: A CASE REPORT ON RARE ADVERSE EFFECT OF PEMBROLIZUMAB. MEDICINA-KAUNAS. 2019?55:176", "literaturereference_normalized": "acute tubulointerstitial nephritis a case report on rare adverse effect of pembrolizumab", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20191217", "receivedate": "20191217", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17162201, "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": "US-DRREDDYS-USA/USA/19/0117025", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "PANTOPRAZOLE SODIUM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "077619", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "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": "PANTOPRAZOLE SODIUM DR TABLETS 20MG AND 40MG" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "OLANZAPINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "076133", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AT NIGHT", "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": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OLANZAPINE FILM-COATED TABLET" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ONDANSETRON" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "076183", "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": "8", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ONDANSETRON" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEVOTHYROXINE" }, "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": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "75", "drugstructuredosageunit": "004", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOTHYROXINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PROMETHAZINE HYDROCHLORIDE" }, "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": "25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROMETHAZINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISONE" }, "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": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "80", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "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": "COTRIMOXAZOLE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METHOTREXATE" }, "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": "METHOTREXATE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "FOLIC ACID" }, "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": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FOLIC ACID." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PROCHLORPERAZINE" }, "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": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROCHLORPERAZINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DOCETAXEL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "204193", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "SHE HAS RECEIVED 3 CYCLES SO FAR", "drugenddate": null, "drugenddateformat": null, "drugindication": "LUNG NEOPLASM MALIGNANT", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "3", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "125", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOCETAXEL." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "PANTOPRAZOLE SODIUM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "077619", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "GASTROOESOPHAGEAL REFLUX DISEASE", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "40", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PANTOPRAZOLE SODIUM DR TABLETS 20MG AND 40MG" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "PEMETREXED" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "LUNG NEOPLASM MALIGNANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PEMETREXED." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ROSUVASTATIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AT NIGHT", "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": "ROSUVASTATIN." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "CARBOPLATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "LUNG NEOPLASM MALIGNANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "550", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBOPLATIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "TWO DOSES BEFORE AND AFTER CHEMOTHERAPY", "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": "8", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LORAZEPAM" }, "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": ".5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LORAZEPAM." } ], "patientagegroup": null, "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haemoglobin decreased", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tubulointerstitial nephritis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Chills", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "White blood cell count decreased", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BASNET S, DHITAL R, THARU B. ACUTE TUBULOINTERSTITIAL NEPHRITIS: A CASE REPORT ON RARE ADVERSE EFFECT OF PEMBROLIZUMAB. MEDICINA (KAUNAS, LITHUANIA). 2019 MAY?55(5):1-5. DOI:10.3390/MEDICINA55050176", "literaturereference_normalized": "acute tubulointerstitial nephritis a case report on rare adverse effect of pembrolizumab", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20191217", "receivedate": "20191210", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17132721, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200122" } ]

{ "abstract": "The risk of serious bacterial infectious events (SIEs) after an RTX course used in severe and refractory cases of systemic autoimmune diseases (SAID) is well known. Risk factors for SIEs merit investigation. For this case-control study, data were collected in a single centre of internal medicine and included all patients who received rituximab (RTX) for SAID between 2005 and 2011 (rheumatoid arthritis was excluded). Sixty-nine patients with SAID received a total of 87 RTX courses. Thirteen SIEs were reported in 12 patients leading to death in 5 patients. Patients with a history of SIE were significantly older (63.6±18.8 vs 48.8±16.7; p=0.0091), suffered most frequently of diabetes mellitus (33.3% vs 5.3%, p=0.015), had a lower CD19 count (1.0±1.2/mm3 vs 3.9±7.2/mm3) and had most frequently a prednisone dose>15 mg/day (91.7% vs 47.7%) at the start of the first RTX course. The SIE rate was 18.7 per 100 patient-years. At the initiation of the RTX course, risk factors for SIEs were lower IgG levels (OR=0.87, 95%CI=0.77-0.99, p=0.03), lower CD19 count (OR=0.85, 95%CI=0.73-1.00) and creatinine clearance≤45 ml/min (OR=7.78, 95%CI=1.36-44.38, p=0.002). Conversely history of pneumococcal vaccination significantly decreased the risk of SIEs (OR=0.11, 95%CI=0.03-0.41, p=0.0009). Concomitant treatment with prednisone at a dose>15 mg/day significantly increased the SIE risk (OR=8.07, 95%CI=1.94-33.59, p=0.0004). SIEs are frequent in SAID treated with RTX, particularly in patients receiving high-dose corticosteroids, in patients with renal insufficiency and in patients with low IgG levels or a low CD19 count.", "affiliations": "National Reference Centre for Systemic Autoimmune Diseases, Department of Internal Medicine, Claude Huriez Hospital, Université de Lille Nord-de-France, Lille, France.", "authors": "Heusele|Marion|M|;Clerson|Pierre|P|;Guery|Benoit|B|;Lambert|Marc|M|;Launay|David|D|;Lefevre|Guillaume|G|;Morell-Dubois|Sandrine|S|;Maillard|Hélène|H|;Le Gouellec|Noémie|N|;Hatron|Pierre-Yves|PY|;Hachulla|Eric|E|", "chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; D018501:Antirheumatic Agents; D007074:Immunoglobulin G; D000069283:Rituximab; D011241:Prednisone", "country": "Germany", "delete": false, "doi": "10.1007/s10067-014-2509-2", "fulltext": "\n==== Front\nClin Rheumatol\nClin Rheumatol\nClinical Rheumatology\n0770-3198\n1434-9949\nSpringer London London\n\n24487486\n2509\n10.1007/s10067-014-2509-2\nOriginal Article\nRisk factors for severe bacterial infections in patients with systemic autoimmune diseases receiving rituximab\nHeusele Marion 1\nClerson Pierre 2\nGuery Benoit 3\nLambert Marc 1\nLaunay David 1\nLefevre Guillaume 1\nMorell-Dubois Sandrine 1\nMaillard Hélène 1\nLe Gouellec Noémie 1\nHatron Pierre-Yves 1\nHachulla Eric +33-320444296 +33-320444062 ehachulla@chru-lille.fr\n\n14\n1 National Reference Centre for Systemic Autoimmune Diseases, Department of Internal Medicine, Claude Huriez Hospital, Université de Lille Nord-de-France, Lille, France\n2 Orgamétrie Biostatistiques Roubaix, Roubaix, France\n3 Infectious Diseases Department, Claude Huriez Hospital, Pavillon Fourrier, Université de Lille Nord-de-France, Lille, France\n4 Department of Internal Medicine, Hôpital Claude Huriez, 59037 Lille, France\n2 2 2014\n2 2 2014\n2014\n33 6 799805\n30 10 2013\n12 1 2014\n19 1 2014\n© The Author(s) 2014\nOpen Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.\nThe risk of serious bacterial infectious events (SIEs) after an RTX course used in severe and refractory cases of systemic autoimmune diseases (SAID) is well known. Risk factors for SIEs merit investigation. For this case–control study, data were collected in a single centre of internal medicine and included all patients who received rituximab (RTX) for SAID between 2005 and 2011 (rheumatoid arthritis was excluded). Sixty-nine patients with SAID received a total of 87 RTX courses. Thirteen SIEs were reported in 12 patients leading to death in 5 patients. Patients with a history of SIE were significantly older (63.6 ± 18.8 vs 48.8 ± 16.7; p = 0.0091), suffered most frequently of diabetes mellitus (33.3 % vs 5.3 %, p = 0.015), had a lower CD19 count (1.0 ± 1.2/mm3 vs 3.9 ± 7.2/mm3) and had most frequently a prednisone dose >15 mg/day (91.7 % vs 47.7 %) at the start of the first RTX course. The SIE rate was 18.7 per 100 patient-years. At the initiation of the RTX course, risk factors for SIEs were lower IgG levels (OR = 0.87, 95%CI = 0.77–0.99, p = 0.03), lower CD19 count (OR = 0.85, 95%CI = 0.73–1.00) and creatinine clearance ≤ 45 ml/min (OR = 7.78, 95%CI = 1.36–44.38, p = 0.002). Conversely history of pneumococcal vaccination significantly decreased the risk of SIEs (OR = 0.11, 95%CI = 0.03–0.41, p = 0.0009). Concomitant treatment with prednisone at a dose >15 mg/day significantly increased the SIE risk (OR = 8.07, 95%CI = 1.94–33.59, p = 0.0004). SIEs are frequent in SAID treated with RTX, particularly in patients receiving high-dose corticosteroids, in patients with renal insufficiency and in patients with low IgG levels or a low CD19 count.\n\nKeywords\n\nInfectious risk\nRituximab\nSystemic autoimmune diseases\nSystemic lupus erythematosus\nVasculitis\nissue-copyright-statement© Clinical Rheumatology 2014\n==== Body\nIntroduction\n\nBiologic agents are regularly used for the management of systemic autoimmune diseases (SAID) refractory to conventional therapy or dependent of high corticosteroid doses [1]. Rituximab (RTX) is a monoclonal antibody that targets CD20+ B cells. The CD20 antigen is restricted to B lymphocytes at the pre-B cell stage but is not present in mature plasma cells or stem cells [2]. Peripheral B cell depletion lasts for an average of 6–9 months and sometimes longer [3]. B cells that return from the bone marrow to the peripheral blood after depletion are immature or naive, rather than memory B cells [4]. This delayed development of memory cells appears to persist for several years after RTX treatment [5].\n\nDespite two negative randomized trials in systemic lupus erythematosus (SLE) [6, 7], RTX is frequently used in severe and refractory SLE. The positive results of two randomized clinical trials in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis [8, 9] will increase their use in this indication, sometimes as a first line therapy. The increased risk of infection due to RTX use in SAID has already been reported upon [10, 11]. The risk of serious infectious events (SIEs) remains several months after an RTX course, the majority within the 6 months of the RTX infusion [12]. The main goal of the study was to identify the risk factors for the SIEs occurring within 12 months after the first RTX administration in any course of RTX.\n\nMaterials and methods\n\nMethod\n\nThe primary objective of our study was to evaluate the risk factors of SIEs in RTX treated patients. This is a case–control study. Cases for analysis were defined as “RTX courses with occurrence of SIEs” and controls as “RTX courses without SIEs”. Data were collected in a single centre of internal medicine (National Centre for Rare Systemic Auto-immune Diseases, Lille, France). All patients who received off-label RTX for SAID between 2005 and 2011 were included in the study. Due to the individual and nominative dispensation of this drug, the central pharmaceutical department was able to forward an exhaustive list of all the patients treated in our department. There were no exclusion criteria; all patients were taken into account. A course of RTX was defined as IV infusions of either 2 × 1,000 mg given 2 weeks apart or 4 × 375 mg/m2 given 4 weeks apart. At each RTX infusion, 100-mg methylprednisolone was systematically administered intravenously to prevent perfusion reactions. SIEs were defined as any infection which led to hospitalization and/or death and/or required treatment with intravenous antibiotic/antiviral drugs. Nosocomial infections were defined as localized or systemic conditions that resulted from adverse reactions to the presence of (an) infectious agent(s) or its toxin(s) and that were not present or incubating at the time of hospital admission. For most bacterial nosocomial infections, this means that the infection usually becomes evident 48 h or more after admission [13]. History of hospitalization of at least 48 h within the previous 90 days [14] was also collected to individualize a subset of patients corresponding to health care-associated infections [15].\n\nThis research was authorized by the French competent authority dealing with research on human biological samples namely the French Ministry of Research. The authorization number is DC 2008 642. To issue such authorization, the Ministry of Research has sought the advice of an independent ethics committee, namely the “Comité de Protection des Personnes”. The committee voted positively on the quality of information provided to patients and the obtainment of consent for the intended use in research. Therefore, we attest that this study was conducted in accordance with French regulations concerning human research, and no breach to clinical research rules was observed.\n\nStatistics\n\nSIEs were right censored at 12 months after the first perfusion of RTX for each treatment course. The influence of patient’s characteristics at the start of an RTX course was estimated by logistic regression models. Some patients underwent several courses of RTX, and, as analysis had focus on each RTX course and not on each patient, these RTX courses for a same patient could not be assumed to be independent. Therefore, the analysis was adjusted for clustered data (procedure SURVEYLOGISTIC). Results are expressed as odds ratios with their two-sided 95 % confidence intervals. Analyses were conducted using the SAS 9.1.3 statistical software (SAS Institute, Cary, NC, USA).\n\nResults\n\nPatients\n\nSixty-nine patients entered the study, and none were lost to follow-up. Among them, 55 patients received one course of treatment, 10 received two courses and 4 received three courses. A total of 87 RTX courses involving 69 patients were analysed. Fifty-six patients (81.2 %) were female; the mean age was 51.4 ± 18.1 years. Patients were suffering from SLE (n = 22), Sjögren’s syndrome-associated vasculitis (n = 14), ANCA-associated vasculitis (n = 9), idiopathic mixed cryoglobulinaemia vasculitis (n = 10), haematologic autoimmune disorders (autoimmune haemolytic anaemia/idiopathic thrombocytopenic purpura/acquired haemophilia with anti-factor VIII antibodies) (n = 12), myositis (n = 3) or catastrophic antiphospholipid syndrome (n = 1). RTX was mostly given to patients considered to be refractory to conventional therapy including corticosteroids and at least one immunosuppressive drug (n = 64, 92.8 %) or to patients who were dependent on a high dose of corticosteroid (i.e. prednisone 20 mg or more per day) for the purpose of corticosteroid sparing (n = 5, 7.2 %). Forty-three (62.3 %) patients had received pneumococcal vaccination (40 before and 3 after the first RTX course). Twelve patients experienced at least one SIE during or after an RTX course; one patient experienced two SIEs after the first and the third cure, respectively. Characteristics of patients with or without SIE before the first cure are given in Table 1. Comparisons involved 12 patients with at least one SIE and 57 patients who never had SIE. Patients with a history of SIE were significantly older, suffered most frequently of diabetes mellitus, had a lower CD19 count and had most frequently a prednisone dose >15 mg/day at the start of the first RTX course.Table 1 Characteristics of patients with or without history of severe infection events\n\nStatus of the patients at the start of the first rituximab course\tPatients with history of SIEs (n = 12)\tPatients without history of SIEs (n = 57)\tp\t\nMean age +/− SD\t63.6 ± 18.8\t48.8 ± 16.7\t0.0091\t\nGender: male/female\t3 (25 %)/9\t10 (17.5 %)/47\t0.68\t\nSLE\t3 (25 %)\t19 (33.3 %)\t0.74\t\nSjögren\t1 (8.3 %)\t13 (22.8 %)\t0.44\t\nANCA vasculitis\t2 (16.7)\t7 (12.3 %)\t0.65\t\nIdiopathic cryoglobulinaemia vasculitis\t4 (33.3 %)\t6 (10.5 %)\t0.06\t\nHaematologic autoimmune disorders\t4 (33.3 %)\t8 (14.0 %)\t0.20\t\nDiabetes mellitus\t4 (33.3 %)\t3 (5.3 %)\t0.015\t\nGammaglobulin level (g/l)\t7.9 ± 5.4\t11.4 ± 5.8\t0.18\t\nIgG level (g/l)\t7.5 ± 4.1\t11.9 ± 7.3\t0.20\t\nLymphocyte count (100/mm3)\t656.5 ± 597.1\t1,353.1 ± 1,057.5\t0.20\t\nCD19 count (/mm3)\t1.0 ± 1.2\t3.9 ± 7.2\t0.03\t\nCD4 count (100/mm3)\t550.1 ± 551.4\t605.9 ± 465.6\t0.78\t\nCreatinine clearance (ml/min)\t75.9 ± 41.4\t85.4 ± 31.2\t0.37\t\nCreatinine clearance ≤45 ml/min\t4 (33.3 %)\t3 (5.3 %)\t0.15\t\nCreatinine clearance ≤60 ml/min\t5 (41.7 %)\t13 (22.8 %)\t0.28\t\nConcomitant immunosuppressive drug a\t2 (16.7 %)\t20 (35.1 %)\t0.31\t\nPrevious immunosuppressive drug a\t3 (25 %)\t23 (40.4 %)\t0.51\t\nPrednisone >15 mg/day\t11 (91.7 %)\t27 (47.4 %)\t0.005\t\namethotrexate (N = 9), azathioprine (N = 8), leflunomide (N = 4), mycophenolate mofetil (N = 4), cyclophosphamide (N = 1)\n\nRTX courses\n\nMean number of RTX perfusions was 2.9 ± 1.1 perfusions per RTX course. In patients who received several RTX courses, the mean delay between two courses was 36.6 ± 19.2 months. Immediate tolerability was good in all patients. Side effects were mild and common: diarrhoea (n = 2), headaches (n = 3), hyperthermia (n = 3), asthenia (n = 3), flu-like symptoms (n = 2) and mild upper respiratory tract infections (n = 11). One patient developed a serum sickness with arthralgia, cutaneous rash and hyperthermia 8 days after the end of the second course with a rapid spontaneous favourable evolution despite the first course having been well tolerated. During RTX courses, concomitant treatments were immunosuppressive drugs (n = 26, 29.9 %) and prednisone at a dose >15 mg/day (n = 41, 47.1 %). These treatments were pursued for a further 6 months after the end of the RTX course.\n\nLaboratory monitoring\n\nIg levels, CD4 lymphocyte count and CD19 lymphocyte count were monitored. Due to the observational nature of the study, data were not collected at regular intervals. Before the first RTX infusion for each cure, the mean IgG level was 9.9 ± 6.9 g/l (n = 51), and lymphocyte counts were 1,267 ± 976/mm3 with 627 ± 474 CD4/mm3 and 3.4 ± 6.4 CD19/mm3. During the 6 following months, the mean IgG level decreased to a nadir of 8.7 ± 4.8 g/mm3 (n = 56) compared to IgA or IgM which both remained virtually unchanged. Sixteen out of 42 patients with documented IgG values experienced an IgG level below 6 g/l, and ten had a nadir below 5 g/l. Post course CD19 counts were documented in 59 patients, and 31 (52.5 %) had no CD19 (i.e. a count equal to 0/mm3) after the RTX course. CD4 count decreased from 627 ± 474/mm3 to a nadir of 469 ± 384/mm3. In 14 out of 58 documented patients, the nadir was <200/mm3.\n\nSevere infections\n\nTwelve patients experienced at least one SIE during or after an RTX course (17.4 % of patients). Thirteen SIEs were reported (14.9 % of RTX courses). All were bacterial or suspected bacterial infections. Within 6 months following the first infusion of a course, we observed 11 SIEs in 11 patients (12.6 % of RTX courses). Two other SIEs (one pneumonia and one sinusitis that occurred, respectively, 208 days and 345 days after the first RTX infusion of the course) occurred more than 6 months after the RTX course. Baseline characteristics of cases and controls at beginning of the RTX course are given in Table 2. Severe infection rate was 18.7 per 100 patient-years. Individual data of SIEs are provided in Table 3. However, if data are analysed as a percentage of the numbers of patients in each group, some particularities seem to emerge: 3 lupus patients out of 22 developed an SIE (13 %) in contrast to 2 out of 9 ANCA vasculitis (22 %), 4 out of 12 with a haematologic autoimmune disorder (33 %) and 4 out of 10 with idiopathic cryoglobulinaemia vasculitis (40 %). Over the 12-month period following the start of RTX course, five patients died from infections (5/12), and one died due to another cause (Paget’s disease of the breast at month 6). None of those who died from infection had received pneumococcal vaccination, and all had received prednisone at a dose >15 mg/day concomitant with RTX. Four of the five infected deceased patients were older than 70 years old.Table 2 Individual data of patients with severe infections\n\n\tSex/age\tDiagnosis\tCT and IS at time of SIE\tPV\tInfection/time from the RTX course\tPathogen\tOutcome\t\n1\tF/45\tV/SG\tP > 15 mg/day\tY\tBronchitis/month 2\t–\tFavourable\t\n2\tM/72\tV/CG\tP > 15 mg/day\tN\tFebrile neutropenia/month 1\tStreptococcus pneumoniae\tDeath\n\nToxic shock syndrome\n\n\t\n3\tF/49\tSLE\tP < 15 mg/day\tY\tPneumonia/month 6\t–\tFavourable\t\n4\tF/73\tSLE\tP < 15 mg/day\tN\tHand cellulitis/month 3\tStaphylococcus aureus methy-R\tFavourable\t\n5\tF/75\tAH\tP > 15 mg/day\tN\tPneumonia/month 1\tPseudomonas aeruginosa nombreux Pneumocystis + Candida albicans + Enterobacter cloacae (nosocomial infection)\tDeath related to infection\t\n6\tF/75\tV/CG\tP > 15 mg/day\tN\tSuspected endocarditis/month 1\t–\tDeath related to acute renal failure and infection\t\n7\tM/66\tAH\tP > 15 mg/day\tY\tSepticemia/month 2\tEnterococcus faecalis (possible nosocomial infection)\tFavourable\t\n8\tF/21\tSLE\tIS + P > 15 mg/day\tN\tPneumonia/month 1\t–\n\n(possible nosocomial infection)\n\n\tFavourable\t\n9\tF/90\tAH\tP > 15 mg/day\tN\tFebrile neutropenia/month 2\tEscherichia coli (nosocomial infection)\tFavourable\t\n10\tF/55\tW\tP > 15 mg/day\tN\tPneumonia/month 1\tEnterococcus faecalis + Clostridium clostridiform + Bacterium lentum + Staphylococcus epidermidis + Stenotrophomonas maltrophilia (nosocomial infection)\tDeath related to infection\t\n11\tF/77\tAIHA\tP > 15 mg/day\tN\tPost-surgical pneumonia/month 1\t–\n\n(nosocomial infection)\n\n\tDeath following lung surgery in a septic context\t\n12\tF/47\tSLE\tP > 15 mg/day\tN\tSinusitis/month 11\tStreptococcus pneumoniae PSDP + Haemophilus influenzae\tFavourable\t\n13\tM/70\tW\tP > 15 mg/day\tN\tPneumonia/month 10\tStreptococcus pneumoniae + Haemophilus influenzae\tFavourable\t\nV vasculitis, SG Sjögren syndrome, CG cryoglobulinaemia, SLE systemic lupus erythematosus, AH acquired haemophilia, W Wegener’s disease, AIHA autoimmune haemolytic anaemia, RTX rituximab, PV pneumococcal vaccination, D death, Y yes, N no, CT concomitant treatments, P prednisone, IS immunosuppressive drug\n\nTable 3 Risk factors of baseline characteristics regarding the risk of severe bacterial infection (univariate analysis)\n\n\tORa\t95%CI\tP\t\nAge (years)\t1.05\t[0.99–1.10]\t0.08\t\nFemale sex\t0.58\t[0.13–2.61]\t0.48\t\nTreatment with IVIg within 3 months prior to RTX course\t1.74\t[0.31–9.75]\t0.53\t\nImmunosuppressive drugs within 6 months before RTX course\t0.82\t[0.24–2.84]\t0.75\t\nConcomitant treatment with immunosuppressive drugs\t0.38\t[0.07–1.97]\t0.25\t\nHigh-dose IV methylprednisolone within 1 month before RTX course\t2.17\t[0.54–8.71]\t0.28\t\nConcomitant treatment with prednisone >15 mg/day\t8.07\t[1.94–33.59]\t0.004\t\nStatin use\t1.92\t[0.42–8.76]\t0.40\t\nCreatinine clearance >60 ml/min\t0.51\t[0.14–1.85]\t0.31\t\nCreatinine clearance ≤60 ml/min\t1.94\t[0.54–7.00]\t0.31\t\nCreatinine clearance ≤45 ml/min\t7.78\t[1.36–44.38]\t0.02\t\nHospitalisation >48 h within 180 days before RTX course\t1.94\t[0.55–6.87]\t0.30\t\nPneumococcal vaccination\t0.11\t[0.03–0.41]\t0.0009\t\nNadir of gammaglobulin rate during the 6 months after RTX course (g/l)\t0.67\t[0.52–0.86]\t0.002\t\nIgG level at start of RTX course (g/l)\t0.87\t[0.77–0.99]\t0.03\t\nLymphocyte count at start of RTX course (100/mm3)\t0.83\t[0.64–1.08]\t0.17\t\nCD19 count at start of RTX course (/mm3)\t0.85\t[0.73–1.00]\t0.05\t\nCD4 count at start of RTX course (100/mm3)\t0.96\t[0.76–1.21\t0.71\t\nOR odds ratio, RTX rituximab\n\na13 cases and 74 controls; OR provided by univariate regression models\n\nStreptococcus pneumoniae was identified in 3/13 SIEs, one febrile neutropenia and sepsis that occurred within 1 month after the first dose of RTX course and one sinusitis and one pneumonia having occurred, respectively, 208 and 345 days after the beginning of the RTX course. For these two patients, the relationship with RTX was considered as probable as IgG levels were <6 g/l (respectively, 5.9 g/l and 1.79 g/l) at the time of infection. Six out of the 11 SIEs observed during the 6 months following the RTX course were nosocomial infections (occurring during a hospitalization period or during the 2 following days).\n\nFactors associated with SIEs occurring within 12 months following RTX courses\n\nRisk factors for SIEs were investigated by logistic regression models for clustered data (Table 3). At the initiation of the RTX course, the risk factors for SIEs were lower IgG levels (OR = 0.87, 95%CI = 0.77–0.99, p = 0.03), lower CD19 count (OR = 0.85, 95%CI = 0.73–1.00) and creatinine clearance ≤45 ml/min (OR = 7.78 95%CI = 1.36–44.38, p = 0.002). Conversely, history of pneumococcal vaccination significantly decreased the risk of SIEs (OR = 0.11, 95%CI = 0.03–0.41, p = 0.0009). Concomitant treatment with prednisone at a dose >15 mg/day significantly increased the SIE risk (OR = 8.07, 95%CI = 1.94–33.59, p = 0.0004). We did not find a cutoff point either for IgG level (IgG <6 g/l: OR = 2.19, 95%CI = 0.52–9.22, p = 0.28) nor for gamma globulins level (gamma globulins <6 g/l: OR = 1.77 95%CI = 0.55–5.74, p = 0.34). Odds ratio for age at the time of RTX course did not reach statistical significance (p = 0.08) most probably partly due to the small number of events.\n\nDiscussion\n\nThe main goal of this case–control study was to investigate risk factors for SIE in patients who received off-label RTX for SAID. Within 12 months following the first infusion of each RTX course, we observed 13 SIEs in 12 patients most of them occurring within the 2 months after the first perfusion of RTX. We found that patients with a history of SIE were significantly older, suffered most frequently of diabetes mellitus, had a lower CD19 count and had most frequently a prednisone dose >5 mg/day at the start of the first RTX course. Moreover, a lower level in gamma globulins, a lower CD19 count and renal failure (creatinine clearance ≤45 ml/min) at initiation of an RTX course increased the risk of SIE. Conversely, the SIE risk was lower in patients having been vaccinated against S. pneumonia. A concomitant treatment with prednisone at a dose >15 mg/day was associated with a higher risk of SIEs.\n\nSevere infectious event rate\n\nSAIDs are at high risk of SIEs with a rate of 18.7 SIEs/100 patient-years. Other studies conducted in rheumatoid arthritis (RA) patients and SLE patients have found lower rates (around 4 to 6 SIEs/100 patient-years) [16, 17]. Diaz Lagarez et al. [10], however, found an 11.2 SIEs/100 patient-years SIE rate in patients suffering from SAID with a 22.6 SIEs/100 patient-years SIE rate in patients treated with more than two RTX courses. The risk of SIEs was not increased by addition of RTX to methotrexate (MTX) when compared to MTX alone. In the randomized EXPLORER study (phase II/III extra renal SLE evaluation of RTX), the SIE rate was lower in the RTX group compared to the placebo group (9.5 % and 17 %, respectively) [7]. Another randomized study [9] compared RTX and cyclophosphamide in patients with ANCA-associated renal vasculitis. There were 19 SIEs in 12 of the 33 patients treated by RTX (36 %) and 7 SIEs in 3 of the 11 patients (27 %) treated with cyclophosphamide. The difference was not significant between the two groups. Three patients died from infection in the RTX group versus one in the cyclophosphamide group. Van Vollenhoven et al. [18] studied the influence of the number of courses on the infection rate in RA patients treated with RTX and MTX. It emerged that neither the number of courses nor the total exposure time to RTX had any effect on the risk of SIEs. In our study, interestingly, patients with SLE seem at far less risk of developing SIEs. Indeed, the fact that the average age of patients with a history of infections is 63 years supports the view that SLE seems to be relatively at low risk for infection (given the fact that most lupus patients are much younger).\n\nPathogen\n\nNo viral infection was observed in this cohort. We highlighted that, in 11 patients who had an SIE during the 6 months following the course, 2 had community pathogens, and 4 other patients had hospital-related pathogens. Six SIEs occurred in patients with a past history of an at least 48-h hospitalization within the 90 days before the SIE, suggesting that the SIE could be nosocomial. Similarly, Gottenberg et al. found pathogens frequently identified as possibly nosocomial and included Pseudomonas aeruginosa, Escherichia coli, and Staphylococcus aureus [17]. Thus, there is an increased risk of nosocomial infection which calls for caution in the use of RTX in the context of a previous prolonged hospitalization.\n\nPneumococcal vaccination\n\nOf the patients who developed SIEs, 72.7 % had not received pneumococcal vaccine before or during the RTX course versus 28.9 % of the patients who did not develop SIEs. In the subgroup of patients who had not received pneumococcal vaccine before the RTX course, one had severe pneumococcal sepsis and died, and two others had documented pneumococcal disease, albeit after the 6-month period following the RTX course. In the subgroup of vaccinated patients, one had received a pneumococcal vaccination 8 months after the first course (therefore, 3 months before a pneumococcal infection (patient 12)). The lymphocytic depletion was still complete at the time of the vaccination (CD19 number = 0/mm3), probably explaining the lack of efficacy of the vaccination. This highlights the importance of pneumococcal vaccination before the first RTX course (at least 3 to 4 weeks when possible) as recommended [19] and also the need to update all other non-live attenuated vaccines. The high number of pneumococcal infections has modified our practice. We now recommend pneumococcal vaccination in all SAID patients 3 to 4 weeks before the first course of RTX, when possible. If not, we propose pneumococcal vaccination simultaneously with the first RTX administration although it is known that the immune response against pneumococcal vaccination is reduced in RTX-treated patients even when the vaccine is administrated 28 weeks after the RTX course [3].\n\nBasal IgG level\n\nDespite a lack of data concerning the IgG levels, it emerged that a high IgG level at baseline was associated with a lower risk of SIEs. Common observations showed that IgG’s are the most important Ig for protective immunity and that patients who have a low IgG level have an increased risk of SIEs. However, in the Van Vollenhoven et al. study [18], the effect of IgG at baseline was not significant. We advise discussion on the use of IVIg in patients who have an IgG level <5 g/l before RTX treatment, particularly in patients who have a past history of severe infection.\n\nCorticosteroid dosage\n\nIn 81.8 % of RTX courses with SIEs, the patients were concomitantly receiving prednisone at a dose >15 mg/day versus 42.1 % of RTX courses without SIE. In a meta-analysis focusing on the infectious risk in patients taking corticosteroids, no SIEs occurred when the prednisone daily dose was lower than 10 mg [20]. When possible, corticosteroids should be used at low doses in association with RTX. In lupus nephritis for example, it has previously been shown that remission is possible with immunosuppressive drugs and corticosteroids at a dose of 10 mg/day [21].\n\nLimitations\n\nThe major limitation of the study is its retrospective nature. Nevertheless, due to the traceability of RTX dispensation, all SAIDs treated in our department during the 2005–2011 period were collected, and no patients were lost to follow-up. The lack of a control group of patients suffering from SAID not exposed to RTX definitely makes it difficult to attribute the high rate of SIEs to the RTX use. Due to the multiple aspects of SAIDs, we cannot rule out that the type of SAID may influence the SIE risk. Multivariate analysis was not possible due to the small number of events. Finally, due to the low number of patients involved who were retreated, it is not possible to evaluate the effect of retreatment on the risk of SIEs.\n\nConclusions\n\nThis study identified four main risk factors associated with an increased risk of SIEs in SAID patients treated with RTX: high-dose corticosteroids (>15 mg/day), renal insufficiency (creatinine clearance ≤45 ml/min), a low IgG level and a low CD19 count. The high number of pneumococcal infections has modified our practice. We would recommend pneumococcal vaccination in all SAID patients 3 to 4 weeks prior to the first course of RTX if possible or simultaneously to the first RTX course if not possible in case of an emergency situation. IVIg could be discussed in patients who have an IgG level <5 g/l, particularly if SIEs occur, though this deserves further studies. Last but not least, we recommend, when possible, to limit the corticosteroid dose below 15 mg/day or to rapidly decrease the corticosteroid dose below 15 mg/day after induction treatment in SAID treated with RTX.\n\nWe thank Stephen Mulligan who reviewed the article for the English spelling.\n\nConflict of interest\n\nMarion Heusele, Pierre Clerson, Benoit Guery, Marc Lambert, David Launay, Guillaume Lefevre, Sandrine Morell-Dubois, Hélène Maillard, Noémie Le Gouellec and Pierre-Yves Hatron have declared no conflict of interest. Eric Hachulla has received consultancy fees or research grant funding from Roche and GSK, less than 10,000€.\n==== Refs\nReferences\n\n1. Ramos-Casals M Brito-Zerón P Muñoz S Soto MJ Biogeas Study Group A systematic review of the off-label use of biological therapies in systemic autoimmune diseases Medicine (Baltimore) 2008 87 345 364 10.1097/MD.0b013e318190f170 19011506\n2. Stashenko P Nadler LM Hardy R Schlossman SF Characterization of a human B lymphocyte-specific antigen J Immunol 1980 125 1678 1685 6157744\n3. Keystone E Fleischmann R Emery P Safety and efficacy of additional courses of rituximab in patients with active rheumatoid arthritis: an open-label extension analysis Arthritis Rheum 2007 56 3896 3908 10.1002/art.23059 18050221\n4. St Clair EW Good and bad memories following rituximab therapy Arthritis Rheum 2010 62 1 5 10.1002/art.25039 20039422\n5. Muhammad K Roll P Einsele H Dörner T Tony HP Delayed acquisition of somatic hypermutations in repopulated IGD+CD27+ memory B cell receptors after rituximab treatment Arthritis Rheum 2009 60 2284 2293 10.1002/art.24722 19644860\n6. Rovin BH Furie R Latinis K Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the Lupus Nephritis Assessment with Rituximab study Arthritis Rheum 2012 64 1215 1226 10.1002/art.34359 22231479\n7. Merrill JT Neuwelt CM Wallace DJ Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus: the randomized, double-blind, phase II/III systemic lupus erythematosus evaluation of rituximab trial Arthritis Rheum 2010 62 222 233 10.1002/art.27233 20039413\n8. Stone JH Merkel PA Spiera R Rituximab versus cyclophosphamide for ANCA-associated vasculitis N Engl J Med 2010 363 221 232 10.1056/NEJMoa0909905 20647199\n9. Jones RB Tervaert JW Hauser T Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis N Engl J Med 2010 363 211 220 10.1056/NEJMoa0909169 20647198\n10. Diaz-Lagares C Perez-Alvarez R Garcia-Hernandez FJ Rates of, and risk factors for, severe infections in patients with systemic autoimmune diseases receiving biological agents off-label Arthritis Res Ther 2011 13 R112 10.1186/ar3397 21745378\n11. Terrier B Amoura Z Ravaud P Safety and efficacy of rituximab in systemic lupus erythematosus: results from 136 patients from the French AutoImmunity and Rituximab registry Arthritis Rheum 2010 62 2458 2466 10.1002/art.27541 20506527\n12. Tony HP Burmester G Schulze-Koops H Safety and clinical outcomes of rituximab therapy in patients with different autoimmune diseases: experience from a national registry (GRAID) Arthritis Res Ther 2011 13 R75 10.1186/ar3337 21569519\n13. Garner JS Jarvis WR Emori TG Horan TC Hughes JM Olmsted RN CDC definitions for nosocomial infections APIC infection control and applied epidemiology: principles and practice 1996 St. Louis Mosby A-1 A-20\n14. Kollef MH Napolitano LM Solomkin JS Health care-associated infection (HAI): a critical appraisal of the emerging threat-proceedings of the HAI summit Clin Infect Dis 2008 47 Suppl 2 S55 S99 10.1086/590937 18778223\n15. Lujan M Gallego M Rello J Healthcare-associated infections. A useful concept? Curr Opin Crit Care 2009 15 419 424 10.1097/MCC.0b013e32832e9956 19553808\n16. Fleischmann RM Safety of biologic therapy in rheumatoid arthritis and other autoimmune diseases: focus on rituximab Semin Arthritis Rheum 2009 38 265 280 10.1016/j.semarthrit.2008.01.001 18336874\n17. Gottenberg JE Ravaud P Bardin T Risk factors for severe infections in patients with rheumatoid arthritis treated with rituximab in the autoimmunity and rituximab registry Arthritis Rheum 2010 62 2625 2632 10.1002/art.27555 20506353\n18. van Vollenhoven RF Emery P Bingham CO 3rd Longterm safety of patients receiving rituximab in rheumatoid arthritis clinical trials J Rheumatol 2010 37 558 567 10.3899/jrheum.090856 20110520\n19. Pham T Fautrel B Gottenberg JE Rituximab (MabThera) therapy and safety management. Clinical tool guide Joint Bone Spine 2008 75 Suppl 1 S1 S99 18708020\n20. Stuck AE Minder CE Frey FJ Risk of infectious complications in patients taking glucocorticosteroids Rev Infect Dis 1989 11 954 963 10.1093/clinids/11.6.954 2690289\n21. Pepper R Griffith M Kirwan C Rituximab is an effective treatment for lupus nephritis and allows a reduction in maintenance steroids Nephrol Dial Transplant 2009 24 3717 3723 10.1093/ndt/gfp336 19617257\n\n", "fulltext_license": "CC BY", "issn_linking": "0770-3198", "issue": "33(6)", "journal": "Clinical rheumatology", "keywords": null, "medline_ta": "Clin Rheumatol", "mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D058846:Antibodies, Monoclonal, Murine-Derived; D018501:Antirheumatic Agents; D001327:Autoimmune Diseases; D001424:Bacterial Infections; D016022:Case-Control Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007074:Immunoglobulin G; D008180:Lupus Erythematosus, Systemic; D008297:Male; D008875:Middle Aged; D011241:Prednisone; D012307:Risk Factors; D000069283:Rituximab; D016896:Treatment Outcome; D014657:Vasculitis", "nlm_unique_id": "8211469", "other_id": null, "pages": "799-805", "pmc": null, "pmid": "24487486", "pubdate": "2014-06", "publication_types": "D016428:Journal Article", "references": "20110520;21569519;20506527;20647198;19011506;22231479;20039413;6157744;18336874;19617257;18708020;19644860;19553808;20506353;18050221;2690289;18778223;21745378;20039422;20647199", "title": "Risk factors for severe bacterial infections in patients with systemic autoimmune diseases receiving rituximab.", "title_normalized": "risk factors for severe bacterial infections in patients with systemic autoimmune diseases receiving rituximab" }

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RISK FACTORS FOR SEVERE BACTERIAL INFECTIONS IN PATIENTS WITH SYSTEMIC AUTOIMMUNE DISEASES RECEIVING RITUXIMAB. 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RISK FACTORS FOR SEVERE BACTERIAL INFECTIONS IN PATIENTS WITH SYSTEMIC AUTOIMMUNE DISEASES RECEIVING RITUXIMAB. 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RISK FACTORS FOR SEVERE BACTERIAL INFECTIONS IN PATIENTS WITH SYSTEMIC AUTOIMMUNE DISEASES RECEIVING RITUXIMAB. 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RISK FACTORS FOR SEVERE BACTERIAL INFECTIONS IN PATIENTS WITH SYSTEMIC AUTOIMMUNE DISEASES RECEIVING RITUXIMAB. 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RISK FACTORS FOR SEVERE BACTERIAL INFECTIONS IN PATIENTS WITH SYSTEMIC AUTOIMMUNE DISEASES RECEIVING RITUXIMAB.. 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RISK FACTORS FOR SEVERE BACTERIAL INFECTIONS IN PATIENTS WITH SYSTEMIC AUTOIMMUNE DISEASES RECEIVING RITUXIMAB.. CLIN-RHEUMATOL. 2014;33:799-805", "literaturereference_normalized": "risk factors for severe bacterial infections in patients with systemic autoimmune diseases receiving rituximab", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20150729", "receivedate": "20150729", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11320393, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20151125" } ]

{ "abstract": "Electroconvulsive therapy and concomitant lithium therapy remain a matter of debate because of increased rates of adverse events. Current recommendations include monitoring lithium levels and reducing lithium to minimally effective dose. We present a report on protracted effects of lithium intoxication as electroconvulsive therapy 8 days after intoxication and under normal lithium serum levels resulted in a prolonged seizure. Electroencephalogram recordings before stimulation showed electroencephalogram correlates of subsiding lithium intoxication most likely due to protracted lithium influx and efflux of the central nervous system.", "affiliations": "Department of Psychiatry, Psychotherapy and Psychosomatics, University Hospital RWTH; and JARA-Translational Brain Medicine, RWTH Aachen University, Aachen, Germany.;Department of Psychiatry, Psychotherapy and Psychosomatics, University Hospital RWTH; and JARA-Translational Brain Medicine, RWTH Aachen University, Aachen, Germany.;Department of Psychiatry, Psychotherapy and Psychosomatics, University Hospital RWTH; and JARA-Translational Brain Medicine, RWTH Aachen University, Aachen, Germany.", "authors": "Augustin|Marc|M|;Karakavuz|Rahsan|R|;Riester|Luise|L|;Grözinger|Michael|M|", "chemical_list": "D016651:Lithium Carbonate", "country": "United States", "delete": false, "doi": "10.1097/YCT.0000000000000719", "fulltext": null, "fulltext_license": null, "issn_linking": "1095-0680", "issue": "37(1)", "journal": "The journal of ECT", "keywords": null, "medline_ta": "J ECT", "mesh_terms": "D000368:Aged; D001921:Brain; D003863:Depression; D004359:Drug Therapy, Combination; D004565:Electroconvulsive Therapy; D004569:Electroencephalography; D005260:Female; D006333:Heart Failure; D006353:Heart-Assist Devices; D006801:Humans; D016651:Lithium Carbonate", "nlm_unique_id": "9808943", "other_id": null, "pages": "67-70", "pmc": null, "pmid": "33600119", "pubdate": "2021-03-01", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Lithium Is Likely to Persist in the Brain: Clinical Implications for Electroconvulsive Therapy.", "title_normalized": "lithium is likely to persist in the brain clinical implications for electroconvulsive therapy" }

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"activesubstancename": "CHOLECALCIFEROL" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "25.000 IU, 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": "25", "drugstructuredosageunit": "025", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CHOLECALCIFEROL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PHENPROCOUMON" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK (DOSAGE ACCORDING TO COAGULATION STATUS)", "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": "PHENPROCOUMON" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 MG, UNKNOWN", "drugenddate": null, "drugenddateformat": null, "drugindication": "Seizure", "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": "5", "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "RECEIVED TOTAL OF 4MG IN THREE INJECTIONS OF 1, 1 AND 2MG", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLONAZEPAM" } ], "patientagegroup": null, "patientonsetage": "68", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20170101" } }, "primarysource": { "literaturereference": "Augustin M, Karakavuz R, Riester L, Grozinger M. Lithium Is Likely to Persist in the Brain: Clinical Implications for Electroconvulsive Therapy. JOURNAL OF ECT. 2021;37(1):67-70", "literaturereference_normalized": "lithium is likely to persist in the brain clinical implications for electroconvulsive therapy", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20220120", "receivedate": "20211228", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20238964, "safetyreportversion": 4, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220423" }, { "companynumb": "DE-GLAXOSMITHKLINE-DE2021GSK057926", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "HYDROCHLOROTHIAZIDE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "40780", "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "25 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "Diuretic therapy", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2015", "drugstartdateformat": "602", "drugstructuredosagenumb": "25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROCHLOROTHIAZIDE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RAMIPRIL" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, 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"drugstartdateformat": null, "drugstructuredosagenumb": "3", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ROCURONIUM BROMIDE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "SIMVASTATIN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "40 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": "40", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SIMVASTATIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "SUCCINYLCHOLINE CHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 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": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SUCCINYLCHOLINE CHLORIDE" } ], "patientagegroup": null, "patientonsetage": "68", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Seizure", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Disorientation", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Malaise", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Tremor", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sedation complication", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Somnolence", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hyponatraemia", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Head titubation", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20170101" } }, "primarysource": { "literaturereference": "Augustin M, Karakavuz R, Riester L, Grozinger M.. Lithium Is Likely to Persist in the Brain: Clinical Implications for Electroconvulsive Therapy. The journal of ECT.. 2021;37 (1):67-70", "literaturereference_normalized": "lithium is likely to persist in the brain clinical implications for electroconvulsive therapy", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20220122", "receivedate": "20210318", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19024557, "safetyreportversion": 4, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220423" }, { "companynumb": "DE-TEVA-2021-DE-1995640", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RAMIPRIL" }, "drugadditional": "3", "drugadministrationroute": "048", 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"drugstartdateformat": null, "drugstructuredosagenumb": "25000", "drugstructuredosageunit": "025", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CHOLECALCIFEROL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PHENPROCOUMON" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DOSAGE ACCORDING TO COAGULATION STATUS", "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": "PHENPROCOUMON" } ], "patientagegroup": "6", "patientonsetage": "68", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Sedation complication", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Somnolence", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20170101" } }, "primarysource": { "literaturereference": "Augustin M, Karakavuz R, Riester L, Grozinger M. Lithium Is Likely to Persist in the Brain: Clinical Implications for Electroconvulsive Therapy. J-ECT 2021;37(1):67-70.", "literaturereference_normalized": "lithium is likely to persist in the brain clinical implications for electroconvulsive therapy", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20220121", "receivedate": "20220106", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20305888, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20220424" }, { "companynumb": "DE-GLAXOSMITHKLINE-DE2021GSK057926", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RAMIPRIL" }, "drugadditional": "3", "drugadministrationroute": 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null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Corynebacterium infection", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLINDAMYCIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "SIMVASTATIN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "40 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "Product used for 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"drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "3", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ROCURONIUM BROMIDE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MIRTAZAPINE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "30 MILLIGRAM", "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": "30", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MIRTAZAPINE" } ], "patientagegroup": null, "patientonsetage": "68", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Seizure", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Disorientation", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tremor", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Malaise", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hyponatraemia", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sedation complication", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Somnolence", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20170101" } }, "primarysource": { "literaturereference": "Augustin M, Karakavuz R, Riester L, Grozinger M.et.al.. Lithium Is Likely to Persist in the Brain: Clinical Implications for Electroconvulsive Therapy.. The journal of ECT. 2021;37(1):67-70", "literaturereference_normalized": "lithium is likely to persist in the brain clinical implications for electroconvulsive therapy", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20220124", "receivedate": "20210824", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19740236, "safetyreportversion": 5, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220423" }, { "companynumb": "DE-CorePharma LLC-2124181", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TORSEMIDE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "076894", "drugbatchnumb": "Unknown", "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": "2015", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TORSEMIDE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LITHIUM CARBONATE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": "Unknown", "drugcharacterization": "1", "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": "450", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LITHIUM CARBONATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "HYDROCHLOROTHIAZIDE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": "Unknown", "drugcharacterization": "1", "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": "2015", "drugstartdateformat": "602", "drugstructuredosagenumb": "25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROCHLOROTHIAZIDE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RAMIPRIL" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": "Unknown", "drugcharacterization": "1", "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": "2015", "drugstartdateformat": "602", "drugstructuredosagenumb": "2.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RAMIPRIL" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "4", "drugadministrationroute": "048", "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": "3", "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": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "24.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "24.1", "reactionoutcome": "2" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20170101" } }, "primarysource": { "literaturereference": "Augustin M, et al. Lithium Is Likely to Persist in the Brain: Clinical Implications for Electroconvulsive Therapy. Journal of ECT 37: 67-70, No. 1, Mar 2021. 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"activesubstancename": "PANTOPRAZOLE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 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": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PANTOPRAZOLE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "QUETIAPINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "25 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": "25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "QUETIAPINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CHOLECALCIFEROL" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "25000 INTERNATIONAL UNIT", "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": "25000", "drugstructuredosageunit": "025", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CHOLECALCIFEROL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PHENPROCOUMON" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK,DOSAGE ACCORDING TO COAGULATION STATUS", "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": "PHENPROCOUMON" } ], "patientagegroup": null, "patientonsetage": "68", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20170101" } }, "primarysource": { "literaturereference": "Augustin M, Karakavuz R, Riester L, Grozinger M. Lithium is likely to persist in the brain: Clinical implications for electroconvulsive therapy. Journal of Electroconvulsive Therapy. 2021;37(1):67-70", "literaturereference_normalized": "lithium is likely to persist in the brain clinical implications for electroconvulsive therapy", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20220103", "receivedate": "20220103", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20281781, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220423" } ]

{ "abstract": "BACKGROUND\nAcute generalized exanthematous pustulosis (AGEP) is a rare and severe cutaneous reaction usually triggered by drugs. Other causative factors such as viral infections are rarely involved. In this study, we report a case of AGEP caused by a spider bite.\n\n\nMETHODS\nA 56-year-old woman was referred to the allergy unit after a spider bite at the left popliteal fossa, while gardening, 5 days earlier. The offending spider was captured and identified by an entomologist as belonging to the Loxosceles rufescens species. No acute reaction was observed; however, after 24 hours, due to the occurrence of typical dermonecrotic skin lesions associated with erythema and edema, Cefuroxime and Clindamycin were administered intramuscularly after medical advice was given. Almost 72 hours after the spider bite, an erythematous and partly edematous eruption appeared locally in the gluteus area bilaterally, which progressively expanded to the trunk, arms and femors. Within 24 hours dozens of small, pinhead sized, non-follicular pustules were present, mainly in the folds. The patient complained of a burning sensation of the skin in addition to pruritus; and simultaneously had a fever of 38-39 degrees C as the eruption expanded.\n\n\nCONCLUSIONS\nA spider bite may represent a possible causative factor of AGEP. A spider's venom contains sphingomyelinase that stimulates the release of IL8 and GM-CSF, which are involved in AGEP pathogenesis. Whether or not the con-current use of antibiotics has an effect in AGEP appearance when combined with a spider's venom, cannot be excluded.", "affiliations": "Allergy Clinical Research Center, Allergy Unit, 2nd Department of Dermatology and Venereology, Attikon University General Hospital, Medical School, University of Athens, Greece. mak-mik@hol.gr", "authors": "Makris|Michael|M|;Spanoudaki|Nektaria|N|;Giannoula|Fani|F|;Chliva|Caterina|C|;Antoniadou|Anastasia|A|;Kalogeromitros|Dimitrios|D|", "chemical_list": "D002981:Clindamycin; D002444:Cefuroxime", "country": "England", "delete": false, "doi": "10.2332/allergolint.08-CR-0035", "fulltext": null, "fulltext_license": null, "issn_linking": "1323-8930", "issue": "58(2)", "journal": "Allergology international : official journal of the Japanese Society of Allergology", "keywords": null, "medline_ta": "Allergol Int", "mesh_terms": "D000818:Animals; D002444:Cefuroxime; D002981:Clindamycin; D004487:Edema; D004890:Erythema; D005076:Exanthema; D005260:Female; D006801:Humans; D008875:Middle Aged; D012867:Skin; D012882:Skin Tests; D001098:Spider Bites", "nlm_unique_id": "9616296", "other_id": null, "pages": "301-3", "pmc": null, "pmid": "19307779", "pubdate": "2009-06", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Acute generalized exanthematous pustulosis (AGEP) triggered by a spider bite.", "title_normalized": "acute generalized exanthematous pustulosis agep triggered by a spider bite" }

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"reactionoutcome": "1" }, { "reactionmeddrapt": "Leukocytosis", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "SPANOUDAKI N, GIANNOULA F, CHLIVA C, ANTONIADOU A, KALOGEROMITROS D. 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{ "abstract": "Bordetella bronchiseptica infection is a common cause of pneumonia in animals but rarely causes disease in humans. Additionally, coinfection with Pneumocystis jirovecii is very uncommon and is occasionally seen in patients with acquired immunodeficiency syndrome (AIDS). We report a case of a 61-year-old HIV-negative man, who presented with hypoxic respiratory failure 2 days after completion of systemic intravenous antibiotic treatment for B bronchiseptica. His past medical history was significant for a benign thymoma. The patient was found to be coinfected with B bronchiseptica and P jirovecii. Laboratory results showed panhypogammaglobulinemia and low absolute B- and CD4 T-cells. Therefore, the patient was diagnosed with Good's syndrome. However, despite treatment with intravenous antibiotics and intravenous immunoglobulin, the patient continued to deteriorate and expired. This patient demonstrates the importance of recognizing this rare immunodeficiency early in order to improve morbidity and mortality. Furthermore, this case highlights the importance of early immunoglobulin screening in the presence of asymptomatic thymoma.", "affiliations": "Emory University School of Medicine, Atlanta, GA, USA.;Emory University School of Medicine, Atlanta, GA, USA.;Emory University School of Medicine, Atlanta, GA, USA.;Emory University School of Medicine, Atlanta, GA, USA.", "authors": "Bhargava|Ankit|A|;Eisenstadt|Rachel|R|;Shih|Jennifer A|JA|;Sueblinvong|Viranuj|V|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1177/2324709618802869", "fulltext": "\n==== Front\nJ Investig Med High Impact Case RepJ Investig Med High Impact Case RepHICsphicJournal of Investigative Medicine High Impact Case Reports2324-7096SAGE Publications Sage CA: Los Angeles, CA 10.1177/232470961880286910.1177_2324709618802869Case ReportA Good Case of Recurrent Pneumonia Bhargava Ankit MD1Eisenstadt Rachel MD1Shih Jennifer A. MD1Sueblinvong Viranuj MD11 Emory University School of Medicine,\nAtlanta, GA, USAViranuj Sueblinvong, Department of Medicine,\nEmory University School of Medicine, 615 Michael Street NE, Suite 205, Atlanta,\nGA 30322, USA. Email: vsuebli@emory.edu29 9 2018 Jan-Dec 2018 6 232470961880286914 6 2018 17 8 2018 30 8 2018 © 2018 American Federation for Medical\nResearch2018American Federation for Medical\nResearchThis article is distributed under the terms of the Creative Commons\nAttribution 4.0 License (http://www.creativecommons.org/licenses/by/4.0/) which\npermits any use, reproduction and distribution of the work without further\npermission provided the original work is attributed as specified on the SAGE\nand Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Bordetella bronchiseptica infection is a common cause of\npneumonia in animals but rarely causes disease in humans. Additionally,\ncoinfection with Pneumocystis jirovecii is very uncommon and is\noccasionally seen in patients with acquired immunodeficiency syndrome (AIDS). We\nreport a case of a 61-year-old HIV-negative man, who presented with hypoxic\nrespiratory failure 2 days after completion of systemic intravenous antibiotic\ntreatment for B bronchiseptica. His past medical history was\nsignificant for a benign thymoma. The patient was found to be coinfected with\nB bronchiseptica and P jirovecii.\nLaboratory results showed panhypogammaglobulinemia and low absolute B- and CD4\nT-cells. Therefore, the patient was diagnosed with Good’s syndrome. However,\ndespite treatment with intravenous antibiotics and intravenous immunoglobulin,\nthe patient continued to deteriorate and expired. This patient demonstrates the\nimportance of recognizing this rare immunodeficiency early in order to improve\nmorbidity and mortality. Furthermore, this case highlights the importance of\nearly immunoglobulin screening in the presence of asymptomatic thymoma.\n\nGood’s syndromeBordetella bronchisepticaPneumocystis jiroveciirecurrent pneumoniacover-dateJanuary-December 2018\n==== Body\nIntroduction\nGood’s syndrome is a rare entity that causes B- and T-cell immunodeficiency in\nadults, leading to an increase in susceptibility to encapsulated organisms, fungal,\nand opportunistic infections (OIs).1 This case highlights the importance of maintaining a high clinical suspicion\nfor uncommon immunodeficiency conditions in patients who present with unusual\ncombinations of infection.2 Appropriate workup to obtain a diagnosis will allow for timely delivery of\nappropriate treatment.\n\nCase Report\nA 61-year-old homeless man with a past medical history significant for benign\nspindle-cell thymoma presented with acute hypoxic respiratory failure. Two months\nprior, he was treated for Bordetella bronchiseptica pneumonia and\nempyema with intravenous (IV) antibiotics and right pleural decortication.\nEvaluation during the first hospitalization was negative for HIV, hepatitis B\ninfection, syphilis, blastomycosis, and coccidioidomycosis. He was discharged but\nwas subsequently rehospitalized within 1 week with recurrent pneumonia. During this\nsecond hospitalization, he was treated with another 2-week course of antibiotics\nwith some improvement in symptoms and was discharged home. Two days after being\ndischarged, he presented to our institute with hypoxic respiratory failure requiring\nendotracheal intubation. Pertinent findings on physical examination were fever,\nhypoxia, and tachycardia. Oral candidiasis was noted. Lung auscultation revealed\ncoarse and mechanical breath sounds bilaterally. Chest radiographic findings showed\nbilateral patchy airspace opacities (Figure 1A). Computed tomography scan of the\nchest showed a stable, large anterior mediastinal mass, multiple cavitary lesions,\nand diffuse ground-glass opacities (Figure 1B). The patient was started on broad-spectrum IV antibiotics\nwith cefepime and vancomycin. Examination of the bronchoalveolar lavage revealed\nB bronchiseptica and Pneumocystis jirovecii.\nThe patient’s antibiotics regimen was changed to piperacillin/tazobactam,\nsulfamethoxazole-trimethoprim with prednisone, and fluconazole. Repeat HIV serology\nwas negative. Laboratory results showed panhypogammaglobulinemia and low total B-\nand CD4 T-cells (Table\n1). IV immunoglobulin (IG) treatment (400 mg/kg every 3-4 weeks) was\ninitiated. He was evaluated for possible thymectomy but was not a surgical candidate\ndue to his clinical condition. His clinical status continued to deteriorate, and he\nsubsequently suffered cardiac arrest and death.\n\nFigure 1. Chest radiographic findings at the time of hospital admission. (A) Chest\nX-ray showing endotracheal tube and diffuse ground glass opacity and (B)\nrepresentative cut of chest computed tomography scan showing bilateral\nground glass opacity and cavitary lesions.\n\nTable 1. Laboratory Results.\n\nTest\tResult\tNormal Range\t\nComplete blood count\t\n Hemoglobin\t9.9 (g/dL)\t12.9-16.1 (g/dL)\t\n White blood cell count\t9.4 (×103 cell/µL)\t4.2-9.1 (×103 cell/µL)\t\n  Neutrophil (%)\t90\t\t\n  Lymphocyte (%)\t7\t\t\n  Monocyte (%)\t3\t\t\n  Absolute neutrophil\t8.36 (×103 cell/µL)\t0.67-6.41 (×103 cell/µL)\t\n  Absolute lymphocyte\t0.64 (×103 cell/µL)\t0.72-3.29 (×103 cell/µL)\t\n  Absolute monocyte\t0.31 (×103 cell/µL)\t0.14-0.71 (×103 cell/µL)\t\n Platelet count\t302 (×103 cell/µL)\t150-400 (×103 cell/µL)\t\nImmunophenotype\t\n Absolute B cell (CD19)\t<1 (cell/µL)\t91-610 (cell/µL)\t\n CD4\t203 (cell/µL)\t430-1800 (cell/µL)\t\nImmunoglobulin (Ig)\t\n Total IgG\t367\t620-1400 mg/dLa\t\n Total IgM\t11\t45-250 mg/dLa\t\n Total IgA\t60\t80-350 mg/dLa\t\n Total IgE\t<1\t<1 mg/dLa\t\na Depicts a normal value in patients without acute infection.\n\nDiscussion\nThe eponymous Dr Good first described the association of thymoma,\nhypogammaglobulinemia, and increased susceptibility to OI in 1954. Good’s syndrome\nhas since been classified as an adult-onset immune deficiency with low to absent\nB-cells, derangement in cell-mediated immunity (CD8:CD4 imbalance, low CD4 count),\nand thymoma, without formal diagnostic criteria.3 The etiology of this immune dysfunction remains elusive. Good’s syndrome is\ndistinct from common variable immunodeficiency in the presence of both\nhypogammaglobulinemia and reduced B-cell populations. This disease process clarifies\nthe role of the thymus both in educating T-cells and producing an appropriate\nresponse in B-cells. Two proposed theories for the etiology of associated\nhypogammaglobulinemia in patients with thymoma, including bone marrow suppression\nand paraneoplastic phenomena, supported by the association with pure red cell\naplasia.4,5\n\nWhile relatively rare, the incidence among patients with thymoma and\nhypogammaglobulinemia may be as high as 6% to 11%.4 A mean age at the time of diagnosis is 59.1 years (12-90 years).6 In 2.4% of patients who first presented with thymoma, 37.9% presented with\nboth thymoma and infection, whereas only 19.7% presented with infection.7 Autoimmunity is a common phenomenon in patients with Good’s syndrome. About\n58.6% of patients have a secondary autoimmune condition, most commonly pure red cell\naplasia (34.8%), myasthenia gravis (15.7%), and oral lichen planus\n(12.4%).5,8,9 The clinical\ncourse of Good’s syndrome has been reported to be more severe when compared with\ncommon variable immunodeficiency, with a 10-year survival of 33% versus 95%, respectively.7 Interestingly, T-cell count does not accurately correlate with associated\nrisk of OI for patients with Good’s syndrome. Chest radiography can miss thymoma in\nup to 25% of patients.10 Due to deficiency of B- and T-cells, patients with Good’s syndrome are\nsusceptible to a variety of infections, including encapsulated bacteria (ie,\nHaemophilus, Streptococcus, Pseudomonas, Klebsiella,\nBordetella), fungi (ie, Candida, Pneumocystis jirovecii),\nviral infections, and protozoa (ie, Giardia).7,11 Diagnosis should be made\nthrough radiologic evaluation of thymoma, measurement of IG serum levels,\nphenotyping of lymphocytes, evaluation for B-cell population depletion, and CD8:CD4\nT-cell derangement.4 Specific treatment of Good’s syndrome includes high-dose IVIG (400 mg/kg IV\nevery 3-4 weeks) to improve humoral immune response and to help prevent\nlife-threatening OIs. Thymectomy is recommended to prevent other immunological\nmanifestations of thymoma including myasthenia gravis, pure red cell aplasia, and\npernicious anemia.3,10 However, several reports suggest that hypogammaglobulinemia\npersists following thymectomy, and patients with Good’s syndrome remain at risk for\nOI.12,13\n\nOur patient’s presentation demonstrates the importance of early recognition of this\nrare immunodeficiency.2 A delay in the diagnosis may result in increased morbidity and mortality.\nThis case highlights the importance of early reflexive IG screening, even in the\npresence of asymptomatic thymoma. In the presence of unexplained OI alongside\nhistory of thymoma, a high suspicion for acquired immune deficiency may allow for\nexpedient delivery of appropriate therapy.\n\nIn summary, Good’s syndrome should be suspected in patients present with uncommon\nencapsulated infection (ie, Bordetella spp) and OIs. IVIG should be\nadministered to prevent life-threatening OIs. Reflexive immunophenotyping and IG\nlevels in patients with asymptomatic thymomas may allow early diagnosis of Good’s\nsyndrome and early implementation of treatment.\n\nAuthors’ Note: This case was previously presented and published in an abstract form at the 2017\nAnnual Scientific Meeting of the American College of Allergy, Asthma and Immunology.2\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the\nresearch, authorship, 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: Our institution does not require ethical approval for reporting individual\ncases.\n\nInformed Consent: Informed consent for patient information to be published in this article was not\nobtained because the patient expired and we were unable to locate his\nfamily.\n==== Refs\nReferences\n1 \nGauba V Kelleher S Raines MF. \nA case of inadvertent ocular perforation and intravitreal\ninjection of depomedrone during peribulbar injection. Good visual prognosis\nwith delayed vitrectomy . Eye (Lond) .\n2003 ;17 :1039 -1040 .14704757 \n2 \nEisenstadt R Sueblinvong V Shih J. \nP295 Good syndrome: importance of early\ndiagnosis . Ann Allerg Asthma Immunol .\n2017 ;119 :S75 -S76 .\n3 \nNarahari NK Gongati PK Kakarla B Nizami MI Boddula RP Sattavarapu LR. \nThymoma-associated immunodeficiency: a diagnostic challenge for\nthe clinician . Asian Cardiovasc Thorac Ann .\n2017 ;25 :146 -149 .28068785 \n4 \nTavakol M Mahdaviani SA Ghaemi MR et al \nGood’s syndrome-association of the late onset\ncombined immunodeficiency with thymoma: review of literature and case\nreport . Iran J Allergy Asthma Immunol .\n2018 ;17 :85 -93 .29512373 \n5 \nOkui M Yamamichi T Asakawa A Harada M Horio H. \nPure red cell aplasia associated with Good\nsyndrome . Korean J Thorac Cardiovasc Surg .\n2017 ;50 :119 -122 .28382272 \n6 \nSun X Shi J Wang M Xu K Xiao Y. \nGood’s syndrome patients hospitalized for infections: a\nsingle-center retrospective study . Medicine\n(Baltimore) .\n2015 ;94 :e2090 .26632723 \n7 \nKelesidis T Yang O. \nGood’s syndrome remains a mystery after 55 years: a systematic\nreview of the scientific evidence . Clin\nImmunol .\n2010 ;135 :347 -363 .20149753 \n8 \nSasson SC Davies S Chan R Davies L Garsia R. \nCerebral toxoplasmosis in a patient with myasthenia gravis and\nthymoma with immunodeficiency/Good’s syndrome: a case\nreport . BMC Infect Dis .\n2016 ;16 :457 .27576953 \n9 \nMotegi S Uchiyama A Yamada K Toki S Amano H Ishikawa O. \nLichen planus complicated with thymoma: report of three Japanese\ncases and review of the published work . J\nDermatol .\n2015 ;42 :1072 -1077 .26076752 \n10 \nDetterbeck FC Zeeshan A. \nThymoma: current diagnosis and treatment .\nChin Med J (Engl) .\n2013 ;126 :2186 -2191 .23769581 \n11 \nJoven MH Palalay MP Sonido CY. \nCase report and literature review on Good’s syndrome, a form of\nacquired immunodeficiency associated with thymomas .\nHawaii J Med Public Health .\n2013 ;72 :56 -62 .23467629 \n12 \nQu J Lu X Gao Q Zhang Y. \nGood syndrome, a rare cause of refractory chronic diarrhea and\nrecurrent pneumonia in a Chinese patient after thymectomy .\nClin Vaccine Immunol .\n2013 ;20 :1097 -1098 .23697574 \n13 \nTernavasio-de la Vega HG Velasco-Tirado V Pozo-Rosado L et al \nPersistence of immunological alterations after\nthymectomy in Good’s syndrome: a clue to its pathogenesis .\nCytometry B Clin Cytom .\n2011 ;80 :339 -342 .21520407\n\n", "fulltext_license": "CC BY", "issn_linking": "2324-7096", "issue": "6()", "journal": "Journal of investigative medicine high impact case reports", "keywords": "Bordetella bronchiseptica; Good’s syndrome; Pneumocystis jirovecii; recurrent pneumonia", "medline_ta": "J Investig Med High Impact Case Rep", "mesh_terms": null, "nlm_unique_id": "101624758", "other_id": null, "pages": "2324709618802869", "pmc": null, "pmid": "30283805", "pubdate": "2018", "publication_types": "D016428:Journal Article", "references": "23769581;26076752;28068785;23697574;14704757;26632723;27576953;20149753;23467629;29512373;28382272;21520407", "title": "A Good Case of Recurrent Pneumonia.", "title_normalized": "a good case of recurrent pneumonia" }

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"actiondrug": "6", "activesubstance": { "activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "017376", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RESPIRATORY FAILURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SULFAMETHOXAZOLE/TRIMETHOPRIM" } ], "patientagegroup": null, "patientonsetage": "61", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "BHARGAVA, A.. A GOOD CASE OF RECURRENT PNEUMONIA. JOURNAL OF INVESTIGATIVE MEDICINE HIGH IMPACT CASE REPORTS. 2018?6:10.1177/2324709618802869", "literaturereference_normalized": "a good case of recurrent pneumonia", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20181030", "receivedate": "20181023", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15542332, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" } ]

{ "abstract": "Lymphoma has been reported to worsen the prognosis of COVID-19 partly because it disturbs the normal production of antibodies. We treated a man with mantle cell lymphoma treated with rituximab, who developed severe COVID-19 with viral shedding that lasted for 78 days. He stayed in the intensive care unit for 28 days and did not respond to any treatment against COVID-19. His increased oxygen demand at rest eventually resolved despite the absence of anti-SARS-CoV-2-IgG. This case illustrates that recovery from COVID-19 can occur without antibody production, and that even patients with an inability to produce antibodies can recover from severe COVID-19. It also illustrates that lymphoma patients who develop severe COVID-19 while on rituximab therapy can recover from a prolonged viral shedding state if the acute lung injury can be overcome.", "affiliations": "Department of Infectious Diseases, Yokohama Municipal Citizen's Hospital. 1-1 Mitsuzawanishi-cho, Kanagawa Ward, Yokohama City, Kanagawa 221-0855, Japan. Electronic address: jevousremerciebeaucoup@hotmail.co.jp.;Department of Infectious Diseases, Yokohama Municipal Citizen's Hospital. 1-1 Mitsuzawanishi-cho, Kanagawa Ward, Yokohama City, Kanagawa 221-0855, Japan.;Department of Infectious Diseases, Yokohama Municipal Citizen's Hospital. 1-1 Mitsuzawanishi-cho, Kanagawa Ward, Yokohama City, Kanagawa 221-0855, Japan.;Department of Infectious Diseases, Yokohama Municipal Citizen's Hospital. 1-1 Mitsuzawanishi-cho, Kanagawa Ward, Yokohama City, Kanagawa 221-0855, Japan.;Department of Infectious Diseases, Yokohama Municipal Citizen's Hospital. 1-1 Mitsuzawanishi-cho, Kanagawa Ward, Yokohama City, Kanagawa 221-0855, Japan.;Department of Infectious Diseases, Yokohama Municipal Citizen's Hospital. 1-1 Mitsuzawanishi-cho, Kanagawa Ward, Yokohama City, Kanagawa 221-0855, Japan.", "authors": "Horiuchi|Hiroshi|H|;Sasaki|Hiroaki|H|;Miyazaki|Kazuhito|K|;Miyata|Nobuyuki|N|;Yoshimura|Yukihiro|Y|;Tachikawa|Natsuo|N|", "chemical_list": null, "country": "Netherlands", "delete": false, "doi": "10.1016/j.jiac.2021.11.018", "fulltext": null, "fulltext_license": null, "issn_linking": "1341-321X", "issue": null, "journal": "Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy", "keywords": "Antibody; COVID-19; Immunocompromised state; Lymphoma; Rituximab; SARS-CoV-2", "medline_ta": "J Infect Chemother", "mesh_terms": null, "nlm_unique_id": "9608375", "other_id": null, "pages": null, "pmc": null, "pmid": "34887178", "pubdate": "2021-11-25", "publication_types": "D016428:Journal Article", "references": null, "title": "Recovery from severe persistent COVID-19 without evidence of an anti-SARS-CoV-2 antibody response in a man with mantle cell lymphoma treated with rituximab.", "title_normalized": "recovery from severe persistent covid 19 without evidence of an anti sars cov 2 antibody response in a man with mantle cell lymphoma treated with rituximab" }

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"METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "11153", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "FOR 3 DAYS", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "11153", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "80 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "80", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "11153", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "120 MG", "drugenddate": null, "drugenddateformat": null, 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null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "80", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "11153", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "40 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "40", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "11153", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE" } ], "patientagegroup": null, "patientonsetage": "75", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Immunosuppression", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "COVID-19", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "Horiuchi, H.. Recovery from severe persistent COVID-19 without evidence of an anti-SARS-CoV-2 antibody response in a man with mantle cell lymphoma treated with rituximab. Journal of Infection and Chemotherapy. 2022;28(2):329-332", "literaturereference_normalized": "recovery from severe persistent covid 19 without evidence of an anti sars cov 2 antibody response in a man with mantle cell lymphoma treated with rituximab", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20220222", "receivedate": "20220222", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20501582, "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-LUPIN PHARMACEUTICALS INC.-2022-06133", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "209097", "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 GRAM FOR 3 DAYS", "drugenddate": null, "drugenddateformat": null, "drugindication": "COVID-19", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": "3", "drugtreatmentdurationunit": "804", "medicinalproduct": "METHYLPREDNISOLONE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "209097", "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK TAPERING DOSE", "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": "METHYLPREDNISOLONE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "REMDESIVIR" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "200 MG, SINGLE ON DAY 1", "drugenddate": null, "drugenddateformat": null, "drugindication": "COVID-19", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "REMDESIVIR" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "REMDESIVIR" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MG, QD FROM DAY 2 TO DAY 10", "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": "REMDESIVIR" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "4 MG STARTED ON DAY 6", "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": "DEXAMETHASONE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "HUMAN IMMUNOGLOBULIN G" }, "drugadditional": "4", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "12.5 GRAM, QD (FROM DAY 21 TO 25)", "drugenddate": null, "drugenddateformat": null, "drugindication": "COVID-19", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "12.5", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HUMAN IMMUNOGLOBULIN G" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "IVERMECTIN" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "12 MG, SINGLE ON DAY 29", "drugenddate": null, "drugenddateformat": null, "drugindication": "COVID-19", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IVERMECTIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "INTERFERON BETA-1B" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "9.6 MILLION INTERNATIONAL UNIT, QOD (FROM DAY 39-42 DAYS)", "drugenddate": null, "drugenddateformat": null, "drugindication": "COVID-19", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "2", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INTERFERON BETA-1B" } ], "patientagegroup": null, "patientonsetage": "75", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "SARS-CoV-2 RNA increased", "reactionmeddraversionpt": "25.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug ineffective for unapproved indication", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Horiuchi H, Sasaki H, Miyazaki K, Miyata N, Yoshimura Y, Tachikawa N. Recovery from severe persistent COVID-19 without evidence of an anti-SARS-CoV-2 antibody response in a man with mantle cell lymphoma treated with rituximab. Journal of Infection and Chemotherapy. 2022;28(2):329-332", "literaturereference_normalized": "recovery from severe persistent covid 19 without evidence of an anti sars cov 2 antibody response in a man with mantle cell lymphoma treated with rituximab", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20220427", "receivedate": "20220427", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20755595, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220721" } ]

{ "abstract": "The evolution of pulmonary disease in cystic fibrosis (CF) usually begins when bacteria get trapped in mucus in the lungs and become established as a chronic infection. While most CF patients experience periods of stability, pulmonary exacerbations (PEs) can occur multiple times per year and result in permanent damage to the lungs. Little is known of the shift from a period of stability to a PE, but this shift is likely to be attributed to changes in the bacterial community. Here, we identified changes in the lung microbiota to determine if they reflect patient health, indicate the onset of exacerbations, or are related to antibiotic treatment. In contrast to most bacterial studies on CF, we collected weekly samples from an adult CF patient over a period of 3 years and performed quantitative PCR (qPCR) and Illumina sequencing on those samples. While many DNA-based studies have shown the CF microbiota to be relatively stable, we observed an increase in the total bacterial abundance over time (P < 0.001), while the number of different taxa (bacterial richness) and the number of different taxa and their abundances (diversity) significantly decreased over time (P < 0.03), which was likely due to repeated antibiotic exposure. Using genus-specific primers with qPCR, we observed an increase in the abundance of Burkholderia multivorans, a CF-associated pathogen, prior to the occurrence of a PE (P = 0.006). Combining these DNA-based techniques with frequent sampling identified a potential initiator for exacerbations and described a response of the CF microbiota to time and antibiotic treatment not observed in previous CF microbiota studies.", "affiliations": "Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, North Carolina, USA.;Bioinformatics Services Division, Department of Bioinformatics and Genomics, University of North Carolina at Charlotte, Kannapolis, North Carolina, USA.;Department of Bioinformatics and Genomics, University of North Carolina at Charlotte, Charlotte, North Carolina, USA.;Department of Bioinformatics and Genomics, University of North Carolina at Charlotte, Charlotte, North Carolina, USA.;Department of Bioinformatics and Genomics, University of North Carolina at Charlotte, Charlotte, North Carolina, USA.;Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, North Carolina, USA trsteck@uncc.edu.", "authors": "Stokell|Joshua R|JR|;Gharaibeh|Raad Z|RZ|;Hamp|Timothy J|TJ|;Zapata|Malcolm J|MJ|;Fodor|Anthony A|AA|;Steck|Todd R|TR|", "chemical_list": "D000900:Anti-Bacterial Agents; D012329:RNA, Bacterial; D012336:RNA, Ribosomal, 16S", "country": "United States", "delete": false, "doi": "10.1128/JCM.02555-14", "fulltext": null, "fulltext_license": null, "issn_linking": "0095-1137", "issue": "53(1)", "journal": "Journal of clinical microbiology", "keywords": null, "medline_ta": "J Clin Microbiol", "mesh_terms": "D000328:Adult; D000900:Anti-Bacterial Agents; D058491:Bacterial Load; D044822:Biodiversity; D002908:Chronic Disease; D003550:Cystic Fibrosis; D018450:Disease Progression; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D054892:Metagenome; D064307:Microbiota; D018410:Pneumonia, Bacterial; D012329:RNA, Bacterial; D012336:RNA, Ribosomal, 16S; D013183:Sputum; D016896:Treatment Outcome", "nlm_unique_id": "7505564", "other_id": null, "pages": "237-47", "pmc": null, "pmid": "25392361", "pubdate": "2015-01", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": "22717533;20585638;17387214;17586667;22872870;21151003;22903521;21664196;23955772;15044219;11562614;20181491;21796216;21700674;18356026;11782518;20880410;21270069;21405970;24100376;22451929;17586664;14670805;15528712;20631810;19027279;21177905;20844762;21326348;23028285;23049765;22807668;19801464;23190732;22135293;17056226;24451123;23823492", "title": "Analysis of changes in diversity and abundance of the microbial community in a cystic fibrosis patient over a multiyear period.", "title_normalized": "analysis of changes in diversity and abundance of the microbial community in a cystic fibrosis patient over a multiyear period" }

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"activesubstancename": "MINOCYCLINE\\MINOCYCLINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MINOCYCLINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CIPROFLOXACIN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "019537", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC PROPHYLAXIS", "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": null, "activesubstance": { "activesubstancename": "AZTREONAM" }, "drugadditional": null, "drugadministrationroute": "045", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZTREONAM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BACTRIM" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TOBRAMYCIN" }, "drugadditional": null, "drugadministrationroute": "045", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TOBRAMYCIN." }, { "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": "ANTIBIOTIC PROPHYLAXIS", "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": "5", "patientonsetage": "30", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective for unapproved indication", "reactionmeddraversionpt": "19.1", "reactionoutcome": null }, { "reactionmeddrapt": "Infective pulmonary exacerbation of cystic fibrosis", "reactionmeddraversionpt": "19.1", "reactionoutcome": null }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "19.1", "reactionoutcome": null }, { "reactionmeddrapt": "Burkholderia infection", "reactionmeddraversionpt": "19.1", "reactionoutcome": null }, { "reactionmeddrapt": "Drug resistance", "reactionmeddraversionpt": "19.1", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "STOKELL J R; GHARAIBEH R Z; HAMP T J; ZAPATA M J; FODOR A A; ET AL. ANALYSIS OF CHANGES IN DIVERSITY AND ABUNDANCE OF THE MICROBIAL COMMUNITY IN A CYSTIC FIBROSIS PATIENT OVER A MULTIYEAR PERIOD. J.CLIN.MICROBIOL.. 2015;53, NO. 1:237-47", "literaturereference_normalized": "analysis of changes in diversity and abundance of the microbial community in a cystic fibrosis patient over a multiyear period", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160914", "receivedate": "20160914", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12743627, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20161109" } ]

{ "abstract": "BACKGROUND\nMultiple medications have been associated with pancreatitis, however, data in the pediatric population are scarce secondary to the nonspecific presentation and infrequent diagnosis. The aim of this report is to characterize drug-induced pancreatitis in an adolescent patient.\n\n\nMETHODS\nA 16-year-old African-American female presented with a surgical site infection 8 weeks after a motor vehicle accident with multiple traumas. Two weeks prior to the admission, the patient was hospitalized for a urinary tract infection (UTI) and was initiated on sulfamethoxazole/trimethoprim (TMP/SMX) daily for UTI prophylaxis. On day 13, the patient was diagnosed with acute pancreatitis with an amylase level of 187 units/L (normal = 30-110) and a lipase level of 987 units/L (normal = 23-208). TMP/SMX was discontinued, and pancreatic enzyme levels decreased but did not reach normal. The patient was asymptomatic at discharge.\n\n\nCONCLUSIONS\nTMP/SMX was identified as the likely etiology of pancreatitis by the medical team. Evaluation with the Naranjo algorithm indicated a \"possible\" adverse drug reaction.\n\n\nCONCLUSIONS\nAcute pancreatitis can have significant morbidity and mortality in the pediatric population but can go undiagnosed due to its lower incidence. Pediatric patients presenting with idiopathic abdominal pain should be evaluated for pancreatitis and drug therapy should be reviewed for potential causative agents.", "affiliations": "The University of Tennessee Health Science Center College of Pharmacy, Memphis, TN, USA sdickey5@uthsc.edu.;Department of Pharmacy, Le Bonheur Children's Hospital, Memphis, TN, USA.;Department of Clinical Pharmacy, The University of Tennessee Health Science Center College of Pharmacy, Knoxville, TN, USA.", "authors": "Dickey|Susan E|SE|;Mabry|William A|WA|;Hamilton|Leslie A|LA|", "chemical_list": "D000892:Anti-Infective Agents, Urinary; D015662:Trimethoprim, Sulfamethoxazole Drug Combination", "country": "United States", "delete": false, "doi": "10.1177/0897190015585750", "fulltext": null, "fulltext_license": null, "issn_linking": "0897-1900", "issue": "28(4)", "journal": "Journal of pharmacy practice", "keywords": "Bactrim; adverse effect; pancreatitis; pediatrics; sulfamethoxazole/trimethoprim", "medline_ta": "J Pharm Pract", "mesh_terms": "D015746:Abdominal Pain; D000063:Accidents, Traffic; D000208:Acute Disease; D000293:Adolescent; D000892:Anti-Infective Agents, Urinary; D005260:Female; D006801:Humans; D009104:Multiple Trauma; D010195:Pancreatitis; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D014552:Urinary Tract Infections", "nlm_unique_id": "8900945", "other_id": null, "pages": "419-24", "pmc": null, "pmid": "26040998", "pubdate": "2015-08", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Possible Sulfamethoxazole/Trimethoprim-Induced Pancreatitis in a Complicated Adolescent Patient Posttraumatic Injury.", "title_normalized": "possible sulfamethoxazole trimethoprim induced pancreatitis in a complicated adolescent patient posttraumatic injury" }

[ { "companynumb": "US-GLENMARK PHARMACEUTICALS-2016GMK023058", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "090828", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "URINARY TRACT INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRIMETHOPRIM SULFAMETHOXAZOLE" } ], "patientagegroup": null, "patientonsetage": "16", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pancreatitis acute", "reactionmeddraversionpt": "19.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "DICKEY S E, MABRY W A, HAMILTON L A. POSSIBLE SULFAMETHOXAZOLE/TRIMETHOPRIM-INDUCED PANCREATITIS IN A COMPLICATED ADOLESCENT PATIENT POSTTRAUMATIC INJURY.. JOURNAL OF PHARMACY PRACTICE.. 2015;28(4):419-24", "literaturereference_normalized": "possible sulfamethoxazole trimethoprim induced pancreatitis in a complicated adolescent patient posttraumatic injury", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170213", "receivedate": "20170213", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13224964, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" }, { "companynumb": "US-SA-2015SA016875", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "PRAZOSIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNK", "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": "PRAZOSIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "FERROUS SULFATE ANHYDROUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNK", "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": "IRON SULFATE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "RIFAMPIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "050420", "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": "RIFAMPICIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS URINARY TRACT INFECTION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SULFAMETHOXAZOLE AND TRIMETHOPRIM" } ], "patientagegroup": "4", "patientonsetage": "16", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lipase increased", "reactionmeddraversionpt": "18.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Pancreatitis", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Amylase increased", "reactionmeddraversionpt": "18.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Abdominal pain", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "DICKEY SE, MABRY WA, HAMILTON LA. POSSIBLE SULFAMETHOXAZOLE/TRIMETHOPRIM-INDUCED PANCREATITIS IN A COMPLICATED ADOLESCENT PATIENT POSTTRAUMATIC INJURY. J PHARM PRACT. 2015 AUG 25;28(4):419-24. DOI: 10.1177/0897190015585750", "literaturereference_normalized": "possible sulfamethoxazole trimethoprim induced pancreatitis in a complicated adolescent patient posttraumatic injury", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20150806", "receivedate": "20150211", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10786124, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20151125" }, { "companynumb": "US-DRREDDYS-USA/USA/15/0048958", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "CEFTAZIDIME" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "URINARY TRACT INFECTION PSEUDOMONAL", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFTAZIDIME." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ACETAMINOPHEN\\HYDROCODONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "POST-TRAUMATIC PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACETAMINOPHEN/HYDROCODONE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "RIFAMPIN" }, "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": "RIFAMPIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PRAZOSIN" }, "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, 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POSSIBLE SULFAMETHOXAZOLE/TRIMETHOPRIM-INDUCED PANCREATITIS IN A COMPLICATED ADOLESCENT PATIENT POSTTRAUMATIC INJURY. 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{ "abstract": "A 67-year-old man known for metastatic colon cancer received treatment with oxaliplatin and developed severe acute kidney injury requiring dialysis. Renal biopsy revealed severe acute tubular necrosis. Acute kidney injury is a rare but severe adverse effect of oxaliplatin administration.", "affiliations": "Department of Medicine , McGill University Health Centre , Montreal, QC , Canada.;Division of Nephrology, Department of Medicine , Jewish General Hospital , Montreal, QC , Canada.", "authors": "Filewod|Niall|N|;Lipman|Mark L|ML|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1093/ckj/sft148", "fulltext": "\n==== Front\nClin Kidney JClin Kidney JckjndtplusClinical Kidney Journal2048-85052048-8513Oxford University Press 2585935510.1093/ckj/sft148sft148Clinical CasesClinical ReportsSevere acute tubular necrosis observed subsequent to oxaliplatin administration Filewod Niall 1Lipman Mark L. 21 Department of Medicine, McGill University Health Centre, Montreal, QC, Canada2 Division of Nephrology, Department of Medicine, Jewish General Hospital, Montreal, QC, CanadaCorrespondence and offprint requests to: Niall Filewod; E-mail: niall.filewod@mail.mcgill.ca2 2014 29 12 2013 29 12 2013 7 1 68 70 21 10 2013 19 11 2013 © The Author 2013. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For permissions, please email: journals.permissions@oup.com.2013This 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 non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comA 67-year-old man known for metastatic colon cancer received treatment with oxaliplatin and developed severe acute kidney injury requiring dialysis. Renal biopsy revealed severe acute tubular necrosis. Acute kidney injury is a rare but severe adverse effect of oxaliplatin administration.\n\nAKIATNdialysisoxaliplatin\n==== Body\nBackground\nOxaliplatin is a chemotherapeutic agent used for the treatment of colon cancer. It has been in use for over a decade and is generally well tolerated. The drug does not commonly cause renal insufficiency [1]. However, oxaliplatin may rarely result in acute tubular necrosis (ATN) [2], renal tubular acidosis [3, 4] and hemolytic anemia with subsequent renal failure [5]. We present a case of severe ATN observed subsequent to oxaliplatin administration.\n\nCase report\nOur patient was a 67-year-old man known for colon adenocarcinoma, for which he received FOLFOX chemotherapy (leucovorin, fluorouracil, and oxaliplatin, 13 cycles) and radiation before undergoing surgery. Three years later, he was treated for two small spinal metastases, receiving 2 years of A-FOLFIRI (bevacizumab, leucovorin, fluorouracil, irinotecan), and a further 6 months of bevacizumab and capecitabine. FOLFOX was restarted in September 2012; a first cycle was well tolerated. During the second cycle, however, shortly after the start of the oxaliplatin infusion, the patient became flushed and complained of chest tightness. The infusion was stopped and these symptoms subsided; when the infusion was restarted 30 min later, they quickly recurred. Oxaliplatin was stopped and the patient received the remainder of his leucovorin and fluorouracil infusions without incident. He denied taking other medications.\n\nFour hours after receiving oxaliplatin, Mr G. voided dark urine which was positive for blood on dipstick. The following day, at home, he became oliguric. He then began to pass bright red blood per rectum. He presented to hospital 3 days after his chemotherapy.\n\nAt presentation he had acute kidney injury (creatinine 1072 µmol/L, from a baseline in the 80s). He remained oliguric in response to intravenous fluid administration and hemodialysis was initiated in due course. He had a new normocytic anemia (Hb 123 g/L, previously 144 g/L) and was thrombocytopenic (platelet count 27 × 109/L) and leukopenic (WBC 1.7 × 109/L). A peripheral blood smear revealed polychromatophilia, fragmented cells, burr cells and ovalocytes. Urine dipstick revealed 5 g/L of protein and was positive for blood. Haptoglobin was normal.\n\nHis lower GI bleeding continued and his hemoglobin fell to 80 g/L, necessitating transfusion. His absolute neutrophil count continued to decrease, and he was admitted to hematology for febrile neutropenia. Laboratory studies revealed a negative direct antiglobulin test. Haptoglobin, bilirubin and fibrinogen were normal. Anti-nuclear and anti-glomerular basement membrane antibodies were not detected. Screening for hepatitis B and C was negative. A renal biopsy was obtained, revealing severe ATN.\n\nSubsequently, his blood counts recovered. After endoscopy his lower GI bleed was attributed to angiodysplasia at the anastomotic site of his prior bowel resection. Although he was initially dialysis dependent, he gradually recovered his renal function, and by 1 month post-discharge his creatinine had fallen to 97 µmol/L.\n\nDiscussion\nOxaliplatin-induced acute kidney injury is a rare event, with only 10 cases previously reported (Table 1). In six, hemolysis and a positive DAT suggested ATN as a consequence of immune-mediated hemolysis [2, 6–10], which has been described as a result of oxaliplatin-dependent anti-RBC antibodies [7, 8]. In the three cases where DAT was confirmed negative, renal biopsy was suggestive of ATN as a direct drug effect [11–13].\nTable 1. Previously reported cases of acute kidney injury after oxaliplatin administration\n\nYear\tAuthors\tNo. of cycles oxaliplatin previously received\tPresenting symptoms\tHemoglobinuria?\tChange in creatinine (mmol/L)\tChange in hemoglobin (g/L)\tOther markers of hemolysis\tDAT positive?\tRequired dialysis?\tOutcome (renal function only)\tPathologic diagnosis\t\n2002\tPinotti et al.\t16\tAbdominal pain, fever\tYes\t⇑ 7.3 mg/dL\tNA\tNA\tNA\tNo\tRecovered\tATN\t\n2005\tLabaye et al.\t10\tNA\tNA\t73 ⇑ 1126\t⇓ 98\tNA\tNo\tYes\tRecovered\tATN\t\n2006\tDahabreh et al.\t4\tDiscolored urine\tYes\t1.1 mg/dL ⇑ 3.1 mg/dL\t138 ⇓ 120\tFragmented RBC, elevated LDH, elevated indirect bilirubin\tNo\tNo\tRecovered\tNA\t\n2009\tPhan et al.\t5\tLow back pain, dark urine, oliguria\tNA\t68 ⇑1078\t142 ⇓ 107\tIncreased LDH, schiztocytes\tNo\tYes\tRecovered\tATN\t\n1999\tDesrame et al.\t41\tBack pain, fever, chills, schleral icterus, dark urine\tNA\t⇑ 471\t119 ⇓ 48\tElevated LDH, bilirubin, absent haptoglobin\tYes\tYes\tNo recovery\tNA\t\n2003\tHofheinz et al.\t5\tDark urine, jaundice\tNA\t⇑ 631\t104 ⇓ 67\tElevated LDH\tYes\tNo\tRecovered\tNA\t\n2007\tCobo et al.\t14\tLow back pain, dark urine, oliguria\tYes\t1.5 ⇑ 7.5 mg/dL\t123 ⇓ 84\tElevated LDH\tYes\tNo\tRecovered\tNA\t\n2007\tButi et al.a\t10\tNA\tNA\t⇑ 7.08 mg/dL\t112 ⇓ 86\tNA\tYes\tNA\tNA\tNA\t\n2010\tUlusakarya et al.\t12\tAbdominal pain, fever, chills\tYes\t⇑ 359\t128 ⇓ 113\tHaptoglobin decreased, LDH increased\tYes\tYes\tRecovered\tNA\t\n2012\tIto et al.\t33\tBack pain\tYes\t0.65 ⇑ 8.8 mg/dL\t82 ⇓ 56\tLow haptoglobin, elevated LDH\tYes\tYes\tRecovered\tNA\t\nCases are divided on the basis of direct antigen test result; highlighted cases are those in which pathological diagnosis was obtained.\n\nNA, not available; RBC, red blood cells.\n\naAbstracted from another reference.\n\n\n\nATN via direct tubular toxicity is most consistent with the laboratory and pathological findings in this case. We believe this to be the fourth case of biopsy-proven ATN as a consequence of oxaliplatin-mediated tubular toxicity.\n\nIn common with previously reported cases, our patient eventually recovered the majority of his renal function. In contrast to previously reported cases, our patient was found to be glucose-6-phosphate dehydrogenase deficient. The G6PD deficiency in our patient could potentially have provided an alternative mechanism for hemolysis-induced ATN but the normal serological markers of hemolysis do not support this possibility. It is also unclear whether our patient's prolonged exposure to oxaliplatin placed him at a higher risk of AKI—while prolonged exposure has been implicated as a risk factor for oxaliplatin-dependent immune-mediated hemolysis, previously reported cases of oxaliplatin-induced ATN have been observed after as few as four cycles of treatment [9, 11, 14].\n\nOxaliplatin-induced ATN is thus a rare but serious complication of the commonly used FOLFOX chemotherapy regimen. Oncologists and nephrologists should be aware of this dramatic adverse effect of oxaliplatin administration.\n\nConflict of interest statement\nNone declared.\n==== Refs\nReferences\n1 Extra JM Espie M Calvo F Phase I study of oxaliplatin in patients with advanced cancer Cancer Chemother Pharmacol 1990 25 299 303 doi:10.1007/BF00684890 2295116 \n2 Ito I Ito Y Mizuno M A rare case of acute kidney injury associated with autoimmune hemolytic anemia and thrombocytopenia after long-term usage of oxaliplatin Clin Exp Nephrol 2012 16 490 494 doi:10.1007/s10157-012-0620-8 22450906 \n3 Linch M Cunningham D Mingo O Renal tubular acidosis due to oxaliplatin Ann Oncol 2007 18 805 806 doi:10.1093/annonc/mdm080 17389529 \n4 Negro A Grasselli C Galli P Oxaliplatin-induced proximal renal tubular acidosis Intern Emerg Med 2010 5 267 268 doi:10.1007/s11739-009-0331-7 19937480 \n5 Noronha V Burtness B Murren J Oxaliplatin induces a delayed immune-mediated hemolytic anemia: a case report and review of the literature Clin Colorectal Cancer 2005 5 283 286 doi:10.3816/CCC.2005.n.041 16356307 \n6 Buti S Ricco M Chiesa MD Oxaliplatin-induced hemolytic anemia during adjuvant treatment of a patient with colon cancer: a case report Anticancer Drugs 2007 18 297 300 doi:10.1097/CAD.0b013e3280102f4b 17264762 \n7 Cobo F Oxaliplatin-induced immune hemolytic anemia: a case report and review of the literature Anticancer Drugs 2007 18 973 17667605 \n8 Desrame J Broustet H de Tailly PD Oxaliplatin-induced haemolytic anaemia Lancet 1999 354 1179 1180 doi:10.1016/S0140-6736(99)03827-1 10513718 \n9 Hofheinz RD Nguyen XD Buchheidt D Two potential mechanisms of oxaliplatin-induced haemolytic anaemia in a single patient Cancer Chemother Pharmacol 2004 53 276 277 doi:10.1007/s00280-003-0731-8 14676977 \n10 Ulusakarya A Misra S Haydar M Acute renal failure related to oxaliplatin-induced intravascular hemolysis Med Oncol 2010 27 1425 1426 doi:10.1007/s12032-009-9263-3 19565364 \n11 Dahabreh I Tsoutsos G Tseligas D Hemolytic uremic syndrome following the infusion of oxaliplatin: case report BMC Clin Pharmacol 2006 6 5 doi:10.1186/1472-6904-6-5 16968538 \n12 Labaye J Sarret D Duvic C Renal toxicity of oxaliplatin Nephrol Dial Transplant 2005 20 1275 1276 doi:10.1093/ndt/gfh826 15827046 \n13 Pinotti G Martinelli B A case of acute tubular necrosis due to oxaliplatin Ann Oncol 2002 13 1951 1952 doi:10.1093/annonc/mdf311 12453866 \n14 Phan NT Heng AE Lautrette A Oxaliplatin-induced acute renal failure presenting clinically as thrombotic microangiopathy: think of acute tubular necrosis NDT Plus 2009 2 254 256 doi:10.1093/ndtplus/sfp008 25984004\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "2048-8505", "issue": "7(1)", "journal": "Clinical kidney journal", "keywords": "AKI; ATN; dialysis; oxaliplatin", "medline_ta": "Clin Kidney J", "mesh_terms": null, "nlm_unique_id": "101579321", "other_id": null, "pages": "68-70", "pmc": null, "pmid": "25859355", "pubdate": "2014-02", "publication_types": "D016428:Journal Article", "references": "16356307;22450906;25984004;15827046;17667605;19937480;17264762;14676977;12453866;2295116;17389529;10513718;16968538;19565364", "title": "Severe acute tubular necrosis observed subsequent to oxaliplatin administration.", "title_normalized": "severe acute tubular necrosis observed subsequent to oxaliplatin administration" }

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{ "abstract": "OBJECTIVE\nWe report three cases of ocular inflammation and polymyalgia rheumatica without concomitant giant-cell arteritis.\n\n\nMETHODS\nReport of three cases.\n\n\nRESULTS\nPolymyalgia rheumatica onset was at a mean age of 66.7 years, and ocular inflammation, which developed 7-21 months later, was bilateral in all patients. Ocular inflammation presented as episcleritis, scleritis, or anterior uveitis, and it emerged during the tapering of low-dose prednisolone prescribed for polymyalgia rheumatica in all patients. Recurrence of ocular inflammation was observed in two patients.\n\n\nCONCLUSIONS\nOcular inflammation associated with polymyalgia rheumatica was often bilateral and occurred during steroid tapering. Although this presentation is relatively uncommon, polymyalgia rheumatica should be considered in the differential diagnosis of older patients presenting with ocular inflammation, especially those with proximal myalgia and elevated inflammatory markers.", "affiliations": "a Department of Ophthalmology , The University of Tokyo Hospital , Tokyo , Japan.;a Department of Ophthalmology , The University of Tokyo Hospital , Tokyo , Japan.;a Department of Ophthalmology , The University of Tokyo Hospital , Tokyo , Japan.", "authors": "Arai|Takahiro|T|;Tanaka|Rie|R|;Kaburaki|Toshikatsu|T|", "chemical_list": "D005938:Glucocorticoids; D009883:Ophthalmic Solutions; D011239:Prednisolone; D005469:Fluorometholone", "country": "England", "delete": false, "doi": "10.1080/09273948.2017.1278776", "fulltext": null, "fulltext_license": null, "issn_linking": "0927-3948", "issue": "26(5)", "journal": "Ocular immunology and inflammation", "keywords": "Giant-cell arteritis; ocular inflammation; polymyalgia rheumatica; scleritis; uveitis", "medline_ta": "Ocul Immunol Inflamm", "mesh_terms": "D000284:Administration, Oral; D000368:Aged; D003937:Diagnosis, Differential; D004359:Drug Therapy, Combination; D005260:Female; D005469:Fluorometholone; D013700:Giant Cell Arteritis; D005938:Glucocorticoids; D006801:Humans; D008297:Male; D008875:Middle Aged; D009883:Ophthalmic Solutions; D011111:Polymyalgia Rheumatica; D011239:Prednisolone; D015423:Scleritis; D014606:Uveitis, Anterior", "nlm_unique_id": "9312169", "other_id": null, "pages": "779-782", "pmc": null, "pmid": "28282736", "pubdate": "2018", "publication_types": "D016422:Letter", "references": null, "title": "Ocular Inflammation Associated with Polymyalgia Rheumatica without Concomitant Giant-Cell Arteritis: A Report of Three Cases.", "title_normalized": "ocular inflammation associated with polymyalgia rheumatica without concomitant giant cell arteritis a report of three cases" }

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OCULAR INFLAMMATION ASSOCIATED WITH POLYMYALGIA RHEUMATICA WITHOUT CONCOMITANT GIANT?CELL ARTERITIS: A REPORT OF THREE CASES. OCULAR IMMUNOLOGY AND INFLAMMATION. 2017?1?4.", "literaturereference_normalized": "ocular inflammation associated with polymyalgia rheumatica without concomitant giant cell arteritis a report of three cases", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20180727", "receivedate": "20180727", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15209221, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20181010" } ]

{ "abstract": "OBJECTIVE\nHepatocellular Carcinoma (HCC) is the sixth most common malignancy and the third most common cause of cancer mortality worldwide. We aimed to assess the effect of novel treatment options on the survival of HCC patients.\n\n\nMETHODS\nThis retrospective study included all HCC patients diagnosed between 2000 and 2013 referred to the Davidoff center and treated by a multidisciplinary team.\n\n\nRESULTS\nThe analysis included 321 patients (median age, 64 years; 74.8% males; 74.1% viral carriers; 76.0% cirrhosis; 56.7% diagnosis at an early stage). The estimated hazard ratio by multivariate analysis for the effect of the period of diagnosis (2007-2013 vs. 2000-2006) on survival was 0.72 (95% CI: 0.54-0.96; p=0.027). There was no difference in the distribution by CP score, by BCLC stage at diagnosis or in the proportion of patients undergoing surgical procedures (liver transplantation or resection). In the later time frame, there was a significant decrease in the proportion of patients undergoing percutaneous treatments (14.6% vs.4.2%, p=0.004) and embolization (46.9% vs.24.6%, p=0.001), and a significant increase in radiotherapy (1.5% vs. 8.4%, p=0.009) and treatment with sorafenib (6% vs. 18.3%, p=0.002).\n\n\nCONCLUSIONS\nTechnological/pharmaceutical innovations have led to advancement in HCC treatment. Since there was no significant difference in the proportion of patients undergoing surgical procedures during the evaluated timeframe, the improved survival may stem from better management of advanced stage patients by a multidisciplinary team.", "affiliations": "1. Institute of Oncology, Davidoff Center, Rabin Medical Center, Petah Tikva, Israel;;3. Liver Institute; Rabin Medical Center, Petah Tikva, Israel;; 2. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel;;2. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel;; 4. Department of Imaging; Rabin Medical Center, Petah Tikva, Israel;;2. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel;; 3. Liver Institute; Rabin Medical Center, Petah Tikva, Israel;;2. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel;; 3. Liver Institute; Rabin Medical Center, Petah Tikva, Israel;;2. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel;; 5. Department of Organ Transplantation; Rabin Medical Center, Petah Tikva, Israel;;2. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel;; 6. Department of Pathology, Rabin Medical Center, Petah Tikva, Israel.;1. Institute of Oncology, Davidoff Center, Rabin Medical Center, Petah Tikva, Israel;; 2. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel;;1. Institute of Oncology, Davidoff Center, Rabin Medical Center, Petah Tikva, Israel;;1. Institute of Oncology, Davidoff Center, Rabin Medical Center, Petah Tikva, Israel;; 2. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel;", "authors": "Moore|Assaf|A|;Cohen-Naftaly|Michal|M|;Benjaminov|Ofer|O|;Braun|Marius|M|;Issachar|Assaf|A|;Mor|Eitan|E|;Tovar|Anna|A|;Sarfaty|Michal|M|;Gordon|Noa|N|;Stemmer|Salomon M|SM|", "chemical_list": null, "country": "Australia", "delete": false, "doi": "10.7150/jca.14721", "fulltext": null, "fulltext_license": null, "issn_linking": "1837-9664", "issue": "7(8)", "journal": "Journal of Cancer", "keywords": "hepatocellular carcinoma; liver transplantation; retrospective study.; sorafenib", "medline_ta": "J Cancer", "mesh_terms": null, "nlm_unique_id": "101535920", "other_id": null, "pages": "883-9", "pmc": null, "pmid": "27313777", "pubdate": "2016", "publication_types": "D016428:Journal Article", "references": "21374666;22353262;15918147;10518312;25547503;19790142;18308583;22300468;18236117;23547075;24475823;17197965;16890600;19058754;17570226;21296855;16488051;2990661;25450706;18835117", "title": "Radiotherapy and Sorafenib in the Management of Patients with Hepatocellular Carcinoma Have Led to Improved Survival: A Single Center Experience.", "title_normalized": "radiotherapy and sorafenib in the management of patients with hepatocellular carcinoma have led to improved survival a single center experience" }

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{ "abstract": "OBJECTIVE\nThe coexistence of RAS and BRAF mutations is extremely rare, occurring in approximately 0.05% of patients with metastatic colorectal cancer (mCRC). Starting from a case presentation, this review aims to examine the prevalence, clinical, histopathological and molecular features of tumors with concomitant mutations.\n\n\nMETHODS\nCase report and systematic review. We performed a systematic literature search in PubMed and EMBASE using the following MeSH terms: \"coexistence\" OR \"concomitant\" AND \"RAS\" AND \"BRAF\" AND \"colorectal cancer\" from the inception of the databases onwards.\n\n\nRESULTS\nWe present the case of a 53-year-old man diagnosed with metastatic rectal adenocarcinoma with both a KRAS and a BRAF mutation. The review included eleven papers reporting on a total of 30 mCRC cases with concomitant RAS and BRAF mutations. The male/female ratio was 11/5. The average age was 58.5 years. The tumor was located in nine cases on the right colon and in two cases in the left colon. 43.3% of subjects had liver metastases, and 6.6% had lung metastases. Next-generation sequencing (NGS) was used in 36.6% of cases and polymerase chain reaction (PCR) in 16.6% of cases. KRAS mutations were present in 83.3% of patients and NRAS mutations in 16.6% of patients. Survival could be assessed in 10 patients and the median was 21.1 months (about 30% lower than the survival in the general mCRC population).\n\n\nCONCLUSIONS\nThe results of this systematic review suggest the need to design a cohort study (either prospective or retrospective) to better characterize the patients with concomitant RAS and BRAF mutations and to establish the optimal treatment for this rare situation.", "affiliations": "\"Gr.T.Popa\" University of Medicine and Pharmacy Iasi, Romania. . vlad_afrasanie@yahoo.com.;Gr. T. Popa University of Medicine and Pharmacy, Iași; Oncology Dept., Regional Institute of Oncology, Iași, Romania. . gaftonbogdan@yahoo.com.;Gr. T. Popa University of Medicine and Pharmacy, Iași; Oncology Dept., Regional Institute of Oncology, Iași, Romania. m.marinca@gmail.com.;Gr. T. Popa University of Medicine and Pharmacy, Iași; Oncology Dept., Regional Institute of Oncology, Iași, Romania. teodora_alexa@yahoo.com.;Gr. T. Popa University of Medicine and Pharmacy, Iași; Oncology Dept., Regional Institute of Oncology, Iași, Romania. lucmir@gmail.com.;Gr. T. Popa University of Medicine and Pharmacy, Iași, Romania. abcrusu@gmail.com.;Gr. T. Popa University of Medicine and Pharmacy, Iași, Romania. anca_vi@yahoo.com.;Gr. T. Popa University of Medicine and Pharmacy, Iași; Gastroenterology Dept., Sf. Spiridon University Clinical Emergency Hospital, Iași, Romania. balan.gheo@yahoo.com.;Titu Maiorescu University of Medicine, Bucharest; Oncology Dept., Fundeni Clinical Institute, Bucharest, Romania. adina.croitoru09@yahoo.com.", "authors": "Afrăsânie|Vlad-Adrian|VA|;Gafton|Bogdan|B|;Marinca|Mihai Vasile|MV|;Alexa-Stratulat|Teodora|T|;Miron|Lucian|L|;Rusu|Cristina|C|;Ivanov|Anca-Viorica|AV|;Balan|Gheorghe G|GG|;Croitoru|Adina-Emilia|AE|", "chemical_list": "C117307:KRAS protein, human; D008565:Membrane Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)", "country": "Romania", "delete": false, "doi": "10.15403/jgld-1003", "fulltext": null, "fulltext_license": null, "issn_linking": "1841-8724", "issue": "29(2)", "journal": "Journal of gastrointestinal and liver diseases : JGLD", "keywords": null, "medline_ta": "J Gastrointestin Liver Dis", "mesh_terms": "D000230:Adenocarcinoma; D024221:Antineoplastic Protocols; D015179:Colorectal Neoplasms; D005260:Female; D020558:GTP Phosphohydrolases; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008113:Liver Neoplasms; D008175:Lung Neoplasms; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D000071185:Pharmacogenomic Testing; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D012004:Rectal Neoplasms; D012007:Rectum; D066066:Response Evaluation Criteria in Solid Tumors; D016019:Survival Analysis", "nlm_unique_id": "101272825", "other_id": null, "pages": "251-256", "pmc": null, "pmid": "32530992", "pubdate": "2020-06-03", "publication_types": "D002363:Case Reports; D000078182:Systematic Review", "references": null, "title": "The Coexistence of RAS and BRAF Mutations in Metastatic Colorectal Cancer: A Case Report and Systematic Literature Review.", "title_normalized": "the coexistence of ras and braf mutations in metastatic colorectal cancer a case report and systematic literature review" }

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"drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXALIPLATIN." } ], "patientagegroup": null, "patientonsetage": "53", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Malignant neoplasm progression", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Proteinuria", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Hepatic failure", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Malignant anorectal neoplasm", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Neuropathy peripheral", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "AFRASANIE V, GAFTON B, MARINCA M, ALEXA?STRATULAT T, MIRON L, RUSU C. THE COEXISTENCE OF RAS AND BRAF MUTATIONS IN METASTATIC COLORECTAL CANCER: A CASE REPORT AND SYSTEMATIC LITERATURE REVIEW. 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THE COEXISTENCE OF RAS AND BRAF MUTATIONS IN METASTATIC COLORECTAL CANCER: A CASE REPORT AND SYSTEMATIC LITERATURE REVIEW. JOURNAL OF GASTROINTESTINAL AND LIVER DISEASES. 2020 MAY 13?29(2):253?258. 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THE COEXISTENCE OF RAS AND BRAF MUTATIONS IN METASTATIC COLORECTAL CANCER: A CASE REPORT AND SYSTEMATIC LITERATURE REVIEW. JOURNAL OF GASTROINTESTINAL AND LIVER DISEASES. 2020 JUN?29 (2):253?258.", "literaturereference_normalized": "the coexistence of ras and braf mutations in metastatic colorectal cancer a case report and systematic literature review", "qualification": "3", "reportercountry": "RO" }, "primarysourcecountry": "RO", "receiptdate": "20200701", "receivedate": "20200701", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17967862, "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" } ]

{ "abstract": "The treatment algorithm for metastatic non-small cell lung cancers (NSCLCs) has been evolving rapidly due to the development of new therapeutic agents. Although guidelines are provided by National Comprehensive Cancer Network (NCCN) for treatment options according to biomarker testing results, sequentially applying the three main modalities (chemotherapy, targeted therapy and immunotherapy) remains an ad hoc practice in clinic. In light of recent FDA approval of dabrafenib and trametinib combination for metastatic NSCLCs with BRAF V600E mutation, one question arises due to insufficient clinical data is if the targeted therapy should be used before immunotherapy in patients with both BRAF V600E and PD-L1 expression.\nWe present a case of 74-year-old female, former smoker with metastatic lung adenocarcinoma. The BRAF V600E mutation among other abnormalities was identified by comprehensive genomic profiling. The patient had an excellent 2-year response to the combination of pemetrexed and sorafenib. The patient was then treated with dabrafenib due to the presence of the BRAF V600E mutation and intolerance to cytotoxic chemotherapy. Not only the patient had an 18-month durable response to dabrafenib, she experienced outstanding quality of life with no serious adverse effects. At the time of symptomatic progression, the patient was then treated with two cycles of pembrolizumab based on her positive PD-L1 staining (90%). She had early response and came off pembrolizumab due to side effects. Seven months after initiation of pembrolizumab, the patient is off all the therapy and is currently asymptomatic. The patient is surviving with metastatic disease for over 7 years as of to date.\nBy appropriately sequencing the three main modalities of systemic therapies, we are able to achieve long-term disease control with minimal side effects even in a geriatric patient with multiple comorbidities. We argue that it is reasonable to first use a BRAF inhibitor before considering immunotherapy for NSCLCs positive for both BRAF V600E and PD-L1.", "affiliations": "Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029 USA.;Department of Internal Medicine, OSF St., Francis Medical Center, University of Illinois College of Medicine at Peoria, Peoria, IL 61605 USA.;Foundation Medicine, Inc., Cambridge, MA 02141 USA.;Illinois CancerCare, P.C., Peoria, IL 61615 USA.", "authors": "Li|Shuyu D|SD|0000-0002-1163-8339;Martial|Annia|A|;Schrock|Alexa B|AB|;Liu|Jane J|JJ|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1186/s40164-017-0089-y", "fulltext": "\n==== Front\nExp Hematol OncolExp Hematol OncolExperimental Hematology & Oncology2162-3619BioMed Central London 8910.1186/s40164-017-0089-yCase ReportExtraordinary clinical benefit to sequential treatment with targeted therapy and immunotherapy of a BRAF V600E and PD-L1 positive metastatic lung adenocarcinoma http://orcid.org/0000-0002-1163-8339Li Shuyu D. shuyudan.li@mssm.edu 12Martial Annia annia.martial@gmail.com 3Schrock Alexa B. aschrock@foundationmedicine.com 4Liu Jane J. JLiu@illinoiscancercare.com 51 0000 0001 0670 2351grid.59734.3cDepartment of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029 USA 2 Sema4, A Mount Sinai Venture, Stamford, CT 06902 USA 3 0000 0001 0741 4132grid.430852.8Department of Internal Medicine, OSF St., Francis Medical Center, University of Illinois College of Medicine at Peoria, Peoria, IL 61605 USA 4 Foundation Medicine, Inc., Cambridge, MA 02141 USA 5 grid.428927.2Illinois CancerCare, P.C., Peoria, IL 61615 USA 6 11 2017 6 11 2017 2017 6 297 9 2017 27 10 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\nThe treatment algorithm for metastatic non-small cell lung cancers (NSCLCs) has been evolving rapidly due to the development of new therapeutic agents. Although guidelines are provided by National Comprehensive Cancer Network (NCCN) for treatment options according to biomarker testing results, sequentially applying the three main modalities (chemotherapy, targeted therapy and immunotherapy) remains an ad hoc practice in clinic. In light of recent FDA approval of dabrafenib and trametinib combination for metastatic NSCLCs with BRAF V600E mutation, one question arises due to insufficient clinical data is if the targeted therapy should be used before immunotherapy in patients with both BRAF V600E and PD-L1 expression.\n\nCase presentation\nWe present a case of 74-year-old female, former smoker with metastatic lung adenocarcinoma. The BRAF V600E mutation among other abnormalities was identified by comprehensive genomic profiling. The patient had an excellent 2-year response to the combination of pemetrexed and sorafenib. The patient was then treated with dabrafenib due to the presence of the BRAF V600E mutation and intolerance to cytotoxic chemotherapy. Not only the patient had an 18-month durable response to dabrafenib, she experienced outstanding quality of life with no serious adverse effects. At the time of symptomatic progression, the patient was then treated with two cycles of pembrolizumab based on her positive PD-L1 staining (90%). She had early response and came off pembrolizumab due to side effects. Seven months after initiation of pembrolizumab, the patient is off all the therapy and is currently asymptomatic. The patient is surviving with metastatic disease for over 7 years as of to date.\n\nConclusions\nBy appropriately sequencing the three main modalities of systemic therapies, we are able to achieve long-term disease control with minimal side effects even in a geriatric patient with multiple comorbidities. We argue that it is reasonable to first use a BRAF inhibitor before considering immunotherapy for NSCLCs positive for both BRAF V600E and PD-L1.\n\nElectronic supplementary material\nThe online version of this article (10.1186/s40164-017-0089-y) contains supplementary material, which is available to authorized users.\n\nKeywords\nNon-small cell lung cancerBRAF V600EPD-L1Targeted therapyImmunotherapySequential treatmentissue-copyright-statement© The Author(s) 2017\n==== Body\nBackground\nThe treatment paradigm for metastatic non-small cell lung cancers (NSCLCs) has been evolving rapidly due to new therapeutic options [1]. In metastatic, non-small cell, non-squamous lung cancer patients, three groups can be defined based on tumor molecular testing results, each paired with a specific first-line systemic therapy of proven clinical benefit. Patients in the first group are positive for sensitizing EGFR mutations, ALK or ROS1 rearrangement with the matched targeted tyrosine kinase inhibitors (TKIs) as the first-line treatment. In the second group, patients are PD-L1 immunohistochemistry positive (≥ 50%) and EGFR, ALK, ROS1 negative, and single agent pembrolizumab is a FDA-approved first-line therapy. Patients in the third group are EGFR, ALK, ROS1, and PD-L1 negative, paired with systemic chemotherapy plus or minus pembrolizumab as the first-line option. Significant progress has also been made to develop predictive biomarkers for PD-1/PD-L1 immune checkpoint blockade therapy [2, 3].\n\nIn addition to EGFR, ALK and ROS1, emerging evidences have demonstrated clinical benefit to therapies against BRAF [4–7], MET [8–10], RET [11, 12] or HER2 [13, 14] in NSCLCs harboring activating mutations. Most notably, FDA approved dabrafenib and trametinib combination for metastatic NSCLCs with BRAF V600E mutation on June 22, 2017 (https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm564331.htm). In light of this recent regulatory approval, one question arises due to insufficient clinical data is if the targeted therapy should be used before immunotherapy in patients with both BRAF V600E and PD-L1 expression.\n\nCase presentation\nA 74-year-old female, former smoker had resected stage III lung adenocarcinoma and was treated with adjuvant concurrent chemoradiation with carboplatin and paclitaxel in 2008 (Fig. 1). The patient’s surgical resection specimen was tested for EGFR amplification by FISH (ARUP Laboratories) and KRAS mutation analysis (GenPath Diagnostics), and the results indicated EGFR was non-amplified and KRAS was wild type at codons 12, 13, and 61. Her medical history includes hypertension, hyperlipidemia, GERD (gastroesophageal reflux disease), SVT (supraventricular tachycardia), chronic kidney disease and osteoporosis. The patient developed metastatic recurrent lung cancer with malignant pleural effusion in 2010. The EGFR mutation analysis by real-time PCR (Clarient Diagnostic Services) was done on the pleural effusion specimen and none of the 29 known mutations, deletions and insertions found in exons 18–21 of the EGFR tyrosine kinase domain was detected. The patient was then treated with pemetrexed and sorafenib on trial (NCCTG N0626 study, http://ascopubs.org/doi/abs/10.1200/jco.2011.29.15_suppl.7513) with a durable response for more than 2 years (Fig. 1). The treatment was stopped in 2012 due to intolerance. Afterwards, the patient was on observation for 2 years until she developed symptomatic progression with extensive bony metastasis in 2014 (Figs. 1, 2a). Her left pelvic metastasis biopsy specimen was used for genomic profiling and PD-L1 staining (see below). She was treated with palliative radiation, followed by carboplatin and pemetrexed. Cytotoxic chemotherapy was discontinued after 2 months due to profound toxicities which required hospitalization, despite of dose reductions (Fig. 1).Fig. 1 Oncology history of the patient\n\n\nFig. 2 \na PET scan of the patient before initiation of dabrafenib reveals metastatic disease to the left iliac bone, C2 and L3-4 vertebral bodies. The C2 lesion’s SUV max was 7; the lesion at L3 had a SUV max of 7.1; the left acetabulum lesion’s SUV max was 5.1 prior to starting dabrafenib. b After 4 months of dabrafenib therapy, near complete resolution of PET activity in the areas of bone metastases was demonstrated without any new site of disease. Upon the best response to dabrafenib achieved, the metabolic activity resolved at C2 and L3 lesions. The left acetabulum lesion only had a very small focus of residual uptake that the max SUV was not measured\n\n\n\n\nTo explore additional therapeutic options, we then performed comprehensive genomic profiling (CGP) using the FoundationOne® panel (http://foundationone.com/). The CGP identified the BRAF V600E mutation as well as inactivating mutations in tumor suppressors including ATM. In addition, the tumor mutation burden was low—five per megabase and the tumor was microsatellite stable (MSS). The full report of the CGP is provided as Additional file 1. Based on this genetic profile, the patient was started on dabrafenib [7] in April 2015 (Fig. 1). Dabrafenib was used at 150 mg PO BID throughout the treatment course. She had excellent clinical and radiographic responses (Fig. 2b). Her performance status drastically improved. Her only noticeable side effect was hypokalemia that was managed with oral and IV potassium replacement. The patient developed increase of metabolic activity from two disease sites on PET scan suggestive of disease progression without clinical symptoms 7 months after initiation of dabrafenib. Based on the phase II trial [6] reported in 2015 ASCO annual meeting demonstrating activity of dabrafenib and trametinib combination in BRAF mutated lung cancers, our patient was offered the addition of trametinib. However, she did not tolerate the combination and stopped trametinib after 1 week. The patient was asymptomatic from her metastatic lung cancer until the 19th month into the dabrafenib therapy, when she developed productive cough and restaging scan revealed new hypermetabolic upper abdominal lymph node metastases at the gastrohepatic ligament, precaval and peripancreatic retroperitoneum (Fig. 1).\n\nThe patient was discontinued from dabrafenib and started on pembrolizumab based on her positive PD-L1 staining (90%) in December 2016 (Fig. 1). The treatment was complicated by immune mediated colitis and pneumonitis which promptly responded to systemic steroids. The dose and duration of steroids used for treating pneumonitis are as follows: prednisone 40 mg daily for 1 weeks, followed by 20 mg daily for 5 days, 10 mg daily for 5 days, 5 mg daily for 5 days, then off. Her colitis was successfully treated in the similar fashion. A repeat CT scan 12 days after initiation of pembrolizumab was done for the work-up of abdominal pain, confirmed colitis, but also demonstrated decreased size of the gastric hepatic ligament node and resolution of the peripancreatic nodule, consistent with early response. She was able to stop steroid and became asymptomatic from her disease and prior treatment effects in March 2017. As of July 2017, the patient has no signs of disease progression after only two doses of pembrolizumab (200 mg IV) 7 weeks apart without additional therapy (Fig. 1). The patient has not had any hospitalization after the initiation of dabrafenib. It is noted that a recent pooled analysis of advanced melanoma (http://ascopubs.org/doi/abs/10.1200/JCO.2017.73.2289) also showed the patients who discontinued PD-1 checkpoint blockade antibodies continue to benefit from the treatment.\n\nDiscussion and conclusions\nWe present a case of BRAF V600E positive and PD-L1 positive metastatic lung adenocarcinoma. The patient exhibited excellent response for more than 18 months to single agent dabrafenib. Although serious adverse events (AEs) were observed in 42% of patients in the single-arm, phase II trial of dabrafenib [7] with skin toxicities as the most frequent grade 3 or worse AEs, the patient in our case only displayed manageable hypokalemia with no skin toxicity.\n\nPrior to dabrafenib, the patient also demonstrated 2-year response to a pemetrexed and sorafenib based regimen. After the treatment was stopped, the patient had another 2 years of stable disease before disease progression. This excellent response could be partially due to the presence of the BRAF V600E mutation. Although previous phase III studies of sorafenib in NSCLC failed to meet primary end points [15], BRAF mutation status was neither used in trial design nor analyzed retrospectively as a biomarker. Our results suggest BRAF activating mutations could be a patient stratification marker in NSCLC trials incorporating sorafenib. Notably, a recent case report demonstrated efficacy of sorafenib in a NSCLC harboring activating BRAF G469V mutation, but no response in synchronous BRAF wild type-hepatocellular carcinoma [16].\n\nAs our patient was positive for PD-L1 (90%), pembrolizumab treatment was initiated and the patient demonstrated response with stable disease radiographically. Since the tumor harbors an inactivating mutation in ATM, the response to anti-PD1 therapy is also consistent with previous studies that DNA repair deficiency predicts immunotherapy response [17, 18]. Interestingly, our patient has a low tumor mutation burden (TMB). The presence of the BRAF V600E mutation, high PD-L1 expression, and response to pembrolizumab in our case supports a recent preliminary report (http://www.abstractsonline.com/pp8/#!/4292/presentation/1306) that TMB-low/PD-L1-high NSCLCs are enriched for BRAF mutations suggesting BRAF alterations in this group may trigger immune responses moderated by PD-L1 expression.\n\nSystemic chemotherapy in advanced NSCLC results in a median overall survival (OS) of only 8 to 12 months and a median progression-free survival (PFS) of 5 to 6 months [19–21]. First line targeted TKIs significantly improved outcome: 10–14 months of PFS and 20–32 months of OS for EGFR-TKIs [22–27], and 15.3 months of PFS and 36.8 months of OS (http://abstracts.asco.org/199/AbstView_199_183873.html) for ALK-TKIs. It is remarkable that our patient is surviving with metastatic lung cancer for over 7 years as of to date. From this case, we argue that it is reasonable to consider a BRAF inhibitor before utilizing immunotherapy in patients with BRAF V600E-positive and PD-L1 positive metastatic NSCLC. Our patient had excellent quality of life and more than 18 months of disease control on a BRAF inhibitor. She has been free of hospitalization and emergency room visit since the initiation of dabrafenib. This demonstrated a successful case of transitioning advanced lung cancer into a chronic disease. The advent of targeted therapy and immunotherapy made it possible to achieve long-term disease control with minimal side effects even in a geriatric patient with multiple comorbidities. Appropriately sequencing the three main modalities of systemic therapies (cytotoxic chemotherapy, targeted therapy and immunotherapy) to achieve long-term disease control and minimize side effect is the ultimate goal in modern age of lung cancer care, and this case report provides practicing oncologists a valuable reference.\n\nWe should also point out that in addition to considering each therapeutic modality individually, there are significant efforts to explore combination of immunotherapy plus standard chemotherapy or combination of immunotherapy plus radiotherapy [28–30]. For example, in a phase II study of pembrolizumab in combination with carboplatin and pemetrexed in chemotherapy-naïve, advanced non-squamous NSCLCs, the pembrolizumab plus chemotherapy group achieved an objective response rate of 55% in comparison to 29% in the chemotherapy alone group while the incidence of grade 3 or worse treatment-related adverse events was similar between the two groups [29]. Progression-free survival was also significantly longer with pembrolizumab plus chemotherapy compared with chemotherapy alone [29]. In a phase I study, radiation therapy in combination with pembrolizumab is evaluated (NCT02318771), and immune biomarkers for treatment failure in a specific case was reported [28]. Collectively, these studies may represent a future direction to develop more effective treatment options for NSCLCs.\n\nWe recognize the limitation of a single case report and several factors one should take into considerations. Although our case suggests sequencing BRAF-TKIs followed by pembrolizumab might be considered for advanced NSCLCs positive for both BRAF V600E and PD-L1, this is only a single case for which the clinical decision was made based on this particular patient’s prior treatment history, response and side effects. Additional clinical studies are needed to provide more clinical evidences. In metastatic NSCLCs driven by other oncogenes with available matched TKIs, the patients often do not benefit from immunotherapy. For example, a meta-analysis of randomized trials comparing immune checkpoint inhibitors against chemotherapy as second line therapy in EGFR-mutant advanced NSCLC concluded immune checkpoint inhibitors do not improve OS over that with docetaxel [31]. A recent study presented in 2017 ASCO annual meeting also shows that NSCLCs harboring MET exon-14 alterations responded poorly to immunotherapy, even in PD-L1 positive patients (http://abstracts.asco.org/199/AbstView_199_189471.html). Moreover, a small percentage of patients develop hyper-progressive disease (HPD) after treatment with immune checkpoint inhibitors, and this hyper-progression appears to be associated with MDM2 amplification or EGFR alterations in a recent study [32]. We also need to consider AEs when TKIs and immunotherapy are administered concurrently or sequentially. For example, in EGFR-mutant NSCLCs, nivolumab and erlotinib combination was associated with 19% of grade 3 toxicities, and osimertinib and durvalumab combination resulted in significantly elevated incidence of interstitial lung disease [33]. In our case, the patient experienced colitis and pneumonitis upon pembrolizumab treatment, although they were mitigated through systemic steroids. Nevertheless, extra caution should be exercised to ensure sequential or concurrent treatment with targeted TKIs and immunotherapy are applied safely.\n\nIn conclusion, here we present a unique case of NSCLC where we transitioned an advanced lung cancer into a chronic disease in a geriatric patient. Sequential treatment with BRAF-TKIs and immunotherapy could provide significant clinical benefit to metastatic lung adenocarcinomas positive for both BRAF V600E and PD-L1.\n\nAdditional file\n\n\nAdditional file 1. Full report of comprehensive genomic profiling (CGP) based on FoundationOne® panel.\n\n\n\n\nAbbreviations\nNSCLCnon-small cell lung cancer\n\nTKItyrosine kinase inhibitor\n\nCGPcomprehensive genomic profiling\n\nAEadverse event\n\nOSoverall survival\n\nPFSprogression-free survival\n\nTMBtumor mutation burden\n\nElectronic supplementary material\n\nThe online version of this article (10.1186/s40164-017-0089-y) contains supplementary material, which is available to authorized users.\n\nAuthors’ contributions\nJJL designed the study. AM, ABS, and JJL collected the data. SDL, AM, ABS and JJL analyzed and interpreted the data. SDL and JJL wrote the manuscript. All authors read and approved the final manuscript.\n\nAcknowledgements\nWe thank Dr. Paul Fishkin for helpful discussion of this work.\n\nCompeting interests\nAM and JJL declare no competing interest. SDL is an employee of Sema4, a Mount Sinai venture. ABS in an employee of Foundation Medicine, Inc. with stock ownership.\n\nAvailability of data and materials\nNot applicable.\n\nConsent for publication\nInformed consent was obtained from the patient.\n\nEthics approval and consent to participate\nNeed for approval was waived. Informed consent was obtained from the patient.\n\nFunding\nNot applicable.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Dholaria B Hammond W Shreders A Lou Y Emerging therapeutic agents for lung cancer J Hematol Oncol 2016 9 1 138 10.1186/s13045-016-0365-z 27938382 \n2. Diggs LP Hsueh EC Utility of PD-L1 immunohistochemistry assays for predicting PD-1/PD-L1 inhibitor response Biomak Res 2017 5 12 10.1186/s40364-017-0093-8 \n3. 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Ahn MJ Sun JM Lee SH Ahn JS Park K EGFR TKI combination with immunotherapy in non-small cell lung cancer Expert Opin Drug Saf 2017 16 4 465 469 10.1080/14740338.2017.1300656 28271729\n\n", "fulltext_license": "CC BY", "issn_linking": "2162-3619", "issue": "6()", "journal": "Experimental hematology & oncology", "keywords": "BRAF V600E; Immunotherapy; Non-small cell lung cancer; PD-L1; Sequential treatment; Targeted therapy", "medline_ta": "Exp Hematol Oncol", "mesh_terms": null, "nlm_unique_id": "101590676", "other_id": null, "pages": "29", "pmc": null, "pmid": "29142786", "pubdate": "2017", "publication_types": "D002363:Case Reports", "references": "22851564;18506025;20573926;28351930;25765070;27765535;23533264;22285168;25971938;27825636;27663515;16775247;11784875;26724471;27283860;20022809;27354481;27938382;21783417;26287849;28331612;23610105;27080216;27745820;26729443;27388325;27234522;26028255;19692680;26200454;25971939;17167137;28271729", "title": "Extraordinary clinical benefit to sequential treatment with targeted therapy and immunotherapy of a BRAF V600E and PD-L1 positive metastatic lung adenocarcinoma.", "title_normalized": "extraordinary clinical benefit to sequential treatment with targeted therapy and immunotherapy of a braf v600e and pd l1 positive metastatic lung adenocarcinoma" }

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EXTRAORDINARY CLINICAL BENEFIT TO SEQUENTIAL TREATMENT WITH TARGETED THERAPY AND IMMUNOTHERAPY OF A BRAF V600E AND PD?L1 POSITIVE METASTATIC LUNG ADENOCARCINOMA. 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EXTRAORDINARY CLINICAL BENEFIT TO SEQUENTIAL TREATMENT WITH TARGETED THERAPY AND IMMUNOTHERAPY OF A BRAF V600E AND PD-L1 POSITIVE METASTATIC LUNG ADENOCARCINOMA.. EXPERIMENTAL HEMATOLOGY AND ONCOLOGY. 2017;6 (1)", "literaturereference_normalized": "extraordinary clinical benefit to sequential treatment with targeted therapy and immunotherapy of a braf v600e and pd l1 positive metastatic lung adenocarcinoma", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20171223", "receivedate": "20171223", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14321243, "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": "Rituximab is a chimeric anti-CD20 monoclonal antibody used to treat CD20+ non-Hodgkin's lymphoma. Although pulmonary adverse reactions such as cough, rhinitis, bronchospasm, dyspnea and sinusitis are relatively common, other respiratory conditions like cryptogenic organizing pneumonia, interstitial pneumonitis and diffuse alveolar hemorrhage have rarely been reported. Only 2 possible cases of rituximab-associated hypersensitivity pneumonitis have been described to date. We present a case of hypersensitivity pneumonitis with classic radiographic and histopathologic findings in a patient treated with rituximab who responded to prednisone.", "affiliations": "Division of Pulmonary, Critical Care and Sleep Medicine, University of Florida, Gainesville, Florida, USA. Adriano.Tonelli@medicine.ufl.edu", "authors": "Tonelli|Adriano R|AR|;Lottenberg|Richard|R|;Allan|Robert W|RW|;Sriram|P S|PS|", "chemical_list": "D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D000069283:Rituximab", "country": "Switzerland", "delete": false, "doi": "10.1159/000163069", "fulltext": null, "fulltext_license": null, "issn_linking": "0025-7931", "issue": "78(2)", "journal": "Respiration; international review of thoracic diseases", "keywords": null, "medline_ta": "Respiration", "mesh_terms": "D000542:Alveolitis, Extrinsic Allergic; D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D008875:Middle Aged; D000069283:Rituximab", "nlm_unique_id": "0137356", "other_id": null, "pages": "225-9", "pmc": null, "pmid": "18843175", "pubdate": "2009", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "11675350;17596682;11843813;11920277;12826649;15021060;15062594;15307117;15512824;1878140;10498591;15572545;15857843;17229654;17242239;17597477;11692086", "title": "Rituximab-induced hypersensitivity pneumonitis.", "title_normalized": "rituximab induced hypersensitivity pneumonitis" }

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{ "abstract": "BACKGROUND\nIdiopathic retroperitoneal abscesses are insidious, occult illnesses with high mortality if inadequately drained. Endoscopic ultrasound-guided drainage is an alternative to percutaneous or surgical drainage, it is not widely performed for retroperitoneal abscesses other than peripancreatic fluid collection.\nWe present a 76-year-old Japanese woman with abdominal pain, high fever, and a history of rheumatism on treatment with immunosuppressants.\nThe patient was diagnosed with idiopathic retroperitoneal abscess based on results obtained from her clinical course and findings on computed tomography.\n\n\nMETHODS\nWe performed Endoscopic ultrasound-guided drainage. After we performed needle puncture via the descending portion of the duodenum, the fistula was expanded using a dilator, and a double-pigtail stent and endoscopic nasobiliary drainage tube were inserted.\n\n\nRESULTS\nThe patient was kept nil by mouth, together with intravenous antibiotic therapy, and repeated washing of the abscess cavity with saline was performed. After that, we confirmed disappearance of the cavity, and, after removing the tubes, commenced oral feeding. We were able to avoid surgery in this immunosuppressed patient.\n\n\nCONCLUSIONS\nEndoscopic ultrasound (EUS)-guided abscess drainage can be overall considered a safe and useful procedure. We also propose the double-stent method, with both internal and external stents, for the treatment of idiopathic retroperitoneal abscesses.", "affiliations": "Department of Gastroenterology, Oita San-ai Medical Center, Oita city Department of Gastroenterology, Faculty of Medicine, Oita University, Yuhu city, Japan.", "authors": "Sagami|Ryota|R|;Tsuji|Hiroaki|H|;Nishikiori|Hidefumi|H|;Murakami|Kazunari|K|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1097/MD.0000000000009132", "fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 29390314MD-D-17-0643210.1097/MD.0000000000009132091324500Research ArticleClinical Case ReportEndoscopic ultrasound-guided transduodenal drainage of idiopathic retroperitoneal abscess in an immunocompromised patient A case reportSagami Ryota MDa∗Tsuji Hiroaki MDaNishikiori Hidefumi MDaMurakami Kazunari MD, PhDbNA. a Department of Gastroenterology, Oita San-ai Medical Center, Oita cityb Department of Gastroenterology, Faculty of Medicine, Oita University, Yuhu city, Japan.∗ Correspondence: Ryota Sagami, Department of Gastroenterology, Oita San-ai Medical Center, Oita city 8701151, Japan (e-mail: sagami1985@yahoo.co.jp).12 2017 15 12 2017 96 50 e91322 11 2017 9 11 2017 Copyright © 2017 the Author(s). Published by Wolters Kluwer Health, Inc.2017This is an open access article distributed under the Creative Commons Attribution-NoDerivatives License 4.0, which allows for redistribution, commercial and non-commercial, as long as it is passed along unchanged and in whole, with credit to the author. http://creativecommons.org/licenses/by-nd/4.0Abstract\nRationale:\nIdiopathic retroperitoneal abscesses are insidious, occult illnesses with high mortality if inadequately drained. Endoscopic ultrasound-guided drainage is an alternative to percutaneous or surgical drainage, it is not widely performed for retroperitoneal abscesses other than peripancreatic fluid collection.\n\nPatient concerns:\nWe present a 76-year-old Japanese woman with abdominal pain, high fever, and a history of rheumatism on treatment with immunosuppressants.\n\nDiagnoses:\nThe patient was diagnosed with idiopathic retroperitoneal abscess based on results obtained from her clinical course and findings on computed tomography.\n\nInterventions:\nWe performed Endoscopic ultrasound—guided drainage. After we performed needle puncture via the descending portion of the duodenum, the fistula was expanded using a dilator, and a double-pigtail stent and endoscopic nasobiliary drainage tube were inserted.\n\nOutcomes:\nThe patient was kept nil by mouth, together with intravenous antibiotic therapy, and repeated washing of the abscess cavity with saline was performed. After that, we confirmed disappearance of the cavity, and, after removing the tubes, commenced oral feeding. We were able to avoid surgery in this immunosuppressed patient.\n\nLessons:\nEndoscopic ultrasound (EUS)-guided abscess drainage can be overall considered a safe and useful procedure. We also propose the double-stent method, with both internal and external stents, for the treatment of idiopathic retroperitoneal abscesses.\n\nKeywords\nabscess drainageEUS-guided drainageidiopathic retroperitoneal abscessimmunosuppressed conditiontransduodenal punctureOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nIdiopathic retroperitoneal abscesses are insidious and occult illnesses that have a high mortality rate if not adequately drained. Hence, they require early diagnosis and appropriate drainage.[1] Retroperitoneal abscesses develop from infections of retroperitoneal organs and other diseases, including malignancies, trauma, and perforation.[2] Sometimes, the cause of abscess formation is unknown, and could be because of immunosuppression for any reason. Conventionally, when the infection cannot be controlled, preoperative computed tomography (CT) or ultrasonography (US) -guided percutaneous drainage is performed. However, drainage using these imaging modalities is associated with the problems of inadequate visualization of some of the anatomic structures, such as blood vessels, which might be in the path of the puncture needle. Further, surgical drainage is an invasive procedure that should be avoided in immunocompromised individuals, if possible. Endoscopic ultrasound (EUS) provides greater spatial resolution and better anatomic detail than US and CT. EUS allows clear visualization of the needle and evaluation of blood flow along the path of the needle. EUS-guided drainage has been performed for various abscesses, including peri-pancreatic fluid collection, with a high success rate.[3–7] The method is safe and has good outcomes, and should be considered an alternative to percutaneous and surgical drainage. Placement of a double-pigtail plastic stent and endoscopic nasobiliary drainage (ENBD) tube into the abscess cavity via the duodenum allows histological and bacteriological evaluation of the abscess, along with repeated wash. We report here a case of retroperitoneal abscess in an immunocompromised patient that we drained using EUS, followed by ENBD tube insertion into the abscess cavity via the duodenum.\n\n2 Case presentation\n2.1 Preoperative evaluation\nThis case report was approved by the Medical Ethics Committee at Oita San-ai Medical Center and was conducted in accordance with the Declaration of Helsinki. Informed consent was obtained from the patient in writing.\n\nA 76-year-old Japanese woman was admitted to the emergency room complaining of abrupt onset right abdominal pain with high fever. The patient had a history of rheumatism from the age of 60 years, for which she was on treatment with a drug combination that included immunosuppressants (bucillamine, 200 mg/d, and methotrexate, 4 mg/wk). Clinical examination revealed elevated body temperature (38.7°C) and right abdominal pain on palpation. Blood biochemistry revealed high blood leukocyte (13,330/mm3) and lactate levels (18 mg/dL). Other biological tests were normal. Unenhanced CT revealed a 9.1 cm × 4.2 cm × 11.7 cm large mass with increased peripheral fatty tissue in the retroperitoneal cavity below the right kidney and the horizontal portion of the duodenum. Contrast-enhanced CT revealed a hypo-enhanced mass (Fig. 1). Based on clinical and imaging findings, it appeared that the abscess was due to duodenal perforation or secondary to immunosuppression. However, since free air was not recognized and the patient's general condition was good, we conservatively observed the patient while keeping her nil by mouth and in conjunction with intravenous antibiotic therapy (meropenem: 1 g/d, clindamycin: 2.4 g/d) for 3 days. However, since her clinical symptoms and blood inflammatory parameters did not improve (blood leukocytes; 23,040/mm3), we decided to perform EUS-guided drainage.\n\nFigure 1 Idiopathic retroperitoneal abscess on CT and EUS. A and B, A 9.1 cm × 4.2 cm × 11.7 cm large mass in the retroperitoneal cavity below the right kidney and horizontal portion of the duodenum was revealed on unenhanced CT (surrounded by red arrows). C, A hypoenhanced mass was revealed on contrast-enhanced CT (in between the red arrows). D, EUS showed the peripheral rim of the abscess, solid necrotic structure, and partition wall inside the lesion (in between the red arrows). CT= computed tomography, EUS= endoscopic ultrasound.\n\n2.2 The process of EUS-guided drainage\nEUS via the descending and horizontal portions of the duodenum revealed the peripheral rim of the abscess, solid necrotic structure, and partition wall inside the abscess (Fig. 1). After confirming that there was almost no blood flow along the proposed needle track by Doppler, we performed needle puncture through the posterior wall of the descending part of the duodenum to the wall of the abscess using a 19-gauge needle (EZ shot 3 plus; Olympus Medical Systems, Tokyo, Japan), aspirated the whitish colored purulent fluid and injected iodixanol as the contrast agent. Then, we passed a 0.025-inch guidewire (VisiGlide 2; Olympus Medical Systems) into the abscess, inserted a double-lumen catheter (Uneven Double Lumen Cannula; Piolax Medical Devices, Tokyo, Japan), and placed another guidewire. Next, the fistula was expanded using an 8.5-Fr wire-guided diathermic dilator (Cysto-Gastro-Set; Endo-Flex GmbH, Voerde, Germany), following which we placed a 7-Fr 10 cm long double-pigtail catheter (Zimmon Biliary Stent; Cook Medical, Tokyo, Japan) from the abscess cavity to the duodenum and a 7-Fr 250 cm long ENBD tube, (Nasal Biliary Drainage Set; Cook Medical) (Fig. 2) to more efficiently wash the interior of the abscess.\n\nFigure 2 EUS-guided idiopathic retroperitoneal abscess drainage with internal and external stent placement. After confirming that there was almost no blood flow along the path of the needle by Doppler, we performed needle puncture via the descending portion of the duodenum using a 19-gauge needle. Then, we passed a 0.025-inch guidewire into the abscess, inserted, a double-lumen catheter, and placed another guidewire. After expanding the fistula with an 8.5-Fr wire-guided diathermic dilator, we placed a 7-Fr, 10 cm double-pigtail stent (left red arrow) and 7-Fr, 250 cm endoscopic nasobiliary drainage (ENBD) tube (right red arrow). D, Under endoscopy, the internal stent and ENBD tube were placed via a duodenal fistula into the abscess. Infected fluid was seen draining out of the stent and fistula into the duodenum by endoscopy. EUS= endoscopic ultrasound.\n\n2.3 Postoperative observation\nMicrobiological evaluation of the abscess fluid revealed the presence of E coli and the results of cytology were not malignant. We treated the patient conservatively by with-holding oral intake and giving intravenous antibiotic therapy (melopenem and clindamycin), along with washing the abscess cavity with 40 mL saline 6 times a day via the ENBD tube. On day 14 after the abscess drainage, improvement in her clinical symptoms and inflammatory parameters on blood tests (blood leukocytes: 5790/mm3, C reactive protein: 0.03 mg/dL, maximum: 18.1 mg/dL) were observed. We changed the antibiotic to sulbactam/cefoperazone 2 g/d and continued maintaining the patient on parenteral nutrition. On day 31, after confirming the disappearance of the abscess cavity on contrast X-ray (Fig. 3A) and CT, we pulled out the ENBD tube and stent under gastrointestinal endoscopic visualization and commenced oral feeding. On day 41, the patient was discharged from the hospital. CT follow-up after 3 months revealed that the abscess had not recurred (Fig. 3B). With our management strategy, we were able to avoid surgery in this immunocompromised patient.\n\nFigure 3 Resolution of the abscess. On day 31, we confirmed disappearance of the abscess cavity on contrast X-ray. The red arrow shows traces of the abscess cavity. The abscess did not recur, as seen on CT performed 3 months after discharge. CT= computed tomography.\n\n3 Discussion\nEarly diagnosis and appropriate drainage of idiopathic retroperitoneal abscesses are essential for preventing prolonged sepsis and the associated high mortality.[1]\n\nThe retroperitoneum is a potential space between the peritoneum and transversalis fascia with defined boundaries. The source of retroperitoneal infections is usually from organs such as the kidneys, ureters, duodenum, pancreas, and portions of the ascending and descending colon. Intestinal perforation secondary to malignancies or diverticulitis, appendicitis, pancreatitis, biliary tract disease, peptic ulcer disease, trauma and inflammatory bowel disease, and osteomyelitis of vertebral bodies can all cause retroperitoneal abscesses.[2] A majority of patients with retroperitoneal abscesses are immunosuppressed. For uncontrolled infection, treatment usually consists of surgical drainage in conjunction with intravenous antibiotic therapy.[1] CT- and US-guided percutaneous drainage, which are the usual procedures for preoperative evaluation and treatment, have many drawbacks. US-guidance is sometimes preferred over CT because the needle is visualized in real time. However, it is difficult to visualize the needle due to overlying bowel gas and inability to clearly delineate intervening tissues.[8]\n\nEUS provides greater spatial resolution and allows better visualization of anatomic details than US and CT. It offers clear and consistent visualization of the needle in real time, allowing avoidance of intervening vasculature, and with less interference by bowel gas.[3] Originally, EUS-guided fine needle aspiration (FNA) was performed for preoperative evaluation of idiopathic abdominal masses, including abscesses, with a sensitivity and specificity of diagnosis of 83% and 100%, respectively.[8] EUS-guided drainage is currently performed as an alternative to surgery for peri-pancreatic fluid collections, including pancreatitis, abscesses and pseudocysts, and is also performed for hepatic, splenic, sigmoid diverticular, perirectal, and pelvic abscesses, with a high success rate.[3,4] The utility of EUS-guided drainage of peri-pancreatic fluid collections and pelvic abscesses, in particular, has been previously adequately reported.[5,6] In a systematic review, the clinical success and adverse events rates of EUS-guided pancreatic pseudocyst drainage appeared to be comparable with that of surgical or percutaneous drainage, although the EUS approach reduced hospital stay and cost, and improved postprocedure quality of life.[5] In another study, the technical and clinical success rates of EUS-guided pelvic abscess drainage were 100% and 91.9% respectively, and the long-term success rate was 86.5% at a median follow-up period of 64 months.[6] In a study on liver abscess drainage, EUS-guided liver abscess drainage using a fully covered metallic stent resulted in a short hospital stay, high clinical success rate (100%), and low adverse event rate (0%) compared with percutaneous drainage.[7] Intra-abdominal abscesses arise from intraperitoneal (liver, spleen, stomach) and retroperitoneal (kidney, pancreas, spine, muscular elements) viscera.[8] If an abscess can be visualized by EUS, EUS-guided drainage can be performed. EUS-guided retroperitoneal abscess drainage is safer and less invasive, especially for patients in an immunocompromised state, compared with other drainages. We usually place a double-pigtail plastic stent or metallic stent as the internal fistula, and/or ENBD tube as the external fistula. In this case, by placing a pigtail plastic stent and ENBD tube, we could evaluate the abscess histologically, to determine whether or not it was malignant, and bacteriologically. We could choose the appropriate intravenous antibiotic therapy depending on the drug sensitivity of the species. We could also repeatedly wash the abscess cavity using the ENBD tube, and could evaluate the cavity using contrast injected via the ENBD tube, which significantly contributed to the reduction in the size of the abscess cavity.\n\nOne possible disadvantage of our method, which requires mention, is the possibility of needle tract seeding from malignancies. However, the rate of tumor seeding after EUS-FNA is probably very low.[9,10]\n\nEUS-guided abscess drainage can be overall considered a safe and useful procedure. We also propose the double-stent method, with both internal and external stents, for the treatment of idiopathic retroperitoneal abscesses. We reported the valuable case of idiopathic retroperitoneal abscess treated by EUS-guided drainage without surgery.\n\nAcknowledgments\nThe author thank endoscopy engineers of Oita San-ai Medical Center, for their helpful technical assistance with EUS-guided drainage.\n\nAbbreviations: CT= computed tomography, ENBD= endoscopic nasobiliary drainage, EUS= endoscopic ultrasound, FNA= fine needle aspiration, US= ultrasonography.\n\nThe authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n[1] Crepps JT Welch JP Orlando R 3rd \nManagement and outcome of retroperitoneal abscesses . Ann Surg \n1987 ;205 :276 –81 .3827363 \n[2] Oluwole SF Adekunle A Akintan B \nRetroperitoneal abscess . J Natl Med Assoc \n1983 ;75 :693 –700 .6887273 \n[3] Prasad GA Varadarajulu S \nEndoscopic ultrasound-guided abscess drainage . Gastrointest Endosc Clin N Am \n2012 ;22 :281 –90 .22632950 \n[4] Seewald S Ang TL Teng KY \nEndoscopic ultrasound-guided drainage of abdominal abscesses and infected necrosis . Endoscopy \n2009 ;41 :166 –74 .19214899 \n[5] Teoh AY Dhir V Jin ZD \nSystematic review comparing endoscopic, percutaneous and surgical pancreatic pseudocyst drainage . World J Gastrointest Endosc \n2016 ;8 :310 –8 .27014427 \n[6] Poincloux L Caillol F Allimant C \nLong-term outcome of endoscopic ultrasound-guided pelvic abscess drainage: a two-center series . Endoscopy \n2017 ;49 :484 –90 .28196390 \n[7] Ogura T Masuda D Saori O \nClinical outcome of endoscopic ultrasound-guided liver abscess drainage using self-expandable covered metallic stent (with Video) . Dig Dis Sci \n2016 ;61 :303 –8 .26254774 \n[8] Catalano MF Sial S Chak A \nEUS-guided fine needle aspiration of idiopathic abdominal masses . Gastrointest Endosc \n2002 ;55 :854 –8 .12024140 \n[9] Ngamruengphong S Xu C Woodward TA \nRisk of gastric or peritoneal recurrence, and long-term outcomes, following pancreatic cancer resection with preoperative endosonographically guided fine needle aspiration . Endoscopy \n2013 ;45 :619 –26 .23881804 \n[10] Zhu H Jiang F Zhu J \nAssessment of morbidity and mortality associated with endoscopic ultrasound-guided fine-needle aspiration for pancreatic cystic lesions: a systematic review and meta-analysis . Dig Endosc \n2017 ;29 :667 –75 .28218999\n\n", "fulltext_license": "CC BY-ND", "issn_linking": "0025-7974", "issue": "96(50)", "journal": "Medicine", "keywords": null, "medline_ta": "Medicine (Baltimore)", "mesh_terms": "D018784:Abdominal Abscess; D000368:Aged; D004322:Drainage; D019160:Endosonography; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D010532:Peritoneal Diseases", "nlm_unique_id": "2985248R", "other_id": null, "pages": "e9132", "pmc": null, "pmid": "29390314", "pubdate": "2017-12", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Endoscopic ultrasound-guided transduodenal drainage of idiopathic retroperitoneal abscess in an immunocompromised patient: A case report.", "title_normalized": "endoscopic ultrasound guided transduodenal drainage of idiopathic retroperitoneal abscess in an immunocompromised patient a case report" }

[ { "companynumb": "JP-ACCORD-062904", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "040716", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATIC DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUCILLAMINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATIC DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "200", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUCILLAMINE" } ], "patientagegroup": null, "patientonsetage": "76", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Escherichia infection", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Retroperitoneal abscess", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "SAGAMI R, TSUJI H, NISHIKIORI H, MURAKAMI K. ENDOSCOPIC ULTRASOUND-GUIDED TRANSDUODENAL DRAINAGE OF IDIOPATHIC RETROPERITONEAL ABSCESS IN AN IMMUNOCOMPROMISED PATIENT: A CASE REPORT. MEDICINE (UNITED STATES). 2017?96(50):ARTICLE NUMBER E9132", "literaturereference_normalized": "endoscopic ultrasound guided transduodenal drainage of idiopathic retroperitoneal abscess in an immunocompromised patient a case report", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20180125", "receivedate": "20180125", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14435864, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180509" } ]

{ "abstract": "Crizotinib was the first clinically available inhibitor of the tyrosine kinase ALK, and next-generation ALK inhibitors, such as alectinib, are now under development. Although crizotinib is generally well tolerated, severe esophageal injury has been reported as a rare but serious adverse event of crizotinib therapy. We now describe the successful treatment with alectinib of a patient who developed crizotinib-induced esophageal ulceration.", "affiliations": "Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Center for Clinical and Translational Research, Kyushu University Hospital, Fukuoka, Japan. Electronic address: okamotoi@kokyu.med.kyushu-u.ac.jp.;Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Department of Comprehensive Clinical Oncology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.;Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Center for Clinical and Translational Research, Kyushu University Hospital, Fukuoka, Japan.", "authors": "Yoneshima|Yasuto|Y|;Okamoto|Isamu|I|;Takano|Tomotsugu|T|;Enokizu|Aimi|A|;Iwama|Eiji|E|;Harada|Taishi|T|;Takayama|Koichi|K|;Nakanishi|Yoichi|Y|", "chemical_list": "D002227:Carbazoles; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C582670:alectinib", "country": "Ireland", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0169-5002", "issue": "88(3)", "journal": "Lung cancer (Amsterdam, Netherlands)", "keywords": "Alectinib; Anaplastic lymphoma kinase (ALK); Crizotinib; Esophageal ulceration; Non-small-cell lung cancer (NSCLC)", "medline_ta": "Lung Cancer", "mesh_terms": "D002227:Carbazoles; D002289:Carcinoma, Non-Small-Cell Lung; D000077547:Crizotinib; D019723:Endoscopes; D004935:Esophageal Diseases; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D008875:Middle Aged; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D014456:Ulcer", "nlm_unique_id": "8800805", "other_id": null, "pages": "349-51", "pmc": null, "pmid": "25837798", "pubdate": "2015-06", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Successful treatment with alectinib after crizotinib-induced esophageal ulceration.", "title_normalized": "successful treatment with alectinib after crizotinib induced esophageal ulceration" }

[ { "companynumb": "JP-PFIZER INC-2015121001", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CRIZOTINIB" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "202570", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": "250 MG, 2X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "250", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CRIZOTINIB" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SODIUM ALGINATE" }, "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": "SODIUM ALGINATE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CRIZOTINIB" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "202570", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "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": "CRIZOTINIB" } ], "patientagegroup": null, "patientonsetage": "52", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Oesophageal ulcer", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "YONESHIMA, Y.. SUCCESSFUL TREATMENT WITH ALECTINIB AFTER CRIZOTINIB-INDUCED ESOPHAGEAL ULCERATION. LUNG CANCER. 2015;88(3):349-351", "literaturereference_normalized": "successful treatment with alectinib after crizotinib induced esophageal ulceration", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20170911", "receivedate": "20150414", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11026048, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171127" } ]

{ "abstract": "Kidney involvement in multiple myeloma can result in kidney failure. Unlike Waldenström macroglobulinemia, hyperviscosity syndrome is a rare occurrence in multiple myeloma. Timely detection of hyperviscosity syndrome and initiation of plasma exchange to remove paraproteins can significantly alter the clinical course and be potentially lifesaving. We report a case of hospitalized patient with kidney failure due to multiple myeloma not in remission who experienced shortened hemodialysis sessions due to early dialysis filter failure due to hyperviscosity, which was later corrected with plasmapheresis. When confirmation of high levels of serum free light chains (sFLCs) was attempted, sFLC was initially reported as \"not detectable.\" This false-negative result reflected a laboratory artifact caused by a high abundance of sFLCs, known as antigen excess or hook phenomenon. Manual serial dilutions led to unmasking of markedly elevated κ light chain levels. This case exemplifies that patients with multiple myeloma can exhibit clinically challenging kidney manifestations even after becoming dialysis dependent.", "affiliations": "Department of Nephrology, Ochsner Medical Center, New Orleans, LA.;Department of Nephrology, Ochsner Medical Center, New Orleans, LA.;Department of Nephrology, Ochsner Medical Center, New Orleans, LA.;Department of Pathology, Ochsner Medical Center, New Orleans, LA.;Department of Nephrology, Ochsner Medical Center, New Orleans, LA.", "authors": "Kanduri|Swetha Rani|SR|;LeDoux|Jason R|JR|;Kovvuru|Karthik|K|;Wu|Qingli|Q|;Velez|Juan Carlos|JC|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1016/j.xkme.2021.02.011", "fulltext": "\n==== Front\nKidney Med\nKidney Med\nKidney Medicine\n2590-0595\nElsevier\n\nS2590-0595(21)00076-5\n10.1016/j.xkme.2021.02.011\nCase Report\nMultiple Myeloma, Hyperviscosity, Hemodialysis Filter Clogging, and Antigen Excess Artifact: A Case Report\nKanduri Swetha Rani svetarani@gmail.com\n1∗\nLeDoux Jason R. 1\nKovvuru Karthik 1\nWu Qingli 2\nVelez Juan Carlos 13\n1 Department of Nephrology, Ochsner Medical Center, New Orleans, LA\n2 Department of Pathology, Ochsner Medical Center, New Orleans, LA\n3 Ochsner Clinical School, The University of Queensland, Brisbane, Queensland, Australia\n∗ Address for Correspondence: Swetha Rani Kanduri, MD, Department of Nephrology, Ochsner Medical Center, 1514 Jefferson Hwy, Clinic Tower 5th Floor, New Orleans, LA 70121. svetarani@gmail.com\n21 4 2021\nJul-Aug 2021\n21 4 2021\n3 4 649652\n© 2021 The Authors\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).\nKidney involvement in multiple myeloma can result in kidney failure. Unlike Waldenström macroglobulinemia, hyperviscosity syndrome is a rare occurrence in multiple myeloma. Timely detection of hyperviscosity syndrome and initiation of plasma exchange to remove paraproteins can significantly alter the clinical course and be potentially lifesaving. We report a case of hospitalized patient with kidney failure due to multiple myeloma not in remission who experienced shortened hemodialysis sessions due to early dialysis filter failure due to hyperviscosity, which was later corrected with plasmapheresis. When confirmation of high levels of serum free light chains (sFLCs) was attempted, sFLC was initially reported as “not detectable.” This false-negative result reflected a laboratory artifact caused by a high abundance of sFLCs, known as antigen excess or hook phenomenon. Manual serial dilutions led to unmasking of markedly elevated κ light chain levels. This case exemplifies that patients with multiple myeloma can exhibit clinically challenging kidney manifestations even after becoming dialysis dependent.\n\nIndex Words\n\nHook phenomenon\nantigen excess\nhyper viscosity syndrome\nmultiple myeloma\nplasma exchange\n==== Body\nIntroduction\n\nKidney involvement in patients with multiple myeloma is common.1 Hyperviscosity syndrome is a severe complication that necessitates emergent plasma exchange for paraprotein removal. Hyperviscosity syndrome, commonly described in Waldenström macroglobulinemia, is less frequently reported in patients with multiple myeloma (2%-6%).2 The revised International Myeloma Work Group has incorporated serum free light chain (sFLC) ratio as a biomarker in the diagnosis of multiple myeloma.3 Given their short half-life, sFLCs are clinically useful for monitoring response to therapy. However, sFLC assays could be subject to methodological variations, resulting in spuriously low values.4 We describe an unusual case of multiple myeloma in a patient with kidney failure dependent on hemodialysis presenting with hyperviscosity syndrome who later exhibited the antigen excess artifact.\n\nCase Report\n\nA women in her mid-50s had multiple myeloma diagnosed 5 months before the index admission. She had an abnormal M band on the gamma portion of serum protein electrophoresis, immunofixation (IFE) gel suggestive of free κ light chain monoclonal protein, diffuse κ free light chains at 2,190 mg /dL on IFE, and κ:λ ratio of 3,696. A bone marrow biopsy specimen revealed 70% to 80% plasma cells and hypercellularity. She subsequently received 2 cycles of bortezomib, cyclophosphamide, and dexamethasone, and 1 cycle of high-dose cyclophosphamide, carfilzomib, and dexamethasone, the last cycle being 1 month before the index admission, without attaining clinical remission. Her kidney function declined and she required kidney replacement therapy. She was declared as having end-stage kidney disease 2 months before the index admission.\n\nThe authors were not directly involved in the care of the patient on the previous hospital admission. At that time, the treating physicians opted not to perform a kidney biopsy because it was believed that there was overwhelming clinical evidence to establish a clinical diagnosis of myeloma cast nephropathy (severe oliguric kidney failure and substantially elevated κ free light chains) and the risk for bleeding complications was deemed high (frailty and thrombocytopenia).\n\nIn the index admission, the patient presented to the emergency department with confusion and weakness. On examination, she was afebrile and tachycardic, with blood pressure of 150/90 mm Hg. Significant laboratory values included serum albumin level of 1.8 g/L, serum urea nitrogen level of 12 mg/dl, serum creatinine level of 5.1 mg/dL, κ light chain level < 0.04 mg/dL, and λ light chain level of 0.19 mg/dL. Computed tomography of the head and infectious workup were negative, and the patient did not report missing any of her dialysis sessions.\n\nOne hour into the patient’s scheduled hemodialysis session, the dialysis filter clotted and the treatment was interrupted. This session was resumed with the addition of a 2,000-unit heparin bolus and saline solution for prefilter dilution at blood flow rate of 250 mL/min, dialysate flow rate of 700 mL/min, and an F160 membrane (Fresenius Optiflux). However, the filter clotted again several times (once after 8 minutes and again after 15 minutes). Extremely elevated transmembrane pressure was recorded despite the administration of perceived adequate anticoagulation. Serum viscosity was then measured and found to be profoundly elevated at 7.88 centipoise (cP) (normal, 1.1-1.3 cP). A diagnosis of hyperviscosity syndrome was made and emergent plasma exchange was initiated.\n\nAt that time, serum protein electrophoresis and IFE reported elevated free κ light chains at 6,380 mg /dL; this contrasted with concurrent sFLCs analyzed by @Freelite SPA PLUS (The Binding Site Group Limited Birmingham) that revealed κ light chains < 0.04 mg/dL and λ of 0.19 mg/dL, values that did not correlate with other laboratory results or disease severity. This raised suspicion of the antigen excess artifact, or hook phenomenon. We conjointly worked with the clinical laboratory team and performed manual dilutions of 1:1,000 and 1:10,000, which resulted in substantially elevated κ light chain levels at 129,910 mg/dL. Her neurologic condition improved moderately after 3 sessions of plasma exchange. Unfortunately, the patient could not tolerate further rounds of chemotherapy due to side effects and her disease progressed. Multidisciplinary team discussions were held and the patient opted for hospice care.\n\nDiscussion\n\nOur case illustrates 2 important and relatively underappreciated concepts in the management of multiple myeloma. First, the phenomenon of hyperviscosity syndrome. Lambda free light chains exist as dimers with molecular weight of 45 kDa, as compared with κ light chains which exist as monomers with molecular weight of 22.5 kDa. As glomerular filtration rate declines, kidney clearance of sFLCs decreases and therefore the potential for light chain accumulation is high, with subsequent risk for hyperviscosity syndrome. Additionally, light chain clearance through the reticuloendothelial system is unaffected by the molecular weight of the light chains, such that the serum half-lives of both λ and κ light chains become similar, leading to an increased median sFLC ratio among patients with kidney failure.5 Although hyperviscosity syndrome is occasionally reported among patients with multiple myeloma,2 the presentation of recurrent hemodialysis filter clots secondary to hyperviscosity in a dialysis patient with multiple myeloma makes our case unique.\n\nTimely initiation of plasma exchange to remove paraproteins can significantly alter the clinical course and be potentially lifesaving. The neurological condition of our patient improved moderately after 3 plasma exchange sessions. In addition to correcting hyperviscosity, which was the likely cause of clinical presentation, reduction in free light chain burden helped lower dialysis transmembrane pressures and allowed for successful completion of hemodialysis sessions. This case highlights the importance of considering plasma exchange in conjunction with hemodialysis in dialysis-dependent patients with multiple myeloma presenting with hyperviscosity (Fig 1).Figure 1 Algorithm for an approach to patients with multiple myeloma and kidney failure requiring kidney replacement therapy. Abbreviations: chemo, chemotherapy; cP, centipoise.\n\nThe second concept encountered in this case was the co-existence of antigen excess, reported in 1% to 10% of samples from patients with multiple myeloma.6 This phenomenon is explained by a substantially elevated antigen concentration that exceeds antibody levels, resulting in spuriously low antigen antibody complexes and negative results. The hook phenomenon, as encountered with sFLCs, is synonymous to the prozone effect that is reported with intact immunoglobulins.7 Our patient had spuriously low reported κ and λ values. This finding likely was secondary to excess κ chain burden, overwhelming the concentration of antibodies and thereby impairing the assay performance. Polyclonal antibodies of the sFLC assay recognize epitopes on the constant region of light chains, which are exposed when light chains remain in free forms.8 Currently, multiple commercial assays are available for measuring sFLCs: Freelite,9 an immune nephelometric/turbidimetric assay; N latex FLC assay (Siemens Healthcare Diagnostics),10 based on monoclonal antibodies; and Sebia FLC, enzyme-linked immunosorbent assay (ELISA) based assays.11\n\nOther methodological variations in analyzing sFLC assay include overestimation, which is secondary to polymerization of free light chains, exposing multiple epitopes and thereby generating falsely higher values.12 Nonlinear variations with a 2-fold or higher difference in sFLC values with various dilutions were reported as well.13 Lot-to-lot variation of sFLC concentrations of 8% to 45% have been reported with Freelite assay.14 Automated machine flags and delta checks can be incorporated to alarm unusual values.15 Sample dilutions,4,16 monoclonal antibodies,17 and more sophisticated modalities such as ELISA-based assays (Sebia FLC) and mass spectrometry help detect antigen excess.11,18 Table 14,6,11, 12, 13, 14, 15, 16, 17, 18, 19, 20 describes the challenges in analyzing sFLC assays and potential recommendations.Table 1 Methodological Variations in Analyzing Serum Free Light Chain Results and Recommendations\n\nMethodological Variation in Analyzing Serum Free Light Chain Levels\tRecommendations\t\nAntigen excess/hook phenomenon6\tSample dilutions4,16\nDelta checks15\nAutomated flags15\nELISA-based assay11\nMass spectrometry18\nMonoclonal antibodies (less effect)17\nCombination serologies, SPEP, UPEP, IFE19\t\nOverestimation12\tELISA11\nMass spectrometry18\t\nNon linearity13\tFurther dilutions13\nELISA, mass spectrometry11,18\t\nLot-to-lot variation14\tMonoclonal antibodies (less effect)17\t\nCross-reactivity with intact immunoglobulin13\tMonoclonal antibodies20\t\nAbbreviations: ELISA, enzyme-linked immunosorbent assay; IFE, immunofixation; SPEP, serum protein electrophoresis; UPEP, urine protein electrophoresis.\n\nIn conclusion, prompt attention should be paid to dialysis-dependent patients with multiple myeloma who exhibit hemodialysis interruptions due to dialysis filter clotting, and have a low threshold to consider hyperviscosity syndrome. Early initiation of plasma exchange could be potentially lifesaving. Additionally, the antigen excess artifact, although rare is encountered in 1% to 10% cases of active multiple myeloma. ELISA-based assays and mass spectrometry are relatively more sophisticated and help mitigate some errors. Careful consideration of clinical context and combined interpretation of various serologic tests, including serum protein electrophoresis, IFE, and sFLC, is advised to guide clinical decision making.\n\nArticle Information\n\nAuthors’ Full Names and Academic Degrees\n\nSwetha Rani Kanduri, MD, Jason R. LeDoux, APRN, Karthik Kovvuru, MD, Qingli Wu, PhD, and Juan Carlos Velez, MD.\n\nSupport\n\nNone.\n\nFinancial Disclosure\n\nThe authors declare that they have on relevant financial interests.\n\nPatient Protections\n\nThe authors declare that they have obtained consent from the patient reported in this article for publication of the information about her that appears within this Case Report.\n\nPeer Review\n\nReceived January 4, 2021. Evaluated by 1 external peer reviewer, with direct editorial input from the Editor-in-Chief. Accepted in revised form February 21, 2021.\n\nComplete author and article information provided before references.\n==== Refs\nReferences\n\n1 Reule S. Sexton D.J. Solid C.A. Chen S.C. Foley R.N. ESRD due to multiple myeloma in the United States, 2001-2010 J Am Soc Nephrol 27 5 2016 1487 1494 26516209\n2 Mehta J. Singhal S. Hyperviscosity syndrome in plasma cell dyscrasias Semin Thromb Hemost 29 5 2003 467 471 14631546\n3 Rajkumar S.V. Dimopoulos M.A. Palumbo A. Blade J. Merlini G. Mateos M.V. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma Lancet Oncol 15 12 2014 e538 e548 25439696\n4 Levinson S.S. Hook effect with lambda free light chain in serum free light chain assay Clin Chim Acta 411 21-22 2010 1834 1836 20667445\n5 Hutchison C.A. Harding S. Hewins P. Mead G.P. Townsend J. Bradwell A.R. Quantitative assessment of serum and urinary polyclonal free light chains in patients with chronic kidney disease Clin J Am Soc Nephrol 3 6 2008 1684 1690 18945993\n6 Rassner M.P. Seidl M. Salzer U. Rajkumar S.V. Epting T. Wäsch R. Cast nephropathy and deceptively low absolute serum free light chain levels: resolution of a challenging case and systematic review of the literature Clin Lymphoma Myeloma Leuk 18 1 2018 e1 e7 29066226\n7 Talamo G. Castellani W. Dolloff N.G. Prozone effect of serum IgE levels in a case of plasma cell leukemia J Hematol Oncol 3 1 2010 32 20828419\n8 Kang S.Y. Suh J.T. Lee H.J. Yoon H.J. Lee W.I. Clinical usefulness of free light chain concentration as a tumor marker in multiple myeloma Ann Hematol 84 9 2005 588 593 15883850\n9 Bradwell A.R. Carr-Smith H.D. Mead G.P. Tang L.X. Showell P.J. Drayson M.T. Highly sensitive, automated immunoassay for immunoglobulin free light chains in serum and urine Clin Chem 47 4 2001 673 675 11274017\n10 te Velthuis H. Knop I. Stam P. van den Broek M. Bos H.K. Hol S. N Latex FLC - new monoclonal high-performance assays for the determination of free light chain kappa and lambda Clin Chem Lab Med 49 8 2011 1323 1332 21663464\n11 Lutteri L. Aldenhoff M.-C. Cavalier E. Evaluation of the new Sebia free light chain assay using the AP22 ELITE instrument Clin Chim Acta 487 2018 161 167 30243748\n12 Abraham R.S. Charlesworth M.C. Owen B.A. Benson L.M. Katzmann J.A. Reeder C.B. Trimolecular complexes of lambda light chain dimers in serum of a patient with multiple myeloma Clin Chem 48 10 2002 1805 1811 12324506\n13 Tate J. Bazeley S. Sykes S. Mollee P. Quantitative serum free light chain assay--analytical issues Clin Biochem Rev 30 3 2009 131 140 19841696\n14 Tate J.R. Mollee P. Dimeski G. Carter A.C. Gill D. Analytical performance of serum free light-chain assay during monitoring of patients with monoclonal light-chain diseases Clin Chim Acta 376 1-2 2007 30 36 16945362\n15 McCudden C.R. Voorhees P.M. Hammett-Stabler C.A. A case of hook effect in the serum free light chain assay using the Olympus AU400e Clin Biochem 42 1 2009 121 124 18996106\n16 Bosmann M. Kössler J. Stolz H. Walter U. Knop S. Steigerwald U. Detection of serum free light chains: the problem with antigen excess Clin Chem Lab Med 48 10 2010 1419 1422 20626301\n17 Pretorius C.J. Klingberg S. Tate J. Wilgen U. Ungerer J.P. Evaluation of the N Latex FLC free light chain assay on the Siemens BN analyser: precision, agreement, linearity and variation between reagent lots Ann Clin Biochem 49 pt 5 2012 450 455 22764186\n18 VanDuijn M.M. Jacobs J.F.M. Wevers R.A. Engelke U.F. Joosten I. Luider T.M. Quantitative measurement of immunoglobulins and free light chains using mass spectrometry Anal Chem 87 16 2015 8268 8274 26168337\n19 Shaheen S.P. Levinson S.S. Serum free light chain analysis may miss monoclonal light chains that urine immunofixation electrophoreses would detect Clin Chim Acta 406 1 2009 162 166 19410572\n20 Nakano T. Nagata A. ELISAs for free human immunoglobulin light chains in serum: improvement of assay specificity by using two specific antibodies in a sandwich detection method J Immunol Methods 293 1-2 2004 183 189 15541287\n\n", "fulltext_license": "CC BY", "issn_linking": "2590-0595", "issue": "3(4)", "journal": "Kidney medicine", "keywords": "Hook phenomenon; antigen excess; hyper viscosity syndrome; multiple myeloma; plasma exchange", "medline_ta": "Kidney Med", "mesh_terms": null, "nlm_unique_id": "101756300", "other_id": null, "pages": "649-652", "pmc": null, "pmid": "34401731", "pubdate": "2021", "publication_types": "D002363:Case Reports", "references": "11274017;14631546;20828419;18996106;20667445;26516209;15883850;26168337;21663464;30243748;15541287;18945993;29066226;19410572;25439696;16945362;20626301;22764186;12324506;19841696", "title": "Multiple Myeloma, Hyperviscosity, Hemodialysis Filter Clogging, and Antigen Excess Artifact: A Case Report.", "title_normalized": "multiple myeloma hyperviscosity hemodialysis filter clogging and antigen excess artifact a case report" }

[ { "companynumb": "US-AMGEN-USASP2021134835", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CARFILZOMIB" }, "drugadditional": "3", "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", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARFILZOMIB" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "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": "DEXAMETHASONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "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": "CYCLOPHOSPHAMIDE." }, { "actiondrug": null, "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": "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": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Plasma cell myeloma", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hyperviscosity syndrome", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Thrombosis in device", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KOVVURU K. MULTIPLE MYELOMA, HYPERVISCOSITY, HEMODIALYSIS FILTER CLOGGING, AND ANTIGEN EXCESS ARTIFACT: A CASE REPORT. KIDNEY MEDICINE. 2021?3 (4):649?652", "literaturereference_normalized": "multiple myeloma hyperviscosity hemodialysis filter clogging and antigen excess artifact a case report", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210906", "receivedate": "20210906", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19790485, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" } ]

{ "abstract": "Developing countries can improve their pharmacovigilance systems by analysing their own medication safety data.\nThe aims of this study were to characterize Uganda's reported adverse drug reaction (ADR) onsets in 2012-2015 that were registered on VigiBase® by 31 December 2017, to document delays in international visibility and the influence of covariates on this delay from ADR onsets in 2013 + 2014, to examine data quality, and to illustrate analytical approaches for safety data, particularly for patients receiving antiretroviral therapy (ART).\nInternational delay was defined as elapsed time from complete ADR onset date to entry date on VigiBase®, with covariates examined using Cox proportional hazards regression. Simple random sampling was used to locate the paper-based ADR forms for data quality assurance. Disproportionality for signal detection focused on serious singleton ADR onsets in patients receiving ART.\nUganda's VigiBase® had 1018 patient entries with complete ADR onset dates: 260 in 2012, 293 in 2013, 305 in 2014 and 160 in 2015. Only 16% (154/953) of ADR onsets in 2012-2015 were in patients aged < 20 years for whom randomly sampled ADR forms were less fully completed; 87% (889/1018) comprised a singleton sign/symptom; half were serious. Median delay from ADR onset to international visibility was 11 months for ADR onsets in 2013 + 2014, and longest for healthcare professionals other than pharmacists and physicians. Disproportionality for serious ADR onsets in patients receiving ART included anaemia with zidovudine, renal impairment with tenofovir, Stevens-Johnson syndrome with nevirapine and skin rash with efavirenz.\nBarely one ADR onset per day was registered on VigiBase® from those submitted to Uganda's National Pharmacovigilance Centre during 2012-2014; only one in six was from patients aged < 20 years. Paediatric pharmacovigilance requires more emphasis in Uganda. Delays from reported ADR onset to international visibility on VigiBase® need to reduce dramatically. Quality assurance revealed rectifiable data entry deficits. Signal detection performed well for patients receiving ART.", "affiliations": "1Department of Pharmacology and Therapeutics, Makerere University, College of Health Sciences, P. O. Box 21124, Kampala, Uganda.;National Pharmacovigilance Centre, National Drug Authority, Kampala, Uganda.;National Pharmacovigilance Centre, National Drug Authority, Kampala, Uganda.;3MRC Biostatistics Unit, University of Cambridge, Cambridge, UK.", "authors": "Kiguba|Ronald|R|0000-0002-2636-4115;Ndagije|Helen B|HB|;Nambasa|Victoria|V|;Bird|Sheila M|SM|", "chemical_list": null, "country": "New Zealand", "delete": false, "doi": "10.1007/s40290-018-0253-7", "fulltext": "\n==== Front\nPharmaceut MedPharmaceut MedPharmaceutical Medicine1178-2595Springer International Publishing Cham 25310.1007/s40290-018-0253-7Original Research ArticleAdverse Drug Reaction Onsets in Uganda’s VigiBase®: Delayed International Visibility, Data Quality and Illustrative Signal Detection Analyses http://orcid.org/0000-0002-2636-4115Kiguba Ronald +256701840683kiguba@gmail.com 1Ndagije Helen B. hbyomire@nda.or.ug 2Nambasa Victoria vnambasa@nda.or.ug 2Bird Sheila M. sheila.bird@mrc-bsu.cam.ac.uk 341 0000 0004 0620 0548grid.11194.3cDepartment of Pharmacology and Therapeutics, Makerere University, College of Health Sciences, P. O. Box 21124, Kampala, Uganda 2 National Pharmacovigilance Centre, National Drug Authority, Kampala, Uganda 3 0000000121885934grid.5335.0MRC Biostatistics Unit, University of Cambridge, Cambridge, UK 4 0000 0004 1936 7988grid.4305.2University of Edinburgh College of Medicine and Veterinary Medicine, Edinburgh, UK 17 11 2018 17 11 2018 2018 32 6 413 427 © The Author(s) 2018Open AccessThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial 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.Introduction\nDeveloping countries can improve their pharmacovigilance systems by analysing their own medication safety data.\n\nObjective\nThe aims of this study were to characterize Uganda’s reported adverse drug reaction (ADR) onsets in 2012–2015 that were registered on VigiBase® by 31 December 2017, to document delays in international visibility and the influence of covariates on this delay from ADR onsets in 2013 + 2014, to examine data quality, and to illustrate analytical approaches for safety data, particularly for patients receiving antiretroviral therapy (ART).\n\nMethods\nInternational delay was defined as elapsed time from complete ADR onset date to entry date on VigiBase®, with covariates examined using Cox proportional hazards regression. Simple random sampling was used to locate the paper-based ADR forms for data quality assurance. Disproportionality for signal detection focused on serious singleton ADR onsets in patients receiving ART.\n\nResults\nUganda’s VigiBase® had 1018 patient entries with complete ADR onset dates: 260 in 2012, 293 in 2013, 305 in 2014 and 160 in 2015. Only 16% (154/953) of ADR onsets in 2012–2015 were in patients aged < 20 years for whom randomly sampled ADR forms were less fully completed; 87% (889/1018) comprised a singleton sign/symptom; half were serious. Median delay from ADR onset to international visibility was 11 months for ADR onsets in 2013 + 2014, and longest for healthcare professionals other than pharmacists and physicians. Disproportionality for serious ADR onsets in patients receiving ART included anaemia with zidovudine, renal impairment with tenofovir, Stevens–Johnson syndrome with nevirapine and skin rash with efavirenz.\n\nConclusions\nBarely one ADR onset per day was registered on VigiBase® from those submitted to Uganda’s National Pharmacovigilance Centre during 2012–2014; only one in six was from patients aged < 20 years. Paediatric pharmacovigilance requires more emphasis in Uganda. Delays from reported ADR onset to international visibility on VigiBase® need to reduce dramatically. Quality assurance revealed rectifiable data entry deficits. Signal detection performed well for patients receiving ART.\n\nElectronic supplementary material\nThe online version of this article (10.1007/s40290-018-0253-7) contains supplementary material, which is available to authorized users.\n\nhttp://dx.doi.org/10.13039/100008288Alborada Trustissue-copyright-statement© Springer Nature Switzerland AG 2018\n==== Body\nKey Points\n\nBarely one adverse drug reaction (ADR) onset per day was registered on VigiBase® from those submitted to Uganda’s National Pharmacovigilance Centre during 2012–2014; only one in six were from patients aged < 20 years.\t\nMedian delay from reported ADR onset to international visibility on VigiBase® was 11 months for ADR onsets in 2013 + 2014.\t\nQuality assurance revealed rectifiable data entry deficits. Nonetheless, our illustrative signal detection analyses performed well for patients receiving antiretroviral therapy.\t\n\n\n\nIntroduction\nThe global visibility of a country’s pharmacovigilance system is evidenced by its involvement in the World Health Organization (WHO) Programme for International Drug Monitoring (PIDM), which had 131 full member countries and 26 associates by 13 March 2018: 35 of 54 African countries were full members and seven were associates [1]. Uganda became a full member of the WHO–PIDM in 2007 and quickly established a regional network by which its National Pharmacovigilance Centre (NPC) disseminates information, conducts training and receives pharmacovigilance reports [1, 2].\n\nUganda is divided into 127 districts grouped into four administrative regions: central, eastern, northern and western. Uganda’s population was around 40 million in 2014, two-thirds of whom were aged < 20 years [3]. HIV infection, malaria and tuberculosis contribute significantly to morbidity and mortality. Thus, medicines for these three infectious diseases represent a large proportion of reported adverse drug reactions (ADRs)—a pattern that is similar in other sub-Saharan African (SSA) countries [4, 5]. Uganda’s public healthcare sector operates on a referral basis from village health teams through primary care facilities (health centres at levels II, III and IV) to district/general hospitals (49), regional referral hospitals (RRHs) (14) and, at the apex, national referral hospitals (2). Each RRH is a designated regional pharmacovigilance centre responsible for receiving ADR reports from lower-level health facilities and transmitting them to the NPC. Private health facilities have similar structures to public health facilities. There exist 63 private not-for-profit hospitals and 27 private for-profit hospitals.\n\nGiven the low rate of spontaneous ADR reporting in Uganda, as in other SSA countries [6, 7], its NPC introduced online ADR reporting in 2015 [8]. The NPC also participated in novel pharmacovigilance initiatives globally, such as the piloting of targeted spontaneous reporting of suspected renal toxicity of tenofovir-based antiretroviral therapy (ART) regimens, which included surveillance of 10,225 patients during 2012–2014 [9]. However, more interventions are required to significantly increase Uganda’s rate of ADR reporting.\n\nPharmacovigilance in Uganda and other low-resource settings can be strengthened through collaborations that directly promote both the rate and the quality of ADR reporting and, in so doing, augment signal detection. The use of smartphone applications in pharmacovigilance could galvanize ADR reporting in SSA, including from patients and the general public [3, 10]. The 40th Annual Meeting of Representatives of NPCs in the WHO-PIDM was held in Kampala, Uganda, in November 2017, with the theme “Smart safety surveillance where resources are limited” [11]. Besides improving the rate and quality of ADR reporting, SSA countries in the WHO-PIDM also need to demonstrate that they can undertake timely country-specific analyses of extant drug safety data and act on these results to give prompt feedback to ADR reporters, the general public and government/private agencies [12].\n\nWe illustrate a series of analytical and pharmacovigilance approaches for Uganda that may be deployed by Africa’s NPCs and other countries with young pharmacovigilance systems as they expand their pharmacovigilance databases and improve feedback to reporters. The aims of this paper are as follows:Describe the characteristics of ADR onsets in 2012–2015 that were internationally visible on VigiBase® by 31 December 2017.\n\nDocument the international delay distribution of ADR onsets in 2012–2015 and, for ADR onsets in 2013 + 2014, covariate influences on their being internationally visible within 1 year.\n\nIllustrate analytical methods for:3.1 appraising how peer-reviewed published ADR reports on pharmacovigilance are represented in Uganda’s VigiBase®,\n\n3.2 quality control of the initial-stage assessment of ADR onsets reported to the NPC and\n\n3.3 signal detection by profiling three specific ART medicines with known associated ADR onsets, and for patients whose ART medication excluded the trio of drugs, and by highlighting almost surely iatrogenic ADR onsets.\n\n\n\n\n\n\n\nMethods\nStudy Approach\nThe research was conducted over 10 days in February 2018. The pharmacist/statistician team (RK/SMB) obtained approval from the NPC team (VN/HBN) to gain access to Uganda’s anonymised ADR reports that had been registered on the Uppsala Monitoring Centre (UMC) de-duplicated international database, VigiBase®, by 31 December 2017. This review focused on ADR onsets with known start dates in 2012–2015. For simplicity and to minimize loss of generality, we analysed only ADR onsets whose VigiBase® serial number began UG-NDA, and we did not analyse dosages [13]. See the Electronic Supplementary Material (ESM) for details of how pharmacovigilance reports are processed in Uganda’s VigiBase®. An initial data-orientation exercise provided insight into how to structure the subsequent formal data analyses. Key areas for formal analyses included (1) characteristics of the ADR onsets and their seasonal reporting patterns, (2) elapsed time from ADR onset to international registration on VigiBase® and the covariate influences on delayed international visibility, (3) data quality, (4) VigiBase® registration of exceptional ADRs from Uganda that were already published in peer-reviewed journals, (5) illustration of signal detection analyses for serious singleton ADR onsets stratified by ART status and (6) pharmacovigilance of antituberculosis medications.\n\nDelayed International Registration of Adverse Drug Reaction (ADR) Onsets and Covariate Influences\nWe defined international delay as the time between ADR onset and the date of entry on VigiBase®, which marked its international visibility. We documented the distribution of international delays for ADRs in four separate calendar years: 2012, 2013, 2014 and 2015. Separation was necessary because the delay distribution for ADR onsets in 2015 was incompletely observed as the maximum observable delay was only 2 years for ADR onsets as late as 31 December 2015.\n\nIn any registry, the sequence of event dates is a key issue. In deriving delay distributions, simplifications were made with minimal loss of generality. First, only complete ADR onset dates (year-month-day) were considered. Second, if the ADR onset comprised more than one sign/symptom, each with its own complete onset date, then the latest complete onset date (within same year as the earliest) was recorded as the ADR onset date.\n\nOnly for 2013 + 2014 ADR onsets did we examine how their delay distribution was influenced by five covariates: patient’s sex, patient’s age group, qualification of reporter, seriousness of suspected ADR and whether the patient encountered a multiplicity of completely dated signs/symptoms. We used proportional hazards regression to analyse the joint influence of this set of covariates on the achievement of international delays of less than 1 year.\n\nQuality Assurance of 45 Randomly Sampled ADR Forms\nFor quality assurance, RK/SMB also reviewed three sets of ADR forms to explore the influence of reporter’s qualification, tendency for only a single sign/symptom to be described and relative infrequency of ADR reports for individuals aged < 20 years. We illustrate the value of simple random sampling for quality control via three random samples, each of 15 ADR forms, for ADR onsets in 2013 + 2014 by (1) 61 pharmacist reporters, (2) 62 physician reporters and (3) 92 individuals aged < 20 years. The quality of ADR form completion was subjectively scored from 1 (low) to 5 (high) by RK and compared with VigiBase®. Besides the quality score, we abstracted data on whether the patient had received ART, whether the reporter described a multiplicity of reactions, whether dose details were provided and whether other medications were used besides the “suspected” drug. We also recorded the date of ADR onset, the date the ADR form was received by the NPC and the presence/absence of signatures from first and second ADR causality assessors.\n\nAppraisal of Uganda’s VigiBase® for Exceptional Peer-Reviewed Published ADRs\nWe also investigated exceptional ADRs in the SSA literature, namely, (1) ADR onsets mentioning paralysis (to look for cases linked to intramuscular injection of quinine into the gluteal muscle, as first reported by Ugandan surgeons [14]) and (2) ADR onsets mentioning diclofenac (as per the report by Kiguba et al. [12] detailing a healthcare professional’s [HCP] suspicion of diclofenac-related haemoptysis in Uganda when only two such case reports had been published internationally).\n\nIllustrative Signal Detection Approaches\nIatrogenic ADR Onsets\nWe inspected exceptional Medical Dictionary for Regulatory Activities (MedDRA) terms associated with serious singleton ADRs for which the ADR was almost surely iatrogenic. We focused on instances where only a single drug was reported since even a single serious ADR onset may be sufficient to occasion a pharmacovigilance alert. Where several drugs were used, we identified the co-prescribed suspect and concomitant drugs. Exceptional MedDRA terms that almost surely indicate an iatrogenic ADR include gynaecomastia in an otherwise healthy male patient, acute tardive dyskinesias or erythema multiforme [15].\n\nDisproportionality\nFor serious singleton ADRs reported to Uganda’s NPC, the majority had received ART so that signal detection for serious ADRs was necessarily stratified by the presence/absence of ART. We illustrate signal detection using the disproportionality method, introduced by Finney [16–19]. We concentrate primarily on the stratum of serious singleton ADR onsets in 2012–2014 experienced by Ugandan patients who had received ART.\n\nInitially, we illustrate the power of disproportionality for three ART medicines licensed well before 2012 and with known serious ADRs as follows: anaemia (zidovudine), renal impairment/increased blood creatinine (tenofovir) and Stevens–Johnson syndrome (SJS) (nevirapine). We profile each of these trio drugs (zidovudine, tenofovir, nevirapine) using selected MedDRA terms including anaemia, renal impairment/increased blood creatinine and SJS. However, we also investigated hepatocellular damage and the MedDRA terms ‘rash’, ‘rash: specified’ and ‘urticaria’. Profiles are also shown for patients receiving ART who received none of the trio of zidovudine, tenofovir, nevirapine and for patients receiving ART who received/did not receive co-trimoxazole (subsequently referred to as sulfamethoxazole; trimethoprim), an antibacterial.\n\nWe coded every patient with a serious singleton ADR onset according to whether the patient had received (1 = yes) or not (0 = no) ART, zidovudine, tenofovir, nevirapine or any of the trio drugs (zidovudine, tenofovir, nevirapine).\n\nWe compare the major profiles of MedDRA terms for serious singleton ADR onsets in 2012–2014 in patients receiving ART who received at least one of the above trio versus those who received only non-trio ART. We describe the simple exploratory methods by which we tracked down the source of the detected signal (using Fisher’s exact test).\n\nPharmacovigilance of Antituberculosis Medications\nThe NPC team took close interest in the pharmacovigilance of antituberculosis medications, including bedaquiline, a new molecule recently introduced globally [20], and kanamycin for multidrug-resistant tuberculosis (MDR-TB) [21–23]. Thus, these drugs were factored into our illustrative analyses.\n\nResults\nCharacteristics of ADR Onsets\nAfter excluding 12 patient entries coded as UG-UNEPI and 150 with incomplete onset dates (39 in 2012, 27 in 2013, 49 in 2014, 35 in 2015), 1018 patient entries were registered on Uganda’s VigiBase® for 1 January 2012 to 31 December 2017 with a complete latest onset date in 2012–2015. Of these patient entries, 260 ADR onset dates were in 2012, 293 were in 2013, 305 were in 2014 and only 160 were in 2015 (Table 1). The 1018 ADR onsets included 18 fatalities and a foetal death (whose mother had received efavirenz).Table 1 Characteristics of the 1018 adverse drug reaction onsets with completely ascertained latest onset date in 2012–2015 and registered on Uganda’s VigiBase® by 31 December 2017\n\nCharacteristic\tOnset yeara\t\n2012\t2013\t2014\t2015\t2012–2015\t\nTotal number of ADR onsets\t260\t293\t305\t160\t1018\t\nNumber of fatal ADR onsetsb\t5\t3\t7\t3\t18\t\nDelay distribution (days) of the international registration of ADR onsetsc\t\n 25th percentile\t259\t220\t163\t167\t\t\n Median delay\t571\t334\t329\t341\t\n 75th percentile\t783\t624\t633\t457\t\n 80th percentile\t825\t729\t686\t483\t\n 90th percentile\t1042\t956\t766\t581\t\nCovariate distributions of ADR onsets by onset year (% when covariate is known)\t\n Patient sex (missing for 22/1018 [2%])\t\n  Female\t183 (72)\t190 (66)\t193 (65)\t83 (53)\t649 (65)\t\n  Male\t70 (28)\t97 (34)\t106 (35)\t74 (47)\t347 (35)\t\n  Unknown\t7\t6\t6\t3\t22\t\n Patient’s age group, years (missing for 65/1018 [6%])\t\n   < 20\t46 (20)\t43 (16)\t49 (17)\t16 (10)\t154 (16)\t\n  20–29\t57 (24)\t68 (25)\t65 (22)\t19 (12)\t209 (22)\t\n  30–39\t66 (28)\t76 (28)\t81 (28)\t45 (29)\t268 (28)\t\n  40–49\t36 (15)\t60 (22)\t49 (17)\t39 (25)\t184 (19)\t\n   ≥ 50\t29 (12)\t26 (10)\t47 (16)\t36 (23)\t138 (14)\t\n  Unknown\t26\t20\t14\t5\t65\t\n Qualification of reporter (missing for 151/1018 [15%])\t\n  Pharmacist\t12 (5)\t19 (9)\t43 (16)\t19 (13)\t93 (11)\t\n  Physician\t58 (25)\t31 (14)\t30 (11)\t11 (7)\t130 (15)\t\n  Other HCP\t157 (69)\t170 (77)\t193 (73)\t122 (80)\t644 (74)\t\n  Non-HCP\t2\t\t\t\t\t\n  Not known\t31\t73\t39\t8\t151\t\n Seriousness of ADR onset\t\n  Serious\t112 (43)\t131 (45)\t151 (50)\t114 (71)\t508 (50)\t\n  No data entry\t148 (57)\t162 (55)\t154 (50)\t46 (29)\t510 (50)\t\n Multiple or single signs/symptoms with fully ascertained onset date(s)\t\n  Single\t225 (87)\t255 (87)\t261 (86)\t148 (92)\t889 (87)\t\n  Multiple\t35 (13)\t38 (13)\t44 (14)\t12 (8)\t129 (13)\t\nData are presented as N (%) unless otherwise indicated\n\nADR adverse drug reaction, HCP healthcare professional\n\naADR onset with completely ascertained onset date: 858 ADR onsets in 2012–2014 and 598 ADR onsets in 2013 + 2014 were observed\n\nbIncludes two cases of anaphylactic shock with onsets in 2014 (case ID 15-00002) and 2015 (15-00250), a case of immediate type 1 hypersensitivity with onset in 2014 (15-00014) and a case of toxic epidermal necrolysis with onset in 2015 (15-00205). Also, one ‘foetal death’ in 2013 not listed as a death in a mother who received efavirenz\n\ncInternational delay distribution for ADR onsets in 2015 is likely to be underestimated because it was not fully ascertained by 31 December 2017\n\n\n\n\nTable 1 also summarizes, for each ADR onset year, the sex and age group of patients whose ADR onset was reported, the reporter’s qualification, whether the registered ADR onset was serious and whether a single or multiple signs/symptoms were registered. Females accounted for 72% of ADR onsets in 2012 (183/253; 95% confidence interval [CI] 67–78), a higher percentage than in 2013 + 2014 (65%, 383/586; 95% CI for difference 0–14) and 2015 (53%, 83/157; 95% CI for difference 10–29). Only 16% (43/273; 95% CI 12–21) of Uganda’s internationally registered ADR onsets in 2012–2015 related to patients aged < 20 years.\n\nQualification of the reporter, when known, was registered most often as ‘other HCP’ (74%). The annual contribution of pharmacists varied from 12 to 43 ADR onsets and that by physicians ranged from 11 to 58. For ADR onsets in 2013 + 2014, pharmacists and physicians contributed about equally (62 and 61 ADR onsets, respectively).\n\nAround half of all reported ADR onsets were serious; the only temporal change was in 2015 when the proportion of serious ADR onsets was higher (71%, 114/160). A remarkably high proportion of registered ADR onsets in 2012–2015 (87%, 889/1018) comprised a singleton sign/symptom (Table 1), which differed by qualification of reporter, with 70% (65/93) of ADR onsets being singleton if reported by pharmacists versus 95% (124/130) by physicians and 89% (574/644) by other HCPs; and 83% (126/151) if the reporter’s qualification was unknown.\n\nWe observed seasonality in the reporting of ADR onsets. Table S1 in the ESM shows significant month-to-month heterogeneity in reported ADR onsets for 2012–2014, with high counts in the rainy months (October, November, April, May)—averaging 0.93 per day (Poisson 95% CI 0.83–1.03)—and low counts in December and January, coincident with vacation—averaging 0.53 per day (Poisson 95% CI 0.42–0.63).\n\nDelayed International Registration of ADR Onsets and Covariate Influences\nConsiderable delays could occur between ADR onset date and the report’s entry date on VigiBase®. Delays of more than 1 year were not infrequent, with some longer than 3 years (Table 1).\n\nTable 2 explores the possible influence of five covariates on the typical delay from ADR onset in 2013 + 2014 to its international visibility on Uganda’s VigiBase®. Neither patient sex nor ADR seriousness appeared to influence the median delay. However, the delay distribution for serious ADR onsets was longer tailed. Pharmacist reporters achieved the shortest median delay (186 days) versus that for physicians (315 days); and other HCPs had the longest median delay (415 days). There is some suggestion that median delay to international visibility increased with the patient’s age group, being lowest for patients aged < 20 years (262 days) and highest for patients aged ≥ 50 years (414 days). Delay until international visibility was considerably shorter if the registered ADR onset had a multiplicity of signs/symptoms (see also Fig. 1).Table 2 International delay distribution by covariate for 598 adverse drug reaction onsets in 2013 + 2014\n\nCovariate\tNumber (%)\tPercentile in days\t\n25th\t50th\t75th\t80th\t\nPatient’s sex (missing, n = 12)\t\n Female\t383 (65)\t190\t330\t628\t691\t\n Male\t203 (35)\t183\t343\t664\t709\t\nPatient’s age group, years (missing, n = 34)\t\n  < 20\t92 (16)\t177\t262\t480\t624\t\n 20–29\t133 (24)\t191\t315\t612\t717\t\n 30–39\t157 (28)\t224\t347\t613\t683\t\n 40–49\t109 (19)\t185\t392\t675\t758\t\n  ≥ 50\t73 (13)\t192\t414\t716\t747\t\nReporter’s qualification (missing, n = 112)\t\n Pharmacist\t62 (13)\t130\t186\t515\t622\t\n Physician\t61 (13)\t179\t306\t624\t687\t\n Other HCP\t363 (75)\t242\t415\t695\t727\t\n Not known\t112\t137\t240\t301\t322\t\nSeriousness of ADR onset\t\n Serious\t282 (47)\t177\t324\t671\t717\t\n No data entry\t316 (53)\t195\t336\t565\t659\t\nMultiple/single signs/symptoms with full ascertained onset date(s)\t\n Single\t516 (86)\t203\t344\t654\t716\t\n Multiplea\t82 (14)\t135\t214\t419\t605\t\nADR adverse drug reaction, HCP healthcare professional\n\naOne in 82 ADR onsets was later found to be a single reaction and so had been miscoded as multiple\n\n\nFig. 1 Covariate influences on the delayed international registration of adverse drug reaction onsets in Uganda’s VigiBase®\n\n\n\n\nTable 3 shows that qualification of reporter, multiplicity of signs/symptoms of suspected ADR onset and age group were the most influential covariates in determining whether a reported ADR onset in 2013 + 2014 was internationally visible within 1 year of the patient’s ADR experience. Only qualification of reporter was significant at the 1% level and showed that the shortest delays were achieved when the reporter was either a pharmacist or the qualification was unknown. By far the longest delays occurred when the reporter was ‘other HCP’.Table 3 Cox proportional hazards regression of covariate influences on international visibility within 1 year for 303 of 553 adverse drug reaction onsets in 2013 + 2014 with known patient sex and age group\n\nCovariate\tUnivariate Log-rank test\tAdjusted HRa\tp value\t\nStatistic\tp value\tHR (95% CI)\t\nPatient sex\t\n Female (ref: male)\t0.14\t0.703\t1.07 (0.84–1.36)\t0.584\t\nSeriousness of ADR onset\t\n Serious (ref: not recorded)\t0.12\t0.734\t1.08 (0.86–1.35)\t0.531\t\nMultiplicity of ADR onset\t\n Multiple (ref: singleton)\t11.23\t< 0.001\t1.46 (1.08–1.99)\t0.015\t\nAge group (PH: linear)b\t9.57\t0.048\t0.90 (0.82–1.00)\t0.041\t\nReporter qualification (ref: pharmacist)\t96.74\t< 0.001\t\t\t\n Physician\t\t\t0.73 (0.46–1.18)\t0.200\t\n Other healthcare professional\t\t\t0.48 (0.34–0.68)\t < 0.001\t\n Unknown\t\t\t1.42 (0.97–2.08)\t0.072\t\nADR adverse drug reaction, CI confidence interval, HR hazard ratio, PH proportional hazards, ref reference category\n\naHR > 1.0 gives < 1 year’s delay in the international registration of ADR onsets\n\nbAge group is coded as 1 = < 20 years, 2 = 20–29 years, 3 = 30–39 years, 4 = 40–49 years, 5 = ≥ 50 years. Log-rank test is on 4 degrees of freedom\n\n\n\n\nQuality Assurance of 45 Randomly Sampled ADR Forms\nOnly 29 of the 45 randomly selected ADR forms were located (64%, 95% CI 50–78). The running mean for the percentage of located ADR forms that cited multiple reactions was (6 + 4 + 5)/(11 + 10 + 8), or 52% (15/29, 95% CI 33–70) (see Table S2 in the ESM), which is significantly higher than recorded in Uganda’s VigiBase®. Only seven of the 15 ADR forms with multiple reactions were correctly registered as a multiplicity on VigiBase®. The six multiple reactions reported by pharmacists were all registered on VigiBase® as multiple reactions. By contrast, only one of the nine multiple reactions recorded by physicians or for individuals aged < 20 years was registered on VigiBase® as a multiplicity (p = 0.0014, Fisher’s exact test).\n\nMean ± standard deviation (SD) RK subjective score (out of 5) for quality of reporting was 4.3 ± 1.01 for pharmacists, 4.2 ± 0.63 for physicians but only 3.0 ± 0.76 for the eight patients aged < 20 years. The pooled SD was 0.83. Thus, the standard error for comparison of scores for the youngest patients versus for ADR reports completed by physicians or pharmacists was 0.34. The quality of completion of ADR reports for children and young adults appeared significantly lower than that of reports from physicians and pharmacists (t test on 26 df − 3.6; p = 0.002).\n\nAppraisal of Uganda’s VigiBase® for exceptional Peer-Reviewed Published ADRs\nDiclofenac-linked haemoptysis: Ten ADR reports in Uganda’s international database to 31 December 2017 mentioned diclofenac as potentially involved in an ADR. Eight of the ten ADR forms were located; none included a description that related, even remotely, to haemoptysis [12]. Of the eight forms, five had an ADR causality assessor sheet; four of the five assessor sheets were signed by the first assessor, but none was counter signed.\n\nQuinine-linked limb paralysis: Of six listed cases, two had UG-UNEPI 2009 codes (one from Kamuli District in eastern Uganda) and one an UG-UNEPI 2011 code (region not specified). None of these three ADR forms was located. The other three cases had UG-NDA codes, two for 2011 (both from Kamuli District, and both of which were located) but the third, provided electronically, was for 2013 (from Kayunga District in eastern Uganda).\n\nThe two located ADR forms from Kamuli District related to intramuscular injection of quinine for the treatment of malaria. Neither specified the injection site (buttock or thigh). The reporter, the first assessor and the date (11 March 2011) was the same for both reports; neither report was co-signed.\n\nADR onset date for the first case (female, aged 32 years, treated during 10–12 November 2010) was not specified on the form but was entered on VigiBase® as the period of quinine treatment (10–12 November 2010). The reporter specified the route as intramuscular, but the route was entered incorrectly on VigiBase® as ‘intrameningeal’. Anaphylaxis and paralysis of right lower limb were reported on the ADR form, but only paralysis was registered on VigiBase®. This first report, dated 17 December 2010, was received at the NPC on 2 March 2011 and first assessed on 11 March 2011. Other drugs used were paracetamol, metronidazole, oral rehydration solution and ciprofloxacin, three of which were entered on VigiBase®; oral rehydration solution was not entered.\n\nThe second case (male, aged 2 years) received intramuscular quinine during 16–18 December 2010. Severe local reaction and paralysis of the limb were reported on the ADR form, but only limb paralysis was registered on VigiBase®. Limb paralysis began on 19 December 2010. Other drugs administered were diclofenac for inflammation and paracetamol for pyrexia, but neither was entered on VigiBase®. This second report, dated 3 January 2011, was received at the NPC on 2 March 2011 and was also first assessed on 11 March 2011 by the same assessor who dealt with the first report, on the same day. The route was entered correctly as intramuscular on VigiBase®.\n\nThe 2013 electronic ADR report related to three ART medications (tenofovir, lamivudine, nevirapine) received for over a year by a 47-year-old female patient. She experienced paraesthesia of both lower limbs for 5 months (onset dated May 2012) and renal impairment. All three were suspected drugs. Unlike the ADR form, VigiBase® listed paraesthesia as the only ADR.\n\nIllustrative Signal Detection Approaches\nMedDRA Terms Linked to Three or More Singleton ADR Onsets\nTable 4 lists the MedDRA terms linked to three or more fully dated singleton ADR onsets in 2012–2014. The listed MedDRA terms account for 267 (77%) of the 346 serious singleton ADR onsets and for 271 (69%) of the 395 not labelled as serious ADR onsets.Table 4 MedDRA terms implicated in three or more single adverse drug reaction onsets in 2012–2014\n\nMedDRA classification\tSingle ADR onsets in 2012–2014 [n (% of all single ADR onsets)]\t\nNon-seriousa (n = 395)\tSeriousa (n = 346)\t\nTotal (n = 346)\tOn ART (n = 252)\tNot on ART (n = 94)\t\nAnaemia\t16 (4)\t54 (16)\t42 (17)\t12 (13)\t\nBurning sensation\t3 (1)\t3 (1)\t3 (1)\t0 (< 3)\t\nDermatitis bullous\t0 (< 1)\t3 (1)\t1 (< 1)\t2 (2)\t\nDizziness\t6 (2)\t3 (1)\t3 (1)\t0 (< 3)\t\nDocumented hypersensitivity\t1 (< 1)\t4 (1)\t3 (1)\t1 (1)\t\nType 1 hypersensitivity\t1 (< 1)\t1 (< 1)\t0 (< 1)\t1 (1)\t\nDrug reaction with eosinophilia\t1 (< 1)\t4 (1)\t4 (2)\t0 (< 3)\t\nGynaecomastiab\t3 (1)\t3 (1)\t3 (1)\t0 (< 3)\t\nHepatocellular injury\t0 (< 1)\t5 (1)\t4 (2)\t1 (1)\t\nLiver injury\t1 (< 1)\t2 (1)\t2 (1)\t0 (< 3)\t\nHepatotoxicity\t0 (< 1)\t1 (< 1)\t1 (< 1)\t0 (< 3)\t\nHepatic function abnormal\t0 (< 1)\t1(< 1)\t0 (< 1)\t1 (1)\t\nJaundice\t13 (3)\t9 (3)\t7 (3)\t2 (2)\t\nJaundice hepatocellular\t0 (< 1)\t1 (< 1)\t0 (< 1)\t1 (1)\t\nLactic acidosis\t0 (< 1)\t3 (1)\t3 (1)\t0 (< 3)\t\nNeuropathy, peripheral\t0 (< 1)\t4 (1)\t4 (2)\t0 (< 3)\t\nRash\t90 (23)\t42 (12)\t31 (12)\t11 (12)\t\nRash: erythematous\t10 (3)\t5 (1)\t5(2)\t0 (< 3)\t\nRash: maculopapular\t28 (7)\t15 (4)\t11 (4)\t4 (4)\t\nRash: popular\t6 (2)\t5 (1)\t4 (2)\t1 (1)\t\nRash: pruritic\t7 (2)\t5 (1)\t3 (1)\t2 (2)\t\nRenal impairment\t2(1)\t16 (5)\t16 (6)\t0 (< 3)\t\nRenal failure\t0 (< 1)\t1 (< 1)\t1 (< 1)\t0 (< 3)\t\nBlood creatinine increased\t2 (1)\t9 (3)\t9 (4)\t0 (< 3)\t\nSkin reaction\t40 (10)\t14 (4)\t7 (3)\t7 (7)\t\nSJS\t12 (3)\t41(12)\t36 (14)\t5 (5)\t\nUrticaria\t29 (7)\t13 (4)\t10 (4)\t3 (3)\t\nADR adverse drug reaction, MedDRA Medical Dictionary for Drug Regulatory Activities, SJS Stevens–Johnson syndrome\n\naMedDRA terms implicated in three or more single adverse drug reaction onsets in 2012–2014 account for 69% (271/395) of non-serious single ADR onsets and 77% (267/346) of serious single ADR onsets\n\nbNot labelled as serious (case ID 14-00462; onset year 2013 [January]: efavirenz I sulfamethoxazole; trimethoprim I lamivudine I tenofovir. 14-00222; onset year 2013 [November]: efavirenz. 14-00218; onset year 2014 [February]: zidovudine I lamivudine I efavirenz I sulfamethoxazole; trimethoprim). Labelled serious (16-00251; onset year 2013 [December]: efavirenz I tenofovir I lamivudine. 17-00068; onset year 2014 [April]: efavirenz. 15-00097; onset year 2014 [October]: efavirenz; lamivudine I tenofovir I sulfamethoxazole; trimethoprim I paclitaxel.). The VigiBase® coding convention uses a semi-colon to designate when a fixed-dose combination has been prescribed (e.g. sulfamethoxazole; trimethoprim) and a vertical symbol (I) to demarcate different drugs (e.g. lamivudine I efavirenz)\n\n\n\n\nIatrogenic ADR Onsets\nTable 5 lists exceptional MedDRA terms, including those indicted as iatrogenic [15], that account for a further 27 singleton ADR onsets in the serious and ‘not labelled as serious’ categories. In Tables 4 and 5, the following iatrogenic ADR onsets are notable: anaphylactic shock with benzylpenicillin; two reports of erythema multiforme in patients who received sulfamethoxazole; trimethoprim (one of whom also received nevirapine); six reports of gynaecomastia in males, all of whom received efavirenz; and tardive dyskinesia in three patients who received metoclopramide (one of whom also received ciprofloxacin and metronidazole).Table 5 Other notable MedDRA terms of single adverse drug reaction onsets in 2012–2014 and the implicated drugs\n\nMedDRA classificationa\tSingle ADR onsets in 2012–2014 [n]\t\nNon-serious (n = 395)\tSerious, n = 346\t\nTotal (n = 346)\tOn ART (n = 252)\tNot on ART (n = 94)\t\nAdverse drug reaction\n13-00406 onset year 2013: praziquantel; described as life threatening—general body weakness, epigastric pain, backache after administration of single 600-mg dose during mass deworming programme\n13-00411 onset year 2013: praziquantel; form not located\t0\t2\t0\t2\t\nAnaphylactic reaction\n13-00093; onset year 2012: nevirapine I zidovudine\n14-00048 onset year 2012: carbamazepine I artemether; lumefantrine\n13-00020; onset year 2012: dapsone\n13-00084; onset year 2012: artemether; lumefantrine\n14-00492; onset year 2014: nevirapine I zidovudine I lamivudine I sulfamethoxazole; trimethoprim\t3\t2\t1\t1\t\nAnaphylactic shock\n15-00002; onset year 2014: benzylpenicillin\t0\t1\t0\t1\t\nErythema multiforme\n12-00082; onset year 2012: sulfamethoxazole; trimethoprim\n14-00274; onset year 2013: nevirapine I sulfamethoxazole; trimethoprim\t0\t2\t1\t1\t\nFanconi syndrome\n16-00060; onset year 2013: tenofovir\n16-00132; onset year 2014: tenofovir I lamivudine I sulfamethoxazole; trimethoprim I atazanavir\t0\t2\t2\t0\t\nFoetal death\n14-00130; onset year: 2013: efavirenz prescribed to mother\t0\t1\t1\t0\t\nHepatorenal syndrome\n14-00582; onset year 2014: tenofovir I lamivudine I efavirenz I sulfamethoxazole; trimethoprim\t0\t1\t1\t0\t\nNeutropenia\n12-00162; onset year 2012: sulfamethoxazole; trimethoprim\n13-00040; onset year 2012: zidovudine\n12-00149; onset year 2012: sulfamethoxazole; trimethoprim\t1\t2\t0\t2\t\nOsteomalacia\n17-00042; onset year 2013: tenofovir I efavirenz I lamivudine I sulfamethoxazole; trimethoprim\n14-00414; onset year 2014: tenofovir I nevirapine I sulfamethoxazole; trimethoprim\t0\t2\t2\t0\t\nParkinsonism at young age\n14-00471; onset year 2013: efavirenz I tenofovir I lamivudine I sulfamethoxazole; trimethoprim\nAged 46 years\t0\t1\t1\t0\t\nPsychotic disorder\n13-00372; onset year 2012: efavirenz I lamivudine; zidovudine\n14-00382; onset year 2013: cycloserine\t0\t2\t1\t1\t\nTardive dyskinesia\n14-00435; onset year 2014: metoclopramide\n14-00271; onset year 2013: metoclopramide\n14-00434; onset year 2014: metoclopramide I ciprofloxacin I metronidazole\t2\t1\t0\t1\t\nVisual impairment\n14-00380; onset year 2014: ethionamide\n15-00143; onset year 2014: ethambutol\t0\t2\t0\t2\t\nVision blurred\n14-00390; onset year 2013: ethambutol\t0\t1\t0\t1\t\nVisual acuity reduced\n15-00156; onset year 2014: ethambutol\t0\t1\t0\t1\t\nPruritus\t12\t2\t0\t2\t\nPurpura\t9\t2\t2\t0\t\nADR adverse drug reaction, MedDRA Medical Dictionary for Drug Regulatory Activities\n\naThe VigiBase® coding convention uses a semi-colon to designate when a fixed-dose combination has been prescribed (e.g., sulfamethoxazole; trimethoprim) and a vertical symbol (I) to demarcate different drugs (e.g. lamivudine I efavirenz)\n\n\n\nTable 5 also highlights two reports of Fanconi syndrome in which tenofovir was the suspected drug, although one patient also received two other ART medicines together with sulfamethoxazole; trimethoprim; one report of foetal death (mother had received efavirenz); and four reports of visual impairment/blurred vision/reduced visual acuity in relation to the antituberculosis medications ethambutol (three cases) or ethionamide (one case).\n\nDisproportionality\nIn Table 4, the MedDRA terms occurring disproportionately in association with serious ADR onsets included anaemia, renal impairment and increased blood creatinine, and SJS. They are precisely the serious ADR onsets that occur disproportionately among patients with serious singleton ADR onsets who were receiving ART.\n\nTable 6 shows clear signals of the following associations in Uganda’s 252 serious singleton ADR onsets in 2012–2014 for patients receiving ART: zidovudine with anaemia (zidovudine 44% [42/96] vs. no zidovudine 0% [0/156]), tenofovir with renal impairment (tenofovir 32% [24/75] vs. no tenofovir 1% [2/177]) and nevirapine with SJS (nevirapine: 25% [31/123] vs. no nevirapine: 4% [5/129]). Notice also ‘rash’, which is otherwise unspecified.Table 6 Signal detection illustrated for specific MedDRA terms of 252 known serious single adverse drug reaction onsets in 2012–2014 in association with specific antiretroviral drugs and drug–drug interactions with sulfamethoxazole; trimethoprim\n\nMedDRA classification of serious single ADRs\tZidovudine\tTenofovir\tNevirapine\tAny of the trio\tSulfamethoxazole; trimethoprim\t\nNo: 156\tYes: 96\tNo: 177\tYes: 75\tNo: 129\tYes: 123\tNo: 29\tYes: 223\tNo: 150\tYes: 102\t\nAnaemia\t0\t42\t42\t0\t25\t17\t0\t42\t21\t21\t\nRenal impairment\t16\t0\t1\t15\t15\t1\t1\t15\t15\t1\t\nRenal failure\t1\t0\t0\t1\t1\t0\t0\t1\t1\t0\t\nBlood creatinine increased\t9\t0\t1\t8\t7\t2\t0\t9\t7\t2\t\nHepatocellular injury\t1\t3\t4\t0\t1\t3\t1\t3\t0\t4\t\nHepatotoxicity\t1\t0\t1\t0\t1\t0\t1\t0\t1\t0\t\nLiver injury\t0\t2\t2\t0\t1\t1\t0\t2\t0\t2\t\nJaundice\t6\t1\t4\t3\t5\t2\t2\t5\t4\t3\t\nRash\t19\t12\t28\t3\t7\t24\t3\t28\t17\t14\t\nRash: specified\t20\t6\t21\t5\t12\t14\t6a\t20a\t21\t5\t\nUrticaria\t10\t0\t7\t3\t8\t2\t5\t5\t9\t1\t\nSJS\t25\t11\t27\t9\t5\t31\t2\t34\t15\t21\t\nSkin reaction\t5\t2\t6\t1\t1\t6\t0\t7\t6\t1\t\nADR adverse drug reaction, MedDRA Medical Dictionary for Drug Regulatory Activities, SJS Stevens–Johnson syndrome\n\naRash specified included maculopapular as follows: 7/223 (3%) trio cases, 4/29 (14%) non-trio cases\n\n\n\n\nWe now focus on the columns of Table 6 headed ‘Any of the trio’. Intriguingly, there is a signal that the 29 patients receiving ART who did not receive zidovudine, tenofovir or nevirapine had a significantly increased risk (38% [11/29]) of ‘rash: specified’ or ‘urticaria’ versus trio patients (11% [25/223]) who reported having a serious singleton ADR (Chi squared on 1 degree of freedom 14.96, p < 0.001).\n\nTable 7 lists the medicines received and the serious ADR onsets experienced by non-trio cases. Efavirenz was prescribed for 23/29 non-trio patients, including all 11 whose serious singleton ADRs were ‘rash: specified’ (6) or ‘urticaria’ (5). Gynaecomastia in a 60-year-old male and foetal death were also listed against efavirenz.Table 7 Medications received by 29 patients receiving antiretroviral therapy (ART) who did not receive any of the trio of the ART drugs zidovudine, tenofovir or nevirapine\n\nNon-trio patients by ID\tMedicationsa\tMedDRA terms\t\n15-00111\tAbacavir\tRenal impairment\t\n15-00124\tAbacavir\tDocumented hypersensitivity\t\n14-00580\tAbacavir I lamivudine I efavirenz I sulfamethoxazole; trimethoprim\tHypersensitivity\t\n14-00481\tAbacavir I lamivudine I efavirenz I sulfamethoxazole; trimethoprim\tVomiting\t\n14-00200\tAtazanavir\tJaundice\t\n14-00258\tAtazanavir\tHepatotoxicity\t\n15-00157\tAtazanavir\tJaundice\t\n14-00284\tEfavirenz I sulfamethoxazole; trimethoprim\tRash: maculopapular\t\n14-00109\tEfavirenz I sulfamethoxazole; trimethoprim\tRash\t\n14-00084\t\nEfavirenz\n\tRash: maculopapular\t\n15-00075\t\nEfavirenz\n\tRash: maculopapular\t\n15-00127\t\nEfavirenz\n\tRash: maculopapular\t\n14-00100\t\nEfavirenz\n\tUrticaria\t\n14-00195\t\nEfavirenz\n\tUrticaria\t\n14-00196\t\nEfavirenz\n\tUrticaria\t\n14-00207\t\nEfavirenz\n\tUrticaria\t\n14-00502\t\nEfavirenz\n\tUrticaria\t\n15-00122\t\nEfavirenz\n\tRash: pruritic\t\n15-00225\t\nEfavirenz\n\tRash: popular\t\n15-00148\t\nEfavirenz\n\tRash\t\n14-00373\t\nEfavirenz\n\tSJS\t\n15-00101\t\nEfavirenz\n\tSJS\t\n17-00068\t\nEfavirenz\n\tGynaecomastia (male, aged 60 years)\t\n15-00144\t\nEfavirenz\n\tPeripheral neuropathy\t\n14-00345\t\nEfavirenz\n\tEye lid disorder\t\n14-00130\t\nEfavirenz\n\tFoetal death\t\n14-00292\tIsoniazid I abacavir I lamivudine I lopinavir; ritonavir I sulfamethoxazole; trimethoprim\tHepatocellular injury\t\n14-00510\tLamivudine I efavirenz I sulfamethoxazole; trimethoprim\tAphthous ulcer\t\n12-00218\tNevirapine I dapsone\tJaundice\t\nBold formatting shows the frequent implication of efavirenz\n\nART antiretroviral therapy, MedDRA Medical Dictionary for Drug Regulatory Activities, SJS Stevens–Johnson syndrome\n\naThe VigiBase® coding convention uses a semi-colon to designate when a fixed-dose combination has been prescribed (e.g. sulfamethoxazole; trimethoprim) and a vertical symbol (I) to demarcate different drugs (e.g. lamivudine I efavirenz)\n\n\n\n\nPharmacovigilance of Antituberculosis Medications\nTables S3 and S4 in the ESM show how we investigated drug–drug interactions between antituberculosis medications and each of zidovudine, sulfamethoxazole; trimethoprim and the trio of zidovudine; tenofovir; nevirapine; see also ototoxicity in patients who received MDR-TB treatment.\n\nDiscussion\nThis paper coincides with the tenth anniversary of the NPC and focuses on over 1000 reports of ADR onsets that occurred during 2012–2015 for which ADR onset dates were complete and the corresponding individual case safety reports (ICSRs) were internationally reported by 31 December 2017 on VigiBase®, the global ICSR database managed by the UMC [24].\n\nDespite a population of 40 million and highly prevalent HIV, malaria and tuberculosis, completely dated ADR onsets reported to Uganda’s NPC were fewer than one per day in 2012–2014 and fewer than eight per million of population annually, despite Uganda’s membership since 2007 of the WHO-PIDM [1, 25]. Moreover, to stimulate reporting, NPC has undertaken targeted reporting of ADRs for patients receiving ART [9] and follow-up of an annual, national cohort of patients who receive treatment for MDR-TB. The NPC’s excellent work on targeted surveillance for ADR onsets in over 10,000 patients who received tenofovir allowed estimation of both the incidence of renal impairment and the under-ascertainment rate by spontaneous reporting [9].\n\nIn addition to the low rate of ADR notifications to the NPC, median delay from ADR onset to its international visibility on VigiBase® was 11 months for ADR onsets in 2013 + 2014. Registration delays arise for a variety of reasons, including to improve data quality and ensure that the NPC’s internationally reported suspected ADR onsets meet the required entry criteria set by the UMC. Delays matter primarily because they slow the detection of safety signals and consequent recommendations on harm-reduction measures. The contribution of the NPC’s regional centres, mostly busy RRHs, to the overall delay from ADR onset to international visibility should be assessed. Historically, we have evidenced a delay of 2 months before the NPC received two within-region reports of paralysis following intramuscular quinine injection.\n\nRegistration on VigiBase®\nwithin 1 year of ADR onset was less likely for reports submitted by HCPs other than pharmacists and physicians but more likely if the VigiBase®-registered ICSR comprised multiple clinical signs/symptoms. Other HCPs may have to negotiate institutional reporting hierarchies before the NPC is informed; alternatively, reports by other HCPs may be subject to more time-consuming cross-checks to pass quality assurance at the NPC. In total, 90% of registered ADR onsets reported by physicians or other HCPs, compared with 70% of those by pharmacists, described a single sign/symptom. As the first stage of assessment at the NPC is performed by intern pharmacists, it is interesting that our random sampling of ADR forms revealed that pharmacists’ descriptions of multiple signs/symptoms was more faithfully represented on VigiBase® than were those described by physicians or pertaining to patients aged < 20 years. The NPC team confirmed a tendency for NPC’s assessors to summarize the reporter’s account of signs/symptoms, yet the text and commentary conveyed in actual ADR reports could be additionally insightful. The NPC’s current training on the use of MedDRA classifications emphasises that each sign/symptom should be coded as detailed by the reporter. Random sampling can be used to check that the NPC’s training has indeed changed practice. The proportion of ADR onsets recorded as serious was highest in 2015: with only half the reports registered, the NPC may have prioritized registering serious ADR onsets.\n\nReporting suspected ADR onsets at the extremes of age is particularly important [18]. Older patients with comorbidities may have been excluded from licensing trials. Medicines initially licensed for use in adults may have undergone less detailed study in children before being approved for paediatric use, or their use could be off-label. Only one in six reported ADR onsets in 2012–2015 and registered on Uganda’s VigiBase® by 31 December 2017 pertained to patients aged < 20 years, and their randomly sampled ADR forms were less well completed. Only two ADR onsets per million of population aged < 20 years (46/23.6) were reported annually. Paediatric pharmacovigilance requires more emphasis in Uganda where, in 2014, 59% of the population was aged < 20 years [3].\n\nWe showed significant seasonality in reported ADR onsets, with a substantially higher rate during the rainy months of October, November, April and May and a low reported ADR onset rate in December and January. The former is likely to be disease related, whereas the December and January low may be a reporting deficit during the Christmas and New Year vacation. Seasonal variation in the spontaneous reporting of suspected ADRs is well-documented in the developed world and should be heeded to mitigate false-positive safety signals for new ADRs when comparison periods are short [26].\n\nFor patients receiving ART, we illustrated signal detection using disproportionality for three selected drugs (zidovudine, tenofovir, nevirapine) with different known serious ADRs (anaemia, renal impairment, SJS). We presented a MedDRA terms profile for each selected drug and for patients who received none of these three. Our illustration of signal detection worked very well; perhaps too well. Each selected drug had been licensed for more than a decade by 2014, so reporters were probably already familiar with each drug’s most serious ADRs. Thus, the reporting of ADR onsets may have more been evidence of the reporters’ knowledge than illustrative of the undoubted potential of Ugandan HCPs to recognise novel serious ADRs [12].\n\nThe serious ADR onsets reported to the NPC for the 29 non-trio patients were sufficient for signal detection related to ‘rash: specified’ and ‘urticaria’. Even this demonstration may have been aided by some spillover from training that reporters could have received in association with NPC’s piloting in 2013 + 2014 of stimulated reporting of ADR onsets for patients who received tenofovir [9]. Moreover, pharmacist RK (but not statistician SMB) already knew that patients receiving efavirenz are at risk of maculopapular rash and urticaria.\n\nSignals will be amplified if reports from stimulated ADR recognition in specifically designed cohorts are amalgamated with spontaneous reports. Ideally, stimulated ADR reports from cohort studies should be specifically identifiable in VigiBase®, but they are not.\n\nBesides deploying disproportionality separately for patients who received ART, we illustrated other approaches to pharmacovigilance, notably, searching—within Uganda’s VigiBase®—for safety reports on published pharmacovigilance signals from SSA [12]; review of ADR fatalities (including foetal death); and inspection of rare serious ADRs, which are almost always iatrogenic [15] and, thus, indict the suspected drug (if it is truly the only medication that the patient received). However, WHO-PIDM countries with few ADR reports can also use global evidence from the UMC’s web-based VigiLyze to support analysis of their national databases [27].\n\nOur purposive, randomly sampled look-backs to actual ADR forms for quality assurance revealed deficits, including that other drugs a patient was receiving did not feature on the VigiBase® entry. Hence, before a rare, serious iatrogenic ADR can be taken as indictment of the suspected drug, it is necessary to check information on the reporter’s ADR form to ensure that other drugs were not documented by the reporter.\n\nLook-back was challenging at the NPC, as a third of randomly sampled ADR forms could not be located. Electronic submission may alleviate the misfiling of paper forms but must allow sufficient space for comment, otherwise context and detail previously written down by reporters may be lost. For the pair of quinine reports from Kamuli District, 2 months passed before they were received at the NPC, whereupon intramuscular was entered differently, the correct entry being made on the basis of the form’s comment section (where route was identified as intramuscular) despite ‘route’ being coded by the reporter as ‘not applicable’. Both reports cited a singleton reaction (paralysis) on VigiBase®, even though both forms mentioned two reactions. Nonetheless, this pair of ADR reports illustrated prompt recognition of serious, specific and exceptional ADR onsets and their timely reporting.\n\nADR reports were sufficient for a causal link to be declared for efavirenz and gynaecomastia, tenofovir and Fanconi syndrome, sulfamethoxazole; trimethoprim and erythema multiforme, and metoclopramide and tardive dyskinesia. The US FDA issued a warning about the latter in August 2011 [28]. NPCs should maintain a national list of ‘almost surely iatrogenic’ MedDRA terms, against which each newly reported ADR onset can be checked. If necessary, the associated medication can then be added to the current watchlist of drugs on which the NPC is conducting enhanced surveillance.\n\nLimitations\nWe analysed Uganda’s de-duplicated VigiBase® and did not review the NPC’s methodology (exact or probabilistic; regional or national) for recognising duplicate reports. Likewise, we did not review whether the ADR onset, as registered on VigiBase®, was a superset or an intersection of the information conveyed by its several reporters. For surety, we also focused on completely dated ADR onsets. Further investigation of the excluded 15% of ADR onsets could be warranted.\n\nSecond, because ADR onsets mostly registered only a single sign/symptom, our analysis concentrated on serious single ADR onsets in 2012–2014. See Table S5 in the ESM for multiple signs/symptoms.\n\nThird, as regional pharmacovigilance centres are not registered on VigiBase®, we could not analyse regional variations, either in ADR reporting rate per million of regional population or in regional contribution to the delay from ADR onset to international visibility on Uganda’s VigiBase®.\n\nFourth, disproportionality for signal detection within the stratum of patients receiving ART may have performed well, despite the limited number of reported ADR onsets (fewer than 1000), because the NPC had undertaken various initiatives to target (or stimulate) the reporting of serious ADR onsets in patients receiving ART, notably tenofovir.\n\nFifth, until Uganda’s VigiBase® differentiates between ADR onsets from spontaneous versus targeted reporting, the performance of disproportionality for signal detection within the subset of spontaneously reported serious ADR onsets cannot be formally assessed and may be less incisive than appears in this paper.\n\nSixth, our three random samples, each of 15 ADR onsets, delivered answers that were less precise than we had intended them to be because one-third (16/45) of the sampled ADR forms could not be located. Future random sampling for quality assurance by Uganda’s NPC and others should take into account that a non-negligible proportion of ADR forms may be difficult to locate, for example, if incorrectly filed.\n\nFinally, with only 10 days for data orientation, quality assurance, formal analyses and discussion of recommendations, the analyses presented are illustrative rather than comprehensive. In particular, we performed no dose-related analyses [13].\n\nRecommendations\nUganda’s academic pharmacists, physicians and surgeons need to demonstrate strong professional commitment to, and leadership in, pharmacovigilance by ensuring that they themselves promptly report to Uganda’s NPC all serious ADR onsets, particularly in young patients. Support from Uganda’s academic professional cadres could increase the rate at which ADR onsets are reported to the NPC by a factor of ten: from < 8 to > 80 per million of population; and from under one report per day to at least ten per day.\n\nIn addition, the NPC needs to dramatically reduce the delay from reported ADR onset to international visibility on Uganda’s VigiBase®. Further investigation into how the median delay of 11 months arises (institutional hierarchies, regional centre delays, quality assurance at NPC) should identify and resolve key contributions to the overall delay. Delay in international visibility hinders signal detection and interventions to reduce harm to patients. Moreover, delay in processing ADR reports also delays feedback to reporters, who should feel valued by the NPC for their efforts in drug safety [12].\n\nWe embarked upon these analyses partly from a keenness to assess the potential for Uganda’s ADR report form, which is already available for online completion [8], to be used in a convenient app that might enhance ADR reporting to the NPC by HCPs, just as the UK’s Yellow Card App has done [3]. Currently, Uganda’s ADR report form is used both for spontaneous reporting of ADRs in the general population of patients and for stimulated reporting in well-defined cohorts of patients being treated for disease X, receiving medication Y, or defined by covariate Z (e.g. age group, region, or healthcare facility). In principle, the same set of spontaneous versus stimulated reporting options applies when introducing an ADR-reporting app for Uganda. From a methodological standpoint, randomized introductions of an ADR-reporting app for Uganda could allow its performance to be quantified in the chosen leadership settings.\n\nConclusions\nBarely one ADR onset per day was registered on VigiBase® from those submitted to Uganda’s National Pharmacovigilance Centre during 2012–2014; with only one in six from patients aged < 20 years. Paediatric pharmacovigilance requires more emphasis in Uganda, where three-fifths of the population is aged < 20 years. Delay from reported ADR onset to international visibility on VigiBase® needs to reduce dramatically. Quality assurance revealed rectifiable data entry deficits. Signal detection performed well for patients receiving ART.\n\nElectronic supplementary material\nBelow is the link to the electronic supplementary material. \nSupplementary material 1 (PDF 301 kb)\n\n \n\n\nFunding\nOpen access was funded by the National Drug Authority in Uganda.The authors gratefully acknowledge Grant support from the Cambridge-Africa ALBORADA Research Fund.\n\nAuthor Contributions\nRK and SMB conceived of the study and participated in its design, implementation and statistical analysis and the drafting of the manuscript. VN and HBN provided access to the data and participated in the drawing of inferences. All authors approved the final manuscript.\n\nConflict of interest\nSMB holds GSK shares. RK, VN, HBN and SMB otherwise have no conflicts of interest that are directly relevant to the content of this article.\n\nEthics approval\nThis article does not contain any studies with human participants or animals performed by any of the authors.\n==== Refs\nReferences\n1. 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Accelerated Approval—SIRTURO (Bedaquiline) 100 mg Tablets. 2012. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2012/204384Orig1s000ltr.pdf. Accessed 10 May 2018.\n21. Ahmad N Ahuja SD Akkerman OW Alffenaar JC Anderson LF Baghaei P Treatment correlates of successful outcomes in pulmonary multidrug-resistant tuberculosis: an individual patient data meta-analysis Lancet. 2018 392 10150 821 834 10.1016/S0140-6736(18)31644-1 30215381 \n22. Farmer PE Better and safer treatment for multidrug-resistant tuberculosis Lancet. 2018 392 10150 798 800 10.1016/S0140-6736(18)32149-4 30215368 \n23. Reuter A Furin J Reducing harm in the treatment of multidrug-resistant tuberculosis Lancet. 2018 392 10150 797 798 10.1016/S0140-6736(18)31670-2 30215367 \n24. WHO Collaborating Centre for International Drug Monitoring. What is VigiBase? 2018. https://www.who-umc.org/vigibase/vigibase/. Accessed 22 Mar 2018.\n25. Ampadu HH Hoekman J de Bruin ML Pal SN Olsson S Sartori D Adverse drug reaction reporting in Africa and a comparison of individual case safety report characteristics between Africa and the rest of the world: analyses of spontaneous reports in VigiBase(R) Drug Saf. 2016 39 4 335 345 10.1007/s40264-015-0387-4 26754924 \n26. Marrero O Hung EY Hauben M Seasonal and geographic variation in adverse event reporting Drugs Real World Outcomes. 2016 3 3 297 306 10.1007/s40801-016-0081-6 27747826 \n27. Uppsala Monitoring Center. Getting the answers you need. 2018. https://www.who-umc.org/vigibase/vigilyze/. Accessed 15 May 2018.\n28. United States Food and Drug Administration. Warning: Tardive Dyskinesia. 2011. https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/017854s058lbl.pdf. Accessed 22 Mar 2018.\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "1178-2595", "issue": "32(6)", "journal": "Pharmaceutical medicine", "keywords": null, "medline_ta": "Pharmaceut Med", "mesh_terms": null, "nlm_unique_id": "101471195", "other_id": null, "pages": "413-427", "pmc": null, "pmid": "30546260", "pubdate": "2018", "publication_types": "D016428:Journal Article", "references": "26754924;29627926;30215367;3203063;3423506;27747826;25749663;23072620;30215368;14748811;25905889;30215381;5124593;29200865", "title": "Adverse Drug Reaction Onsets in Uganda's VigiBase®: Delayed International Visibility, Data Quality and Illustrative Signal Detection Analyses.", "title_normalized": "adverse drug reaction onsets in uganda s vigibase delayed international visibility data quality and illustrative signal detection analyses" }

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ADVERSE DRUG REACTION ONSETS IN UGANDA^S VIGIBASE(?): DELAYED INTERNATIONAL VISIBILITY, DATA QUALITY AND ILLUSTRATIVE SIGNAL DETECTION ANALYSES. 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PHARMACEUTICAL MEDICINE. 2018?32:413 TO 427", "literaturereference_normalized": "adverse drug reaction onsets in uganda s vigibase delayed international visibility data quality and illustrative signal detection analyses", "qualification": "3", "reportercountry": "UG" }, "primarysourcecountry": "UG", "receiptdate": "20181224", "receivedate": "20181224", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15754626, "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": "UG-STRIDES ARCOLAB LIMITED-2019SP006829", "fulfillexpeditecriteria": "1", "occurcountry": "UG", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "NEVIRAPINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "78195", "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": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NEVIRAPINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM" }, "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": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SULFAMETHOXAZOLE AND TRIMETHOPRIM" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Erythema multiforme", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2013" } }, "primarysource": { "literaturereference": "KIGUBA R, NDAGIJE HB, NAMBASA V, BIRD SM. ADVERSE DRUG REACTION ONSETS IN UGANDA^S VIGIBASE: DELAYED INTERNATIONAL VISIBILITY, DATA QUALITY AND ILLUSTRATIVE SIGNAL DETECTION ANALYSES. PHARMACEUT MED. 2018?32(6):413-427", "literaturereference_normalized": "adverse drug reaction onsets in uganda s vigibase delayed international visibility data quality and illustrative signal detection analyses", "qualification": "3", "reportercountry": "UG" }, "primarysourcecountry": "UG", "receiptdate": "20190802", "receivedate": "20190802", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16660366, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20191004" }, { "companynumb": "UG-CIPLA LTD.-2018UG23732", "fulfillexpeditecriteria": "1", "occurcountry": "UG", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "EFAVIRENZ" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "204766", "drugbatchnumb": null, "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": "EFAVIRENZ." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Eyelid disorder", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KIGUBA R, NDAGIJE HB, NAMBASA V, BIRD SM. ADVERSE DRUG REACTION ONSETS IN UGANDA^S VIGIBASE?: DELAYED INTERNATIONAL VISIBILITY, DATA QUALITY AND ILLUSTRATIVE SIGNAL DETECTION ANALYSES. PHARMACEUTICAL MEDICINE. 2018?32:413 TO 427", "literaturereference_normalized": "adverse drug reaction onsets in uganda s vigibase delayed international visibility data quality and illustrative signal detection analyses", "qualification": "3", "reportercountry": "UG" }, "primarysourcecountry": "UG", "receiptdate": "20181221", "receivedate": "20181221", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15749989, "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": "UG-CIPLA LTD.-2018UG23709", "fulfillexpeditecriteria": "1", "occurcountry": "UG", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TENOFOVIR" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "078800", "drugbatchnumb": null, "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" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LAMIVUDINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "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": "LAMIVUDINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "EFAVIRENZ" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "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": "EFAVIRENZ." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Gynaecomastia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201312" } }, "primarysource": { "literaturereference": "KIGUBA R, NDAGIJE HB, NAMBASA V, BIRD SM. ADVERSE DRUG REACTION ONSETS IN UGANDA^S VIGIBASE?: DELAYED INTERNATIONAL VISIBILITY, DATA QUALITY AND ILLUSTRATIVE SIGNAL DETECTION ANALYSES. PHARMACEUTICAL MEDICINE. 2018?32:413 TO 427", "literaturereference_normalized": "adverse drug reaction onsets in uganda s vigibase delayed international visibility data quality and illustrative signal detection analyses", "qualification": "3", "reportercountry": "UG" }, "primarysourcecountry": "UG", "receiptdate": "20181224", "receivedate": "20181221", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15749992, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "UG-CIPLA LTD.-2018UG23712", "fulfillexpeditecriteria": "1", "occurcountry": "UG", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ABACAVIR" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "078119", "drugbatchnumb": null, "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": "ABACAVIR." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Renal impairment", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KIGUBA R, NDAGIJE HB, NAMBASA V, BIRD SM. ADVERSE DRUG REACTION ONSETS IN UGANDA^S VIGIBASE?: DELAYED INTERNATIONAL VISIBILITY, DATA QUALITY AND ILLUSTRATIVE SIGNAL DETECTION ANALYSES. PHARMACEUTICAL MEDICINE. 2018?32:413 TO 427", "literaturereference_normalized": "adverse drug reaction onsets in uganda s vigibase delayed international visibility data quality and illustrative signal detection analyses", "qualification": "3", "reportercountry": "UG" }, "primarysourcecountry": "UG", "receiptdate": "20181224", "receivedate": "20181224", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15755322, "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" }, { "companynumb": "UG-CIPLA LTD.-2018UG23705", "fulfillexpeditecriteria": "1", "occurcountry": "UG", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "NEVIRAPINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "077956", "drugbatchnumb": null, "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": "5", "activesubstance": { "activesubstancename": "TENOFOVIR" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "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" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LAMIVUDINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "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": "LAMIVUDINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Renal impairment", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Paraesthesia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201205" } }, "primarysource": { "literaturereference": "KIGUBA R, NDAGIJE HB, NAMBASA V, BIRD SM. ADVERSE DRUG REACTION ONSETS IN UGANDA^S VIGIBASE?: DELAYED INTERNATIONAL VISIBILITY, DATA QUALITY AND ILLUSTRATIVE SIGNAL DETECTION ANALYSES. PHARMACEUTICAL MEDICINE. 2018?32:413 TO 427", "literaturereference_normalized": "adverse drug reaction onsets in uganda s vigibase delayed international visibility data quality and illustrative signal detection analyses", "qualification": "3", "reportercountry": "UG" }, "primarysourcecountry": "UG", "receiptdate": "20181221", "receivedate": "20181221", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15749990, "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": "UG-STRIDES ARCOLAB LIMITED-2019SP006838", "fulfillexpeditecriteria": "1", "occurcountry": "UG", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METRONIDAZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "070039", "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": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METRONIDAZOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METOCLOPRAMIDE" }, "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": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METOCLOPRAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CIPROFLOXACIN" }, "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": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CIPROFLOXACIN." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Tardive dyskinesia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2014" } }, "primarysource": { "literaturereference": "KIGUBA R, NDAGIJE HB, NAMBASA V, BIRD SM. ADVERSE DRUG REACTION ONSETS IN UGANDA^S VIGIBASE: DELAYED INTERNATIONAL VISIBILITY, DATA QUALITY AND ILLUSTRATIVE SIGNAL DETECTION ANALYSES. PHARMACEUT MED. 2018?32(6):413-427", "literaturereference_normalized": "adverse drug reaction onsets in uganda s vigibase delayed international visibility data quality and illustrative signal detection analyses", "qualification": "3", "reportercountry": "UG" }, "primarysourcecountry": "UG", "receiptdate": "20190802", "receivedate": "20190802", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16660675, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20191004" }, { "companynumb": "UG-CIPLA LTD.-2018UG23692", "fulfillexpeditecriteria": "1", "occurcountry": "UG", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "EFAVIRENZ" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "204766", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIRETROVIRAL THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EFAVIRENZ." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Foetal death", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2013" } }, "primarysource": { "literaturereference": "KIGUBA R, NDAGIJE HB, NAMBASA V, BIRD SM. ADVERSE DRUG REACTION ONSETS IN UGANDA^S VIGIBASE?: DELAYED INTERNATIONAL VISIBILITY, DATA QUALITY AND ILLUSTRATIVE SIGNAL DETECTION ANALYSES. PHARMACEUTICAL MEDICINE. 2018?32:413 TO 427", "literaturereference_normalized": "adverse drug reaction onsets in uganda s vigibase delayed international visibility data quality and illustrative signal detection analyses", "qualification": "3", "reportercountry": "UG" }, "primarysourcecountry": "UG", "receiptdate": "20181224", "receivedate": "20181224", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15754515, "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": "UG-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2018-BI-059500", "fulfillexpeditecriteria": "1", "occurcountry": "UG", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "NEVIRAPINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "020933", "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": "VIRAMUNE" } ], "patientagegroup": null, "patientonsetage": "32", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Blindness", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pruritus", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Death", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Rash maculo-papular", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "NDAGIJE H, NAMBASA V, BIRD S. ADVERSE DRUG REACTION ONSETS IN UGANDA^S VIGIBASE?: DELAYED INTERNATIONAL VISIBILITY, DATA QUALITY AND ILLUSTRATIVE SIGNAL DETECTION ANALYSES. PHARMACEUTICAL MEDICINE (LONDON). 2018?32:6:413-427.", "literaturereference_normalized": "adverse drug reaction onsets in uganda s vigibase delayed international visibility data quality and illustrative signal detection analyses", "qualification": "5", "reportercountry": "UG" }, "primarysourcecountry": "UG", "receiptdate": "20181210", "receivedate": "20181210", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15706735, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "UG-CIPLA LTD.-2018UG23710", "fulfillexpeditecriteria": "1", "occurcountry": "UG", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "EFAVIRENZ" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "204766", "drugbatchnumb": null, "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": "EFAVIRENZ." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Gynaecomastia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201804" } }, "primarysource": { "literaturereference": "KIGUBA R, NDAGIJE HB, NAMBASA V, BIRD SM. ADVERSE DRUG REACTION ONSETS IN UGANDA^S VIGIBASE?: DELAYED INTERNATIONAL VISIBILITY, DATA QUALITY AND ILLUSTRATIVE SIGNAL DETECTION ANALYSES. PHARMACEUTICAL MEDICINE. 2018?32:413 TO 427", "literaturereference_normalized": "adverse drug reaction onsets in uganda s vigibase delayed international visibility data quality and illustrative signal detection analyses", "qualification": "3", "reportercountry": "UG" }, "primarysourcecountry": "UG", "receiptdate": "20181221", "receivedate": "20181221", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15749995, "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": "UG-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2018-BI-059499", "fulfillexpeditecriteria": "1", "occurcountry": "UG", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ZIDOVUDINE" }, "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": "ZIDOVUDINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "NEVIRAPINE" }, "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": "VIRAMUNE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LAMIVUDINE" }, "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": "LAMIVUDINE." } ], "patientagegroup": null, "patientonsetage": "35", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Rash", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "HIV wasting syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Decreased appetite", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Death", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "NDAGIJE H, NAMBASA V, BIRD S. ADVERSE DRUG REACTION ONSETS IN UGANDA^S VIGIBASE?: DELAYED INTERNATIONAL VISIBILITY, DATA QUALITY AND ILLUSTRATIVE SIGNAL DETECTION ANALYSES. PHARMACEUTICAL MEDICINE (LONDON). 2018?32:6:413-427.", "literaturereference_normalized": "adverse drug reaction onsets in uganda s vigibase delayed international visibility data quality and illustrative signal detection analyses", "qualification": "5", "reportercountry": "UG" }, "primarysourcecountry": "UG", "receiptdate": "20181210", "receivedate": "20181210", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15706751, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "UG-CIPLA LTD.-2018UG23733", "fulfillexpeditecriteria": "1", "occurcountry": "UG", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ISONIAZID" }, "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": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ISONIAZID." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ABACAVIR" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "078119", "drugbatchnumb": null, "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": "ABACAVIR." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LOPINAVIR\\RITONAVIR" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "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": "SULFAMETHOXAZOLE\\TRIMETHOPRIM" }, "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": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SULFAMETHOXAZOLE/TRIMETHOPRIM" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LAMIVUDINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "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": "LAMIVUDINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hepatocellular injury", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KIGUBA R, NDAGIJE HB, NAMBASA V, BIRD SM. ADVERSE DRUG REACTION ONSETS IN UGANDA^S VIGIBASE?: DELAYED INTERNATIONAL VISIBILITY, DATA QUALITY AND ILLUSTRATIVE SIGNAL DETECTION ANALYSES. PHARMACEUTICAL MEDICINE. 2018?32:413 TO 427", "literaturereference_normalized": "adverse drug reaction onsets in uganda s vigibase delayed international visibility data quality and illustrative signal detection analyses", "qualification": "3", "reportercountry": "UG" }, "primarysourcecountry": "UG", "receiptdate": "20181224", "receivedate": "20181221", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15750001, "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" }, { "companynumb": "UG-CIPLA LTD.-2018UG23686", "fulfillexpeditecriteria": "1", "occurcountry": "UG", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM" }, "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": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SULFAMETHOXAZOLE/TRIMETHOPRIM" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "NEVIRAPINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "077956", "drugbatchnumb": null, "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": "5", "activesubstance": { "activesubstancename": "TENOFOVIR" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "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" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2014" } }, "primarysource": { "literaturereference": "KIGUBA R, NDAGIJE HB, NAMBASA V, BIRD SM. ADVERSE DRUG REACTION ONSETS IN UGANDA^S VIGIBASE?: DELAYED INTERNATIONAL VISIBILITY, DATA QUALITY AND ILLUSTRATIVE SIGNAL DETECTION ANALYSES. PHARMACEUTICAL MEDICINE. 2018?32:413 TO 427", "literaturereference_normalized": "adverse drug reaction onsets in uganda s vigibase delayed international visibility data quality and illustrative signal detection analyses", "qualification": "3", "reportercountry": "UG" }, "primarysourcecountry": "UG", "receiptdate": "20181221", "receivedate": "20181221", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15749993, "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": "UG-CIPLA LTD.-2018UG23696", "fulfillexpeditecriteria": "1", "occurcountry": "UG", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "NEVIRAPINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "077956", "drugbatchnumb": null, "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": "5", "activesubstance": { "activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM" }, "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": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SULFAMETHOXAZOLE/TRIMETHOPRIM" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Erythema multiforme", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2013" } }, "primarysource": { "literaturereference": "KIGUBA R, NDAGIJE HB, NAMBASA V, BIRD SM. ADVERSE DRUG REACTION ONSETS IN UGANDA^S VIGIBASE?: DELAYED INTERNATIONAL VISIBILITY, DATA QUALITY AND ILLUSTRATIVE SIGNAL DETECTION ANALYSES. PHARMACEUTICAL MEDICINE. 2018?32:413 TO 427", "literaturereference_normalized": "adverse drug reaction onsets in uganda s vigibase delayed international visibility data quality and illustrative signal detection analyses", "qualification": "3", "reportercountry": "UG" }, "primarysourcecountry": "UG", "receiptdate": "20181221", "receivedate": "20181221", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15750003, "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": "UG-CIPLA LTD.-2018UG23687", "fulfillexpeditecriteria": "1", "occurcountry": "UG", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "EFAVIRENZ" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "204766", "drugbatchnumb": null, "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": "EFAVIRENZ." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TENOFOVIR" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "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" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LAMIVUDINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "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": "LAMIVUDINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM" }, "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": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SULFAMETHOXAZOLE/TRIMETHOPRIM" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomalacia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2013" } }, "primarysource": { "literaturereference": "KIGUBA R, NDAGIJE HB, NAMBASA V, BIRD SM. 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{ "abstract": "Ziconotide (ZCN), a nonopioid analgesic, is first-line intrathecal therapy for patients with severe chronic pain refractory to other management options. We describe three cases of ZCN-induced movement disorders.\n\n\n\nCase one is a 64-year-old woman who presented with oro-lingual (OL) dyskinesia with dysesthesias and bilateral upper extremity kinetic tremor. Case two is a 43-year-old man with a 20-month history of ZCN treatment who developed OL dyskinesia with dysesthesias, involuntary left hand and neck movements, hallucinations, dysesthesias on his feet, and gait imbalance. Case three is a 70-year-old man with a 4-month history of ZCN use who developed OL dyskinesia with dysesthesias.\n\n\n\nIntrathecal treatment of pain with ZCN may be complicated by a drug-induced movement disorder where OL dyskinesia is characteristic. The movement disorder is likely to be dose related and reversible with ZCN discontinuation, but a chronic movement disorder is also possible.", "affiliations": "Parkinson's Disease and Movement Disorders Center, Albany Medical Center, Albany, NY, US.;Parkinson's Disease and Movement Disorders Center, Albany Medical Center, Albany, NY, US.;Parkinson's Disease and Movement Disorders Center, Albany Medical Center, Albany, NY, US.;Parkinson's Disease and Movement Disorders Center, Albany Medical Center, Albany, NY, US.;Parkinson's Disease and Movement Disorders Center, Albany Medical Center, Albany, NY, US.;Parkinson's Disease and Movement Disorders Center, Albany Medical Center, Albany, NY, US.", "authors": "Grajny|Kristopher|K|;Durphy|Jennifer|J|;Adam|Octavian|O|;Azher|Sharmeen|S|;Gupta|Megan|M|;Molho|Eric|E|", "chemical_list": "D018712:Analgesics, Non-Narcotic; D020960:omega-Conotoxins; C078452:ziconotide", "country": "England", "delete": false, "doi": "10.5334/tohm.431", "fulltext": "\n==== Front\nTremor Other Hyperkinet Mov (N Y)\nTremor Other Hyperkinet Mov (N Y)\n2160-8288\nTremor and Other Hyperkinetic Movements\n2160-8288 Ubiquity Press \n\n10.5334/tohm.431\nCase Report\nZiconotide-Induced Oro-lingual Dyskinesia: 3 Cases\nGrajny Kristopher MDkris.grajny@gmail.com1 Durphy Jennifer MD1 Adam Octavian MD1 Azher Sharmeen 1 Gupta Megan 1 Molho Eric MD1 1 Parkinson’s Disease and Movement Disorders Center, Albany Medical Center, Albany, NY, US\neCorresponding author: Kristopher Grajny, MD (kris.grajny@gmail.com)\n06 10 2020 \n2020 \n10 3722 5 2020 14 7 2020 Copyright: © 2020 The Author(s)2020This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License (CC-BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. See http://creativecommons.org/licenses/by/4.0/.Background:\nZiconotide (ZCN), a nonopioid analgesic, is first-line intrathecal therapy for patients with severe chronic pain refractory to other management options. We describe three cases of ZCN-induced movement disorders.\n\nCases:\nCase one is a 64-year-old woman who presented with oro-lingual (OL) dyskinesia with dysesthesias and bilateral upper extremity kinetic tremor. Case two is a 43-year-old man with a 20-month history of ZCN treatment who developed OL dyskinesia with dysesthesias, involuntary left hand and neck movements, hallucinations, dysesthesias on his feet, and gait imbalance. Case three is a 70-year-old man with a 4-month history of ZCN use who developed OL dyskinesia with dysesthesias.\n\nConclusions:\nIntrathecal treatment of pain with ZCN may be complicated by a drug-induced movement disorder where OL dyskinesia is characteristic. The movement disorder is likely to be dose related and reversible with ZCN discontinuation, but a chronic movement disorder is also possible.\n\nZiconotideDyskinesiaDysesthesiasOralLingualAuthors received no outside funding for the organization or writing of this manuscript. Dr. Kris Grajny has no financial disclosures. Dr. Jennifer Durphy is part of the speaker’s bureau for Acorda Pharmaceuticals. Dr. Octavian Adam has served as a consultant for Abbott. Sharmeen Azher has no financial disclosures. Megan Gupta has no financial disclosures. Dr. Eric Molho does consulting work as a blinded video rater for CNS Ratings and Mitsubishi Tanabe Pharma. He has clinical trial grants with CHDI/HSG, Impax Pharmaceuticals, MJF/PSG, Biogen, Biohaven Pharmaceuticals, and Enterin inc. He is part of the speaker’s bureau with Neurocrine Biosciences. He has an educational grant with Merz Pharmaceuticals.\n==== Body\nIntroduction\nZiconotide, a nonopioid analgesic approved in 2004, is an uncommon, non-opioid intrathecal therapy for patients with severe chronic pain refractory to other management options. ZCN inhibits nociceptive signal transmission in the spinal cord by selectively blocking presynaptic N-type voltage sensitive calcium channels of the dorsal horn. The drug is delivered via an intrathecal infusion pump. Side effects are dose related and ZCN labelling features a black box warning for severe neuropsychiatric and cognitive adverse events, which have been reported even in patients with no prior history of psychiatric disease [123456]. Although “dyskinesia” is mentioned in a clinical trial report for the drug, almost no literature exists on ZCN-induced movement disorders [7].\n\nCase 1\nA 64-year-old woman with chronic back pain following a resection of spine hemangioblastoma 20 years prior, presented with facial movements. In 2017 she had a ZCN pump placed, titrating to a maximum dose of 6 mcg per day. Her dyskinesias started in November 2018 and she first presented to our clinic in December 2018. Her symptoms consisted of involuntary movements of the lower face and tongue, accompanied by oral dysesthesias described as “a small mouse walks inside my mouth, with pointy toes that is stiff and very painful.” The movements were continuous while awake, and intermittently interfered with swallowing and chewing. There was no history of exposure to dopamine blocking agents such as anti-emetics or antipsychotics.\n\nOn exam, she had continuous, irregular movements of the lower face at rest with lip pursing and retraction, mild lateral deviations of the jaw, undulation of the upper throat and excessive eye blinking. With the mouth open there are writhing movements of the tongue. The movements occur during speech and interfere to a mild degree (see Video). A bilateral upper extremity kinetic tremor is also seen.\n\nVideo Case One is 64-year-old woman with stereotypic tongue and mouth movements. Excessive eye blinking and upper limb action tremor is also seen.\n\nBasic metabolic panel, liver functions, ceruloplasmin, B12, antiphospholipid antibodies, and serum paraneoplastic panel were normal. Her symptoms progressed and she developed delirium with auditory hallucinations. Her ZCN pump was decreased to a dose of 0.25 mcg and her symptoms improved but did not resolve completely. During the summer of 2019, she again developed worsening auditory hallucinations on this lower dose, so the pump was discontinued with gradual resolution of all neurological symptoms.\n\nCase 2\nA 43-year-old man with type 1 diabetes, peripheral neuropathy, peripheral vascular disease, scleroderma, and psoriatic arthritis presented for evaluation of abnormal movements. He had a ZCN pump placed in March 2017 for painful diabetic neuropathy with an excellent response. In September 2018, his pump rate was increased to 7 mcg per day and then further increased in December 2018 to 9 mcg. His symptoms began in November 2018, when he noticed that his tongue was moving around constantly. He would roll his tongue over his teeth, stating it felt like “there was something in his mouth that he needed to clear out.” In January 2019, he developed involuntary movements of the wrists, and he began having motions of his head that his wife describes as “throwing his head back.” In addition, he reported a sensation as if there were “saran-wrap around his feet” and he would move his legs in bed to relieve the sensation. Treatment with trihexyphenidyl, quetiapine and ziprasidone (all started after symptom onset) provided no benefit. Clonidine 0.2 mg daily was somewhat beneficial for dysesthesias.\n\nWe first evaluated him in February 2019. He noted difficulties talking, chewing and swallowing. His movements were more prominent during stress, excitement, or fatigue. He felt he could not suppress them and there was no associated urge. On exam, his speech was dysarthric. He had constant, writhing movements of his tongue within his mouth. He had limited mouth opening and was unable to relax his tongue to the bottom of his mouth. He had intermittent sustained jaw opening and intermittent involuntary movements of the left arm which involved flexion at the elbow and elevation over his head. They would occur intermittently lasting for a couple of seconds. The movements were partially and temporarily attenuated with motor tasks in the limbs and would worsen during speech. Lab testing was normal including serum ceruloplasmin, T4, TSH, B12, ammonia, Lyme C6 ELISA and illicit drug screen.\n\nHis ZCN infusion was discontinued in March 2019. The oral dyskinesia and left arm movements gradually resolved over a period of several months. However, he continued to experience dysesthesias in the lower extremities chronically possibly due to concomitant neuropathy.\n\nCase 3\nA 70-year-old man with cervical spondylosis, chronic cervicalgia and depression was referred for evaluation of involuntary mouth movements. For his neck pain, he had an intrathecal ZCN pump placed in August 2015. In late 2015, he began experiencing hallucinations and disorientation. His ZCN pump was at 2.4 mcg at the time. The ZCN dosage was decreased and these symptoms gradually improved. He first noticed tongue movements starting December 2015. He has a history of lichen planus in the mouth, and he believed that he started using his tongue to soothe the discomfort of the oral lesions. He felt like this was purposeful, but he eventually realized the movements were involuntary. They became more persistent and he had less control over them. He could briefly suppress the movements early in the day, but not later in the day. There was no specific urge associated with the movements and no relief. He also reported tongue sensation of “vibration” or “electricity.” At the patient’s request in August 2016, his ZCN pump was increased to 3.6 mcg to better control his pain. His medications were notable for Keppra 250 mg twice daily and Trileptal 300 mg twice daily as mood stabilizers, and Nortriptyline 25 mg for depression. There had been no exposure to dopamine receptor blocking drugs other than briefly to prochlorperazine several years prior.\n\nHe was evaluated in December 2016 in our movement disorders clinic. On exam, there were stereotypical mouth and tongue movements, which were irregular, arrhythmic, and continuous. He was able to partially suppress these movements. With distracting maneuvers, they were attenuated. There were no involuntary movements of the upper face or limbs. There were no signs of parkinsonism. TSH, B12, Lyme, and serum ceruloplasmin was normal. By March 2017, ZCN had to be stopped due to recurrent hallucinations. The dyskinesia completely resolved within a few weeks.\n\nDiscussion\nHallucinations with ZCN infusions have been well described, but there are very few reports of an associated movement disorder. In an early case report of a single participant in an open label study, transient tongue movement and “nervousness” were felt to be related to a rapid increase in the dose [8]. A more recent case report describes head and upper limb dyskinesia in a pediatric cerebral palsy patient receiving both ZCN and baclofen [9]. We highlight three cases of oral dyskinesia associated with ZCN infusions (See Table 1). While N-type voltage-gated calcium channels are not directly implicated with dyskinesia, there is CNS penetration of ZCN, and off-target impacts are possible. It has also been shown that voltage-gated calcium channels can influence dopaminergic transmission. Specifically, D2 upregulation can result from enhanced calcium channel modulation [10]. Therefore, this indirect effect on dopamine transmission might account for both the hallucinations and dyskinesia observed with ZCN use.\n\nTable 1 Comparison of Three Cases of Ziconotide-Induced Oropharyngeal Dyskinesias.\n\n\tCase 1\tCase 2\tCase 3\t\n\t\nAge\t64\t43\t70\t\nGender\tFemale\tMale\tMale\t\nMedical conditions\tSpinal hemangioblastoma (resected)\tDM1, Peripheral neuropathy, scleroderma, psoriatic arthritis\tCervical spondylosis, depression\t\nCentrally acting medications\tduloxetine 30 mg AM and 60 mg PM, pregabalin 100 mg TID\tcyclobenzaprine 10 mg, hydroxyzine 50 mg, clonazepam 2 mg PRN, topiramate 100 mg BID, vortioxetine 20 mg\tlevetiracetam 500 mg BID, pregabalin 50 mg QHS, nortriptyline 25 mg QHS, oxycodone 10 mg PRN\t\nMovement disorder\tStereotypic tongue movements, lower facial twitching with tactile dysesthesias\tStereotypic tongue movements with tactile dysesthesias\tStereotypic tongue movements with tactile dysesthesias\t\nOther neurological features\tDelayed saccades, bilateral upper extremity kinetic tremor, dysphagia\tInvoluntary left hand and neck movements, hallucinations, tactile dysesthesias on feet, gait imbalance\tN/A\t\nMaximum ZCN dose\t6 mcg\t9 mcg\t3.6 mcg\t\nDuration of ZCN treatment at onset of movement disorder.\t12 months\t20 months\t4 months\t\nOutcome of ZCN discontinuation.\tMild residual dyskinesia\tComplete resolution of movements\tComplete resolution of movements\t\nLegend: ZCN = Ziconotide, QHS = nightly, PRN = as needed, BID = twice daily, TID = three times daily.\n\nFurthermore, all three cases presented with dysesthesias in the mouth associated with these movements. This observation mirrors the case series of oral and genital pain in tardive syndromes reported by Ford et al. and attests to the complex sensorimotor interactions within the PNS and CNS that are evident in tardive dyskinesia and other movement disorders [11]. Additionally, two of the cases reported brief distractibility (Cases two and three) along with some ability to suppress the movements (case three). While distractibility might suggest a functional disorder, there were no other functional exam findings and suppressibility is well known to occur in neuroleptic-induced tardive dyskinesia [12].\n\nEvidence for a causal relationship between intrathecal ZCN and the movement disorder reported here include the temporal association with increased doses of ZCN and the near or complete resolution with ZCN discontinuation. In addition, the cases share a similar anatomic location and a movement disorder phenomenology most consistent with stereotypy. It is also of interest that in all three of our cases, an unpleasant complex oral sensation accompanied the movement disorder, perhaps related to ZCN’s activity at sensory pathways in the spinal cord and sensory integration areas of the brain or off-target interaction of ZCN with dopaminergic pathways.\n\nOne limitation of this case series is that they were analyzed retrospectively as the association between ZCN and involuntary movements was not immediately apparent. Also, the work up for other causes of the movement disorder was not uniform primarily because resolution of the movements with ZCN discontinuation obviated the need for additional diagnostic testing. These cases further suggest that this complication is dose related and may be related to rapid dose increases. Most cases thus far have also been transient, however in one of our cases, the movements did not completely resolve with drug discontinuation raising the possibility that a chronic movement disorder may also be a risk with ZCN.\n\nEthics and Consent\nThe authors confirm that the approval of an institutional review board was not required for this work. Informed consent was not obtained as this was a retrospective case series. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.\n\nFunding Information\nAuthors received no outside funding for the organization or writing of this manuscript.\n\nDr. Kris Grajny has no financial disclosures. Dr. Jennifer Durphy is part of the speaker’s bureau for Acorda Pharmaceuticals. Dr. Octavian Adam has served as a consultant for Abbott. Sharmeen Azher has no financial disclosures. Megan Gupta has no financial disclosures. Dr. Eric Molho does consulting work as a blinded video rater for CNS Ratings and Mitsubishi Tanabe Pharma. He has clinical trial grants with CHDI/HSG, Impax Pharmaceuticals, MJF/PSG, Biogen, Biohaven Pharmaceuticals, and Enterin inc. He is part of the speaker’s bureau with Neurocrine Biosciences. He has an educational grant with Merz Pharmaceuticals.\n\nCompeting Interests\nThe authors have no competing interests to declare.\n\nAuthor Contributions\nKristopher Grajny, MD: Research project organization and execution. Writing of the first manuscript draft. Editing of manuscript drafts.\n\nJennifer Durphy, MD: Research project conception. Manuscript review and critique.\n\nOctavian Adam, MD: Manuscript review and critique. Manuscript video editing.\n\nSharmeen Azher: Research Project execution. Manuscript review and critique.\n\nMegan Gupta: Research Project execution. Manuscript review and critique.\n\nEric Molho, MD: Research project conception. Manuscript review and critique.\n==== Refs\n1 Elan Corporation . Ziconotide (ziconotide) [prescribing information]\nSan Diego, CA \n2004 .\n2 Burdge \nG , Leach \nH , Walsh \nK . Ziconotide-induced psychosis: A case report and literature review\n. Mental Health Clinician . 2018 ; 8 (5 ): 242 –246\n. DOI: 10.9740/mhc.2018.09.242 30206508 \n3 Phan \nSV , Waldfogel \nJM . Ziconotide-induced psychosis: A case report\n. General hospital psychiatry . 2015 ; 37 (1 ): 97 –e11\n. DOI: 10.1016/j.genhosppsych.2014.10.001 \n4 Whitlow \nJ , Mu \nK , Coverdale \nJ , Shah \nA . Ziconotide-associated psychosis treated with Invega\n. Psychiatric Ann . 2015 ; 45 (2 ): 64 –6\n. DOI: 10.3928/00485713-20150212-02 \n5 Obafemi \nA , Roth \nB . Prolonged delirium with psychotic features from omega conotoxin toxicity\n. Pain Med . 2013 ; 14 (3 ): 447 –8\n. DOI: 10.1111/pme.12005 23383992 \n6 Levin \nT , Petrides \nG , Weiner \nJ , Saravay \nS , Multz \nA , Bailine \nS . Intractable delirium associated with ziconotide successfully treated with electroconvulsive therapy\n. Psychosomatics . 2002 ; 43 (1 ): 63 –6\n. DOI: 10.1176/appi.psy.43.1.63 11927761 \n7 Wallace \nMS , Rauck \nR , Fisher \nR , Charapata \nSG , Ellis \nD , Dissanayake \nS , Ziconotide 98-022 Study Group. Intrathecal ziconotide for severe chronic pain: safety and tolerability results of an open-label, long-term trial\n. Anesthesia & Analgesia . 2008 ; 106 (2 ): 628 –637\n. DOI: 10.1213/ane.0b013e3181606fad 18227325 \n8 Ver Donck \nA , Dissanayake \nS , Bostyn \nA , Vercruysse \nP . A prospective, open-label study of long-term intrathecal ziconotide for chronic nonmalignant back pain: A case report\n. Neuromodulation: Technology at the Neural Interface . 2006 ; 9 (1 ): 68 –71\n. DOI: 10.1111/j.1525-1403.2006.00044.x \n9 Pozzi \nM , Piccinini \nL , Giordano \nF , et al. Dyskinesia caused by ziconotide-baclofen combination in an adolescent affected by cerebral palsy\n. Reg Anesth Pain Med . 2014 ; 39 : 172 –173\n. DOI: 10.1097/AAP.0000000000000054 24513956 \n10 Prieto \nGA , Perez-Burgos \nA , Palomero-Rivero \nM , et al. Upregulation of D2-class signaling in dopamine-denervated striatum is in part mediated by D3 receptors acting on CaV2.1 channels via PIP2 depletion\n. J Neurophysiol . 2011 ; 105 (5 ): 2260 –74\n. DOI: 10.1152/jn.00516.2010 21389298 \n11 Ford \nB , Greene \nP , Fahn \nS . Oral and genital tardive pain syndromes\n. Neurology . 1994 \n11 ; 44 (11 ): 21159 DOI: 10.1212/WNL.44.11.2115 \n12 Fahn \nS , Jankovic \nJ , Hallett \nM , Jenner \nP . The Tardive Syndromes: Phenomenology, Pathophysiology, and Treatment In: Principles and Practice of Movement Disorders . Philadelphia : Elselvier \n2007 p. 493 .\n\n", "fulltext_license": "CC BY", "issn_linking": "2160-8288", "issue": "10()", "journal": "Tremor and other hyperkinetic movements (New York, N.Y.)", "keywords": "Dysesthesias; Dyskinesia; Lingual; Oral; Ziconotide", "medline_ta": "Tremor Other Hyperkinet Mov (N Y)", "mesh_terms": "D000328:Adult; D000368:Aged; D018712:Analgesics, Non-Narcotic; D059350:Chronic Pain; D004409:Dyskinesia, Drug-Induced; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020960:omega-Conotoxins", "nlm_unique_id": "101569493", "other_id": null, "pages": "37", "pmc": null, "pmid": "33101763", "pubdate": "2020-10-06", "publication_types": "D002363:Case Reports", "references": "18227325;25459190;7969969;21389298;30206508;11927761;22151595;24513956;23383992", "title": "Ziconotide-Induced Oro-lingual Dyskinesia: 3 Cases.", "title_normalized": "ziconotide induced oro lingual dyskinesia 3 cases" }

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"drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TOPIRAMATE." } ], "patientagegroup": null, "patientonsetage": "43", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective for unapproved indication", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "GRAJNY K, DURPHY J, ADAM O, AZHER S, GUPTA M, MOLHO E. ZICONOTIDE?INDUCED ORO?LINGUAL DYSKINESIA: 3 CASES. TREMOR?OTHER?HYPERKINET?MOV 2020?10:NO. 37.", "literaturereference_normalized": "ziconotide induced oro lingual dyskinesia 3 cases", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210624", "receivedate": "20210624", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19458179, "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-UCBSA-2021029220", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "LEVETIRACETAM" }, "drugadditional": "4", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "250 MILLIGRAM, 2X/DAY (BID)", "drugenddate": null, "drugenddateformat": null, "drugindication": "Affective disorder", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "250", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KEPPRA" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "NORTRIPTYLINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "25 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "Depression", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NORTRIPTYLINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OXCARBAZEPINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MILLIGRAM, 2X/DAY (BID)", "drugenddate": null, "drugenddateformat": null, "drugindication": "Affective disorder", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRILEPTAL" } ], "patientagegroup": null, "patientonsetage": "70", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Grajny K, Durphy J, Adam O, Azher S, Gupta M, Molho E. Ziconotide-induced oro-lingual dyskinesia: 3 cases. Tremor and Other Hyperkinetic Movements. 2020;10(1):1-4", "literaturereference_normalized": "ziconotide induced oro lingual dyskinesia 3 cases", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20220222", "receivedate": "20220222", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20499899, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220423" } ]

{ "abstract": "BACKGROUND\nProlonged antibiotic use is limited by several adverse effects, one of which is Clostridium difficile infection (CDI). The aim of this study was to determine the incidence of CDI in patients receiving chronic antibiotic treatment for Crohn's disease (CD).\n\n\nMETHODS\nWe conducted a retrospective review of 100 patients with CD for which ≥6 months of outpatient antibiotic therapy was prescribed. Data were collected regarding demographics, CD phenotype, treatment history, and CDI. The incidence of CDI in our patient population was calculated and compared with historical controls.\n\n\nRESULTS\n100 patients were studied-60% of men, mean age 23.9 years at CD diagnosis. Eighty-two percent had disease involving the ileum, and 33% had disease involving the colon. The mean duration of antibiotic therapy was 39.6 months (range, 6-217 months). The most commonly prescribed classes of antibiotics were fluoroquinolones (84%), penicillins (57%), and cephalosporins (32%). Forty-nine percent of patients were treated with concomitant thiopurines, 45% with budesonide, and 41% with biologics. The overall incidence of CDI was 2%. This incidence of CDI was lower than previously reported for non-CD patients receiving chronic antibiotics for continuous-flow left ventricular assist device infections (12.5%) and orthopedic prosthesis infections (22.2%).\n\n\nCONCLUSIONS\nThe incidence of CDI is rare in patients receiving chronic antibiotic treatment for CD, and it seems significantly lower than for non-CD populations reported in the literature.", "affiliations": "Division of Digestive and Liver Diseases, Columbia University, New York, New York.", "authors": "Roy|Abhik|A|;Lichtiger|Simon|S|", "chemical_list": "D000900:Anti-Bacterial Agents", "country": "England", "delete": false, "doi": "10.1097/MIB.0000000000000641", "fulltext": null, "fulltext_license": null, "issn_linking": "1078-0998", "issue": "22(3)", "journal": "Inflammatory bowel diseases", "keywords": null, "medline_ta": "Inflamm Bowel Dis", "mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents; D002648:Child; D016360:Clostridioides difficile; D003015:Clostridium Infections; D003424:Crohn Disease; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D009518:New York; D011379:Prognosis; D012189:Retrospective Studies; D012307:Risk Factors; D055815:Young Adult", "nlm_unique_id": "9508162", "other_id": null, "pages": "648-53", "pmc": null, "pmid": "26650148", "pubdate": "2016-03", "publication_types": "D016428:Journal Article", "references": "11781279;6807684;21915178;19273954;19255850;21122489;16330776;19307217;12167685;25337874;19444096;17948930;24478468;21530739;17905821;18484669;20678014;25097707;25685606;17368234;18242222;14684564;24571683;20847294;22907164;23825381;19018661;18240341;23867869;21407187;22179210;21172241;25844959;14633949;21530738;25573674;18268057;20224153;18825144;18513271;9798021;19235886;15168372;18936492", "title": "Clostridium difficile Infection: A Rarity in Patients Receiving Chronic Antibiotic Treatment for Crohn's Disease.", "title_normalized": "clostridium difficile infection a rarity in patients receiving chronic antibiotic treatment for crohn s disease" }

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CLOSTRIDIUM DIFFICILE INFECTION: A RARITY IN PATIENTS RECEIVING CHRONIC ANTIBIOTIC TREATMENT FOR CROHN?S DISEASE.. 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CLOSTRIDIUM DIFFICILE INFECTION: A RARITY IN PATIENTS RECEIVING CHRONIC ANTIBIOTIC TREATMENT FOR CROHN^S DISEASE.. 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CLOSTRIDIUM DIFFICILE INFECTION: A RARITY IN PATIENTS RECEIVING CHRONIC ANTIBIOTIC TREATMENT FOR CROHN^S DISEASE. 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CLOSTRIDIUM DIFFICILE INFECTION: A RARITY IN PATIENTS RECEIVING CHRONIC ANTIBIOTIC TREATMENT FOR CROHN^S DISEASE. 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CLOSTRIDIUM DIFFICILE INFECTION: A RARITY IN PATIENTS RECEIVING CHRONIC ANTIBIOTIC TREATMENT FOR CROHN^S DISEASE. 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CLOSTRIDIUM DIFFICILE INFECTION: A RARITY IN PATIENTS RECEIVING CHRONIC ANTIBIOTIC TREATMENT FOR CROHN?S DISEASE.. 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CLOSTRIDIUM DIFFICILE INFECTION: A RARITY IN PATIENTS RECEIVING CHRONIC ANTIBIOTIC TREATMENT FOR CROHN^S DISEASE. INFLAMM.BOWEL DIS.. 2016;22:648-653", "literaturereference_normalized": "clostridium difficile infection a rarity in patients receiving chronic antibiotic treatment for crohn s disease", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20161108", "receivedate": "20161108", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 12921345, "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": "Rosacea, a frequent chronic inflammatory disease of the adnexal structures, is associated with an increased number of demodex mites. In patients with immunosuppression, it can present in fulminant progressions like granulomatous rosacea. In this specific subgroup of patients, treatment is not only complicated by aggressive occurrences, but is also limited by possible drug interactions with immunosuppressive drugs. We present a case of a 66-year-old lung transplant recipient, who was successfully treated with oral metronidazole and ivermectin cream.", "affiliations": "Klinik für Dermatologie und Venerologie, Universitätsklinikum Freiburg, Medizinische Fakultät, Albert-Ludwigs-Universität Freiburg, Hauptstr. 7, 79104, Freiburg, Deutschland. claudia.andrea.ansorge@uniklinik-freiburg.de.", "authors": "Ansorge|Claudia|C|;Technau-Hafsi|Kristin|K|", "chemical_list": "D007306:Insecticides; D008795:Metronidazole; D007559:Ivermectin", "country": "Germany", "delete": false, "doi": "10.1007/s00105-019-04479-0", "fulltext": null, "fulltext_license": null, "issn_linking": "0017-8470", "issue": "71(2)", "journal": "Der Hautarzt; Zeitschrift fur Dermatologie, Venerologie, und verwandte Gebiete", "keywords": "Demodex mites; Immunosuppression; Ivermectin; Metronidazole; Systemic therapy", "medline_ta": "Hautarzt", "mesh_terms": "D000368:Aged; D000818:Animals; D006801:Humans; D016867:Immunocompromised Host; D007306:Insecticides; D007559:Ivermectin; D008795:Metronidazole; D008924:Mite Infestations; D012393:Rosacea; D066027:Transplant Recipients", "nlm_unique_id": "0372755", "other_id": null, "pages": "134-138", "pmc": null, "pmid": "31560078", "pubdate": "2020-02", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "2964423;28243927;27376863;27869379;27432169;21885154;23647643;29595104;26431451;27869374", "title": "Granulomatous rosacea in a lung transplant recipient : A possible therapy option in a unique group of patients.", "title_normalized": "granulomatous rosacea in a lung transplant recipient a possible therapy option in a unique group of patients" }

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"medicinalproduct": "VALGANCICLOVIR." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LAMIVUDINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "FORMULATION UNKNOWN", "drugdosagetext": "UNK UNK, UNKNOWN FREQ.", "drugenddate": null, "drugenddateformat": null, "drugindication": "INFECTION PROPHYLAXIS", "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": null, "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": 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"reactionoutcome": "6" }, { "reactionmeddrapt": "Granulomatous rosacea", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201306" } }, "primarysource": { "literaturereference": "ANSORGE C, TECHNAU-HAFSI K. GRANULOMATOUS ROSACEA IN A LUNG TRANSPLANT RECIPIENT: A POSSIBLE THERAPY OPTION IN A UNIQUE GROUP OF PATIENTS. DER HAUTARZT. 2019?NO INFORMATION:NO INFORMATION", "literaturereference_normalized": "granulomatous rosacea in a lung transplant recipient a possible therapy option in a unique group of patients", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20200204", "receivedate": "20191115", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17035004, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "DE-ROCHE-2608945", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "ASKED BUT UNKNOWN", "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": "ASKED BUT UNKNOWN", "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": "METRONIDAZOLE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": "ASKED BUT UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "GRANULOMATOUS ROSACEA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "800", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METRONIDAZOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "INFECTION PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, 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null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMIVUDINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ITRACONAZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "INFECTION PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ITRACONAZOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VALGANCICLOVIR" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "INFECTION PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALGANCICLOVIR." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "050722", "drugbatchnumb": "ASKED BUT UNKNOWN", "drugcharacterization": "1", 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"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": "EVEROLIMUS." } ], "patientagegroup": null, "patientonsetage": "66", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Granulomatous rosacea", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Conjunctivitis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "ANSORGE C, TECHNAU-HAFSI K. GRANULOMATOUS ROSACEA IN A LUNG TRANSPLANT RECIPIENT: A POSSIBLE THERAPY OPTION IN A UNIQUE GROUP OF PATIENTS. [GERMAN]. 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"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": "LAMIVUDINE" } ], "patientagegroup": null, "patientonsetage": "66", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Granulomatous rosacea", "reactionmeddraversionpt": "25.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Conjunctivitis", "reactionmeddraversionpt": "25.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Ansorge C, Technau-Hafsi K.. Granulomatous rosacea in a lung transplant recipient : A possible therapy option in a unique group of patients.. 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null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALGANCICLOVIR." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ITRACONAZOLE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "INFECTION PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ITRACONAZOLE." } ], "patientagegroup": null, "patientonsetage": "66", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Conjunctivitis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Granulomatous rosacea", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "ANSORGE C, TECHNAU?HAFSI K. GRANULOMATOUS ROSACEA IN A LUNG TRANSPLANT RECIPIENT : A POSSIBLE THERAPY OPTION IN A UNIQUE GROUP OF PATIENTS. 2019?:?.", "literaturereference_normalized": "granulomatous rosacea in a lung transplant recipient a possible therapy option in a unique group of patients", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20210129", "receivedate": "20191202", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 17098652, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210419" }, { "companynumb": "DE-MYLANLABS-2020M1033391", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", 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"drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "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": "LAMIVUDINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "EVEROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "210130", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "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": "EVEROLIMUS." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ITRACONAZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "INFECTION PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": 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null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "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": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "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": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "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." } ], "patientagegroup": null, "patientonsetage": "66", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Granulomatous rosacea", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "ANSORGE C, TECHNAU-HAFSI K. GRANULOMATOUS ROSACEA IN A LUNG TRANSPLANT RECIPIENT: A POSSIBLE THERAPY OPTION IN A UNIQUE GROUP OF PATIENTS. [GERMAN]. 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GRANULOMATOUS ROSACEA IN A LUNG TRANSPLANT RECIPIENT: A POSSIBLE THERAPY OPTION IN A UNIQUE GROUP OF PATIENTS.. [GERMAN]. HAUTARZT 71. 2020?134-138", "literaturereference_normalized": "granulomatous rosacea in a lung transplant recipient a possible therapy option in a unique group of patients", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20200513", "receivedate": "20200513", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17779215, "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" }, { "companynumb": "DE-ROCHE-2484172", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "EVEROLIMUS" }, "drugadditional": "3", 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GRANULOMATOUS ROSACEA IN A LUNG TRANSPLANT RECIPIENT: A POSSIBLE THERAPY OPTION IN A UNIQUE GROUP OF PATIENTS.. HAUTARZT 2019?:-.", "literaturereference_normalized": "granulomatous rosacea in a lung transplant recipient a possible therapy option in a unique group of patients", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20191204", "receivedate": "20191204", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17109831, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200122" }, { "companynumb": "DE-ACCORD-162957", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "EVEROLIMUS" }, "drugadditional": "3", "drugadministrationroute": null, 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GRANULOMATOUS ROSACEA IN A LUNG TRANSPLANT RECIPIENT: A POSSIBLE THERAPY OPTION IN A UNIQUE GROUP OF PATIENTS. HAUTARZT. 2019. 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{ "abstract": "As a known phenomenon, crossover between sinus node dysfunction and common atrial tachyarrhythmias-most notably, atrial fibrillation and atrial flutter-in older individuals has previously been seen. Here, we present one of the first case series demonstrating a similar relationship between sinus node dysfunction and much rarer etiologies of tachyarrhythmia-that is, postural tachycardia syndrome and inappropriate sinus tachycardia. The exact pathological mechanisms behind these arrhythmias as well as the observation of concurrent nodal dysfunction are poorly understood. Here, we propose both potential mechanistic pathways as well as an initial treatment algorithm for sinus node dysfunction based upon the existing evidence.", "affiliations": "Division of Cardiovascular Medicine, Department of Medicine, University of Toledo, Toledo, OH, USA.;Department of Medicine, University of Toledo, Toledo, OH, USA.;Division of Cardiovascular Medicine, Department of Medicine, University of Toledo, Toledo, OH, USA.", "authors": "Harnish|Paul R|PR|;Shastri|Pinang|P|;Grubb|Blair P|BP|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.19102/icrm.2021.120503", "fulltext": "\n==== Front\nJ Innov Card Rhythm Manag\nJ Innov Card Rhythm Manag\nJICRM\nThe Journal of Innovations in Cardiac Rhythm Management\n2156-3977\n2156-3993\nMediaSphere Medical United States\n\nicrm.2021.120503\n10.19102/icrm.2021.120503\nCase Report\nSick Sinus Syndrome Can Be Associated with Postural Tachycardia Syndrome and Inappropriate Sinus Tachycardia Syndrome\nHarnish Paul R. MD 1\nShastri Pinang MD 2\nGrubb Blair P. MD, FACC, FAHA 1\n1Division of Cardiovascular Medicine, Department of Medicine, University of Toledo, Toledo, OH, USA\n2Department of Medicine, University of Toledo, Toledo, OH, USA\nAddress correspondence to: Paul R. Harnish, MD, 1000 Hollister Road, Apt 1143, Perrysburg, OH 43551, USA. Email: paul.harnish@Utoledo.edu.\nThe authors report no conflicts of interest for the published content.\n\n15 5 2021\n5 2021\n12 5 45264531\n22 7 2020\n09 11 2020\nCopyright: © 2021 Innovations in Cardiac Rhythm Management\n2021\nhttps://creativecommons.org/licenses/by/4.0/ 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 work is properly cited.\nAs a known phenomenon, crossover between sinus node dysfunction and common atrial tachyarrhythmias—most notably, atrial fibrillation and atrial flutter—in older individuals has previously been seen. Here, we present one of the first case series demonstrating a similar relationship between sinus node dysfunction and much rarer etiologies of tachyarrhythmia—that is, postural tachycardia syndrome and inappropriate sinus tachycardia. The exact pathological mechanisms behind these arrhythmias as well as the observation of concurrent nodal dysfunction are poorly understood. Here, we propose both potential mechanistic pathways as well as an initial treatment algorithm for sinus node dysfunction based upon the existing evidence.\n\nInappropriate sinus tachycardia\npostural orthostatic tachycardic syndrome\nsinus node dysfunction\n==== Body\nIntroduction\n\nHere, we examine a rare but known phenomenon in which patients with persistently tachycardic baseline heart rates due to previously diagnosed postural orthostatic tachycardia syndrome (POTS) or inappropriate sinus tachycardia (IST) demonstrate a transition into periods of either transient or sustained symptomatic bradycardia. This is similar in scope to the known crossover between sinus node dysfunction and more common atrial tachyarrhythmias—most notably, atrial fibrillation and atrial flutter—in older individuals.1,2 Given the rarity of POTS and IST in the general population, the frequency as well as the mechanisms of this crossover remain unknown. We detail four separate cases, three of which eventually underwent pacemaker implantation and one of which may require similar treatment in the future.\n\nCase presentations\n\nCase 1\n\nA 20-year-old woman with a known history of POTS and episodes of syncope starting at the age of 13 years presented for evaluation. At the beginning of her disease course, she experienced palpitations, light-headedness, and dizziness, with positional changes. Her symptoms progressed into her teenage years with two to three episodes of syncope per month and recurrent emergency room and physician visits. She was seen by multiple providers and had been labeled as a psychiatric patient until she was ultimately referred to our electrophysiology (EP) clinic due to elevated heart rates associated with her episodes. She underwent tilt-table testing and experienced symptomatic tachycardia up to 143 bpm; variations in blood pressure (BP) from 119/87 to 103/54; and, ultimately, syncope during the study. After a thorough review of her symptoms, she was diagnosed with autonomic dysfunction and orthostatic intolerance consistent with postural tachycardia syndrome. She was treated with intravenous saline infusions as well as ivabradine after failing multiple other medical therapies, including bupropion, fludrocortisone, nebivolol, and droxidopa. After some initial success with this regimen, she was later admitted to the hospital with debilitating episodes of bradycardia at the age of 19 years. All rate-controlling medications were discontinued and an ambulatory monitor was placed. She was found to be in persistent sinus bradycardia with rates in the 30s and 40s, which did not change with repositioning. Due to intractable symptoms despite withdrawal of all rate-controlling agents and a period of monitoring, she ultimately required placement of a dual-chamber pacemaker, with significant improvements in symptoms observed with atrial pacing at a burden of 60% to 70%.\n\nCase 2\n\nA very accomplished 53-year-old female professional musician presented as a patient to our clinic with a long history of debilitating POTS and episodes of syncope, which significantly interfered with her ability to work as well as quality of life. She had undergone extensive evaluation with positive tilt-table testing findings at two prior centers consisting of tachycardia and hypotension prior to referral to our clinic. She had been trialed on multiple medications, including bupropion, droxidopa, and saline infusions, and had shown initial success with medical management with long-term follow-up (see Table 1 for the complete list). About 12 years from the time of her initial diagnosis, however, she experienced an abrupt change in the nature of her syncopal episodes with an advancement in frequency and severity of events and a loss of her usual initial prodrome, raising the potential for significant future trauma. An implantable loop recorder was placed, which revealed new episodes of profound sinus bradycardia with rates dipping into the range of 20 to 39 bpm. Following this discovery, a dual-chamber pacemaker was placed with near-complete resolution of symptoms and requiring pacing at a 60% to 70% burden. She has since returned to a near-normal quality of life a few years out from device placement.\n\nCase 3\n\nA 49-year-old woman with a known history of Sjögren’s syndrome, mitochondrial myopathy, and hypermobility syndrome presented for assessment. Her disease course began with autonomic neuropathy, which included numbness and a sensation of tingling/pruritus in the arms and legs. She was initially diagnosed with autonomic dysfunction at an outside institution after developing episodes of positional tachycardia. She subsequently presented to our EP clinic after years of wide-ranging rates that were initially predominately tachycardic but which progressed into episodes of severe bradycardia. Despite attempts to use multiple medications, including pyridostigmine and dextroamphetamine, she progressed into frank chronotropic incompetence with an average heart rate of 40 bpm. Despite removal of prior rate-controlling agents and attempts at medical therapy, she ultimately required placement of a dual-chamber pacemaker, with subsequent significant improvements in her symptoms. During follow-up pacemaker interrogations, she has proven to require atrial pacing at an 80% burden with cessation of her prior tachycardic episodes.\n\nCase 4\n\nA 32-year-old man with a history of small-fiber neuropathy and Sjögren’s syndrome initially presented with episodes of a racing heart accompanied by light-headedness. He underwent an initial workup, including tilt-table testing, which demonstrated a postural tachycardia response from an initial baseline rate of 60 bpm up to 144 bpm. His tilt test was actually halted early at 20 minutes and 70° of tilt due to a drop in both systolic and diastolic BPs down to 87/70 mmHg. He was initially diagnosed with autonomic dysfunction given the presence of comorbid disease and was followed for a period of time on ivabradine. He then experienced progression into episodes of extreme bradycardia with rates in the 30s as documented by his implantable loop recorder. Around the same time as the worsening of his rhythm-related symptoms, he was diagnosed with early-onset Parkinson’s disease. This serves as an example of another known phenomenon in which autonomic dysfunction precedes neuromuscular symptoms. He is currently being managed medically with cessation of rate-controlling medicines but may eventually require pacing if symptoms persist and prove to correlate with his loop tracings.\n\nDiscussion\n\nPOTS is characterized as a form of dysautonomia resulting in symptoms of orthostatic intolerance such as light-headedness, exercise intolerance, near-syncope with positional changes, fatigue, sweating, tremor, anxiety, and palpitations the typically resolve upon lying down. For many patients, this leads to a profound drop in quality of life as they suffer a decline in functional status even when conducting everyday tasks such as ascending the stairs or getting out of bed. This extends across a wide range of ages, including the very young. The criteria for diagnosis consist of a resting heart rate of greater than 120 bpm on standing or an increase in heart rate by 30 bpm from baseline after standing for 10 minutes. BP is usually preserved upon position change as compared with in the context of orthostatic hypotension, which is the hallmark of autonomic failure. Exclusion of confounding conditions (dehydration, anemia, hypothyroidism) or medications such as vasodilators, diuretics, antidepressants, or anxiolytic agents must be established prior to diagnosis.3\n\nPrimary and secondary forms of POTS are classified based on the proposed etiology of symptoms. Primary partial dysautonomia (or neurogenic) POTS is thought to a pathologic immune-mediated response via serum auto-antibodies to α1-adrenergic receptors in vascular smooth muscle, muscarinic M4 receptors, and α3-Ach receptors on peripheral ganglia.4 Hyperadrenergic states, usually the result of a genetic predisposition, can lead to increased norepinephrine (NE) levels which, together with impaired clearance or decreased uptake, can manifest as anxiety, tremulousness, and elevated diastolic BP.5 Metabolic, systemic, and autoimmune diseases may also manifest as POTS. Common culprits include diabetes mellitus, amyloidosis, heavy metal poisoning, Sjögren’s syndrome, hypermobility syndrome, and paraneoplastic syndrome. In addition, it has been found to be inducible following successful slow pathway atrioventricular nodal ablation.6\n\nDistinguishing POTS from similar syndromes depends on adherence to specific clinical criteria, with the differential including IST syndrome, chronic fatigue syndrome, pheochromocytoma, and neurocardiogenic syncope. Specifically, IST has overlapping features with POTS, which can make proper diagnosis a nebulous task as both disorders result in an increase in heart rate with minimal activity. However, POTS is usually associated with elevations in heart rate in response to changes in the body position, whereas this is possible but not essential to make a diagnosis of IST. Both conditions can be severely debilitating to an affected individual, with at least one reported case of an individual with IST experiencing tachycardia-induced cardiomyopathy.7\n\nTreatment of these related conditions is usually directed toward the modification of autonomic responses as well as rate control initially through medical therapy followed by radiofrequency sinus node ablation for refractory cases. Hyperadrenergic forms of POTS may respond to agents such as labetalol and clonidine due to their sympatholytic activity.8 Low-dose propranolol has also demonstrated efficacy in reducing tachycardia and achieving symptomatic control in POTS.9 Perturbations in serotonin production and regulation can also affect BP and heart rate, signifying a role for selective serotonin reuptake inhibitors in combination with serotonin and NE reuptake inhibitors as a potential adjunct therapy regimen for POTS via the stimulation of the standing vasoconstriction reflex.10 Other medications that have demonstrated success in select cases include fludrocortisone, midodrine, methylphenidate, and pyridostigmine for orthostatic syndromes.11–13 A promising therapy that has been gaining traction recently is ivabradine, a funny sodium channel blocker (iF blocker) that has demonstrated effects including reducing the heart rate and providing symptomatic relief from POTS as well as IST without significant concomitant drops in BP.7,14,15 More invasive methods such as pacemaker placement have also demonstrated efficacy in orthostatic intolerance syndromes that are refractory to medical treatment, specifically with the use of devices capable of responding to BP variations.16\n\nClear mechanisms have yet to be elucidated but include impaired vascular innervation, elevated NE concentrations, α- and β-receptor sensitivity, and baroreceptor dysfunction.17 Particularly, venous dysfunction secondary to impaired innervation can lead to pooling of blood in the legs and improper redistribution of blood to the peripheral circulation, leading to an increase in sympathetic receptor activity on the heart without a concurrent increase in vasoconstriction. Over time, this mismatch in autonomics and circulation may result in circulatory collapse.8 Similar mechanisms behind POTS and IST have been proposed, including intrinsically high sinus node automaticity rates due to ion channel dysfunction and alterations in autonomic nervous system tone together with decreased cardiovagal tone. In particular, abnormal autonomic modulation with elevated sympathetic and diminished parasympathetic tone has been shown to be a component of both POTS and IST.18 In addition, in vitro studies have reported the presence of circulating anti–β-adrenergic receptor antibodies leading to persistent, incremental production of cyclic adenosine monophosphate in IST, suggesting a role for autoimmunity in the development of the condition.19,20 A deficiency in NE transportation due to a single point mutation has also been identified, which can lead to a lack of clearance of NE, triggering excessive sympathetic activation.21\n\nGiven the aforementioned mechanisms for POTS and IST, many previously proposed mechanisms for the overlap between much more common tachycardias—most notably, atrial fibrillation—and sinus node dysfunction may serve as potential avenues to explain the observed transition from pathological tachycardia into bradycardia in these in these rarer cases. The first potential mechanism is that increased intrinsic automaticity due to a genetic channelopathy may induce a more rapid rate of nodal fibrosis. As previously suspected for other types of predominately tachycardic dysrhythmias such as atrial fibrillation, there is likely a degree of atrial anatomical and electrophysiological remodeling that occurs with persistent inappropriately elevated rates. While the etiologies in these cases—namely, POTS and IST—for the elevated rate are much rarer phenomena, the mechanism by which the sinus node degenerates may very well be similar. We know that radiofrequency-induced inflammation and fibrosis of the sinoatrial node lead to dysfunction, with progression into bradycardia. If the channelopathy confines itself specifically to the pacemaker cells of the sinus node, it is reasonable to suppose that they may be prone to a faster rate of fibrosis or dysfunction. Additionally, a second possible mechanism is that, if the pathological driving force behind the initially inappropriately elevated heart rate is for one reason or another halted, the long-term adaptation already undertaken by the central nervous system to combat this process in the form of increased baseline vagal tone would now stand unopposed. This may be the case, for example, in those patients with autoimmune-mediated disease with cessation of auto-antibody production or some new form of antagonism to the antibodies.\n\nFinally, the third and, likely, the hardest to target is a shift in intrinsic autonomic tone in those patients with significant underlying dysautonomia. In the simplest terms, this would constitute a new shift consisting either of significant downregulation of a baseline high sympathetic tone or upregulation of a baseline low parasympathetic tone, resulting in a transition from tachycardia to bradycardia. With at least some proposed theories available to explain the transition point, a rational scheme for treatment and prevention can be postulated. In the case of progressive nodal fibrosis, if the rate of nodal degradation is linked to the degree of tachycardia, then appropriate rate control is paramount. This would include traditional agents such as β-blockers and central calcium channel blockers as well as newer agents, including iF channel blockers. In the case of autoimmune antibody formation, it is reasonable to presume that, over time, these patients develop increased baseline vagal tone. If the offending antibody is antagonized or its production halted, a transition into initial bradycardia is to be expected. This group would stand to benefit from targeted antibody receptor antagonism or immune suppression to reduce the production of the offending antibody. Following the identification and treatment of the driving pathologic force as well as discontinuation of any other medications that may worsen bradycardia, careful observation may prove to be an effective strategy. Lastly, if severe deviation in sympathetic or parasympathetic tone due to dysautonomia is present, there remain few additional therapies outside of mitigating downstream effects. As a last option, patients with progression from POTS or IST into symptomatic bradycardia may ultimately require pacing support due to unacceptably severe limitations in the quality of life.\n\nThis framework allows for the proposal of an initial treatment strategy for patients with an appropriate diagnosis of IST or POTS (Figure 1). Maximally tolerated doses of a β-blocker or calcium channel blocker as well as an iF channel blocker should be considered as primary therapy to limit any associated nodal fibrosis. For patients who demonstrate a transition in baseline rate and symptoms from tachycardia to maintained bradycardia, an event monitor should be deployed and all offending rate-controlling agents should be halted. If bradycardic rates are persistently and inappropriately maintained with associated symptoms, a careful observation period of at least three to four weeks may allow for readjustment in baseline vagal tone. However, if symptoms continue despite these initial steps, the patient should be considered as a candidate for long-term pacing.\n\nConclusion\n\nAs a rare but recurrent phenomenon, it has been observed in our clinic that patients suffering from POTS as well as IST have an increased propensity for progression into sinus node dysfunction consisting of episodes of either transient or sustained symptomatic bradycardia. A proven mechanism for this transition as well as the best management strategies for these cases remain unknown. We suspect the mechanisms of degeneration of the sinus node may be similar to those seen with other tachycardic dysrhythmias, such as atrial fibrillation or atrial flutter. With this case series, we hope to introduce the observation into the literature as a seed for ongoing investigation and to propose our own preliminary management algorithm.\n\nLimitations\n\nThis paper stands as an attempt to describe a witnessed phenomenon at a specialized syncope clinic. Due to the inherently small populations of these patients, the crossover between sinus node dysfunction and POTS/IST is suggested but unproven. A number of patients were evaluated at other centers before being referred to us and every effort was made to accurately summarize prior testing; however, the record may have missing components. Of note, it is a significant limitation that diagnostic electrophysiology studies were not performed preceding pacemaker implantation in these patients.\n\nFigure 1: Proposed treatment pathway. CCB: calcium channel blocker.\n\nTable 1: Patient Characteristics\n\nCase\tAssociated Symptoms\tMedications/Therapies Attempted\tTilt-table Testing\tComorbid Conditions\tPacemaker Implantation (Mode)\t\n1\t• Atypical chest pain\n• Recurrent syncopal episodes\n• Palpitations\n• Nausea\n• Diaphoresis\t• High-salt diet\n• Florinef (D)\n• Ivabradine\n• Modafinil\n• Midodrine (D)\n• Droxidopa (D)\n• Anticholinergics (D)\n• Bupropion\n• Dofetilide\n• Intravenous hydration therapy\tTachycardia increased up to 143 bpm and BP varied from 119/87 to 103/54; patient experienced dizziness and an episode of syncope during the study\t• Anxiety\n• Depression\n• Obesity\tYes (DDD)\t\n2\t• Syncopal episodes\n• Exercise intolerance\n• Palpitations\n• Light-headedness\n• Dizziness\t• Bupropion\n• Droxidopa (D)\n• Midodrine (D)\n• Citalopram (D)\n• Pyridostigmine (D)\n• Modafinil\n• Intravenous hydration therapy\tTilt-table testing was performed at two prior centers before referral to our clinic, with findings consisting of tachycardia and hypotension with presyncopal symptoms\t• Hypermobility syndrome\tYes (DDD)\t\n3\t• Autonomic neuropathy\n• Exercise intolerance\n• Syncope\n• Frequent headaches\n• Chronic fatigue\t• Pyridostigmine\n• Dextroamphetamine\n• Topiramate (D)\tNot performed\t• Sjögren’s syndrome\n• Mitochondrial myopathy\tYes (DDD)\t\n4\t• Light-headedness\n• Presyncope\n• Palpitations\t• Pyridostigmine\n• Tadalafil\n• Midodrine\n• Modafinil\n• Ivabradine\n• Bupropion\n• Dextroamphetamine (D)\tTachycardia increased up to 144 bpm and BP dropped to 87/70 with presyncopal symptoms\t• Sjögren’s syndrome\n• Small-fiber neuropathy\tNo\t\nBP: blood pressure; D: discontinued.\n==== Refs\nReferences\n\n1. 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Gee ME Watkins AK Brown JN Young EJA Ivabradine for the treatment of postural orthostatic tachycardia syndrome: a systematic review Am J Cardiovasc Drugs 2018 18 3 195 204 [CrossRef][PubMed] 29330767\n15. McDonald C Frith J Newton JL Single centre experience of ivabradine in postural orthostatic tachycardia syndrome Europace 2011 13 3 427 430 [CrossRef][PubMed] 21062792\n16. Shortland J Uzun O Wilson D Stuart GA Walsh MA Use of Biotronik closed loop pacemaker to treat recurrent syncope in pediatric patient with dysautonomia HeartRhythm Case Rep 2016 3 1 27 29 [CrossRef][PubMed] 28491761\n17. Muenter Swift N Charkoudian N Dotson RM Suarez GA Low PA Baroreflex control of muscle sympathetic nerve activity in postural orthostatic tachycardia syndrome Am J Physiol Heart Circ Physiol 2005 289 3 H1226 H1233 [CrossRef][PubMed] 15863453\n18. Nwazue VC Paranjape SY Black BK Postural tachycardia syndrome and inappropriate sinus tachycardia: role of autonomic modulation and sinus node automaticity J Am Heart Assoc 2014 3 2 e000700 [CrossRef][PubMed] 24721800\n19. Chiale PA Garro HA Schmidberg J Inappropriate sinus tachycardia may be related to an immunologic disorder involving cardiac beta andrenergic receptors Heart Rhythm 2006 3 10 1182 1186 [CrossRef][PubMed] 17018348\n20. Nattel S Inappropriate sinus tachycardia and beta-receptor autoantibodies: a mechanistic breakthrough? Heart Rhythm 2006 3 10 1187 1188 [CrossRef][PubMed] 17018349\n21. Shannon JR Flattem NL Jordan J Orthostatic intolerance and tachycardia associated with norepinephrine-transporter deficiency N Engl J Med 2000 342 8 541 549 [CrossRef][PubMed] 10684912\n\n", "fulltext_license": "CC BY", "issn_linking": "2156-3977", "issue": "12(5)", "journal": "The Journal of innovations in cardiac rhythm management", "keywords": "Inappropriate sinus tachycardia; postural orthostatic tachycardic syndrome; sinus node dysfunction", "medline_ta": "J Innov Card Rhythm Manag", "mesh_terms": null, "nlm_unique_id": "101589872", "other_id": null, "pages": "4526-4531", "pmc": null, "pmid": "34035985", "pubdate": "2021-05", "publication_types": "D002363:Case Reports", "references": "29330767;25668431;15699262;24721800;16943900;20711750;19572874;19687359;10387140;17018348;17621618;15911704;15863453;28491761;11198485;31495251;30293095;17018349;10684912;10027117;21062792", "title": "Sick Sinus Syndrome Can Be Associated with Postural Tachycardia Syndrome and Inappropriate Sinus Tachycardia Syndrome.", "title_normalized": "sick sinus syndrome can be associated with postural tachycardia syndrome and inappropriate sinus tachycardia syndrome" }

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Sick sinus syndrome can be associated with postural tachycardia syndrome and inappropriate sinus tachycardia syndrome. 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SICK SINUS SYNDROME CAN BE ASSOCIATED WITH POSTURAL TACHYCARDIA SYNDROME AND INAPPROPRIATE SINUS TACHYCARDIA SYNDROME. 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"drugenddateformat": null, "drugindication": "POSTURAL ORTHOSTATIC TACHYCARDIA SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NEBIVOLOL." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Sinus bradycardia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Sinus node dysfunction", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Therapy non-responder", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": 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SICK SINUS SYNDROME CAN BE ASSOCIATED WITH POSTURAL TACHYCARDIA SYNDROME AND INAPPROPRIATE SINUS TACHYCARDIA SYNDROME. THE JOURNAL OF INNOVATIONS IN CARDIAC RHYTHM MANAGEMENT. 2021?12(5):4526?4531", "literaturereference_normalized": "sick sinus syndrome can be associated with postural tachycardia syndrome and inappropriate sinus tachycardia syndrome", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210917", "receivedate": "20210917", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19846911, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" } ]

{ "abstract": "Valproic acid (VPA) is one of the most frequently used antiepileptic drugs for the treatment of focal and generalized epilepsies, absence seizures, and Lennox-Gastaut syndrome (LGS). VPA has been demonstrated to have a negative effect on both the intrinsic and extrinsic coagulation systems and controversy exists about the clinical relevance of such hematological abnormalities. We describe a case of reversible lung hemorrage due to VPA. In English-language literature only two other similar cases (one of which fatal) have been described so far.", "affiliations": "Department of Thoracic Surgery, Morelli Hospital, AOVV, Sondalo, Italy.;Department of Thoracic Surgery, Morelli Hospital, AOVV, Sondalo, Italy.;Department of Thoracic Surgery, Morelli Hospital, AOVV, Sondalo, Italy.;Department of Thoracic Surgery, Morelli Hospital, AOVV, Sondalo, Italy.", "authors": "Inzirillo|Francesco|F|;Giorgetta|Casimiro|C|;Ravalli|Eugenio|E|;Pona|Claudio Della|CD|", "chemical_list": null, "country": "India", "delete": false, "doi": "10.4103/0970-2113.152646", "fulltext": "\n==== Front\nLung IndiaLung IndiaLILung India : Official Organ of Indian Chest Society0970-21130974-598XMedknow Publications & Media Pvt Ltd India LI-32-17510.4103/0970-2113.152646Case ReportDiffuse alveolar hemorrhage due to valproic acid: Case report and review of the literature Inzirillo Francesco Giorgetta Casimiro Ravalli Eugenio Pona Claudio Della Department of Thoracic Surgery, Morelli Hospital, AOVV, Sondalo, ItalyAddress for correspondence: MD. Francesco Inzirillo, Department of Thoracic Surgery, E Morelli Hospital, Via Zubiani 33, Sondalo - 23035, Italy. E-mail: francescoinzirillo@gmail.comMar-Apr 2015 32 2 175 177 Copyright: © Lung India2015This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Valproic acid (VPA) is one of the most frequently used antiepileptic drugs for the treatment of focal and generalized epilepsies, absence seizures, and Lennox-Gastaut syndrome (LGS). VPA has been demonstrated to have a negative effect on both the intrinsic and extrinsic coagulation systems and controversy exists about the clinical relevance of such hematological abnormalities. We describe a case of reversible lung hemorrage due to VPA. In English-language literature only two other similar cases (one of which fatal) have been described so far.\n\nKEY WORDS:\nAlveolar hemorrhagecoagulation disordersvalproic acid\n==== Body\nINTRODUCTION\nValproic acid (VPA) is an antiepileptic drug for the treatment of epilepsy, absence seizures and Lennox-Gastaut syndrome.[1] VPA has a negative effect on coagulation and may cause thrombocytopenia (TCP), platelet abnormalities, alterations of concentrations of various coagulation factors.[23] Such hematological abnormalities may rarely lead to a large hemorrhage and may have a role in increased risk of bleeding after surgery. We describe a case of reversible lung hemorrhage due to VPA. Only two other similar cases have been described in literature.\n\nCASE REPORT\nA 51-old-year female patient treated with VPA, at a dose of 1000 mg per day, for depressive and bipolar disorder, since 2008, was admitted to our hospital with a diagnosis of hemoptysis. Pulmonary bleeding was causing anemia (up to four episodes of hemoptysis a day with the emission of bright red blood and fresh clots). Blood tests showed mild anemia (hemoglobin 9.6 g/dl; hematocrit 28,2%). Bronchoscopy detected diffuse bronchial wall blood painting. The bronchoalveolar lavage (BAL) examination showed a proportion of hemosiderin-laden macrophage (approximately 20%) cultures for bacteria and fungi, mycobacteria, and the autoimmune tests were all negative. The CT scan of the chest showed ground-glass areas localized in the right upper lobe [Figure 1]. Spirometry revealed restrictive abnormality, with diffusion capacity of the lung for carbon monoxide (DLCO) being 70% of the predicted value. A CT scan repeated after six days showed a reduction of the lesions in the upper lobe and the appearance of bilateral ground-glass opacity, mainly in the middle lobe. Only supportive therapy was carried out. VPA was suspended and the result was an immediate disappearance of hemoptysis, without recurrence. Hematological dosage of VPA was 54.7 μg/ml (range 50 to 100 μg/ml). VPA was effectively replaced with carbamazepine and the patient had no psychiatric disorders. After 20 days, the radiological and clinical follow-ups were normal [Figure 2].\n\nFigure 1 CT scan of the thorax showing confluent nodular opacities and ground-glass areas\n\nFigure 2 Follow-up chest X-ray\n\nDISCUSSION\nValproic Acid is used for the treatment of various forms of epilepsies and seizures, especially in the pediatric population. A variety of coagulation disorders, as side effects, have been demonstrated.[4] Some studies have showed a correlation between coagulation disorders and blood drug dosage, while others did not show any relation[2] A significant reduction in platelet count and platelet dysfunction are the most common hematological adverse effects of VPA (incidence range: 5-60%).[15] TCP has been explained by the induction of an immune response against platelets or by the direct toxic effect on bone marrow.[1] Factor XIII-deficiency syndrome was related to the VPA treatment and associated with an increase in perioperative bleeding risk.[36] Acquired von Willebrand disease was demonstrated in 67% of children during VPA treatment.[1] Vitamin K-dependent coagulopathies have been described, but the pathogenetic mechanisms have not been elucidated. The immediate improvement in prothrombin time (PT) after oral vitamin K administration, suggests an exogenous lack of vitamin K; anyway, under normal nutritional conditions, the daily intake is much higher than the daily need of vitamin K, and VPA seems not to influence the intestinal uptake of Vitamin K. A competitive rivalry for some metabolic steps seems to be more reliable.[1] Hypofibrinogenemia is another alteration that has been described.[7] Despite the reported abnormalities, the clinical consequences related to VPA treatment have been described infrequently. There are some reports about hematomas, epistaxis, and increased bleeding after neurosurgery. A review of the English-language Medical Literature revealed the description of only two other cases of VPA treatment–related alveolar bleeding. Diffuse alveolar hemorrhage (DAH) is a life-threatening disorder characterized clinically by hemoptysis, in approximately one-third of the cases,[8] falling hematocrit, diffuse pulmonary infiltrates, and hypoxemic respiratory failure. Bleeding is caused mainly by injury, which causes alterations in the pulmonary microcirculation and subsequently increases permeability, similar to immune-mediated capillaritis and the treatment consists of supportive care, cessation of offending drugs, and if necessary, high-dose steroids, immunosuppressants, and plasmapheresis.[8] One described case,[9] reported a 15-year-old boy receiving VPA treatment since the age of 10 years for myoclonic epilepsy. He developed dyspnea and hemoptysis and radiological examinations revealed bilateral lung infiltrates, suggestive of DAH. The bronchoscopic examination and the BAL fluid study were performed for alveolar hemorrhage. No alterations of coagulation were discovered, but the immediate disappearance of the symptoms and the sudden radiological improvement after two days and seven days, after discontinuation of the drug, were considered as a close association between bleeding and VPA. A platelet dysfunction without thrombocytopenia was the primary hypothesis.\n\nThe second case[10] is of a 30-year-old woman, who was receiving valproic acid since the age of 20 years for generalized seizure disorder, and was hospitalized for severe anemia. Laboratory data showed hemoglobin of 4.9 g/dl, hematocrit of 15%, platelet count of 15,000/μl, and a serum VPA level of 124 μg/ml. The radiological reports showed that she had lower lobe infiltrates and a bone marrow aspirate, which were consistent with the myelodysplastic syndrome. Bronchoscopy and BAL studies implied that it was probably DAH. Unfortunately, the patient died because of respiratory failure due to the evolution of bilateral diffuse pulmonary infiltrates. In the reported case, the bleeding was related to bone marrow suppression. Our clinical case is similar to the first described. In fact the CT scan of the lung showed bilateral ground-glass infiltrates localized first in the right superior lobe and later in the middle lobe, with other diffuse ground-glass opacities bilaterally. Bronchoscopic evaluation revealed the presence of blood in the middle lobe bronchus with a proportion of hemosiderin-laden macrophages (approximately 20%) and all BAL specimens were negative for infection. Autoimmune antibody tests were negative and the platelet count was always normal (the lowest value recorded was 2,43,000/μl). Alterations or deficiency of coagulation factors were not found and a pre-existing disease, predisposing to DAH, (pulmonary or cardiac disorders, especially heart failure or interstitial lung diseases) was not present. An increase in DLCO is usually seen in cases with fresh DAH. Due to the increased availability of intra-alveolar hemoglobin that combines with carbon monoxide. However, our case had reduced DLCO. This may be because the DLCO measurements in our case were done more than 48 hours after admission. The association between bleeding and VPA treatment was diagnosed indirectly, because hemoptysis suddenly disappeared after cessation of VPA therapy and never recurred, with the radiological examinations normalizing after a week.\n\nCONCLUSION\nThe alterations of pulmonary microcirculation can cause DAH, a life-threatening disease, which requires specific supportive treatment. In our case an association between VPA and DAH was suspected and indirectly confirmed by the successful outcome, with no bleeding recurrence after cessation of the drug. VPA therapy is a common cause of various disorders of coagulation that is rarely associated with clinically significant spontaneous bleeding, but rather with an increased risk of postoperative bleeding. DAH is one of the rare VPA-related complications, probably secondary to a combination of several hemostatic disorders. DAH in patients under VPA treatment could disappear with VPA cessation.\n\nACKNOWLEDGEMENT\nSimon Tiberi (Revisor and Language Reviewer)\n\nSource of Support: Nil\n\nConflict of Interest: None declared.\n==== Refs\nREFERENCES\n1 Gerstner T Teich M Bell N Longin E Dempfle CE Brand J Valproate-associated coagulopathies are frequent and variable in children Epilepsia 2006 47 1136 43 16886976 \n2 Igrutinović Z Obradović S Vuletić B Marković S Impact of valproates on h aemostasis and blood cell count in children Srp Arh Celok Lek 2008 136 267 73 18792624 \n3 Teich M Longin E Dempfle CE König S Factor XIII deficiency associated with valproate treatment Epilepsia 2004 45 187 9 14738427 \n4 Banerjea MC Diener W Kutschke G Schneble HJ Korinthenberg R Sutor AH Pro- and anticoagulatory factors under sodium valproate-therapy in children Neuropediatrics 2002 33 215 20 12368993 \n5 Zeller JA Schlesinger S Runge U Kessler C Influence of valproate monotherapy on platelet activation and hematologic values Epilepsia 1999 40 186 9 9952265 \n6 Pohlmann-Eden B Peters CN Wennberg R Dempfle CE Valproate induces reversible factor XIII deficiency with risk of perioperative bleeding Acta Neurol Scand 2003 108 142 5 12859294 \n7 Köse G Arhan E Unal B Ozaydin E Guven A Sayli TR Valproate-associated coagulopathies in children during short-term treatment J Child Neurol 2009 24 1493 8 19482838 \n8 Newsome BR Morales JE Diffuse alveolar hemorrhage South Med J 2011 104 269 74 21606695 \n9 Choi KH Nam TS Kim JT Choi SM Park MS Kim BC Valproate associated diffuse alveolar hemorrhage Eur J Neurol 2011 18 e98 9 21749570 \n10 Sleiman C Raffy O Roué C Mal H Fatal pulmonary hemorrhage during high-dose valproate monotherapy Chest 2000 117 613 10669721\n\n", "fulltext_license": "CC BY-NC-SA", "issn_linking": "0970-2113", "issue": "32(2)", "journal": "Lung India : official organ of Indian Chest Society", "keywords": "Alveolar hemorrhage; coagulation disorders; valproic acid", "medline_ta": "Lung India", "mesh_terms": null, "nlm_unique_id": "8405380", "other_id": null, "pages": "175-7", "pmc": null, "pmid": "25814807", "pubdate": "2015", "publication_types": "D016428:Journal Article", "references": "21606695;21749570;19482838;12859294;18792624;10669721;9952265;12368993;16886976;14738427", "title": "Diffuse alveolar hemorrhage due to valproic acid: Case report and review of the literature.", "title_normalized": "diffuse alveolar hemorrhage due to valproic acid case report and review of the literature" }

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{ "abstract": "The optimal intensity of a conditioning regimen might be dependent on not only age and comorbidities but also disease activity and the type of graft source. We evaluated the outcome of unrelated single cord blood transplantation (CBT) using a conditioning regimen of fludarabine 180 mg/m2, i.v. busulfan 9.6 mg/kg, 4 Gy total body irradiation, granulocyte colony-stimulating factor-combined high-dose cytarabine (12 g/m2) in 23 elderly patients (median, 64 years) with nonremission myeloid malignancies between 2013 and 2018 in our institution. All but 1 patient achieved neutrophil engraftment at a median of 23.5 days (range, 18 to 50). With a median follow-up of 28 months, the probabilities of overall survival (OS), disease-free survival (DFS), and cumulative incidence of relapse at 2 years were 62%, 52%, and 26%, respectively. The cumulative incidences of nonrelapse mortality at 100 days and 2 years were 9% and 22%, respectively. In the univariable analysis a higher proportion of blasts in bone marrow and in peripheral blood and a monosomal or complex karyotype were significantly associated with inferior OS and DFS. Poor cytogenetics were significantly associated with inferior DFS and increased relapse incidence. These data demonstrate that this reduced-toxicity myeloablative conditioning regimen was tolerable and effective in terms of engraftment, relapse, and survival in single CBT for elderly patients with nonremission myeloid malignancies.", "affiliations": "Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. Electronic address: tkonuma@ims.u-tokyo.ac.jp.;Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.;Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.;Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.;Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.;Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.;Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.", "authors": "Konuma|Takaaki|T|;Kato|Seiko|S|;Isobe|Masamichi|M|;Mizusawa|Mai|M|;Oiwa-Monna|Maki|M|;Takahashi|Satoshi|S|;Tojo|Arinobu|A|", "chemical_list": "D019653:Myeloablative Agonists; D003561:Cytarabine; D016179:Granulocyte Colony-Stimulating Factor; D014740:Vidarabine; D002066:Busulfan; C024352:fludarabine", "country": "United States", "delete": false, "doi": "10.1016/j.bbmt.2018.12.004", "fulltext": null, "fulltext_license": null, "issn_linking": "1083-8791", "issue": "25(4)", "journal": "Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation", "keywords": "Busulfan; Cord blood transplantation; Elderly; Granulocyte colony-stimulating factor; Myeloid leukemia; Nonremission", "medline_ta": "Biol Blood Marrow Transplant", "mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002066:Busulfan; D036101:Cord Blood Stem Cell Transplantation; D003561:Cytarabine; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D008297:Male; D008875:Middle Aged; D019653:Myeloablative Agonists; D009190:Myelodysplastic Syndromes; D014740:Vidarabine; D014916:Whole-Body Irradiation", "nlm_unique_id": "9600628", "other_id": null, "pages": "764-770", "pmc": null, "pmid": "30529460", "pubdate": "2019-04", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Reduced-Toxicity Myeloablative Conditioning Consisting of Fludarabine/Busulfan/Low-Dose Total Body Irradiation/Granulocyte Colony-Stimulating Factor-Combined Cytarabine in Single Cord Blood Transplantation for Elderly Patients with Nonremission Myeloid Malignancies.", "title_normalized": "reduced toxicity myeloablative conditioning consisting of fludarabine busulfan low dose total body irradiation granulocyte colony stimulating factor combined cytarabine in single cord blood transplantation for elderly patients with nonremission myeloid malignancies" }

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"drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "3 G/M2, EVERY 12 HOURS", "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": "CYTARABINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LENOGRASTIM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": 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"drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CICLOSPORIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ALBENDAZOLE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "INFECTION PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZOLE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "BUSULFAN" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "020954", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "9.6 MG/KG (TOTAL), UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HAEMATOLOGICAL MALIGNANCY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "9.6", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUSULFEX" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": "30 MG/KG, DAILY DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST GRAFT VERSUS HOST DISEASE", "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": "6", "activesubstance": { "activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, 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null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PENTAMIDINE ISETHIONATE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ACYCLOVIR" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIVIRAL PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACICLOVIR" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "URSODIOL" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "UNK", "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": "URSODEOXYCHOLIC ACID" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Inappropriate schedule of product administration", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulmonary alveolar haemorrhage", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "KONUMA T, KATO S, ISOBE M, MIZUSAWA M, OIWA-MONNA M, TAKAHASHI S, ET AL. REDUCED-TOXICITY MYELOABLATIVE CONDITIONING CONSISTING OF FLUDARABINE/BUSULFAN/LOW-DOSE TOTAL BODY IRRADIATION/GRANULOCYTE COLONY-STIMULATING FACTOR-COMBINED CYTARABINE IN SINGLE CORD BLOOD TRANSPLANTATION FOR ELDERLY PATIENTS WITH NONREMISSION MYELOID MALIGNANCIES. BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION. 2018?000:1-7", "literaturereference_normalized": "reduced toxicity myeloablative conditioning consisting of fludarabine busulfan low dose total body irradiation granulocyte colony stimulating factor combined cytarabine in single cord blood transplantation for elderly patients with nonremission myeloid malignancies", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20190306", "receivedate": "20190207", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15933609, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190417" } ]

{ "abstract": "Neurostimulants may improve or accelerate cognitive and functional recovery after intracerebral hemorrhage (ICH), ischemic stroke (IS), or subarachnoid hemorrhage (SAH), but few studies have described their safety and effectiveness in the intensive care unit (ICU). The objective of this study was to describe amantadine and modafinil administration practices during acute stroke care starting in the ICU and to evaluate safety and effectiveness.\n\n\n\nConsecutive adult ICU patients treated with amantadine and/or modafinil following acute non-traumatic IS, ICH, or SAH were evaluated. Neurostimulant administration data were extracted from the electronic medication administration record, including medication (amantadine, modafinil, or both), starting dose, time from stroke to initiation, and whether the neurostimulant was continued at hospital discharge. Patients were considered responders if they met two of three criteria within 9 days of neurostimulant initiation: increase in Glasgow coma scale (GCS) score ≥ 3 points from pre-treatment baseline, improved wakefulness or participation documented in caregiver notes, or clinical improvement documented in physical or occupational therapy notes. Potential confounders of the effectiveness assessment and adverse drug effects were also recorded.\n\n\n\nA total of 87 patients were evaluable during the 3.7-year study period, including 41 (47%) with ICH, 29 (33%) with IS, and 17 (20%) with SAH. The initial neurostimulant administered was amantadine in 71 (82%) patients, modafinil in 13 (15%), or both in 3 (3%) patients. Neurostimulants were initiated a median of 7 (4.25, 12.75) days post-stroke (range 1-27 days) for somnolence (77%), not following commands (32%), lack of eye opening (28%), or low GCS (17%). The most common starting dose was 100 mg twice daily for both amantadine (86%) and modafinil (54%). Of the 79 patients included in the effectiveness evaluation, 42 (53%) were considered responders, including 34/62 (55%) receiving amantadine monotherapy and 8/24 (33%) receiving both amantadine and modafinil at the time they met the definition of a responder. No patient receiving modafinil monotherapy was considered a responder. The median time from initiation to response was 3 (2, 5) days. Responders were more frequently discharged home or to acute rehabilitation compared to non-responders (90% vs 62%, p = 0.006). Among survivors, 63/72 (88%) were prescribed a neurostimulant at hospital discharge. The most common potential adverse drug effect was sleep disruption (16%).\n\n\n\nNeurostimulant administration during acute stroke care may improve wakefulness. Future controlled studies with a neurostimulant administration protocol, prospective evaluation, and discretely defined response and safety criteria are needed to confirm these encouraging findings.", "affiliations": "Department of Critical Care Services, Neuroscience Institute, Maine Medical Center, 22 Bramhall Street, Portland, ME, 04102, USA.;Department of Critical Care Services, Neuroscience Institute, Maine Medical Center, 22 Bramhall Street, Portland, ME, 04102, USA.;Department of Pharmacy, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.;Department of Critical Care Services, Neuroscience Institute, Maine Medical Center, 22 Bramhall Street, Portland, ME, 04102, USA.;Department of Rehabilitation Medicine, Maine Medical Center, 22 Bramhall Street, Portland, ME, 04102, USA.;Department of Rehabilitation Medicine, Maine Medical Center, 22 Bramhall Street, Portland, ME, 04102, USA.;Department of Critical Care Services, Neuroscience Institute, Maine Medical Center, 22 Bramhall Street, Portland, ME, 04102, USA.;Department of Critical Care Services, Neuroscience Institute, Maine Medical Center, 22 Bramhall Street, Portland, ME, 04102, USA.;Department of Pharmacy, Maine Medical Center, 22 Bramhall Street, Portland, ME, 04102, USA. dgagnon@mmc.org.", "authors": "Leclerc|Angela M|AM|;Riker|Richard R|RR|;Brown|Caitlin S|CS|;May|Teresa|T|;Nocella|Kristina|K|;Cote|Jennifer|J|;Eldridge|Ashley|A|;Seder|David B|DB|;Gagnon|David J|DJ|", "chemical_list": "D000697:Central Nervous System Stimulants; D000547:Amantadine; D000077408:Modafinil", "country": "United States", "delete": false, "doi": "10.1007/s12028-020-00986-4", "fulltext": null, "fulltext_license": null, "issn_linking": "1541-6933", "issue": "34(1)", "journal": "Neurocritical care", "keywords": "Amantadine; Critical care; Intracerebral hemorrhage; Ischemic stroke; Modafinil; Neurostimulant; Rehabilitation; Stroke; Subarachnoid hemorrhage", "medline_ta": "Neurocrit Care", "mesh_terms": "D000328:Adult; D000547:Amantadine; D000697:Central Nervous System Stimulants; D006801:Humans; D007362:Intensive Care Units; D000077408:Modafinil; D012189:Retrospective Studies; D020521:Stroke", "nlm_unique_id": "101156086", "other_id": null, "pages": "102-111", "pmc": null, "pmid": "32435964", "pubdate": "2021-02", "publication_types": "D016428:Journal Article", "references": "30966863;30321906", "title": "Amantadine and Modafinil as Neurostimulants Following Acute Stroke: A Retrospective Study of Intensive Care Unit Patients.", "title_normalized": "amantadine and modafinil as neurostimulants following acute stroke a retrospective study of intensive care unit patients" }

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{ "abstract": "A 78-year-old woman with a long-term ankle spacer with antibacterials developed an intra-articular Candida auris infection. Treatment with systemic antifungal therapy plus an amphotericin B moulded cement spacer was successful.", "affiliations": "a Division of Infectious Diseases , Northwestern University Feinberg School of Medicine , Chicago , IL , USA.;a Division of Infectious Diseases , Northwestern University Feinberg School of Medicine , Chicago , IL , USA.;a Division of Infectious Diseases , Northwestern University Feinberg School of Medicine , Chicago , IL , USA.;c Division of Orthopaedic Surgery , Northwestern University Feinberg School of Medicine , Chicago , IL , USA.;c Division of Orthopaedic Surgery , Northwestern University Feinberg School of Medicine , Chicago , IL , USA.;d Division of Plastic Surgery , Northwestern University Feinberg School of Medicine , Chicago , IL , USA.;a Division of Infectious Diseases , Northwestern University Feinberg School of Medicine , Chicago , IL , USA.;a Division of Infectious Diseases , Northwestern University Feinberg School of Medicine , Chicago , IL , USA.;a Division of Infectious Diseases , Northwestern University Feinberg School of Medicine , Chicago , IL , USA.", "authors": "Roberts|Scott C|SC|http://orcid.org/0000-0001-7348-6716;Zembower|Teresa R|TR|;Bolon|Maureen K|MK|;Kadakia|Anish R|AR|;Gilley|Jasen H|JH|;Ko|Jason H|JH|;Clark|Jessica|J|;Ward-Fore|Sharon|S|;Taiwo|Babafemi O|BO|", "chemical_list": "D000935:Antifungal Agents; D000666:Amphotericin B; D015725:Fluconazole; D000077336:Caspofungin", "country": "United States", "delete": false, "doi": "10.1080/22221751.2019.1625287", "fulltext": "\n==== Front\nEmerg Microbes InfectEmerg Microbes InfectTEMItemi20Emerging Microbes & Infections2222-1751Taylor & Francis 31179850162528710.1080/22221751.2019.1625287CommentarySuccessful treatment of a Candida auris intra-articular infection Emerging Microbes & InfectionsS. C. Roberts et al.http://orcid.org/0000-0001-7348-6716Roberts Scott C. aCONTACTZembower Teresa R. abBolon Maureen K. aKadakia Anish R. cGilley Jasen H. cKo Jason H. dClark Jessica aWard-Fore Sharon aTaiwo Babafemi O. aa Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, IL, USAb Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USAc Division of Orthopaedic Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USAd Division of Plastic Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USACONTACT Scott C. Roberts roberts.scott.c@gmail.comDivision of Infectious Diseases, Northwestern University Feinberg School of Medicine, 645 N Michigan Ave Suite 900, Chicago, IL60611, USA2019 09 6 2019 8 1 866 868 29 1 2019 02 5 2019 27 5 2019 © 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group, on behalf of Shanghai Shangyixun Cultural Communication Co., Ltd2019The Author(s)This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.ABSTRACT\nA 78-year-old woman with a long-term ankle spacer with antibacterials developed an intra-articular Candida auris infection. Treatment with systemic antifungal therapy plus an amphotericin B moulded cement spacer was successful.\n\nKEYWORDS\nCandida aurisamphotericin cement spacerintra-articular infectionNational Institutes of Health10.13039/1000000025T32AI095207-07National Institute of Allergy and Infectious Diseases10.13039/100000060This work was supported by the National Institutes of Health [5T32AI095207-07] and National Institute of Allergy and Infectious Diseases.\n==== Body\nCase\nA 78-year-old female Chicagoland native with a history of a left ankle fracture treated with open reduction and internal fixation in 1990 presented to her local orthopedic surgeon with chronic pain and underwent a left total ankle replacement in November 2016. She did well post-operatively until approximately one month later when she developed wound dehiscence. Superficial wound cultures were negative and after progression on 18 days of amoxicillin/clavulanic acid (875–125 mg) twice-daily, she underwent removal of the hardware, placement of a Palacos® (Heraeus Medical, Hanau, Germany) cement spacer mixed with 1 g of vancomycin and 1.2 g of tobramycin per 40 g of cement, anterior tibial tendon and extensor hallucis longus tendon removal, and left free vastus lateralis flap with a split-thickness skin graft to the open wound site. Operative cultures were negative and she received 6 weeks of empiric intravenous vancomycin 1 g every 8 h and ceftriaxone 2 g every 24 h, then oral ciprofloxacin 500 mg twice-daily and sulfamethoxazole/trimethoprim 800–160 mg twice-daily for an additional three weeks. The wound closed around March 2017; however, 15 months later in June 2018 she presented to plastic surgery clinic with a 1 cm wound dehiscence. She was otherwise well, living at home, and ambulating without any recent travel or hospital exposures except for wound care and outpatient follow up appointments at her local facility. She underwent a deep wound debridement, closure with flap advancement and allograft superficial peroneal nerve reconstruction. Operative findings included fibrinous tissue with the appearance of biofilm. The spacer was not removed as it did not appear involved. Deep wound cultures obtained from this procedure were plated on Blood, Chocolate and MacConkey agar and grew Candida auris in pure culture in moderate amounts after 2 days on Blood and MacConkey agar plates. Identification was confirmed via 18S rRNA sequencing using the ITS1/ITS4 primer sets and D1/D2 DNA sequencing along with combined phenotypic characterization. Candida auris identification was obtained through matching ITS sequences with previously established signatures in the GenBank database. Antifungal susceptibility testing was performed using Sensititre™ YeastOne™ YO3IVD AST Plate (Thermo Scientific™, West Sussex, UK) and minimum inhibitory concentration (MIC) values (in µg/mL) were: fluconazole: 2, micafungin: 0.06, caspofungin: 0.125, 5-fluorocytosine: <0.125, itraconazole: 0.125, voriconazole: <0.03, and amphotericin B: 0.5. The patient was started on oral fluconazole 400 mg daily. Two weeks later, her wound showed increasing erythema and a new area of purulent drainage. Daily fluconazole dose was increased to 600 mg, and she was admitted for surgical intervention. On admission, she was afebrile and hemodynamically stable. A complete blood count and a comprehensive metabolic panel were normal. Given a lack of systemic symptoms, blood cultures were not obtained. She underwent antibiotic spacer removal, debridement of the remaining extensor tendons, partial excision of necrotic distal tibia and talus bones, and placement of a moulded spacer composed of 40 g Palacos® cement mixed with 100 mg of heat-stable powdered amphotericin B deoxycholate (Fungizone). Operative cultures were negative. Postoperatively, she received intravenous micafungin 100 mg daily for 2 weeks followed by oral fluconazole 400 mg daily. The wound has healed and she has regained mobility without any assistive device. She recently noticed onset of hair loss, presumably due to prolonged use of fluconazole. The patient has completed six months of fluconazole 400 mg daily with plans to continue this for at least a year followed by a lower dose, if tolerated.\n\nDiscussion\nC. auris is an emerging nosocomial pathogen with a high potential for multidrug-resistance. First isolated from the external ear canal of a patient in 2009, C. auris has now been detected in 6 continents and 32 countries as of 2018 [1,2]. Prevalence is likely underestimated since C. auris is prone to misidentification, as there are several phylogenetically similar strains such as Candida haemulonii, Candida famata, Candida sake, Rhodotorula glutinis, and Saccharomyces cerevisiae [3,4]. Candida auris strains are clonal and transmissible, and genomic analyses have shown United States isolates are derived from four global regions spread through international travel [5,6].\n\nOur case is noteworthy because bone and joint involvement of C. auris has been rarely reported, and no detailed cases describing spacer and joint involvement exist. Further, antifungal spacer placement, while sometimes utilized for other Candida species, has yet to be described for C. auris [7,8]. Notably, antifungal breakpoints are tentative, and optimal treatment of orthopedic C. auris infection remains speculative with only a few case reports and expert opinions available to assist clinicians. One case describes chronic otomastoiditis that was successfully treated with fluconazole [9]. Another notes sternal osteomyelitis treated with posaconazole, although the patient died shortly afterwards from an unrelated cause [10]. The treatments offered to both cases were based on in-vitro MIC results, as with our case; however, at least one study has found recurrent fluconazole-sensitive C. auris detection from the urine in spite of fluconazole therapy [11]. A third study detected C. auris in the femur of a patient who improved on fluconazole therapy despite an MIC of 256 µg/mL, likely reflecting colonization [12]. Few other studies have reported C. auris isolation in bone and joint spaces although details are unclear. Here, we describe the treatment of a fluconazole-sensitive C. auris intra-articular infection. Our patient received surgical debridement and placement of an amphotericin-impregnated spacer in addition to systemic antifungal therapy, primarily with fluconazole plus two weeks of micafungin given immediately post-surgery.\n\nA cement spacer mixed with powdered amphotericin B was placed given its heat-stable properties, powdered formulations, and the mildly elevated MIC to fluconazole, although the MIC was below the tentative susceptibility cut-off for C. auris [13]. Amphotericin B-impregnated spacers have been utilized for prior Candida infections, but not C. auris. Most, but not all, report eradication of infection when used in conjunction with systemic antifungal therapy. However, numerous challenges exist in using antifungal spacers. Doses in literature are variable and local bone and joint space antifungal concentrations are unknown. Additionally, certain cement mixtures may impact effectiveness; one study found mixture with polymethyl methacrylate, a common component of spacers, increased compressive strength of the cement, however local amphotericin elution was decreased [14]. Concern also exists for the development of resistance given local antifungal dilution, and systemic absorption of amphotericin B may provoke nephrotoxicity.\n\nOur patient has developed alopecia, an uncommon adverse effect of fluconazole seen in doses of 400 mg daily for at least two months and reversible upon discontinuation [15]. This may affect her willingness to take fluconazole long-term.\n\nInfection prevention and control procedures for C. auris have yet to be optimized. Nosocomial outbreaks have been described, and patients can be colonized for months [16–18]. Current recommendations include Standard and Contact Precautions while colonized with reassessments for colonization every 3 months through axillary and groin swabs as well as the prior site of isolation [13]. Recommended strategies to prevent nosocomial spread of C. auris in the operative setting include routine precautions for prevention of surgical site infections, which were employed in this case [13]. Preoperative infusion of a single dose of micafungin was implemented to control a recent outbreak of largely fluconazole-resistant C. auris in the United Kingdom [16]; this was not performed in our patient. Further precautions applied at our facility included education of the operating room, inpatient, and outpatient staff regarding the organism and required infection prevention measures, surgical space suits and shoe covers worn by all operating room staff, bleach and UV light technology cleaning of the operating room, preoperative, and postoperative care units, contact precautions on the inpatient wards with gowns and gloves, 1:1 nursing care, daily room cleanings with bleach containing solution, limited shared equipment that was disposable when able, and prohibited hallway walking. Upon discharge the room was terminally cleaned, disposable curtains changed, and the room was cleaned using UV light technology. For outpatient care, the patient was scheduled as the last visit of the day, was transferred from check-in directly to the room, and was instructed to keep all wounds covered until examination. Additionally, follow-up appointments with orthopedics and infectious diseases were combined to one location and staff wore gloves and gowns with outpatient rooms cleaned with bleach containing solution followed by UV light technology.\n\nThis case highlights a unique case of C. auris infection and our management approach. In contrast to previously reports of azole resistance rates of up to 90%, our isolate was presumed fluconazole sensitive with an MIC of 2 [19]. As this was the first case of C. auris seen at our hospital and no cases were present concurrently, acquired mechanisms of resistance in outbreak settings, such as Y132F and K143R amino acid substitutions in the ERG11 gene, were likely not present [19]. Given a known predisposition for the development of azole resistance with prolonged therapy, systemic echinocandin therapy and an amphotericin B-impregnated spacer were used concurrently. Further insight is needed to determine the utility of the amphotericin B-impregnated spacer used in our patient. We will continue to monitor her since late relapse of intra-articular infection can occur after apparently successful treatment.\n\nDisclosure statement\nNo potential conflict of interest was reported by the authors.\n\nORCID\nScott C. Robertshttp://orcid.org/0000-0001-7348-6716\n==== Refs\nReferences\n[1] Satoh K , Makimura K , Hasumi Y , et al. Candida auris sp. nov., a novel ascomycetous yeast isolated from the external ear canal of an inpatient in a Japanese hospital . Microbiol Immunol . 2009 ;53 (1 ):41 –44 . doi: 10.1111/j.1348-0421.2008.00083.x 19161556 \n[2] Lone SA , Ahmad A. Candida auris – the growing menace to global heath . Mycoses . 2019 . doi:10.1111/myc.12904 . [Epub ahead of print] .\n[3] Kathuria S , Singh PK , Sharma C , et al. Multidrug-resistant Candida auris misidentified as Candida haemulonii: characterization by matrix-assisted laser desorption ionization-time of flight mass spectrometry and DNA sequencing and its antifungal susceptibility profile variability by Vitek-2, CLSI Broth Microdilution, and Etest method . J Clin Microbiol . 2015 ;53 (6 ):1823 –1830 . doi: 10.1128/JCM.00367-15 25809970 \n[4] Mizusawa M , Miller H , Green R , et al. Can multidrug-resistant Candida auris be reliably identified in clinical microbiology laboratories? J Clin Microbiol . 2017 Feb ;55 (2 ):638 –640 . doi: 10.1128/JCM.02202-16 27881617 \n[5] Lockhart SR , Etienne KA , Vallabhaneni S , et al. Simultaneous emergence of multidrug resistant Candida auris on three continents confirmed by whole genome sequencing and epidemiological analyses . Clin Infect Dis . 2017 ;64 :134 –140 . doi: 10.1093/cid/ciw691 27988485 \n[6] Chow NA , Gade L , Tsay SV , et al. Multiple introductions and subsequent transmission of multidrug resistant Candida auris in the USA: a molecular epidemiologic survey . Lancet Infect Dis . 2018 ;18 (12 ):1377 –1384 . doi: 10.1016/S1473-3099(18)30597-8 30293877 \n[7] Cobo F , Rodríguez-Granger J , Sampedro A , et al. Candida prosthetic joint infection. A review of treatment methods . J Bone Jt Infect . 2017 ;2 (2 ):114 –121 . doi: 10.7150/jbji.17699 28540147 \n[8] Kim JK , Lee DY , Kang DW , et al. Efficacy of antifungal-impregnated cement spacer against chronic fungal periprosthetic joint infections after total knee arthroplasty . Knee . 2018 ;25 (4 ):631 –637 . doi: 10.1016/j.knee.2018.04.004 29778657 \n[9] Choi HI , An J , Hwang JJ , et al. Otomastoiditis caused by Candida auris: case report and literature review . Mycoses . 2017 ;60 (8 ):488 –492 . doi: 10.1111/myc.12617 28378904 \n[10] Heath CH , Dyer JR , Pang S , et al. Candida auris sternal osteomyelitis in a man from Kenya visiting Australia, 2015 . Emerg Infect Dis . 2019 ;25 (1 ):192 –194 . doi: 10.3201/eid2501.181321 30561310 \n[11] Vallabhaneni S. Investigation of first seven reported cases of Candida auris, a globally emerging invasive, multi-drug resistant fungus – United States, May 2013 – August 2016 . MMWR Morb Mortal Wkly Rep . 2016 ;65 (44 ):1234 –1237 . doi: 10.15585/mmwr.mm6544e1 27832049 \n[12] Tan YE , Tan AL. Arrival of Candida auris fungus in Singapore: report of the first 3 cases . Ann Acad Med Singapore . 2018 ;47 (7 ):260 –262 .30120434 \n[13] Centers for Disease Control and Prevention \nCandida auris interim recommendations for healthcare facilities and laboratories; [cited 2018 Dec 20]. Available from: https://www.cdc.gov/fungal/diseases/candidiasis/recommendations.html#infection \n[14] Goss B , Lutton C , Weinrauch P , et al. Elution and mechanical properties of antifungal bone cement . J Athroplasty . 2007 ;22 (6 ):902 –908 . doi: 10.1016/j.arth.2006.09.013 \n[15] Pappas PG , Kauffman CA , Perfect J , et al. Alopecia associated with fluconazole therapy . Ann Intern Med . 1995 ;123 (5 ):354 –357 . doi: 10.7326/0003-4819-123-5-199509010-00006 7625624 \n[16] Eyre DW , Sheppard AE , Madder H , et al. A Candida auris outbreak and its control in an intensive care setting . N Engl J Med . 2018 ;379 (14 ):1322 –1331 . doi: 10.1056/NEJMoa1714373 30281988 \n[17] Schelenz S , Hagen F , Rhodes JL , et al. First hospital outbreak of the globally emerging Candida auris in a European hospital . Antimicrob Resist Infect Control . 2016 ;5 :35 . doi: 10.1186/s13756-016-0132-5 27777756 \n[18] Ruiz-Gaitán A , Moret AM , Tasias-Pitarch M , et al. An outbreak due to Candida auris with prolonged colonization and candidaemia in a tertiary care European hospital . Mycoses . 2018 ;61 (7 ):498 –505 . doi: 10.1111/myc.12781 29655180 \n[19] Chowdhary A , Prakash A , Sharma C , et al. A multicentre study of antifungal susceptibility patterns among 350 Candida auris isolates (2009–17) in India: role of the ERG11 and FKS1 genes in azole and echinocandin resistance . J Antimicrob Chemother . 2018 ;73 (4 ):891 –899 . doi: 10.1093/jac/dkx480 29325167\n\n", "fulltext_license": "CC BY", "issn_linking": "2222-1751", "issue": "8(1)", "journal": "Emerging microbes & infections", "keywords": "amphotericin cement spacer; intra-articular infection", "medline_ta": "Emerg Microbes Infect", "mesh_terms": "D000368:Aged; D000666:Amphotericin B; D000935:Antifungal Agents; D002175:Candida; D002177:Candidiasis; D002358:Cartilage, Articular; D000077336:Caspofungin; D004359:Drug Therapy, Combination; D005260:Female; D015725:Fluconazole; D006801:Humans", "nlm_unique_id": "101594885", "other_id": null, "pages": "866-868", "pmc": null, "pmid": "31179850", "pubdate": "2019", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "17826283;19161556;25809970;27777756;27832049;27881617;27988485;28378904;28540147;29325167;29655180;29778657;30120434;30281988;30293877;30561310;30773703;7625624", "title": "Successful treatment of a Candida auris intra-articular infection.", "title_normalized": "successful treatment of a candida auris intra articular infection" }

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{ "abstract": "BACKGROUND\nUlcerative colitis is a lifelong, immunologically mediated disease. Direct-acting antivirals (DAAs) are now available for the treatment of chronic hepatitis C virus (HCV) infection. An interferon-free regimen appears useful, safe and effective for many patients for whom interferon-based treatment is contraindicated.\n\n\nMETHODS\nWe studied a 56-year-old treatment-naïve Japanese man with chronic HCV genotype 2b infection who had ulcerative colitis. This patient was treated with sofosbuvir and ribavirin for 12 weeks. During treatment, diarrhoea and bloody faeces were frequent. After ribavirin was reduced to 400 mg daily, these symptoms decreased. Finally, the patient achieved a sustained virologic response 12 weeks after the stoppage of the treatment.\n\n\nCONCLUSIONS\nClinicians should pay careful attention to the ribavirin dose in the treatment of certain HCV patients with inflammatory bowel disease who are receiving sofosbuvir plus ribavirin.", "affiliations": "Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.;Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan. kandat-cib@umin.ac.jp.;Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.;Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.;Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.;Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.;Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.;Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.;Department of Molecular Virology, Chiba University, Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.;Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.;Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.", "authors": "Ohta|Yuki|Y|;Kanda|Tatsuo|T|;Katsuno|Tatsuro|T|;Yasui|Shin|S|;Haga|Yuki|Y|;Sasaki|Reina|R|;Nakamura|Masato|M|;Wu|Shuang|S|;Nakamoto|Shingo|S|;Arai|Makoto|M|;Yokosuka|Osamu|O|", "chemical_list": "D000998:Antiviral Agents; D012254:Ribavirin; D000069474:Sofosbuvir", "country": "England", "delete": false, "doi": "10.1186/s12876-016-0480-x", "fulltext": "\n==== Front\nBMC GastroenterolBMC GastroenterolBMC Gastroenterology1471-230XBioMed Central London 48010.1186/s12876-016-0480-xCase ReportSuccessful sofosbuvir treatment with ribavirin dose reduction for chronic hepatitis C virus genotype 2 infection in a patient with ulcerative colitis: a case report Ohta Yuki soccersukisuki4@yahoo.co.jp Kanda Tatsuo kandat-cib@umin.ac.jp Katsuno Tatsuro katsuno@faculty.chiba-u.jp Yasui Shin ntcph863@yahoo.co.jp Haga Yuki hagayuki@gmail.com Sasaki Reina reina_sasaki_0925@yahoo.co.jp Nakamura Masato nkmr.chiba@gmail.com Wu Shuang gosyou100@yahoo.co.jp Nakamoto Shingo nakamotoer@yahoo.co.jp Arai Makoto araim-cib@umin.ac.jp Yokosuka Osamu yokosukao@faculty.chiba-u.jp Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670 Japan Department of Molecular Virology, Chiba University, Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670 Japan 11 7 2016 11 7 2016 2016 16 6617 2 2016 7 6 2016 © The Author(s). 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\nUlcerative colitis is a lifelong, immunologically mediated disease. Direct-acting antivirals (DAAs) are now available for the treatment of chronic hepatitis C virus (HCV) infection. An interferon-free regimen appears useful, safe and effective for many patients for whom interferon-based treatment is contraindicated.\n\nCase presentation\nWe studied a 56-year-old treatment-naïve Japanese man with chronic HCV genotype 2b infection who had ulcerative colitis. This patient was treated with sofosbuvir and ribavirin for 12 weeks. During treatment, diarrhoea and bloody faeces were frequent. After ribavirin was reduced to 400 mg daily, these symptoms decreased. Finally, the patient achieved a sustained virologic response 12 weeks after the stoppage of the treatment.\n\nConclusion\nClinicians should pay careful attention to the ribavirin dose in the treatment of certain HCV patients with inflammatory bowel disease who are receiving sofosbuvir plus ribavirin.\n\nKeywords\nCase reportDirect-acting antiviral (DAA)Hepatitis C virus (HCV)Interferon-freeRibavirinUlcerative colitisissue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nInflammatory bowel disease (IBD), which comprises ulcerative colitis and Crohn’s disease, is a chronic immunologically mediated disease [1]. There are high-prevalence populations of IBD in North America and Europe [1]. In India and Japan, the incidence is increasing [1]. Ulcerative colitis is a lifelong, immunologically mediated disease and results from the inappropriate activation of the mucosal immune system by intestinal luminal antigens [2], although the progress in treatment of ulcerative colitis has been observed [2, 3].\n\nThe prevalences of hepatitis B virus (HBV) and hepatitis C virus (HCV) in patients with IBD are similar to those in the general population [4, 5], although these data are controversial [6, 7]. Because the prevalences of HBV and HCV are higher in Asian countries, including Japan, than those in non-Asian countries [8, 9], the management of these infectious diseases is still important in patients with IBD.\n\nInterferon-α, which was previously the most common treatment for HCV, is a proinflammatory cytokine and can provoke a relapse of ulcerative colitis [10]. The synthetic guanosine analogue ribavirin (1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide) is also used for HCV eradication [11, 12]. The exacerbation of ulcerative colitis has also been reported during and/or after combination therapy with peginterferon plus ribavirin for chronic hepatitis C [13–15].\n\nRecent advances in the treatment of patients infected with HCV make it possible to eradicate this virus with interferon-free regimens. Sofosbuvir is a potent nucleotide inhibitor for HCV RNA-dependent polymerase [16]. The combination of sofosbuvir and ribavirin led to higher sustained virologic response (SVR) rates in HCV genotype 2-infected individuals [16]. We report an ulcerative colitis-patient who was chronically infected with HCV genotype 2 and was successfully treated with sofosbuvir plus dose reduction of ribavirin for 12 weeks.\n\nCase presentation\nA 56-year-old man with a 31-year history of ulcerative colitis was diagnosed with HCV infection at age 46. The patient received a blood transfusion at age 4 when he had surgery for his jaw and denied other risk factors for HCV infection, including tattoos or intravenous drug use. The patient drank alcohol (21 g daily) for 20 years; had a medical history of hypertension, IgA nephropathy, type 2 diabetes mellitus and dilated cardiomyopathy; and took several medications for these diseases. His ulcerative colitis was relatively well-controlled with oral sarazopyridine (4500 mg daily) and a sarazopyridine suppository (300 mg daily). The HCV genotype was 2b, and the patient was interferon treatment-naïve because he had ulcerative colitis, an autoimmune disease.\n\nThe patient’s height and body weight were 172 cm and 88.3 kg, respectively, and his body temperature was 35.2 °C. His laboratory findings before treatment are shown in Table 1. Abdominal ultrasound findings showed no masses in the liver and no ascites. Liver stiffness as measured by transient elastography was 7.6 kPa, indicating the absence of cirrhosis. Although he had chronic significant amount of alcohol intake, the ultrasound findings did not show the fatty change of the liver. He wanted to be treated for his chronic hepatitis C.Table 1 Laboratory findings before treatment\n\nItem\tValue\tItem\tValue\tItem\tValue\t\nAST\t51 IU/L\tBUN\t16 mg/dL\tHBsAg\tnegative\t\nALT\t66 IU/L\tCreatinine\t0.68 mg/dL\tAnti-HCV\tpositive\t\nLDH\t256 IU/L\tUA\t4.3 mg/dL\tHCV RNA\t6.4 logIU/mL\t\nALP\t96 IU/L\tNa\t136 mEq/L\tHCV genotype\t2b\t\nγ-GTP\t88 IU/L\tK\t3.9 mEq/L\tAnti-HIV\tnegative\t\nT. Bil\t1.2 mg/dL\tCl\t104 mEq/L\tHyaluronic acid\t37 ng/mL\t\nTP\t7.1 g/dL\tWBC\t5900/μL\tAFP\t7.4 ng/mL\t\nAlbumin\t3.9 g/dL\tRBC\t477 × 104/μL\tPIVKA-II\t32 mAU/mL\t\nAmylase\t83 IU/L\tHemoglobin\t14.4 g/dL\tNH3\n\t58 μg/dL\t\nCPK\t102 IU/L\tHaematocrit\t40.7 %\tHbA1c\t7.8 %\t\nT.CHO\t115 mg/dL\tPlatelets\t15.6 × 104/μL\tCRP\t0.1 mg/dL\t\nTG\t103 mg/dL\tPT\t100 %\t\t\t\n\nAFP α-Fetoprotein, ALP alkaline phosphatase, BUN blood urea nitrogen, CPK creatine phosphokinase, CRP C-reactive protein, HbA1c haemoglobin A1c, LDH lactate dehydrogenase, PIVKA-II protein induced by vitamin K absence or antagonists-II, PT prothrombin time, RBC red blood cell count, T.Bil total bilirubin, T.CHO total cholesterol, TG triglyceride, TP total protein, UA uric acid, WBC white blood cell count\n\n\n\nThe patient was treated with sofosbuvir at 400 mg daily and ribavirin at 600 mg daily. One week after the initiation of this treatment, the patient felt general malaise without any adverse events [white blood cell count (WBC), 7900/μL; hemoglobin, 14.7 g/dL; C-reactive protein (CRP) 0.0 mg/dL; AST, 35 IU/L; and ALT, 49 IU/L]. By week 3, the patient was having up to 10 loose bowel movements per day, with small amounts of blood. As the patient’s HCV RNA became negative and he improved to having 5 loose bowel movements per day by week 4 [WBC, 8600/μL; hemoglobin, 14.3 g/dL; AST, 19 IU/L; and ALT, 19 IU/L], the dose of ribavirin was increased to 800 mg daily. By week 7, however, the patient was having up to 20 loose bowel movements per day, with small amounts of blood, and the dose of ribavirin was decreased to 400 mg daily [WBC, 8200/μL; hemoglobin, 14.7 g/dL; CRP 0.1 mg/dL; AST, 19 IU/L; and ALT, 17 IU/L]. By week 8, the patient improved to having 10 loose bowel movements per day [WBC, 8600/μL; hemoglobin, 14.2 g/dL; CRP 0.1 mg/dL; AST, 20 IU/L; and ALT, 17 IU/L], and by week 11, his diarrhoea had resolved. Finally, the patient was treated with sofosbuvir plus ribavirin for 12 weeks. By week 12 after the initiation of this treatment, the patient’s HCV RNA was negative, and he had achieved a SVR 12 weeks (SVR12) after the stoppage of treatment [WBC, 14400/μL; hemoglobin, 16.2 g/dL; CRP 0.2 mg/dL; AST, 22 IU/L; and ALT, 22 IU/L] (Fig. 1). Three weeks post-treatment, an endoscopic examination of the colon-rectum confirmed that the mucosa was oedematous from the colon transversum to the rectum, although mucosal vascular permeability was reduced from the sigmoid colon to the rectum. The patient did not complain of abdominal pain or fever during treatment.Fig. 1 Clinical course of the patient. ALT alanine transaminase, WBC white blood cells, w weeks, Neg negative\n\n\n\nDiscussion\nIn the present report, we present a 56-year-old HCV genotype 2-infected patient who was diagnosed with ulcerative colitis and achieved a SVR12 after combination treatment with sofosbuvir plus ribavirin for 12 weeks. In Japanese multicentre, open-label phase 3 trial, HCV genotype 2-infected patients received 12 weeks of treatment with 400 mg of sofosbuvir, administered orally once daily, and ribavirin, administered orally twice daily, with doses determined according to body weight (1000 mg daily in patients with a body weight of >80 kg) [17]. But initial dose of the present case was 600 mg daily because we are afraid of adverse events of ribavirin. During treatment, the patient’s diarrhoea worsened, and the reduction of ribavirin with no reduction of sofosbuvir led to improvement in this symptom and the completion of therapy.\n\nThe mechanism of the inhibition of HCV replication by ribavirin is as follows: (1) ribavirin induces mutagenesis in HCV RNA; (2) ribavirin inhibits HCV RNA-dependent polymerase; (3) ribavirin inhibits the inosine monophosphate dehydrogenase enzyme and reduces intracellular guanosine pools, which are essential for HCV replication; and (4) ribavirin stimulates the T helper 1 (Th1) antiviral response, which leads to HCV eradication [8, 11, 12]. Ulcerative colitis is vaguely associated with abnormal Th2 immunity [18]. Although we do not know the exact effects of ribavirin on mucosal immunity, ribavirin worsened the symptoms of the present case with ulcerative colitis.\n\nAlthough 12-week-treatment with sofosbuvir and ribavirin could lead to diarrhoea in 9 % of HCV genotype 2/3-infected patients [16], of interest, 12-week-treatment with sofosbuvir and ledipasvir could lead to diarrhoea in only 4 % of HCV genotype 1-infected patients [19]. We could not completely rule out the possibility that the combination of sofosbuvir plus ribavirin might be responsible, compared the only ribavirin.\n\nOne year before treatment, an endoscopic examination of the colon-rectum demonstrated that mucosal vascular permeability was reduced from the sigmoid colon to the rectum with marked mucus exudates. We could not completely rule out the possibility that this patient had baseline active mucosal disease but asymptomatic and then developed diarrhoea due to the sofosbuvir and ribavirin treatment. Although one important differential diagnosis of flare of ulcerative colitis is infection, as this patient did not have a high fever, we did not perform stool culture or use any antibiotics other than sarazopyridine. So we excluded bacterial infection in this patient.\n\nHCV infection is a current leading cause of HCC in Japan and the United States [12]. This patient should be followed up for the occurrence of HCC [12]. Coexistence of IBD and chronic liver diseases, including chronic hepatitis C, leads to higher mortality rates than IBD alone [20]. Interferon-free therapy with or without ribavirin could increase treatment efficacy and shorten treatment duration compared with previous standards of care, such as peginterferon plus ribavirin treatment. However, the clinician should pay special attention to the use of ribavirin in the management of HCV-infected patients with IBD.\n\nConclusion\nWe studied a HCV genotype 2b-infected patient with an ulcerative colitis exacerbation during sofosbuvir plus ribavirin treatment. The reduction of ribavirin improved this symptom, and the patient finally achieved a SVR12. Clinicians should pay careful attention to the ribavirin dose in the treatment of certain HCV patients with inflammatory bowel diseases, such as ulcerative colitis, in sofosbuvir plus ribavirin treatment.\n\nAbbreviations\nHBV, hepatitis B virus; HCV, hepatitis C virus; IBD, inflammatory bowel disease; SVR, sustained virologic response; SVR12, SVR at 12 weeks; Th, T helper\n\nAcknowledgements\nAuthors thank all Chiba University Hospital’s staff for patient’s care.\n\nFunding\nNot applicable.\n\nAvailability of data and materials\nNot applicable.\n\nAuthors’ contributions\nYO, TK and TK saw the patient and drafted the manuscript. All authors revised manuscript and approved the final manuscript.\n\nCompeting interests\nTK and OY received lecture fees from Gilead Sciences. The other authors have no competing interest to disclose.\n\nConsent for publication\nWritten informed consent was obtained from the patient for the publication of this case report and these data. A copy of the written consent is available for review by the editor of this journal. This case report did not require the review by the Institutional Review Board of Chiba University School of Medicine.\n\nEthics approval and consent to participate\nNot applicable.\n==== Refs\nReferences\n1. Ananthakrishnan AN Epidemiology and risk factors for IBD Nat Rev Gastroenterol Hepatol 2015 12 4 205 17 10.1038/nrgastro.2015.34 25732745 \n2. Lawrance IC Early investigational TNF receptor antagonists for the treatment of ulcerative colitis Expert Opin Investig Drugs 2015 24 6 761 8 10.1517/13543784.2015.1020371 25719407 \n3. Seo GS Chae SC Biological therapy for ulcerative colitis: an update World J Gastroenterol 2014 20 37 13234 8 10.3748/wjg.v20.i37.13234 25309060 \n4. Papa A Felice C Marzo M Andrisani G Armuzzi A Covino M Prevalence and natural history of hepatitis B and C infections in a large population of IBD patients treated with anti-tumor necrosis factor-α agents J Crohns Colitis 2013 7 2 113 9 10.1016/j.crohns.2012.03.001 22464811 \n5. Chevaux JB Nani A Oussalah A Venard V Bensenane M Belle A Prevalence of hepatitis B and C and risk factors for nonvaccination in inflammatory bowel disease patients in Northeast France Inflamm Bowel Dis 2010 16 6 916 24 10.1002/ibd.21147 19885908 \n6. Loras C Saro C Gonzalez-Huix F Mínguez M Merino O Gisbert JP Prevalence and factors related to hepatitis B and C in inflammatory bowel disease patients in Spain: a nationwide, multicenter study Am J Gastroenterol 2009 104 1 57 63 10.1038/ajg.2008.4 19098850 \n7. Lidar M Langevitz P Barzilai O Ram M Porat-Katz BS Bizzaro N Infectious serologies and autoantibodies in inflammatory bowel disease: insinuations at a true pathogenic role Ann N Y Acad Sci 2009 1173 640 8 10.1111/j.1749-6632.2009.04673.x 19758210 \n8. Omata M Kanda T Yu ML Yokosuka O Lim SG Jafri W APASL consensus statements and management algorithms for hepatitis C virus infection Hepatol Int 2012 6 2 409 35 10.1007/s12072-012-9342-y 26201405 \n9. Sarin SK Kumar M Lau GK Abbas Z Chan HL Chen CJ Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update Hepatol Int 2016 10 1 1 98 10.1007/s12072-015-9675-4 26563120 \n10. Sawada K Ohnishi K Fukunaga K Shimoyama T A new treatment for HCV-ulcerative colitis comorbidity intolerant to INF-alpha Am J Gastroenterol 2003 98 1 228 9 12526978 \n11. Kanda T Yokosuka O Imazeki F Tanaka M Shino Y Shimada H Inhibition of subgenomic hepatitis C virus RNA in Huh-7 cells: ribavirin induces mutagenesis in HCV RNA J Viral Hepat 2004 11 6 479 87 10.1111/j.1365-2893.2004.00531.x 15500548 \n12. Kanda T Imazeki F Yokosuka O New antiviral therapies for chronic hepatitis C Hepatol Int 2010 4 3 548 61 10.1007/s12072-010-9193-3 21063477 \n13. Sprenger R Sagmeister M Offner F Acute ulcerative colitis during successful interferon/ribavirin treatment for chronic hepatitis Gut 2005 54 3 438 9 15710996 \n14. Tursi A Rapid onset of ulcerative colitis after treatment with PEG-interferon plus ribavirin for chronic hepatitis C Inflamm Bowel Dis 2007 13 9 1189 90 10.1002/ibd.20152 17427238 \n15. Morimoto K Yamagami H Hosomi S Ohira M Suekane T Kamata N Development of pouchitis with combination therapy with peg-interferon alpha-2b and ribavirin for chronic hepatitis C in a patient with ulcerative colitis who underwent pouch surgery Am J Gastroenterol 2009 104 6 1609 10 10.1038/ajg.2009.120 19491886 \n16. Jacobson IM Gordon SC Kowdley KV Yoshida EM Rodriguez-Torres M Sulkowski MS Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options N Engl J Med 2013 368 20 1867 77 10.1056/NEJMoa1214854 23607593 \n17. Omata M Nishiguchi S Ueno Y Mochizuki H Izumi N Ikeda F Sofosbuvir plus ribavirin in Japanese patients with chronic genotype 2 HCV infection: an open-label, phase 3 trial J Viral Hepat 2014 21 11 762 8 10.1111/jvh.12312 25196837 \n18. Neurath MF Finotto S Glimcher LH The role of Th1/Th2 polarization in mucosal immunity Nat Med 2002 8 6 567 73 10.1038/nm0602-567 12042806 \n19. Kowdley KV Gordon SC Reddy KR Rossaro L Bernstein DE Lawitz E Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis N Engl J Med 2014 370 1879 88 10.1056/NEJMoa1402355 24720702 \n20. Bargiggia S Thorburn D Anderloni A Ardizzone S Giorgi A Bianchi Porro G Is interferon-alpha therapy safe and effective for patients with chronic hepatitis C and inflammatory bowel disease? A case-control study Aliment Pharmacol Ther 2005 22 3 209 15 10.1111/j.1365-2036.2005.02556.x 16091058\n\n", "fulltext_license": "CC BY", "issn_linking": "1471-230X", "issue": "16(1)", "journal": "BMC gastroenterology", "keywords": "Case report; Direct-acting antiviral (DAA); Hepatitis C virus (HCV); Interferon-free; Ribavirin; Ulcerative colitis", "medline_ta": "BMC Gastroenterol", "mesh_terms": "D000998:Antiviral Agents; D003093:Colitis, Ulcerative; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005838:Genotype; D019698:Hepatitis C, Chronic; D006801:Humans; D008297:Male; D008875:Middle Aged; D012254:Ribavirin; D000069474:Sofosbuvir", "nlm_unique_id": "100968547", "other_id": null, "pages": "66", "pmc": null, "pmid": "27401874", "pubdate": "2016-07-11", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "12042806;15710996;19885908;25719407;16091058;19098850;12526978;21063477;25196837;23607593;26563120;25732745;17427238;25309060;15500548;24720702;22464811;19491886;26201405;19758210", "title": "Successful sofosbuvir treatment with ribavirin dose reduction for chronic hepatitis C virus genotype 2 infection in a patient with ulcerative colitis: a case report.", "title_normalized": "successful sofosbuvir treatment with ribavirin dose reduction for chronic hepatitis c virus genotype 2 infection in a patient with ulcerative colitis a case report" }

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SUCCESSFUL SOFOSBUVIR TREATMENT WITH RIBAVIRIN DOSE REDUCTION FOR CHRONIC HEPATITIS C VIRUS GENOTYPE 2 INFECTION IN A PATIENT WITH ULCERATIVE COLITIS: A CASE REPORT. 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SUCCESSFUL SOFOSBUVIR TREATMENT WITH RIBAVIRIN DOSE REDUCTION FOR CHRONIC HEPATITIS C VIRUS GENOTYPE 2 INFECTION IN A PATIENT WITH ULCERATIVE COLITIS: A CASE REPORT. 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SUCCESSFUL SOFOSBUVIR TREATMENT WITH RIBAVIRIN DOSE REDUCTION FOR CHRONIC HEPATITIS C VIRUS GENOTYPE 2 INFECTION IN A PATIENT WITH ULCERATIVE COLITIS: A CASE REPORT. 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null, "medicinalproduct": "RIBAVIRIN." } ], "patientagegroup": "5", "patientonsetage": "56", "patientonsetageunit": "801", "patientsex": "1", "patientweight": "88.3", "reaction": [ { "reactionmeddrapt": "Colitis ulcerative", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "OHTA Y, KANDA T, KATSUNO T, YASUI S, HAGA Y, SASAKI R ET AL.. SUCCESSFUL SOFOSBUVIR TREATMENT WITH RIBAVIRIN DOSE REDUCTION FOR CHRONIC HEPATITIS C VIRUS GENOTYPE 2 INFECTION IN A PATIENT WITH ULCERATIVE COLITIS: A CASE REPORT. BMC GASTROENTEROLOGY. 2016;16:1-4", "literaturereference_normalized": "successful sofosbuvir treatment with ribavirin dose reduction for chronic hepatitis c virus genotype 2 infection in a patient with ulcerative colitis a case report", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20160803", "receivedate": "20160803", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12620091, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20161109" } ]

{ "abstract": "In December 20XX-1, abdominal enhanced CT of a 73-year-old female patient showed a 28mm-in-diameter pancreatic tail cancer with splenic venous invasion. She underwent neoadjuvant GEM/TS-1 combination chemotherapy but abandoned this chemotherapy due to melena and exanthema. She underwent a distal pancreatectomy with lymph node dissemination. In these pathological findings, the tumor was diagnosed as a pancreatic tail cancer with splenic venous invasion(T3, N0, M0, Stage ⅡA). She underwent adjuvant GEM chemotherapy, but she abandoned this chemotherapy due to exanthema and was managed with observation. In September 20XX, she had a postoperative bowel obstruction and was treated with natural light. However, she had a postoperative bowel obstruction again in July, 20XX+1. Fluoroscopic images revealed stenosis in the intestine located 170 cm from the nasal cavity. She underwent open surgery to manage the bowel obstruction. There was a peritoneal tumor with adhesion to each intestine serosa in 3 areas located 80 cm, 100 cm, and 150 cm from the Treitz ligament. Therefore, she underwent a small intestine resection and anastomosis 70 cm to 110 cm from the Treitz ligament. Pathological findings showed that there was a 3mm-in-diameter adenocarcinoma in this peritoneal tumor. In these findings, this final diagnosis was an adhesive intestinal obstruction caused by peritoneal metastasis. Curative resection for single peritoneal recurrent metastasis might be useful for prognosis prolongation.", "affiliations": "Dept. of Gastrointestinal Surgery, Hyogo Prefectural Nishinomiya Hospital.", "authors": "Ota|Hideo|H|;Yokoyama|Shigekazu|S|;Honda|Shoko|S|;Ito|Kazuma|K|;Miyazaki|Hidetaka|H|;Ueda|Hiroki|H|;Takiguchi|Nobuo|N|;Nakai|Shigeto|S|;Matsuno|Hiroshi|H|;Takeoka|Tomohira|T|;Konishi|Ken|K|;Okada|Kazuyuki|K|;Fukunaga|Mutsumi|M|;Kobayashi|Kenji|K|", "chemical_list": null, "country": "Japan", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0385-0684", "issue": "47(4)", "journal": "Gan to kagaku ryoho. Cancer & chemotherapy", "keywords": null, "medline_ta": "Gan To Kagaku Ryoho", "mesh_terms": "D000368:Aged; D005260:Female; D006801:Humans; D007415:Intestinal Obstruction; D010180:Pancreatectomy; D010190:Pancreatic Neoplasms; D010534:Peritoneal Neoplasms; D010537:Peritoneum", "nlm_unique_id": "7810034", "other_id": null, "pages": "718-721", "pmc": null, "pmid": "32389995", "pubdate": "2020-04", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "A Case of Intestinal Obstruction Caused by Peritoneal Metastatic Recurrence One Year after Radical Operation for Pancreatic Cancer.", "title_normalized": "a case of intestinal obstruction caused by peritoneal metastatic recurrence one year after radical operation for pancreatic cancer" }

[ { "companynumb": "JP-TEVA-2021-JP-1882289", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "GEMCITABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "079160", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PANCREATIC CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GEMCITABINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "GIMERACIL\\OTERACIL\\TEGAFUR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PANCREATIC CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TS?1" } ], "patientagegroup": "6", "patientonsetage": "73", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Gastrointestinal disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Ileal ulcer", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rash", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug eruption", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "OTA H, YOKOYAMA S, HONDA S, ITO K, MIYAZAKI H, UEDA H, ET AL. A CASE OF INTESTINAL OBSTRUCTION CAUSED BY PERITONEAL METASTATIC RECURRENCE ONE YEAR AFTER RADICAL OPERATION FOR PANCREATIC CANCER. GAN?TO?KAGAKU?RYOHO 2020?47(4):718?721.", "literaturereference_normalized": "a case of intestinal obstruction caused by peritoneal metastatic recurrence one year after radical operation for pancreatic cancer", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20210225", "receivedate": "20210225", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18936006, "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" }, { "companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2022RR-331917", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "GEMCITABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "78433", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Pancreatic carcinoma", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GEMCITABINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "GIMERACIL\\OTERACIL\\TEGAFUR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Pancreatic carcinoma", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TS-1" } ], "patientagegroup": null, "patientonsetage": "73", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haematochezia", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Intestinal mucosal atrophy", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug eruption", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Ota H, Yokoyama S, Honda S, Ito K, Miyazaki H, Ueda H, et al. A case of intestinal obstruction caused by peritoneal metastatic recurrence one year after radical operation for pancreatic cancer. Gan To Kagaku Ryoho. 2020;47(4):718-721", "literaturereference_normalized": "a case of intestinal obstruction caused by peritoneal metastatic recurrence one year after radical operation for pancreatic cancer", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20220404", "receivedate": "20220404", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20667555, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220721" } ]

{ "abstract": "BACKGROUND\nReports since 2006 have identified proton-pump inhibitor (PPI) therapy as a cause of hypomagnesaemia, in a total of 13 cases.\n\n\nOBJECTIVE\nTo summarize the clinical course of 10 patients (one male, nine female) identified with severe hypomagnesaemia, all of whom were on PPI therapy. A case report illustrates the experience of a severely affected patient.\n\n\nMETHODS\nClinical and biochemical review. Severe hypomagnesaemia was defined as 0.54 mmol/l or less, >4 SD below the mean.\n\n\nRESULTS\nPatients were 68.8 +/- 8.6 years old when they presented with severe hypomagnesaemia, having been on PPI therapy for a mean of 8.3 +/- 3.5 years. Eight patients were on diuretics at initial presentation. There was significant morbidity as eight patients remained on PPI therapy after presentation for a mean of 2.75 +/- 1.54 years. There were 18 emergency hospital admissions with severe hypomagnesaemia. Oral and parenteral magnesium supplements were relatively ineffective at correcting the problem, but stopping PPI therapy lead to prompt resolution of the hypomagnesaemia (within 2 weeks in five carefully monitored patients), with symptomatic benefit. Hypomagnesaemia recurred if PPI therapy was re-introduced because of troublesome dyspepsia. However, pantoprazole, the least potent PPI, largely relieved dyspepsia and hypomagnesaemia did not inevitably develop when combined with oral magnesium supplements.\n\n\nCONCLUSIONS\nThese cases confirm that long-term PPI therapy can cause severe, symptomatic hypomagnesaemia, which resolves when PPI therapy is withdrawn. The serum magnesium should be checked annually in patients on long-term PPI therapy, or if they feel unwell.", "affiliations": "Victoria Hospital, Blackpool FY3 8NR, UK. dr.mackay@bfwhospitals.nhs.uk", "authors": "Mackay|J D|JD|;Bladon|P T|PT|", "chemical_list": "D054328:Proton Pump Inhibitors", "country": "England", "delete": false, "doi": "10.1093/qjmed/hcq021", "fulltext": null, "fulltext_license": null, "issn_linking": "1460-2393", "issue": "103(6)", "journal": "QJM : monthly journal of the Association of Physicians", "keywords": null, "medline_ta": "QJM", "mesh_terms": "D000368:Aged; D005260:Female; D005764:Gastroesophageal Reflux; D006801:Humans; D006996:Hypocalcemia; D008275:Magnesium Deficiency; D008297:Male; D008875:Middle Aged; D054328:Proton Pump Inhibitors; D028761:Withholding Treatment", "nlm_unique_id": "9438285", "other_id": null, "pages": "387-95", "pmc": null, "pmid": "20378675", "pubdate": "2010-06", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Hypomagnesaemia due to proton-pump inhibitor therapy: a clinical case series.", "title_normalized": "hypomagnesaemia due to proton pump inhibitor therapy a clinical case series" }

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"activesubstancename": "LANSOPRAZOLE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "020406", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNK", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "GASTROOESOPHAGEAL REFLUX DISEASE", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "1994", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LANSOPRAZOLE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PANTOPRAZOLE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, 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null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CIMETIDINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "RANITIDINE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNK", "drugdosagetext": "150 MILLIGRAM, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "GASTROOESOPHAGEAL REFLUX DISEASE", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RANITIDINE." } ], "patientagegroup": null, "patientonsetage": "73", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Dyspepsia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Abdominal pain", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Lethargy", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Balance disorder", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypocalcaemia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypomagnesaemia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Circulatory collapse", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Fall", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Chest pain", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Arthralgia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rash pruritic", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Muscle spasms", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tetany", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Paraesthesia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 200506" } }, "primarysource": { "literaturereference": "P T BLADON. HYPOMAGNESAEMIA DUE TO PROTON-PUMP INHIBITOR THERAPY: A CLINICAL CASE SERIES. 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HYPOMAGNESAEMIA DUE TO PROTON-PUMP INHIBITOR THERAPY: A CLINICAL CASE SERIES.. 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"drugdosagetext": "20-40MG DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "GASTROOESOPHAGEAL REFLUX DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "1999", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMEPRAZOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CIMETIDINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "800 MG, 3X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "3", "drugstartdate": "200812", "drugstartdateformat": "610", "drugstructuredosagenumb": "800", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CIMETIDINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RANITIDINE" }, "drugadditional": "3", "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": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RANITIDINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LANSOPRAZOLE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "30-60MG DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "GASTROOESOPHAGEAL REFLUX DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "1994", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LANSOPRAZOLE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "BENDROFLUMETHIAZIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2.5 MG, 1X/DAY", "drugenddate": "2005", "drugenddateformat": "602", "drugindication": "HYPERTENSION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2001", "drugstartdateformat": "602", "drugstructuredosagenumb": "2.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BENDROFLUMETHIAZIDE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PANTOPRAZOLE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "020987", "drugbatchnumb": null, "drugcharacterization": "1", "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": "PANTOPRAZOLE" } ], "patientagegroup": null, "patientonsetage": "73", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Arthralgia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tetany", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Balance disorder", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rash", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Circulatory collapse", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypomagnesaemia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypocalcaemia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Fall", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dyspepsia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Abdominal pain", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Muscle spasms", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Chest pain", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Paraesthesia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Lethargy", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 200506" } }, "primarysource": { "literaturereference": "MACKAY JD, BLADON PT. HYPOMAGNESAEMIA DUE TO PROTON-PUMP INHIBITOR THERAPY: A CLINICAL CASE SERIES. QJM. 2010?103:387-395", "literaturereference_normalized": "hypomagnesaemia due to proton pump inhibitor therapy a clinical case series", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20200416", "receivedate": "20200416", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17675853, "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": "The incidence of colorectal cancer in pregnancy is between 0.002 and 0.008%. Diagnosis is often delayed as symptoms of colorectal cancer can mimic as common complaints of pregnancy. We present the case of a 29-year-old with a history of chronic constipation who presented in the second trimester with abdominal pain, inability to tolerate anything orally and no bowel movement in more than three weeks. Non-contrast MRI at presentation failed to show an obstructing mass. Patient was treated conservatively for presumed pseudo-obstruction secondary to worsening constipation from chronic ondansetron use and pregnancy. After four days without clinical improvement, she had a colonoscopy that revealed a completely obstructing sigmoid mass, which biopsies confirmed was a primary colorectal adenocarcinoma. The patient underwent a total abdominal colectomy. She was referred to medical oncology and began adjuvant chemotherapy consisting of 5-fluorouracil, leucovorin and oxaloplatin four weeks post-operatively.", "affiliations": "Department of Obstetrics and Gynecology, Warren Alpert Medical School of Brown University/Women & Infants Hospital, Providence, RI, USA.;Department of Gastroenterology, Warren Alpert Medical School of Brown University/Women & Infants Hospital, Providence, RI, USA.;Department of Gastroenterology, Warren Alpert Medical School of Brown University/Women & Infants Hospital, Providence, RI, USA.", "authors": "Makhijani|Reeva|R|;Bhagat|Vicky H|VH|;Fayek|Mariam|M|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1177/1753495X17704611", "fulltext": null, "fulltext_license": null, "issn_linking": "1753-495X", "issue": "10(4)", "journal": "Obstetric medicine", "keywords": "Oncology; gastroenterology; general medicine", "medline_ta": "Obstet Med", "mesh_terms": null, "nlm_unique_id": "101464191", "other_id": null, "pages": "198-200", "pmc": null, "pmid": "29225684", "pubdate": "2017-12", "publication_types": "D002363:Case Reports", "references": "18753184;19745695;10520866;15339791;21803658;18357450;21733678;19089778;23481143;20105201;16370042;21642686;23921869;16523466", "title": "Colon cancer presenting as pseudo-obstruction during pregnancy - A case report.", "title_normalized": "colon cancer presenting as pseudo obstruction during pregnancy a case report" }

[ { "companynumb": "US-TARO PHARMACEUTICALS USA.,INC-2017SUN00447", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ONDANSETRON HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "77009", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "VOMITING IN PREGNANCY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ONDANSETRON HYDROCHLORIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "POLYETHYLENE GLYCOLS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, DAILY", "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": "POLYETHYLENE GLYCOL" } ], "patientagegroup": null, "patientonsetage": "29", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Constipation", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Maternal exposure during pregnancy", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Adenocarcinoma of colon", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MAKHIJANI R, BHAGAT VH, FAYEK M. COLON CANCER PRESENTING AS PSEUDO-OBSTRUCTION DURING PREGNANCY - A CASE REPORT. OBSTET MED. 2017?10(4):198-200", "literaturereference_normalized": "colon cancer presenting as pseudo obstruction during pregnancy a case report", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20180102", "receivedate": "20180102", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14341978, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180509" } ]

{ "abstract": "Human herpesvirus 8 (HHV-8), also known as Kaposi's sarcoma (KS)-associated herpesvirus, is involved in KS and other tumors, including multicentric Castleman's disease and primary effusion lymphoma. Rituximab (RTX) is currently used for the treatment of several autoimmune or inflammatory diseases and humoral organ transplant rejection. De novo HHV-8 tumors induced by RTX used for these indications have not been reported previously. This study was undertaken to evaluate de novo HHV-8 tumors induced by RTX.\n\n\n\nIn this retrospective study, we investigated the clinical, virologic, and pathologic features of 5 HIV-negative male patients with HHV-8 tumors induced by RTX therapy.\n\n\n\nPatients were all immunocompromised by previous treatments, which consisted of steroids and/or immunosuppressive agents, and received RTX for insufficient response, disease progression, or transplant rejection. They developed HHV-8 tumors a median of 4 months after beginning treatment with RTX (range 3-13 months). Four patients had at least 1 risk factor for HHV-8, including a high Fitzpatrick skin phototype (of >3) (n = 3) and homosexuality (n = 1). Four patients developed KS (all 4 had skin lesions and 2 had visceral involvement), and 1 patient developed a solid primary effusion lymphoma. RTX was discontinued in all patients, and immunosuppressants were reduced when feasible. After a median follow-up of 20 months, 2 patients died. Remission of KS was complete in 1 patient and partial in 1 patient, and 1 patient had progression.\n\n\n\nOur findings indicate that patients who have a high skin phototype and are at risk of HHV-8 should be carefully screened for HHV-8 before RTX therapy. The safety of RTX, especially in nonlymphomatous disorders, should be carefully evaluated in patients at risk of HHV-8 tumors.", "affiliations": "Sorbonne University, UPMC University of Paris 6, Unité fonctionnelle de Dermatologie, Groupe Hospitalier Pitié-Salpêtrière, AP-HP, Paris, France, and Médecine Interne, Centre Hospitalier Universitaire de Poitiers, Poitiers, France.;Sorbonne University, UPMC University of Paris 6, Département de Médecine Interne et Immunologie Clinique, National Center for Rare Autoimmune and Systemic Diseases and for Autoinflammatory Diseases, AP-HP, Paris, France.;Sorbonne University, UPMC University of Paris 6, Service de Virologie, Groupe Hospitalier Pitié-Salpêtrière, AP-HP, Paris, France.;Sorbonne University, UPMC University of Paris 6, Service de Virologie, Groupe Hospitalier Pitié-Salpêtrière, AP-HP, Paris, France.;Sorbonne University, UPMC University of Paris 6, Département de Médecine Interne et Immunologie Clinique, National Center for Rare Autoimmune and Systemic Diseases and for Autoinflammatory Diseases, AP-HP, INSERM, UMR-S 959, and Département Hospitalo-Universitaire Inflammation-Immunopathologie-Biotherapie, Paris, France.;Sorbonne University, UPMC University of Paris 6, Unité fonctionnelle de Dermatologie, Groupe Hospitalier Pitié-Salpêtrière, AP-HP, INSERM, UMR-S 959, and Département Hospitalo-Universitaire Inflammation-Immunopathologie-Biotherapie, Paris, France.", "authors": "Périer|Amandine|A|;Savey|Léa|L|;Marcelin|Anne-Geneviève|AG|;Serve|Philippe|P|;Saadoun|David|D|;Barete|Stéphane|S|", "chemical_list": "D007155:Immunologic Factors; D000069283:Rituximab", "country": "United States", "delete": false, "doi": "10.1002/art.40217", "fulltext": null, "fulltext_license": null, "issn_linking": "2326-5191", "issue": "69(11)", "journal": "Arthritis & rheumatology (Hoboken, N.J.)", "keywords": null, "medline_ta": "Arthritis Rheumatol", "mesh_terms": "D000328:Adult; D000368:Aged; D001327:Autoimmune Diseases; D006084:Graft Rejection; D016027:Heart Transplantation; D019288:Herpesvirus 8, Human; D006801:Humans; D007155:Immunologic Factors; D007414:Intestinal Neoplasms; D007674:Kidney Diseases; D008175:Lung Neoplasms; D054685:Lymphoma, Primary Effusion; D008297:Male; D008875:Middle Aged; D031300:Retinal Vasculitis; D012189:Retrospective Studies; D000069283:Rituximab; D012514:Sarcoma, Kaposi; D012878:Skin Neoplasms; D014565:Urogenital Neoplasms", "nlm_unique_id": "101623795", "other_id": null, "pages": "2241-2246", "pmc": null, "pmid": "28719723", "pubdate": "2017-11", "publication_types": "D016428:Journal Article", "references": null, "title": "De Novo Human Herpesvirus 8 Tumors Induced by Rituximab in Autoimmune or Inflammatory Systemic Diseases.", "title_normalized": "de novo human herpesvirus 8 tumors induced by rituximab in autoimmune or inflammatory systemic diseases" }

[ { "companynumb": "FR-ORION CORPORATION ORION PHARMA-TREX2017-3836", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "1", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INDUCTION DOSE ON DAY 0 AND 15", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "1", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MAINTENANCE DOSE OF 375 MG/M2 AT MONTH 5 AND 1 GM AT MONTH 10", "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": "RITUXIMAB." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "AZATHIOPRINE" }, "drugadditional": "1", "drugadministrationroute": "065", "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": "AZATHIOPRINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "1", "drugadministrationroute": "065", "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": "METHOTREXATE." } ], "patientagegroup": null, "patientonsetage": "52", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Kaposi^s sarcoma", "reactionmeddraversionpt": "20.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Lymphopenia", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Human herpesvirus 8 infection", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PERIER A,SAVEY L. DE NOVO HUMAN HERPESVIRUS 8 TUMORS INDUCED BY RITUXIMAB IN AUTOIMMUNE OR INFLAMMATORY SYSTEMIC DISEASES. ARTHRITIS RHEUMATOL. 2017 NOV;69(11):2241-6.", "literaturereference_normalized": "de novo human herpesvirus 8 tumors induced by rituximab in autoimmune or inflammatory systemic diseases", "qualification": "1", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20171201", "receivedate": "20171201", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14241824, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180321" }, { "companynumb": "FR-TEVA-2017-FR-831344", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HEART TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CICLOSPORIN" }, { "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": "HEART 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": "RITUXIMAB" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HEART TRANSPLANT", "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": "HUMAN IMMUNOGLOBULIN G" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HEART TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IMMUNE GLOBULIN" } ], "patientagegroup": null, "patientonsetage": "56", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lymphopenia", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Kaposi^s sarcoma", "reactionmeddraversionpt": "20.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "PERIER A, SAVEY L, MARCELIN AG, SERVE P, SAADOUN D, BARETE S. DE NOVO HUMAN HERPESVIRUS 8 TUMORS INDUCED BY RITUXIMAB IN AUTOIMMUNE OR INFLAMMATORY SYSTEMIC DISEASES. ARTHRITIS-RHEUMATOL 2017;69(11):2241-2246.", "literaturereference_normalized": "de novo human herpesvirus 8 tumors induced by rituximab in autoimmune or inflammatory systemic diseases", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20171208", "receivedate": "20171208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14261567, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180321" }, { "companynumb": "FR-TEVA-2017-FR-831346", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "1", 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"METHOTREXATE." } ], "patientagegroup": null, "patientonsetage": "52", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lymphopenia", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Kaposi^s sarcoma", "reactionmeddraversionpt": "20.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "PERIER A, SAVEY L, MARCELIN AG, SERVE P, SAADOUN D, BARETE S. DE NOVO HUMAN HERPESVIRUS 8 TUMORS INDUCED BY RITUXIMAB IN AUTOIMMUNE OR INFLAMMATORY SYSTEMIC DISEASES. ARTHRITIS-RHEUMATOL 2017;69(11):2241-2246.", "literaturereference_normalized": "de novo human herpesvirus 8 tumors induced by rituximab in autoimmune or inflammatory systemic diseases", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20171208", "receivedate": "20171208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14261557, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180321" }, { "companynumb": "FR-MYLANLABS-2017M1074778", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, 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"Lymphopenia", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PERIER A, SAVEY L, MARCELIN AG, SERVE P, SAADOUN D, BARETE S. DE NOVO HUMAN HERPESVIRUS 8 TUMORS INDUCED BY RITUXIMAB IN AUTOIMMUNE OR INFLAMMATORY SYSTEMIC DISEASES. ARTHRITIS-RHEUMATOL 2017;69(11):2241-2246.", "literaturereference_normalized": "de novo human herpesvirus 8 tumors induced by rituximab in autoimmune or inflammatory systemic diseases", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20171129", "receivedate": "20171129", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14233838, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180321" }, { "companynumb": "FR-MYLANLABS-2017M1074833", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTISYNTHETASE SYNDROME", "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": "AZATHIOPRINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "075568", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTISYNTHETASE SYNDROME", "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": "RITUXIMAB" }, "drugadditional": "2", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1GM ON DAY 0 AND 15", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTISYNTHETASE SYNDROME", "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": "46", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Kaposi^s sarcoma", "reactionmeddraversionpt": "20.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Human herpesvirus 8 infection", "reactionmeddraversionpt": "20.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Lymphopenia", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PERIER A, SAVEY L, MARCELIN AG, SERVE P, SAADOUN D, BARETE S. DE NOVO HUMAN HERPESVIRUS 8 TUMORS INDUCED BY RITUXIMAB IN AUTOIMMUNE OR INFLAMMATORY SYSTEMIC DISEASES. ARTHRITIS-RHEUMATOL 2017;69(11):2241-2246.", "literaturereference_normalized": "de novo human herpesvirus 8 tumors induced by rituximab in autoimmune or inflammatory systemic diseases", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20171129", "receivedate": "20171129", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14235126, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180321" }, { "companynumb": "FR-MYLANLABS-2017M1074832", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "1", 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DE NOVO HUMAN HERPESVIRUS 8 TUMORS INDUCED BY RITUXIMAB IN AUTOIMMUNE OR INFLAMMATORY SYSTEMIC DISEASES. 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"patientweight": null, "reaction": [ { "reactionmeddrapt": "Lymphopenia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Kaposi^s sarcoma", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "PERIER, A.. DE NOVO HUMAN HERPESVIRUS 8 TUMORS INDUCED BY RITUXIMAB IN AUTOIMMUNE OR INFLAMMATORY SYSTEMIC DISEASES.. 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DE NOVO HUMAN HERPESVIRUS 8 TUMORS INDUCED BY RITUXIMAB IN AUTOIMMUNE OR INFLAMMATORY SYSTEMIC DISEASES. ARTHRITIS RHEUMATOL. 2017 NOV; 69(11):2241-2246", "literaturereference_normalized": "de novo human herpesvirus 8 tumors induced by rituximab in autoimmune or inflammatory systemic diseases", "qualification": "1", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20171207", "receivedate": "20171207", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14257811, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180321" }, { "companynumb": "FR-MYLANLABS-2018M1011146", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTISYNTHETASE SYNDROME", "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": "AZATHIOPRINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "075568", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTISYNTHETASE SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZATHIOPRINE MYLAN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "2", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 G, UNK ON DAY 0 AND 15, INFUSION", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTISYNTHETASE SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." } ], "patientagegroup": null, "patientonsetage": "46", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Kaposi^s sarcoma", "reactionmeddraversionpt": "21.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Lymphopenia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PERIER A, SAVEY L, MARCELIN AG, SERVE P, SAADOUN D, BARETE S.. DE NOVO HUMAN HERPESVIRUS 8 TUMORS INDUCED BY RITUXIMAB IN AUTOIMMUNE OR INFLAMMATORY SYSTEMIC DISEASES.. ARTHRITIS RHEUMATOL.. 2017?69(11):2241-6", "literaturereference_normalized": "de novo human herpesvirus 8 tumors induced by rituximab in autoimmune or inflammatory systemic diseases", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20180225", "receivedate": "20180225", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14570143, "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": "Warfarin is known to interact with many drugs and can lead to serious consequences. We report a case of 52 years old female patient from Himachal Pradesh. During hospital stay patient developed coagulopathy in form of INR above 10 and bradycardia with ventricular rate on ECG with digoxin level of 3.76 ng/ml. In this way digoxin toxicity was confirmed and it was considered as cause of coagulopathy after ruling out interactions of warfarin.", "affiliations": "Professor.;Assoc. Professor.;Assoc. Professor.;Junior Resident.;Junior Resident.;Junior Resident.;Vikas Banyal.", "authors": "Raina|Rajiv|R|;Kaushik|Madan|M|;Mahajan|Sanjay|S|;Thakur|Roshan|R|;Ritin|||;Satish|||;Banyal|Vikas|V|", "chemical_list": "D014859:Warfarin; D004077:Digoxin", "country": "India", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0004-5772", "issue": "68(3)", "journal": "The Journal of the Association of Physicians of India", "keywords": null, "medline_ta": "J Assoc Physicians India", "mesh_terms": "D001919:Bradycardia; D004077:Digoxin; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008875:Middle Aged; D014859:Warfarin", "nlm_unique_id": "7505585", "other_id": null, "pages": "85-86", "pmc": null, "pmid": "32138495", "pubdate": "2020-03", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Rare Interaction of Warfarin and Digoxin in a Case of Digoxin Toxicity.", "title_normalized": "rare interaction of warfarin and digoxin in a case of digoxin toxicity" }

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S, ET AL.. RARE INTERACTION OF WARFARIN AND DIGOXIN IN A CASE OF DIGOXIN TOXICITY. [IN PROCESS] J ASSOC PHYSICIANS INDIA. 2020?68:3:85-86", "literaturereference_normalized": "rare interaction of warfarin and digoxin in a case of digoxin toxicity", "qualification": "3", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20200403", "receivedate": "20200403", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17622756, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200713" }, { "companynumb": "IN-VISTAPHARM, INC.-VER202003-000692", "fulfillexpeditecriteria": "1", "occurcountry": "IN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DIGOXIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "213000", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "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": "DIGOXIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DIGOXIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "213000", "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": "DIGOXIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": "3", "drugadministrationroute": null, "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": "WARFARIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "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": "WARFARIN" } ], "patientagegroup": "5", "patientonsetage": "52", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Bradycardia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Coagulopathy", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "RAINA R, KAUSHIK M, MAHAJAN S, THAKUR R, RITIN, SATISH. RARE INTERACTION OF WARFARIN AND DIGOXIN IN A CASE OF DIGOXIN TOXICITY. J ASSOC PHYS INDIA. 2020 MAR 01?68(3):85-6.", "literaturereference_normalized": "rare interaction of warfarin and digoxin in a case of digoxin toxicity", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "IN", "receiptdate": "20200407", "receivedate": "20200407", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17639119, "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" }, { "companynumb": "IN-IPCA LABORATORIES LIMITED-IPC-2020-IN-000998", "fulfillexpeditecriteria": "1", "occurcountry": "IN", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "DIGOXIN" }, "drugadditional": 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"drugtreatmentdurationunit": null, "medicinalproduct": "ENOXAPARINE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "International normalised ratio increased", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Coagulopathy", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "RAJIV RAINA1, MADAN KAUSHIK2, SANJAY MAHAJAN2. RARE INTERACTION OF WARFARIN AND DIGOXIN IN A CASE OF DIGOXIN TOXICITY. JOURNAL OF THE ASSOCIATION OF PHYSICIANS OF INDIA. 2020?68:85-86", "literaturereference_normalized": "rare interaction of warfarin and digoxin in a case of digoxin toxicity", "qualification": "3", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20200403", "receivedate": "20200403", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17621102, "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" }, { "companynumb": "IN-BRISTOL-MYERS SQUIBB COMPANY-BMS-2020-026901", "fulfillexpeditecriteria": "1", "occurcountry": "IN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "DIGOXIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "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": "DIGOXIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "WARFARIN SODIUM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "009218", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MILLIGRAM, QD", "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": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN SODIUM." } ], "patientagegroup": null, "patientonsetage": "52", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "International normalised ratio increased", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "RAINA R, KAUSHIK M, MAHAJAN S, THAKUR R, RITIN, SATISH, ET AL. RARE INTERACTION OF WARFARIN AND DIGOXIN IN A CASE OF DIGOXIN TOXICITY. THE JOURNAL OF THE ASSOCIATION OF PHYSICIANS OF INDIA. 2020?68(3):85-6", "literaturereference_normalized": "rare interaction of warfarin and digoxin in a case of digoxin toxicity", "qualification": "3", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20200401", "receivedate": "20200401", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17612663, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200713" }, { "companynumb": "IN-CIPLA LTD.-2020IN05182", "fulfillexpeditecriteria": "1", "occurcountry": "IN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "SPIRONOLACTONE" }, "drugadditional": "3", 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{ "abstract": "Over the last decade a consistent increase in stress-related psychological consequences at the workplace, usually called 'mobbing', has been seen. It claimed physical, psychical and social distress as its victims, leading to an increased incidence of many illnesses, such as psychosomatic disorders (ache, high blood pressure, chronic fatigue and insomnia) and psychiatric disturbances (high level of anxiety, depression and suicidal attempts). It was recently demonstrated that mobbing is significantly widespread among healthcare workers, especially among female nurses. In this report, we illustrate the case of a nurse who, after a brilliant career, underwent mobbing at the workplace, showing depression, anxiety and sleep disorders that required hospitalisation and a substantial intervention.", "affiliations": "Department of Psychiatry, University of Catania, Catania, Italy. signorellims@hotmail.com", "authors": "Signorelli|Maria Salvina|MS|;Costanzo|Maria Cristina|MC|;Cinconze|Maria|M|;Concerto|Carmen|C|", "chemical_list": "D014151:Anti-Anxiety Agents; D017374:Paroxetine; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid; D000525:Alprazolam", "country": "England", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "2013()", "journal": "BMJ case reports", "keywords": null, "medline_ta": "BMJ Case Rep", "mesh_terms": "D000275:Adjustment Disorders; D000525:Alprazolam; D014151:Anti-Anxiety Agents; D003441:Crowding; D003937:Diagnosis, Differential; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008875:Middle Aged; D017374:Paroxetine; D000069583:Pregabalin; D013313:Stress Disorders, Post-Traumatic; D005680:gamma-Aminobutyric Acid", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "23761569", "pubdate": "2013-06-11", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "19297885;18700481;22088163;2278952;14613526;20491378;17628681;18957741;19239514;15525252;18786019;17655532", "title": "What kind of diagnosis in a case of mobbing: post-traumatic stress disorder or adjustment disorder?", "title_normalized": "what kind of diagnosis in a case of mobbing post traumatic stress disorder or adjustment disorder" }

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"UNKNOWN,UNKNOWN,UNKNOWN,UNKNOWN", "drugcharacterization": "3", "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": "1.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALPRAZOLAM." } ], "patientagegroup": null, "patientonsetage": "58", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Adjustment disorder with mixed anxiety and depressed mood", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Suicidal ideation", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Feeling of despair", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Insomnia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anhedonia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Treatment noncompliance", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Labelled drug-drug interaction medication error", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SIGNORELLI M, COSTANZO M, CINCONZE M, CONCERTO C. WHAT KIND OF DIAGNOSIS IN A CASE OF MOBBING: POST?TRAUMATIC STRESS DISORDER OR ADJUSTMENT DISORDER?. 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null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ESCITALOPRAM OXALATE ? BP" } ], "patientagegroup": null, "patientonsetage": "58", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Adjustment disorder with mixed anxiety and depressed mood", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Insomnia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Anhedonia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Labelled drug-drug interaction medication error", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Feeling of despair", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Suicidal ideation", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201201" } }, "primarysource": { "literaturereference": "SIGNORELLI M, COSTANZO M, CINCONZE M, CONCERTO C. WHAT KIND OF DIAGNOSIS IN A CASE OF MOBBING: POST?TRAUMATIC STRESS DISORDER OR ADJUSTMENT DISORDER?. BMJ CASE REP. 2013?1?3", "literaturereference_normalized": "what kind of diagnosis in a case of mobbing post traumatic stress disorder or adjustment disorder", "qualification": "1", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20180810", "receivedate": "20161230", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13077127, "safetyreportversion": 4, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20181010" }, { "companynumb": "IT-MYLANLABS-2016M1057329", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ESCITALOPRAM OXALATE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "077660", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MG TOTAL", "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": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ESCITALOPRAM" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VENLAFAXINE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MG, TOTAL", "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": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VENLAFAXINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ALPRAZOLAM" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1.5 MG TOTAL", "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": "1.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALPRAZOLAM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.5 MG, TOTAL", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": 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"drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "QUETIAPINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VALPROIC ACID" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MG, TOTAL", "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": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALPROIC ACID." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TRAZODONE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "75 MG TOTAL", "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": "75", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAZODONE HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Insomnia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Labelled drug-drug interaction medication error", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anhedonia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Adjustment disorder with mixed anxiety and depressed mood", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Suicidal ideation", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SIGNORELLI MS, COSTANZO MC, CINCONZE M, CONCERTO C.. WHAT KIND OF DIAGNOSIS IN A CASE OF MOBBING: POST-TRAUMATIC STRESS DISORDER OR ADJUSTMENT DISORDER.. 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"drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": ".5 MILLIGRAM 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": ".5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLONAZEPAM." } ], "patientagegroup": null, "patientonsetage": "58", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Depressed mood", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Labelled drug-drug interaction medication error", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Adjustment disorder with mixed anxiety and depressed mood", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Anhedonia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Feeling abnormal", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Social avoidant behaviour", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Anxiety", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Affective disorder", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Insomnia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Tension", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Suicidal ideation", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201201" } }, "primarysource": { "literaturereference": "SIGNORELLI M,COSTANZO M,CINCONZE M,CONCERTO C. WHAT KIND OF DIAGNOSIS IN A CASE OF MOBBING: POST-TRAUMATIC STRESS DISORDER OR ADJUSTMENT DISORDER.", "literaturereference_normalized": "what kind of diagnosis in a case of mobbing post traumatic stress disorder or adjustment disorder", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20170127", "receivedate": "20161228", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13067596, "safetyreportversion": 4, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170428" } ]

{ "abstract": "Post-transplant lymphoproliferative disorders (PTLD) are lymphomas that may arise in organ, bone marrow or stem cell transplant recipients who are taking immunosuppressive drugs to prevent rejection of the transplant. The likelihood of developing PTLD depends on the type of transplant. PTLD is a potentially severe complication of post-transplant treatment, with an uncertain prognosis. Lymphoproliferative disorders can also occur in people taking immunosuppressants for inflammatory bowel disease. This article will explore PTLD and discuss the experience of caring for patients who developed lymphoproliferative conditions and required emergency stoma formation. The emotional and physical impact of surgery upon these patients, who have already experienced a protracted treatment journey, will be explored. Implications for practice for the lymphoma team and stoma nurse specialists involved with the care of these patients will also be considered.", "affiliations": "Coloplast Nurse and Stoma Nurse Specialist, University College London Hospitals NHS Foundation Trust.;Lymphoma Nurse Specialist, University College London Hospitals NHS Foundation Trust.", "authors": "Fulham|Juliette|J|;Plucinski|Micaela|M|", "chemical_list": "D007166:Immunosuppressive Agents", "country": "England", "delete": false, "doi": "10.12968/bjon.2018.27.22.S20", "fulltext": null, "fulltext_license": null, "issn_linking": "0966-0461", "issue": "27(22)", "journal": "British journal of nursing (Mark Allen Publishing)", "keywords": "Immunosuppression; Lymphoma; Post-transplant lymphoproliferative disorder; Stoma; Transplant", "medline_ta": "Br J Nurs", "mesh_terms": "D000328:Adult; D003424:Crohn Disease; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D008232:Lymphoproliferative Disorders; D008297:Male; D009736:Nursing Process; D016377:Organ Transplantation; D010030:Ostomy; D011183:Postoperative Complications; D054047:Surgical Stomas", "nlm_unique_id": "9212059", "other_id": null, "pages": "S20-S26", "pmc": null, "pmid": "30525969", "pubdate": "2018-12-13", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Stoma formation after lymphoproliferative disorders and immunosuppression therapy.", "title_normalized": "stoma formation after lymphoproliferative disorders and immunosuppression therapy" }

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"5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "POST TRANSPLANT LYMPHOPROLIFERATIVE DISORDER", "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": "31", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neuropathy peripheral", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Crohn^s disease", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Proctalgia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sepsis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Post transplant lymphoproliferative disorder", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "FULHAM J, PLUCINSKI M. STOMA FORMATION AFTER LYMPHOPROLIFERATIVE DISORDERS AND IMMUNOSUPPRESSION THERAPY.. BR-J-NURS.. 2018?27(22):S20-S26.", "literaturereference_normalized": "stoma formation after lymphoproliferative disorders and immunosuppression therapy", "qualification": "1", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20191119", "receivedate": "20191119", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17049988, "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": "NVSC2019GB013937", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "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": "POST TRANSPLANT LYMPHOPROLIFERATIVE DISORDER", "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": "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": "POST TRANSPLANT LYMPHOPROLIFERATIVE DISORDER", "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": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "017469", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "POST TRANSPLANT LYMPHOPROLIFERATIVE DISORDER", "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": "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": "POST TRANSPLANT LYMPHOPROLIFERATIVE DISORDER", "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": "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": "POST TRANSPLANT LYMPHOPROLIFERATIVE DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXORUBICINE" } ], "patientagegroup": null, "patientonsetage": "31", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Sepsis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Intestinal fistula", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pancytopenia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiac arrest", "reactionmeddraversionpt": "22.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Gastric ulcer", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Multiple organ dysfunction syndrome", "reactionmeddraversionpt": "22.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Condition aggravated", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "FULHAM J, PLUCINSKI M. STOMA FORMATION AFTER LYMPHOPROLIFERATIVE DISORDERS AND IMMUNOSUPPRESSION THERAPY. BRITISH JOURNAL OF NURSING. 2018?27(22):S20-6", "literaturereference_normalized": "stoma formation after lymphoproliferative disorders and immunosuppression therapy", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20191024", "receivedate": "20191024", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16958149, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200122" }, { "companynumb": "NVSC2019GB013920", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "017469", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK UNK, CYCLIC", "drugenddate": null, "drugenddateformat": null, "drugindication": "POST TRANSPLANT LYMPHOPROLIFERATIVE DISORDER", "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": "DOXORUBICIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK UNK, CYCLIC", "drugenddate": null, "drugenddateformat": null, "drugindication": "POST TRANSPLANT LYMPHOPROLIFERATIVE DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXORUBIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK UNK, CYCLIC", "drugenddate": null, "drugenddateformat": null, "drugindication": "POST TRANSPLANT LYMPHOPROLIFERATIVE DISORDER", "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 UNK, CYCLIC", "drugenddate": null, "drugenddateformat": null, "drugindication": "POST TRANSPLANT LYMPHOPROLIFERATIVE DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK UNK, CYCLIC", "drugenddate": null, "drugenddateformat": null, "drugindication": "POST TRANSPLANT LYMPHOPROLIFERATIVE DISORDER", "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": "31", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Dehydration", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Electrolyte imbalance", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pain", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neutropenic sepsis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gastrointestinal stoma complication", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Treatment failure", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "FULHAM J, PLUCINSKI M. STOMA FORMATION AFTER LYMPHOPROLIFERATIVE DISORDERS AND IMMUNOSUPPRESSION THERAPY. BRITISH JOURNAL OF NURSING. 2018?27(22):S20-6", "literaturereference_normalized": "stoma formation after lymphoproliferative disorders and immunosuppression therapy", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20191024", "receivedate": "20191024", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16957079, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200122" }, { "companynumb": "GB-BAUSCH-BL-2021-024794", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CONCENTRATE FOR SOLUTION FOR INFUSION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "POST TRANSPLANT LYMPHOPROLIFERATIVE DISORDER", "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": "INFLIXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "POWDER FOR SOLUTION FOR INFUSION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CROHN^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": "INFLIXIMAB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MERCAPTOPURINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CROHN^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": "6?MERCAPTOPURINE MONOHYDRATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "POST TRANSPLANT LYMPHOPROLIFERATIVE DISORDER", "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": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "POST TRANSPLANT LYMPHOPROLIFERATIVE DISORDER", "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": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "POST TRANSPLANT LYMPHOPROLIFERATIVE DISORDER", "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": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "POST TRANSPLANT LYMPHOPROLIFERATIVE DISORDER", "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": "31", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Crohn^s disease", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Post transplant lymphoproliferative disorder", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sepsis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neuropathy peripheral", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Proctalgia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "FULHAM J, PLUCINSKI M. STOMA FORMATION AFTER LYMPHOPROLIFERATIVE DISORDERS AND IMMUNOSUPPRESSION THERAPY. BRITISH JOURNAL OF NURSING. 2018?27(22):S20?S26.", "literaturereference_normalized": "stoma formation after lymphoproliferative disorders and immunosuppression therapy", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20210809", "receivedate": "20210719", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19580812, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "GB-BAUSCH-BL-2019-059465", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "POST TRANSPLANT LYMPHOPROLIFERATIVE DISORDER", "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": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CONCENTRATE FOR SOLUTION FOR INFUSION", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "POST TRANSPLANT LYMPHOPROLIFERATIVE DISORDER", "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": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "POST TRANSPLANT LYMPHOPROLIFERATIVE DISORDER", "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": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "POST TRANSPLANT LYMPHOPROLIFERATIVE DISORDER", "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": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "40070", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "POST TRANSPLANT LYMPHOPROLIFERATIVE DISORDER", "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": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "OFF LABEL USE", "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": "42", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Melaena", "reactionmeddraversionpt": "22.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Anaemia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Hydrocephalus", "reactionmeddraversionpt": "22.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Altered state of consciousness", "reactionmeddraversionpt": "22.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Cerebral infarction", "reactionmeddraversionpt": "22.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "FULHAM J, PLUCINSKI M. STOMA FORMATION AFTER LYMPHOPROLIFERATIVE DISORDERS AND IMMUNOSUPPRESSION THERAPY. BR-J-NURS. 2018?27(22):S20-S26.", "literaturereference_normalized": "stoma formation after lymphoproliferative disorders and immunosuppression therapy", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20191108", "receivedate": "20191108", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17011042, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200122" }, { "companynumb": "GB-ROCHE-2468565", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DOXORUBICIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "POST TRANSPLANT LYMPHOPROLIFERATIVE DISORDER", "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": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "103705", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INFUSION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "POST TRANSPLANT LYMPHOPROLIFERATIVE DISORDER", "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": "POST TRANSPLANT LYMPHOPROLIFERATIVE DISORDER", "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": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "POST TRANSPLANT LYMPHOPROLIFERATIVE DISORDER", "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": "VINCRISTINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "POST TRANSPLANT LYMPHOPROLIFERATIVE DISORDER", "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": "42", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hydrocephalus", "reactionmeddraversionpt": "22.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Altered state of consciousness", "reactionmeddraversionpt": "22.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Intentional product use issue", "reactionmeddraversionpt": "22.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "22.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Melaena", "reactionmeddraversionpt": "22.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Cerebral infarction", "reactionmeddraversionpt": "22.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Anaemia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "J F, PLUCINSKI M. STOMA FORMATION AFTER LYMPHOPROLIFERATIVE DISORDERS AND IMMUNOSUPPRESSION THERAPY. BR-J-NURS 2018?7(22):S20-S26.", "literaturereference_normalized": "stoma formation after lymphoproliferative disorders and immunosuppression therapy", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20191118", "receivedate": "20191118", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17041932, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200122" }, { "companynumb": "GB-CELLTRION INC.-2019GB025914", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "INFLIXIMAB" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "POWDER FOR SOLUTION FOR INFUSION", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CROHN^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": "INFLIXIMAB (UNKNOWN)" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "POST TRANSPLANT LYMPHOPROLIFERATIVE DISORDER", "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": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CONCENTRATE FOR SOLUTION FOR INFUSION", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "POST TRANSPLANT LYMPHOPROLIFERATIVE DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB (UNKNOWN)" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "POST TRANSPLANT LYMPHOPROLIFERATIVE DISORDER", "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": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "POST TRANSPLANT LYMPHOPROLIFERATIVE DISORDER", "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": "DOXORUBICIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "POST TRANSPLANT LYMPHOPROLIFERATIVE DISORDER", "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": "MERCAPTOPURINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CROHN^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": "6-MERCAPTOPURINE MONOHYDRATE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Post transplant lymphoproliferative disorder", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Proctalgia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sepsis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Crohn^s disease", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neuropathy peripheral", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "FULHAM J, PLUCINSKI M.. STOMA FORMATION AFTER LYMPHOPROLIFERATIVE DISORDERS AND IMMUNOSUPPRESSION THERAPY. BR-J-NURS. 2018?27(22):S20-S26", "literaturereference_normalized": "stoma formation after lymphoproliferative disorders and immunosuppression therapy", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20191030", "receivedate": "20191030", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16977080, "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": "GB-BAXTER-2019BAX024658", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "POST TRANSPLANT LYMPHOPROLIFERATIVE DISORDER", "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": "DOXORUBICIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "050718", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INFUSION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "POST TRANSPLANT LYMPHOPROLIFERATIVE DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXIL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "012142", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "POWDER FOR SOLUTION FOR INJECTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "POST TRANSPLANT LYMPHOPROLIFERATIVE DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE INJECTION 1G" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "POST TRANSPLANT LYMPHOPROLIFERATIVE DISORDER", "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": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "POST TRANSPLANT LYMPHOPROLIFERATIVE DISORDER", "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": "31", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Sepsis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Stoma site reaction", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pancytopenia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Intestinal haemorrhage", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Skin exfoliation", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "FULHAM J, PLUCINSKI M. STOMA FORMATION AFTER LYMPHOPROLIFERATIVE DISORDERS AND IMMUNOSUPPRESSION THERAPY. THE BRITISH JOURNAL OF NURSING. 2018?27(22):S20-S26.", "literaturereference_normalized": "stoma formation after lymphoproliferative disorders and immunosuppression therapy", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20191212", "receivedate": "20191203", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17105855, "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": "GB-ROCHE-2502420", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "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": "POST TRANSPLANT LYMPHOPROLIFERATIVE DISORDER", "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": "VINCRISTINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "POST TRANSPLANT LYMPHOPROLIFERATIVE DISORDER", "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": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "POST TRANSPLANT LYMPHOPROLIFERATIVE DISORDER", "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": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "POST TRANSPLANT LYMPHOPROLIFERATIVE DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DOXORUBICIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INFUSION", "drugdosagetext": "LIPOSOMAL", "drugenddate": null, "drugenddateformat": null, "drugindication": "POST TRANSPLANT LYMPHOPROLIFERATIVE DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXIL" } ], "patientagegroup": null, "patientonsetage": "31", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Intestinal haemorrhage", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pancytopenia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sepsis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Skin exfoliation", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "FULHAM J, PLUCINSKI M. STOMA FORMATION AFTER LYMPHOPROLIFERATIVE DISORDERS AND IMMUNOSUPPRESSION THERAPY. HE BRITISH JOURNAL OF NURSING 2018?27(22):S20-S26.", "literaturereference_normalized": "stoma formation after lymphoproliferative disorders and immunosuppression therapy", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20191226", "receivedate": "20191226", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17200845, "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" }, { "companynumb": "GB-CELLTRION INC.-2020GB018355", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "POST TRANSPLANT LYMPHOPROLIFERATIVE DISORDER", "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": "DOXORUBICIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INFUSION", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "POST TRANSPLANT LYMPHOPROLIFERATIVE DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXIL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "POST TRANSPLANT LYMPHOPROLIFERATIVE DISORDER", "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": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "POWDER FOR SOLUTION FOR INJECTION", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "POST TRANSPLANT LYMPHOPROLIFERATIVE DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE INJECTION 1G" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CONCENTRATE FOR SOLUTION FOR INFUSION", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "POST TRANSPLANT LYMPHOPROLIFERATIVE DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB (UNKNOWN)" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Intestinal haemorrhage", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Stoma site reaction", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sepsis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pancytopenia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Skin exfoliation", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "FULHAM J, PLUCINSKI M.. STOMA FORMATION AFTER LYMPHOPROLIFERATIVE DISORDERS AND IMMUNOSUPPRESSION THERAPY. THE BRITISH JOURNAL OF NURSING. 2018?27(22):S20-S26", "literaturereference_normalized": "stoma formation after lymphoproliferative disorders and immunosuppression therapy", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20200210", "receivedate": "20200210", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17395165, "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": "GB-BAXTER-2019BAX023364", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DOXORUBICIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "050718", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INFUSION", "drugdosagetext": "R-CHOP REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "POST TRANSPLANT LYMPHOPROLIFERATIVE DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXIL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "012142", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "POWDER FOR SOLUTION FOR INJECTION", "drugdosagetext": "R-CHOP REGIMEN", "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": "CYCLOPHOSPHAMIDE INJECTION 1G" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "R-CVP REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "POST TRANSPLANT LYMPHOPROLIFERATIVE DISORDER", "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": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "POST TRANSPLANT LYMPHOPROLIFERATIVE DISORDER", "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": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "R-CVP REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "POST TRANSPLANT LYMPHOPROLIFERATIVE DISORDER", "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": "CIPROFLOXACIN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CROHN^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": "CIPROFLOXACIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "R-CHOP REGIMEN", "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": "VINCRISTINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "012142", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "POWDER FOR SOLUTION FOR INJECTION", "drugdosagetext": "R-CVP REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "POST TRANSPLANT LYMPHOPROLIFERATIVE DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE INJECTION 1G" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "R-CHOP REGIMEN", "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": "PREDNISOLONE." } ], "patientagegroup": null, "patientonsetage": "31", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Neutropenic sepsis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "FULHAM J, PLUCINSKI M. STOMA FORMATION AFTER LYMPHOPROLIFERATIVE DISORDERS AND IMMUNOSUPPRESSION THERAPY. 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"reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Crohn^s disease", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Post transplant lymphoproliferative disorder", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neuropathy peripheral", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Proctalgia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sepsis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "FULHAM J, PLUCINSKI M. STOMA FORMATION AFTER LYMPHOPROLIFERATIVE DISORDERS AND IMMUNOSUPPRESSION THERAPY. BR-J-NURS 2018?27(22):S20-S26.", "literaturereference_normalized": "stoma formation after lymphoproliferative disorders and immunosuppression therapy", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20191119", "receivedate": "20191119", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17047481, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200122" }, { "companynumb": "GB-MYLANLABS-2019M1099489", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "AZATHIOPRINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "075568", "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": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZATHIOPRINE." } ], "patientagegroup": null, "patientonsetage": "42", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Small intestinal obstruction", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Post transplant lymphoproliferative disorder", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Leukopenia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pancytopenia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "FULHAM J, PLUCINSKI M. STOMA FORMATION AFTER LYMPHOPROLIFERATIVE DISORDERS AND IMMUNOSUPPRESSION THERAPY. BR-J-NURS 2018?27(22):S20-S26.", "literaturereference_normalized": "stoma formation after lymphoproliferative disorders and immunosuppression therapy", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20191024", "receivedate": "20191024", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16956561, "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": "GB-BAXTER-2019BAX022684", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", 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null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." } ], "patientagegroup": null, "patientonsetage": "42", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cerebral infarction", "reactionmeddraversionpt": "22.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Anaemia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Skin exfoliation", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hydrocephalus", "reactionmeddraversionpt": "22.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Melaena", "reactionmeddraversionpt": "22.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Altered state of consciousness", "reactionmeddraversionpt": "22.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Stoma site 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STOMA FORMATION AFTER LYMPHOPROLIFERATIVE DISORDERS AND IMMUNOSUPPRESSION THERAPY. THE BRITISH JOURNAL OF NURSING. 2018?27(22):S20-S26.", "literaturereference_normalized": "stoma formation after lymphoproliferative disorders and immunosuppression therapy", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20191212", "receivedate": "20191108", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17012481, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200122" } ]

{ "abstract": "In patients with malignant hematological disorders receiving immunosuppressive therapy, invasive pulmonary infections are serious complications that are associated with high morbidity and mortality. In immunocompromised hosts with impaired cellular immunity, two or more organisms may coexist leading to a wide range of clinical and radiological manifestations. Reported here is an old man who was diagnosed to have angioimmunoblastic T-cell lymphoma at King Faisal Specialist Hospital and Research Centre in Riyadh in December 2004. The lymphoma was treated with various immunosuppressive agents including alemtuzumab. In October 2006, the patient was admitted with severe bronchopneumonia caused by Nocardia asteroides and Aspergillus niger that was complicated by septic shock. The invasive pulmonary infections were successfully treated with trimethoprim-sulphamethoxazole, amikacin and liposomal amphotericin-B (amBisome).", "affiliations": "Section of Adult Hematology and Hematopoietic Stem Cell Transplant, King Faisal Cancer Centre, King Faisal Specialist Hospital and Research Centre, P.O. Box: 3354, Riyadh 11211, Saudi Arabia.", "authors": "Al-Anazi|Khalid A|KA|;Aljurf|Mahmoud D|MD|;Al-Mohareb|Fahad I|FI|;Al-Dabal|Laila|L|;Zaitoni|Mohammed|M|;Halim|Majed|M|", "chemical_list": null, "country": "New Zealand", "delete": false, "doi": "10.4137/ccrep.s817", "fulltext": "\n==== Front\nClin Med Case RepClin Med Case RepClinical Medicine. Case Reports1178-6450Libertas Academica ccrep-1-2008-065Case ReportSuccessful Management of Invasive Pulmonary Nocardiosis and Aspergillosis in a Patient with T-Cell Lymphoma: A Case Report Al-Anazi Khalid A. 1Aljurf Mahmoud D. 1Al-Mohareb Fahad I. 1Al-Dabal Laila 2Zaitoni Mohammed 2Halim Majed 31 Section of Adult Hematology and Hematopoietic Stem Cell Transplant, King Faisal Cancer Centre, King Faisal Specialist Hospital and Research Centre, P.O. Box: 3354, Riyadh 11211, Saudi Arabia.2 Section of Pulmonary Medicine, Department of Medicine, King Faisal Specialist Hospital and Research Centre, P.O. Box: 3354, Riyadh 11211, Saudi Arabia.3 Section of Infectious Diseases, Department of Medicine, King Faisal Specialist Hospital and Research Centre, P.O. Box: 3354, Riyadh 11211, Saudi Arabia.Correspondence: Khalid Ahmed Al-Anazi, Associate Consultant, Section of Adult Hematology and Hematopoietic, Stem Cell Transplant, King Faisal Cancer Centre, King Faisal Specialist Hospital and Research Centre, P.O. Box: 3345, Riyadh 11211, Saudi Arabia. Tel: 966 – 01 – 4568477; Fax: 966 – 01 – 4568477; Email: kaa_alanazi@yahoo.com2008 27 5 2008 1 65 71 © 2008 by the authors2008This article is an open-access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).In patients with malignant hematological disorders receiving immunosuppressive therapy, invasive pulmonary infections are serious complications that are associated with high morbidity and mortality. In immunocompromised hosts with impaired cellular immunity, two or more organisms may coexist leading to a wide range of clinical and radiological manifestations.\n\nReported here is an old man who was diagnosed to have angioimmunoblastic T-cell lymphoma at King Faisal Specialist Hospital and Research Centre in Riyadh in December 2004. The lymphoma was treated with various immunosuppressive agents including alemtuzumab. In October 2006, the patient was admitted with severe bronchopneumonia caused by Nocardia asteroides and Aspergillus niger that was complicated by septic shock. The invasive pulmonary infections were successfully treated with trimethoprim-sulphamethoxazole, amikacin and liposomal amphotericin-B (amBisome).\n\nangioimmunoblastic T-cell lymphomainvasive pulmonary infectionsAspergillus nigerNocardia asteroides\n==== Body\nIntroduction\nInfections are the most common cause of morbidity and mortality in patients with malignant disorders (Neuburger and Maschmeyer, 2006). Despite the availability of various antimicrobial agents, pneumonia constitutes the sixth cause of death and the number one cause of death from infection (Waite et al. 2006). Pneumonia can be particularly life-threatening in the elderly, in patients with pre-existing pulmonary or cardiac conditions and in immunocompromised individuals (Waite et al. 2006; Rolston, 2001).\n\nThe spectrum of pulmonary infections depends upon the underlying immunological abnormalities (Rolston, 2001). In cancer patients, several immunological defects may be present, thus making them susceptible to a wide range of opportunistic infections (Rolston, 2001). In individuals with impaired cellular immunity, viral infections e.g. cytomegalovirus (CMV) predominate and may coexist with bacterial (e.g. Legionella, Nocardia etc), mycobacterial and fungal (e.g. Aspergillus, Histoplasma etc) infections (Rolston, 2001). However, pulmonary Nocardia and Aspergillus coinfections have been reported in hematopoietic stem cell transplant recipients and in patients with glomerulonephritis treated with corticosteroids (Hamadani et al. 2008; Varma et al. 1993).\n\nCase Report\nA 67 years old male, a non-smoker, with history of ischaemic heart disease, status post—coronary artery bypass graft, and bronchiectasis was diagnosed to have angioimmunoblastic T-cell lymphoma (AIBTCL), stage III B at King Faisal Specialist Hospital and Research Centre (KFSH&RC) in Riyadh in late December 2004. He presented with: fever, skin rash, generalized external lymphadenopathy and splenomegaly. The blood counts, blood film and bone marrow biopsy were all normal. The renal and hepatic profiles as well as the immunoglobulin levels were within normal limits. Serological tests for CMV, Epstein-Barr virus (EBV), hepatitis C virus and HIV were negative. Computed tomography (CT) scans of chest, abdomen and pelvis showed numerous small lymph nodes in mediastinal, mesenteric and retroperitoneal areas in addition to splenomegaly with focal splenic lesions. Skin biopsy showed atypical lymphohistiocytic changes. A right axillary lymph node biopsy revealed diffuse infiltration with: immunoblasts, lymphocytes, polymorphs, plasma cells, histiocytes and eosinophils with considerable proliferation of small blood vessels. The immunohistochemical stains showed positive: CD1A, CD3, CD4, CD7, CD8, CD15, CD20, CD21, CD30, CD45, CD68 and S100. The gene rearrangement studies revealed a monoclonal T-cell population. The AIBTCL was treated with: prednisone, mycophenolate mofetil and subcutaneous alemtuzumab: 30 mg/month for 4 months. Thereafter the patient developed: CMV infection treated with IV ganciclovir and pulmonary embolism treated with IV heparin then oral warfarin. On 29/10/06, the patient was readmitted with two week history of: fever, cough productive of yellowish sputum and mild dyspnea. He denied any associated chest or abdominal pain, headache or bleeding from any site. Physical examination revealed an unwell elderly male who was in mild respiratory distress. The temperature was 38.7 °C, blood pressure (BP): 112/68 mmHg, pulse rate: 92/minute, respiratory rate: 20/minute and oxygen saturation was 93% on room air. There was pallor but no cyanosis, leg oedema, jaundice or external lymphadenopathy. The inspiratory volume was decreased and coarse crackles were heard over mid and lower lung fields bilaterally. There was no abdominal distension, tenderness or palpable organomegaly. Cardiovascular and neurological examinations did not reveal any abnormality. Full blood count (FBC) showed: WBC: 1.83 × 109/L, Hb: 109 g/L and PLT: 315 × 109/L. Differential cell count (DCC) showed neutrophils of 1.1 and lymphocytes of 0.3. Renal and hepatic profiles were all within normal limits. Blood, urine, stool cultures and CMV antigen test were all negative. Chest radiography showed bronchiectatic changes involving both lower lobes and bilateral nodular infiltration consistent with severe pneumonia. The patient was commenced on IV tazobactam-piperacillin: 4.5 grams thrice daily and gentamicin 2 mg/kg IV twice daily in addition to oxygen via mask at 2–4 Liter/minute and IV fluids at rate of 50–80 cc/hour. Initially the patient had partial response then he started to have higher pyrexia and respiratory distress. On 6/11/2006, the patient was experiencing high grade fever and rigors and his BP dropped to 85/45 mmHg. Septic screens were repeated and the IV antibiotics were replaced by IV meropenem 1 gram thrice daily and IV vancomycin 1 gram twice daily. Later on, BP improved and fever started to subside. A repeat CT scan of the chest showed: bronchiectatic cavities involving the lower lobes of both lungs, bilateral nodular infiltration, areas of segmental consolidation and bilateral pleural thickening (Fig. 1). Echocardiogram showed no vegetations, pericardial effusions or valvular defects and brain CT scan showed no evidence of space occupying lesions. Bronchoscopy was performed and BAL fluid showed scattered lipid laden macrophages and gram positive rods identified later on as Nocardia asteroides (N. asteroides). Special stains for fungi were positive and the fungus was identified as Aspergillus niger (A. niger). BAL fluid was negative for acid fast bacilli, pneumocystis carinii, viral cytopathy and malignant cells. Meanwhile, the previously taken sputum cultures grew branching gram positive rods identified as N. asteroides. However, sputum cultures were negative for acid fast bacilli, candida and aspergillus. Aspergillus galactomannan test was positive. Consequently, the following management modifications were made: vancomycin was stopped and meropenem was continued, IV liposomal amphotericin-B (amBisome) 5 mg/kg/day was commenced in addition to oral trimethoprim-sulphamethoxazole (TMP/SMZ) 960 mg thrice daily as well as IV amikacin 15 mg/kg/day. Later on, the patient started to improve clinically and radiologically and oxygen requirements decreased gradually. One week later, the patient sustained his hemodynamic stability and his clinical improvement so IV meropenem was discontinued. On 20/11/2006, IV amikacin was stopped and IV amBisome was replaced by oral voriconazole. Two days later; the patient was totally asymptomatic and his physical examination showed few basal crackles with good air entry bilaterally. FBC showed WBC: 2.25 × 109/L with neutrophils of 1.4, Hb: 94 g/L and PLT: 147 × 109/L. Renal and hepatic profiles were normal. He was discharged on: voriconazole 200 mg orally twice daily and TMP/SMZ 960 mg orally thrice daily for 6 weeks in addition to warfarin, omeprazole, prophylactic valganciclovir as well as ventolin and atrovent inhalers. Thereafter, the patient had regular follow up at the hematology outpatient clinic and he remained clinically stable.\n\nDiscussion\nAIBTCL, an intermediate grade/aggressive mature peripheral T-cell lymphoma, was first described in the 1970s as a distinct clinical syndrome characterized by: pruritic skin rash, generalized lymphadenopathy, hepatosplenomegaly, hypergammaglobulinemia, anemia and constitutional B symptoms. It occurs in elderly individuals and has no known etiology, although it has associations with: various infections (e.g. EBV, CMV, hepatitis C virus, human herpes viruses 6 and 8, tuberculosis and cryptococcus), antibiotics and autoimmune disorders (e.g. rheumatoid arthritis, vasculitis and thyroid disease) (Dogan et al. 2003). Lymph node histology shows distinctive partial effacement of normal architecture by polymorphic inflammatory infiltrates including large blasts and marked vascular proliferation. The monoclonal T-cell population expressing CD3 and CD4 and the multiple clonal cytogenetic abnormalities are the other distinguishing features. Unfortunately there is no curative treatment, however, single agents such as corticosteroids, cyclosporine-A, alpha-interferon, thalidomide, fludarabine and 2-chlorodeoxyadenosine as well as combinations of cytotoxic drugs e.g. CHOP regimen (cyclophosphamide, doxorubicin, vincristine and prednisone) have been employed in the treatment of AIBTCL. The clinical outcome is generally poor and most of the deaths are infection related (Dogan et al. 2003).\n\nExpression of CD52 occurs in 40% of patients with peripheral T-cell lymphoma. Although other factors may play a role in the in vivo response to alemtuzumab (Campath 1H), an anti-CD52 monoclonal antibody, the estimation of CD52 expression may provide a rationale for the selection of patients with a higher probability of treatment response (Pacciluga et al. 2007). The feasible chemoimmunotherapy (CHOP and alemtuzumab) combination has been shown to be an effective therapeutic modality for peripheral T-cell lymphoma, producing high rates of complete remission, but has also been associated with hematologic toxicity e.g. severe neutropenia and infectious complications including reacivation of CMV and Jacob-Creutzfeldt virus, invasive pulmonary aspergillosis (IPA) in addition to bacterial sepsis and pneumonia (Gallamini et al. 2007).\n\nAll neutropenic patients with pyrexia of unknown etiology having normal chest roentgenograms should undergo high resolution CT scanning as these scans have been shown to have 87% sensitivity and 57% specificity in detecting pneumonic infiltrations in febrile neutropenic patients with unknown foci of infection (Heussel et al. 1999). The favorable safety record, the good diagnotic yield and the frequent therapeutic implications strongly support the use of BAL for the evaluation of pulmonary infiltrates in neutropenic immunocompromised patients. BAL should be combined with the analysis of several sputum cultures as the combined diagnostic yield may reach 63% (Peikert et al. 2005). Current management strategies for febrile neutropenic patients emphasize on risk assessment (Picazo, 2005). The development of risk stratification models has allowed the identification of low risk patients who can exclusively be treated with oral antimicrbials as outpatient (Sipsas et al. 2005). The most important determinants of infection risk are the severity and the duration of neutropenia (Picazo, 2005). Monotherapy with the newer broad spectrum antimicrobials has tended to replace the classic combination therapy. Prompt initiation of empirical antimicrobial treatment has remained the gold standard. However, empirical administration of glycopeptides, e.g. vancomycin, without documentation of gram-positive infection is no longer favored. The initiation of empirical antifungal therapy in persistently febrile neutropenic patients has become a common practice, especially recently, after the introduction of the new, more effective and less toxic antifungal agents (Sipsas et al. 2005).\n\nDuring the past several decades, there has been a steady increase in the frequency of opportunistic fungal infections in immunocompromised individuals (Ascioglu et al. 2002). IPA is the most common fungal pulmonary infection in immunocompromised patients (Herbrecht et al. 2004). The main risk factors for aspergillosis are: hematopoietic stem cell and solid organ transplants, hematologic malignancy, AIDS and various pulmonary disorders (Patterson et al. 2000). The diagnosis of IPA is based on: clinical, radiological and mycological data. The clinical signs have low specificity. The most typical CT scan findings are: nodules with or without the halo or the air crescent sign (Herbrecht et al. 2004). High resolution MDCT angiography has been shown to be a feasible technique to depict directly vessel occlusion in the setting of suspected fungal infection, particularly for early diagnosis of angioinvasive pulmonary aspergillosis in immunocompromised hosts (Sonnet et al. 2005). The sensitivity of microscopy and culture of non-invasive collected samples is low. Galactomannan and nucleic acid detection in the serum or in the BAL fluid help to confirm the diagnosis (Herbrecht et al. 2004). However, the diagnosis of IPA can only be confirmed by histological determination of invasion of lung tissue by Aspergillus species or presence of positive cultures for Aspergillus in a sample obtained from a sterile site by an invasive procedure e.g. lung biopsy (Kristan et al. 2002; Ascioglu et al. 2002; Maertens et al. 2004). Open lung biopsy has very low morbidity and is recommended to establish the diagnosis of IPA. In a retrospective study performed in patients with malignant hematological disorders suspected of having IPA clinically and radiologically, only 53% of patients were proven to have IPA, the remaining 47% of patients were shown to have other etiologies e.g. organizing pneumonia, pulmonary hemorrhage or pneumonia due to other infections e.g. tuberculosis, CMV and candida (Kim et al. 2002). Recent studies have also shown that the lesions of IPA in neutropenic immunocompromised patients differ from those in non-neutropenic individuals in that they predominantly consist of angioinvasion and intraalveolar hemorrhage and that the innate host defences largely contribute to the histological patterns observed in IPA (Stergiopoulou et al. 2007). Optimal therapeutic stratigies include: prevention of contamination in at high risk patients, early initiation of antifungal therapy, surgical resection in patients having hemoptesis and lesions close to lage blood vessels and treatment of the underlying disease condition so as to restore a certain degree of immunity. The crude mortality is high and is strongly correlated not only with the type and the stage of the underlying disease but also with the extent of aspergillosis (Herbrecht et al. 2004; Patterson et al. 2000).\n\nFor many years, treatment of severe fungal infections had been limited to amphotericin-B and flucytosine. Fortunately, the past few years have brought remarkable advancements in antifungal pharmacotherapy as several new antifungals have been introduced (Battegay and Fluckiger, 2003). With the advent of the new triazoles e.g. voriconazole and the lipid formulations of amphotericin-B in addition to the echinocandins e.g. caspofungin, invasive aspergillosis has become treatable. The lipid formulations of amphoteircin-B have shown a clear advantage in reducing the side effects e.g. nephrotoxicity of amphotericin-B (Battegay and Fluckiger, 2003). Caspofungin has been shown to be as effective as and generally better tolerated than liposomal amphotericin B when given as empirical antifungal therapy in patients with prolonged neutropenia having persistent pyrexia (Walsh et al. 2004). It has demonstrated clinical efficacy when administered as first-line empirical therapy in patients with persistent febrile neutropenia, as salvage therapy in patients refractory to or intolerant of standard antifungal therapies and as combination therapy in difficult-to-treat patients refractory to or intolerant of standard therapies (Maertens, 2006). Voriconazole has become a primary therapeutic modality for invasive aspergillosis, despite the concerns about the development of drug-resistant fungi (Aperis and Mylonaki, 2006). Studies in patients with invasive aspergillosis have shown that voriconazole use led to better responses and improved survival and resulted in fewer severe adverse effects than the standard approach of initial therapy with amphotericin B (Herbrecht et al. 2002).\n\nIn case of intolerance to or failure of treatment with caspofungin or voriconazole, one of the new echinocandins e.g. micafungin or triazoles e.g. posaconazole can be used as an alternative salvage antifungal therapy (Walsh et al. 2007; Herbrecht et al. 2004).\n\nNocardia infections develop in patients with underlying lung pathology e.g. cystic fibrosis, bronchiectasis or chronic obstructive airway disease as well as in immunocompromised individuals e.g. those receiving corticosteroids and other immunosuppressive agents, organ transplant recipients and cancer patients specially those with lymphoreticular neoplasms. The most commonly involved organs are: the lungs, the central nervous system and the skin (Yildiz and Doganay, 2006; Matulionyte et al. 2004; Pifarre et al. 2001; Hui et al. 2003). However, disseminated infections are rather uncommon. The most frequently isolated species is N. asteroides (Matulionyte et al. 2004; Hui et al. 2003). Pulmonary nocardiosis is an important cause of opportunistic infections in immunocompromised hosts and the incidence of this infection is increasing (Yildiz and Doganay, 2006; Hui et al. 2003). It commonly presents as a chronic debilitating illness with radiological manifestations resembling pulmonary tuberculosis or lung cancer (Yildiz and Doganay, 2006; Matulionyte et al. 2004). In immunocompromised hosts, a fulminant disease resembling acute bacterial pneumonia may occasionally be encountered (Yildiz and Doganay, 2006). The median time between the onset of symptoms and the diagnosis of nocardia infection is about 30 days (Matulionyte et al. 2004). Clinically mild symptoms are common, but variable and nonspecific radiological changes including extensive nodular lung involvement that resemble cannonballs of metastatic cancer may be encountered (Pifarre et al. 2001; Hui et al. 2003; Tripodi et al. 2001). Recurrence of the infection and complications may also occur (Matulionyte et al. 2004). The diagnosis depends upon a high degree of suspicion so as to alert microbiologists and pathologists to employ special methods for identification of the organism (Yildiz and Doganay, 2006). Early diagnosis of pulmonary nocardiosis can be established upon culturing specimens of lung lesions obtained by BAL or fine-needle aspirate (Tripodi et al. 2001). Susceptibility studies and tests of antibiotic synergism should guide the therapy (Tripodi et al. 2001). The isolates are usually susceptible to: TMP/SMZ, carbapenems, amikacin, ceftriaxone, ciprofloxacin and tazobactam-piperacillin (Yildiz and Doganay, 2006; Matulionyte et al. 2004; Hui et al. 2003; Tripodi et al. 2001). Despite the development of drug resistance in some strains, the sulpha combinations e.g. TMP/SMZ are still the first line agents in the management of nocardiosis and carbapenems should be used as an alternative therapeutic modality in severely ill patients (Yildiz and Doganay, 2006; Matulionyte et al. 2004). A synergistic combination of a beta-lactam/beta-lactamase inhibitor with ciprofloxacin or amikacin followed by a short course of TMP/SMZ may result in eradication of nocardial disease and may reduce the need for long-term therapy (Tripodi et al. 2001). Delayed diagnosis, systemic infection and neurological involvement carry poor prognosis, while early recognition of the organism and prompt treatment have good outcome and may result in complete cures (Yildiz and Doganay, 2006; Matulionyte et al. 2004).\n\nThe patient presented was severely immunocompromised and had several predisposing factors for the invasive pulmonary infections encountered including: his advanced age; having multiple medical illnesses including bronchiectasis; having the T-cell lymphoma treated with various immunosuppressive drugs including corticosteroids; having a recent CMV infection and having moderately severe neutropenia prior to and during the latest hospitalization. We believe that the immunosuppressive therapy administered to this patient, particularly alemtuzumab, contributed not only to the development of both invasive lung infections, but also to the reactivation of CMV, particularly as he developed neutropenia and lymphopenia several months following this immununotherapy. He presented with severe bronchopneumonia clinically and diffuse nodular lung infiltration in addition to segmental consolidation radiologically. As he did not have appropriate antimicrobial cover initially, he developed the septic shock. However, the septic episode was successfully managed with meropenem, vancomycin in addition to the other supportive measures taken. Thereafter, the antimicrobial therapy was modified when nocardia and aspergillus were cultured from sputum and BAL fluid. Subsequently, the patient made an excellent clinical and radiological recovery although the treatment was rather prolonged.\n\nConclusion\nEven in septic immunocompromised hosts, slowly growing organisms and microorganisms that are difficult to culture or isolate should always be included in the differential diagnosis. Taking enough cultures and septic screens, making thorough and repeated physical assessment and requesting all the necessary investigations including high resolution CT scans are essential in the management of septic episodes and severe infections. At times, invasive diagnostic procedures such as bronchoscopy, BAL and even open lung biopsies may become essential to determine the causative microorganisms of certain pulmonary infections.\n\nFigure 1 A high resolution CAT scan of the lungs.\n\nThe CAT scan shows: bronchiectatic changes, areas of pneumonic consolidation and diffuse nodular pulmonary infiltration.\n==== Refs\nReferences\nAperis G Mylonakis E 2006 Newer triazole antifungal agents: pharmacology, spectrum, clinical efficacy and limitations Expert Opin Investig Drugs 15 579 602 \nAscioglu S Rex JH de Pauw B Bennett JE Bille J Crokaert F Denning DW Donnelly JP Edwards JE 2002 Defining opportunistic invasive fungal infections in immunocompromised patients with cancer and hematopoietic stem cell transplants: an international consensus Clin Infect Dis 34 7 14 11731939 \nBattegay M Fluckiger V 2003 Therapy of severe fungal infections Internist 44 1549 56 14689198 \nDogan A Attygalle AD Kyriakou C 2003 Angioimmunoblastic T-cell lymphoma Br J Haematol 121 681 91 12780782 \nGallamini A Zaja F Patti C Billio A Specchia MR Tucci A Levis A Manna A Secondo V 2007 Alemtuzumab (Campath 1H) and CHOP chemotherapy as first-line treatment of peripheral T-cell lymphoma: results of a GITIL (Gruppo Italiano Terapie Innovative nei Linfomi) prospective multicenter trial Blood 110 2316 23 17581918 \nHamadani M Benson DM Blum W Garzon R Devine SM 2008 Pulmonary nocardia and aspergillus co-infection in a patient with chronic graft-versus-host-disease Transpl Infect Dis 10 24 6 17651365 \nHerbrecht R Denning DW Patterson TF Bennet JE Greene RE Oestmann J-W Kern WV Marr KA Ribaud P for the Invasive Fungal Infections Group of the Europian Organisation for Research and Treatment of Cancer and the Global Aspergillus Study Group 2002 Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis N Engl Med J 347 408 15 \nHerbrecht R Natarajan-Ame S Letscher-Bru V Canuet M 2004 Invasive pulmonary aspergillosis Semin Respir Crit Care Med 25 191 202 16088462 \nHeussel CP Kauczor HU Heussel GE Fischer B Begrich M Mildenberger P Thelen M 1999 Pneumonia in febrile neutropenic patients and in bone marrow and blood stem-cell transplant recipients: use of high-resolution computed tomography J Clin Oncol 17 796 805 10071269 \nHui CH Au VW Rowland K Slavorinek JP Gordon DL 2003 Pulmonary nocardiosis revisited: experience of 35 patients at diagnosis Respir Med 97 709 17 12814159 \nKim K Lee MH Kim J Lee KS Kim SM Jung MP Han J Sung KW Kim WS 2002 Importance of open lung biopsy in the diagnosis of invasive pulmonary aspergillosis in patients with hematologic malignancies Am J Hematol 71 75 9 12353303 \nKristan SS Kern I Music E 2002 Invasive pulmonary aspergillosis Respiration 69 521 5 12457005 \nMaertens J 2006 Caspofungin: an advanced treatment approach for suspected or confirmed invasive aspergillosis Int J Antimicrob Agents 27 457 67 16701980 \nMatulionyte R Rohner P Uckay I Lew D Garbino J 2004 Secular trends of nocardia infection over 15 years in a tertiary care hospital J Clin Pathol 57 807 12 15280400 \nNeuburger S Maschmeyer G 2006 Update on management of infections in cancer patients and stem cell transplant patients Ann Hematol 85 345 56 16532331 \nPatterson TF Kirkpatrick WR White M 2000 Invasive aspergillosis: disease spectrum, treatment practice and outcomes Medicine 79 250 60 10941354 \nPeikert T Rana S Edell ES 2005 Safety, diagnostic yield and therapeutic implications of flexible bronchoscopy in patients with febrile neutropenia and pulmonary infiltrates 2005 Mayo Clin Proc 80 1414 20 16295020 \nPicazo JJ 2005 Management of the febrile neutropenic patient Int J Antimicrob Agents 26 S120 122 0924–8579 16243492 \nPiccaluga PP Agostinelli C Righi S Zinzani PL Pileri SA 2007 Expression of CD52 in peripheral T-cell lymphoma Haematologica 92 566 7 17488672 \nPifarre R Teixido B Vila M Duran M Garcia JM Morerra J 2001 Pulmonary nocardiosis as a cause of radiographic imaging of multiple pulmonary nodules Arch Bronconeumol 37 511 2 11734142 \nRolston KV 2001 The spectrum of pulmonary infections in cancer patients Curr Opin Oncol 13 218 23 11429477 \nSipsas NV Bodey GP Kontoyannis DP 2005 Perspectives for the management of febrile neutropenic patients with cancer in the 21st century Cancer 103 1103 13 15666328 \nSonnet S Buitrago-Tellez CH Tamm M Christen S Steinbrich W 2005 Direct detection of angioinvasive pulmonary aspergillosis in immunocompromised patients: preliminary results with high resolution 16- MDCT angiography Am J Roentgenol 184 746 51 15728592 \nStergiopoulou T Meletiadis J Roilides E Kleiner DE Schaufele R Roden M Harrington S Dad L Segal B 2007 Host-dependent patterns of tissue injury in invasive pulmonary aspergillosis Am J Clin Pathol 127 349 55 17276936 \nTripodi MF Adinolfi LE Adreana A Sarnataro G Durante Mangoni E Gamberdella M Casillo R Farina C Utili R 2001 Treatment of pulmonary nocardiosis in heart-transplant patients: importance of susceptibility studies Clin Transplant 15 415 20 11737119 \nVarma PP Chugh S Gupta KL Sakuga V Chugh KS 1993 Invasive pulmonary aspergillosis and nocardiosis in an immunocompromised host J Assoc Physicians India 41 237 8 8270580 \nWaite S Jeudy J White CS 2006 Acute lung infections in normal and immunocompromised hosts Radiol Clin North Am 44 295 315 16500210 \nWalsh TJ Raad I Patterson TF Chandrasekar P Donowitz GR Graybill R Greene RE Hachem R Hadley S 2007 Trearment of invasive aspergillosis with posaconazole in patients who are refractory to or intolerant of conventional therapy: an externally controlled trial Clin Infect Dis 44 2 12 17143808 \nWalsh TJ Teppler H Donowitz GR Maertens JA Baden LR Dmoszynska A Cornely OA Bourque MR Lupinacci RJ 2004 Caspofungin versus liposomal amphotericin B for empirical antifungal therapy in patients with persistent fever and neutropenia N Engl J Med 351 1391 402 15459300 \nYildiz O Doganay M 2006 Actinomycoses and Nocardia pulmonary infections Curr Opin Pulm Med 12 228 34 16582679\n\n", "fulltext_license": "CC BY", "issn_linking": "1178-6450", "issue": "1()", "journal": "Clinical medicine. Case reports", "keywords": "Aspergillus niger; Nocardia asteroides; angioimmunoblastic T-cell lymphoma; invasive pulmonary infections", "medline_ta": "Clin Med Case Rep", "mesh_terms": null, "nlm_unique_id": "101515695", "other_id": null, "pages": "65-71", "pmc": null, "pmid": "24179349", "pubdate": "2008", "publication_types": "D002363:Case Reports", "references": "17581918;8270580;16582679;14689198;11737119;11731939;15280400;10071269;12780782;16088462;12457005;17143808;15728592;11429477;16532331;16295020;12167683;16732713;12353303;15666328;16701980;17276936;15459300;17488672;12814159;10941354;11734142;17651365;16500210;16243492", "title": "Successful management of invasive pulmonary nocardiosis and aspergillosis in a patient with T-cell lymphoma: a case report.", "title_normalized": "successful management of invasive pulmonary nocardiosis and aspergillosis in a patient with t cell lymphoma a case report" }

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"drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GANCICLOVIR." } ], "patientagegroup": null, "patientonsetage": "67", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Respiratory distress", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Septic shock", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pyrexia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2006" } }, "primarysource": { "literaturereference": "AL-ANAZI, K.. SUCCESSFUL MANAGEMENT OF INVASIVE PULMONARY NOCARDIOSIS AND ASPERGILLOSIS IN A PATIENT WITH T-CELL LYMPHOMA: A CASE REPORT. CLINICAL MEDICINE: CASE REPORTS. 2008?1:65-71", "literaturereference_normalized": "successful management of invasive pulmonary nocardiosis and aspergillosis in a patient with t cell lymphoma a case report", "qualification": "3", "reportercountry": "SA" }, "primarysourcecountry": "SA", "receiptdate": "20191128", "receivedate": "20191128", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17088010, "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": "The analgesic flupirtine has been linked to cases of severe idiosyncratic drug-induced liver injury (sFILI). We therefore examined whether N-acetylcysteine (NAC) and glucocorticoid therapy is effective in the management of sFILI.\n\n\n\nIn a retrospective cohort study efficacy of NAC-infusion and oral prednisolone treatments on liver-function-tests (LFTs) and clinical outcome of 21 sFILI cases was evaluated by comparing it to an external cohort of 30 sFILI cases not receiving the antidote. LFTs were also assayed in human hepatocyte cultures treated with flupirtine for 96 hours. Additionally, modulation of glutathione stores in cultures of human hepatocytes treated with 80 drugs was investigated.\n\n\n\nUpon admission, patients presented Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin elevations of up to 90-, 35- and 30-fold of upper limits of normal (ULN) respectively. The average INR was 2.2, and 50% of patients had a high Model for end-stage liver disease (MELD) score of ≥25 and included 5 cases of 28-32. The combined NAC/prednisolone treatment was well tolerated and led to significant ALT, AST and INR improvements within 2 weeks. However, the hyperbilirubinaemia resolved slowly. Two patients with late start of NAC/prednisolone treatment developed hepatic encephalopathy and required liver transplantation; the remaining patients recovered without long-term sequela. Based on serum biochemistries sFILI cases resolved more rapidly (P < .01) when compared to untreated sFILI patients and included a case with fatal outcome. Additionally, in vitro studies revealed glutathione depletion as a common culprit for drugs with liver liabilities.\n\n\n\nBased on these initial findings a prospective randomized clinical trial (RCT) is needed to confirm safety and efficacy of NAC/prednisolone treatment in sFILI.", "affiliations": "Centre for Pharmacology and Toxicology, Hannover Medical School, Hannover, Germany.;Section of Hepatology, Clinic for Gastroenterology and Rheumatology, University Hospital Leipzig, Leipzig, Germany.;Section of Hepatology, Clinic for Gastroenterology and Rheumatology, University Hospital Leipzig, Leipzig, Germany.", "authors": "Borlak|Jürgen|J|0000-0003-1558-9519;van Bömmel|Florian|F|;Berg|Thomas|T|", "chemical_list": "D000631:Aminopyridines; D000700:Analgesics; D000931:Antidotes; D015415:Biomarkers; D005938:Glucocorticoids; D011239:Prednisolone; D005978:Glutathione; C034161:flupirtine; D000111:Acetylcysteine", "country": "United States", "delete": false, "doi": "10.1111/liv.13538", "fulltext": null, "fulltext_license": null, "issn_linking": "1478-3223", "issue": "38(2)", "journal": "Liver international : official journal of the International Association for the Study of the Liver", "keywords": "N-acetylcysteine; antidote; flupirtine-induced liver injury; prednisolone", "medline_ta": "Liver Int", "mesh_terms": "D000111:Acetylcysteine; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000631:Aminopyridines; D000700:Analgesics; D000931:Antidotes; D015415:Biomarkers; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury; D018450:Disease Progression; D004359:Drug Therapy, Combination; D005260:Female; D005938:Glucocorticoids; D005978:Glutathione; D022781:Hepatocytes; D006801:Humans; D007262:Infusions, Intravenous; D008099:Liver; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D011239:Prednisolone; D020127:Recovery of Function; D012189:Retrospective Studies; D012720:Severity of Illness Index; D016896:Treatment Outcome", "nlm_unique_id": "101160857", "other_id": null, "pages": "365-376", "pmc": null, "pmid": "28782153", "pubdate": "2018-02", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "N-acetylcysteine and prednisolone treatment improved serum biochemistries in suspected flupirtine cases of severe idiosyncratic liver injury.", "title_normalized": "n acetylcysteine and prednisolone treatment improved serum biochemistries in suspected flupirtine cases of severe idiosyncratic liver injury" }

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N-ACETYLCYSTEINE AND PREDNISOLONE TREATMENT IMPROVED SERUM BIOCHEMISTRIES IN SUSPECTED FLUPIRTINE CASES OF SEVERE IDIOSYNCRATIC LIVER INJURY. LIVER-INT. 2018?38(2):365-376", "literaturereference_normalized": "n acetylcysteine and prednisolone treatment improved serum biochemistries in suspected flupirtine cases of severe idiosyncratic liver injury", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20180402", "receivedate": "20180402", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14704434, "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": "DE-VALIDUS PHARMACEUTICALS LLC-DE-2018VAL000573", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUPIRTINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BACK PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUPIRTINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUPIRTINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "MUSCULOSKELETAL DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUPIRTINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METOPROLOL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "017963", "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": "METOPROLOL." } ], "patientagegroup": null, "patientonsetage": "73", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BORLAK J, VAN BOMMEL F, BERG T. 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N-ACETYLCYSTEINE AND PREDNISOLONE TREATMENT IMPROVED SERUM BIOCHEMISTRIES IN SUSPECTED FLUPIRTINE CASES OF SEVERE IDIOSYNCRATIC LIVER INJURY. 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N-ACETYLCYSTEINE AND PREDNISOLONE TREATMENT IMPROVED SERUM BIOCHEMISTRIES IN SUSPECTED FLUPIRTINE CASES OF SEVERE IDIOSYNCRATIC LIVER INJURY. 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N-ACETYLCYSTEINE AND PREDNISOLONE TREATMENT IMPROVED SERUM BIOCHEMISTRIES IN SUSPECTED FLUPIRTINE CASES OF SEVERE IDIOSYNCRATIC LIVER INJURY. 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N-ACETYLCYSTEINE AND PREDNISOLONE TREATMENT IMPROVED SERUM BIOCHEMISTRIES IN SUSPECTED FLUPIRTINE CASES OF SEVERE IDIOSYNCRATIC LIVER INJURY. 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N?ACETYLCYSTEINE AND PREDNISOLONE TREATMENT IMPROVED SERUM BIOCHEMISTRIES IN SUSPECTED FLUPIRTINE CASES OF SEVERE IDIOSYNCRATIC LIVER INJURY. LIVER INTERNATIONAL. 2018 FEB?38 (2):365?376.", "literaturereference_normalized": "n acetylcysteine and prednisolone treatment improved serum biochemistries in suspected flupirtine cases of severe idiosyncratic liver injury", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20200703", "receivedate": "20180328", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14688296, "safetyreportversion": 9, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20201102" }, { "companynumb": "DE-TEVA-2018-DE-866470", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUPIRTINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 (UNIT NOT STATED)", "drugenddate": null, "drugenddateformat": null, "drugindication": "BACK PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUPIRTINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METOPROLOL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "74141", "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": "METOPROLOL." } ], "patientagegroup": null, "patientonsetage": "51", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "BORLAK J, VAN BOMMEL F, BERG T. N-ACETYLCYSTEINE AND PREDNISOLONE TREATMENT IMPROVED SERUM BIOCHEMISTRIES IN SUSPECTED FLUPIRTINE CASES OF SEVERE IDIOSYNCRATIC LIVER INJURY. 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VAN BOMMEL F? BERG T.. N-ACETYLCYSTEINE AND PREDNISOLONE TREATMENT IMPROVED SERUM BIOCHEMISTRIES IN SUSPECTED FLUPIRTINE CASES OF SEVERE IDIOSYNCRATIC LIVER INJURY.. LIVER INTERNATIONAL.. 2018?38 (2):365-376", "literaturereference_normalized": "n acetylcysteine and prednisolone treatment improved serum biochemistries in suspected flupirtine cases of severe idiosyncratic liver injury", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20190709", "receivedate": "20190329", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16135829, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20191004" }, { "companynumb": "DE-TEVA-2018-DE-866441", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUPIRTINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 (UNIT NOT STATED)", "drugenddate": null, "drugenddateformat": null, "drugindication": "BACK PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUPIRTINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METOPROLOL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "74141", "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": "METOPROLOL." } ], "patientagegroup": null, "patientonsetage": "73", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "BORLAK J, VAN BOMMEL F, BERG T. N-ACETYLCYSTEINE AND PREDNISOLONE TREATMENT IMPROVED SERUM BIOCHEMISTRIES IN SUSPECTED FLUPIRTINE CASES OF SEVERE IDIOSYNCRATIC LIVER INJURY. 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N-ACETYLCYSTEINE AND PREDNISOLONE TREATMENT IMPROVED SERUM BIOCHEMISTRIES IN SUSPECTED FLUPIRTINE CASES OF SEVERE IDIOSYNCRATIC LIVER INJURY. 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N-ACETYLCYSTEINE AND PREDNISOLONE TREATMENT IMPROVED SERUM BIOCHEMISTRIES IN SUSPECTED FLUPIRTINE CASES OF SEVERE IDIOSYNCRATIC LIVER INJURY. LIVER-INT 2018?38 (2):365-376. BORLAK J, VAN BOMMEL F, BERG T. N-ACETYLCYSTEINE AND PREDNISOLONE TREATMENT IMPROVED SERUM BIOCHEMISTRIES IN SUSPECTED FLUPIRTINE CASES OF SEVERE IDIOSYNCRATIC LIVER INJURY. LIVER INTERNATIONAL 2017?38:365-76.", "literaturereference_normalized": "n acetylcysteine and prednisolone treatment improved serum biochemistries in suspected flupirtine cases of severe idiosyncratic liver injury", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20180628", "receivedate": "20180329", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14694769, "safetyreportversion": 4, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180711" }, { "companynumb": "DE-MYLANLABS-2018M1047989", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "AMITRIPTYLINE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "086009", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MG, QD", "drugenddate": "20090217", "drugenddateformat": "102", "drugindication": "BACK PAIN", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "200809", "drugstartdateformat": "610", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMITRIPTYLINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUPIRTINE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MG, QD", "drugenddate": "20090217", "drugenddateformat": "102", "drugindication": "BACK PAIN", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "200809", "drugstartdateformat": "610", "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KATADOLON /00890102/" } ], "patientagegroup": null, "patientonsetage": "31", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "60", "reaction": [ { "reactionmeddrapt": "Acute hepatic failure", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hepatic encephalopathy", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20090217" } }, "primarysource": { "literaturereference": "BORLAK J., VAN BOMMEL F., BERG T.,.. N?ACETYLCYSTEINE AND PREDNISOLONE TREATMENT IMPROVED SERUM BIOCHEMISTRIES IN SUSPECTED FLUPIRTINE CASES OF SEVERE IDIOSYNCRATIC LIVER INJURY.. LIVER INT.. 2018?38(2):365?376", "literaturereference_normalized": "n acetylcysteine and prednisolone treatment improved serum biochemistries in suspected flupirtine cases of severe idiosyncratic liver injury", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20180706", "receivedate": "20180706", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15114982, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20181010" }, { "companynumb": "DE-BAUSCH-BL-2018-008055", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUPIRTINE" }, 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"reactionoutcome": "2" }, { "reactionmeddrapt": "Jaundice", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BORLAK J, VAN BOMMEL F, BERG T. N-ACETYLCYSTEINE AND PREDNISOLONE TREATMENT IMPROVED SERUM BIOCHEMISTRIES IN SUSPECTED FLUPIRTINE CASES OF SEVERE IDIOSYNCRATIC LIVER INJURY. LIVER INTERNATIONAL. 2017?38(2):365-376.", "literaturereference_normalized": "n acetylcysteine and prednisolone treatment improved serum biochemistries in suspected flupirtine cases of severe idiosyncratic liver injury", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": null, "receiptdate": "20180507", "receivedate": "20180405", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14719132, "safetyreportversion": 4, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180711" }, { "companynumb": "DE-TEVA-2018-DE-866435", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": 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"drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IBUPROFEN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BISOPROLOL" }, "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": "BISOPROLOL" } ], 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N-ACETYLCYSTEINE AND PREDNISOLONE TREATMENT IMPROVED SERUM BIOCHEMISTRIES IN SUSPECTED FLUPIRTINE CASES OF SEVERE IDIOSYNCRATIC LIVER INJURY. 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N-ACETYLCYSTEINE AND PREDNISOLONE TREATMENT IMPROVED SERUM BIOCHEMISTRIES IN SUSPECTED FLUPIRTINE CASES OF SEVERE IDIOSYNCRATIC LIVER INJURY.. 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"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": "IBUPROFEN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEVOTHYROXINE SODIUM" }, "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": "L-THYROXIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "RAMIPRIL" }, "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": "RAMIPRIL." } ], "patientagegroup": null, "patientonsetage": "71", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BORLAK, J.. N-ACETYLCYSTEINE AND PREDNISOLONE TREATMENT IMPROVED SERUM BIOCHEMISTRIES IN SUSPECTED FLUPIRTINE CASES OF SEVERE IDIOSYNCRATIC LIVER INJURY.. LIVER INTERNATIONAL. 2018?38 (2):365-376", "literaturereference_normalized": "n acetylcysteine and prednisolone treatment improved serum biochemistries in suspected flupirtine cases of severe idiosyncratic liver injury", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20190211", "receivedate": "20180504", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14849695, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" }, { "companynumb": "DE-JNJFOC-20180320043", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "BISOPROLOL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "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": "BISOPROLOL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "IBUPROFEN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "019012", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLETS", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BACK PAIN", "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": "IBUPROFEN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "019012", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLETS", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "MUSCULOSKELETAL DISORDER", "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": "DICLOFENAC" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": "70 (DAYS)", "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": "DICLOFENAC" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUPIRTINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BACK PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "200", "drugstructuredosageunit": "032", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUPIRTINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUPIRTINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "MUSCULOSKELETAL DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "200", "drugstructuredosageunit": "032", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUPIRTINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PANTOPRAZOLE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "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": "PANTOPRAZOLE" } ], "patientagegroup": "5", "patientonsetage": "59", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "21.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Jaundice", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BORLAK J, VAN BOMMEL F, BERG T. N-ACETYLCYSTEINE AND PREDNISOLONE TREATMENT IMPROVED SERUM BIOCHEMISTRIES IN SUSPECTED FLUPIRTINE CASES OF SEVERE IDIOSYNCRATIC LIVER INJURY. LIVER INTERNATIONAL FEB-2018?38 (2):365-376. BORLAK J, VAN BOMMEL F, BERG T. N-ACETYLCYSTEINE AND PREDNISOLONE TREATMENT IMPROVED SERUM BIOCHEMISTRIES IN SUSPECTED FLUPIRTINE CASES OF SEVERE IDIOSYNCRATIC LIVER INJURY. LIVER INTERNATIONAL 2017?XX:XX.", "literaturereference_normalized": "n acetylcysteine and prednisolone treatment improved serum biochemistries in suspected flupirtine cases of severe idiosyncratic liver injury", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20181203", "receivedate": "20180328", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14688295, "safetyreportversion": 6, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190204" }, { "companynumb": "DE-PFIZER INC-2018210336", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "OMEPRAZOLE" }, "drugadditional": "3", "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": "OMEPRAZOLE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "IBUPROFEN" }, "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": "IBUPROFEN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEVOTHYROXINE SODIUM" }, "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": "L-THYROXIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METAMIZOLE" }, "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": "METAMIZOLE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CELECOXIB" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "020998", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": "600", "drugcumulativedosageunit": "003", "drugdosageform": "CAPSULE, HARD", "drugdosagetext": "100 MG, WEEKLY", "drugenddate": "20080407", "drugenddateformat": "102", "drugindication": null, "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "20080227", "drugstartdateformat": "102", "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CELEBREX" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TRAMADOL HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": "12300", "drugcumulativedosageunit": "003", "drugdosageform": "TABLET", "drugdosagetext": "300 MG, 1X/DAY", "drugenddate": "20080407", "drugenddateformat": "102", "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "20080227", "drugstartdateformat": "102", "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAMADOLOR HEXAL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "SIMVASTATIN" }, "drugadditional": "3", "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": "SIMVASTATIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEVOTHYROXINE SODIUM" }, "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": "LEVOTHYROXINE SODIUM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "POLYETHYLENE GLYCOLS" }, "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": "MACROGOL" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "FLUPIRTINE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": "16400", "drugcumulativedosageunit": "003", "drugdosageform": "TABLET", "drugdosagetext": "400 MG, 1X/DAY", "drugenddate": "20080407", "drugenddateformat": "102", "drugindication": "OSTEOPOROSIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "20080227", "drugstartdateformat": "102", "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KATADOLON S" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DICLOFENAC" }, "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": "DICLOFENAC" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CALCIUM CARBONATE\\ERGOCALCIFEROL" }, "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": "CALCIUM/VITAMIN D /01204201/" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CELECOXIB" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "020998", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": "600", "drugcumulativedosageunit": "003", "drugdosageform": "CAPSULE, HARD", "drugdosagetext": "600 MG PER WEEK", "drugenddate": "200804", "drugenddateformat": "610", "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "20080222", "drugstartdateformat": "102", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CELEBREX" } ], "patientagegroup": null, "patientonsetage": "64", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "90", "reaction": [ { "reactionmeddrapt": "Hepatic necrosis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "4" }, { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "21.0", "reactionoutcome": "4" }, { "reactionmeddrapt": "Aspartate aminotransferase increased", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "International normalised ratio abnormal", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Chromaturia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Alanine aminotransferase increased", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Blood alkaline phosphatase increased", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Fatigue", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20080408" } }, "primarysource": { "literaturereference": "BORLAK, J.. N-ACETYLCYSTEINE AND PREDNISOLONE TREATMENT IMPROVED SERUM BIOCHEMISTRIES IN SUSPECTED FLUPIRTINE CASES OF SEVERE IDIOSYNCRATIC LIVER INJURY. LIVER INTERNATIONAL. 2018?38(2):365-376", "literaturereference_normalized": "n acetylcysteine and prednisolone treatment improved serum biochemistries in suspected flupirtine cases of severe idiosyncratic liver injury", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20180613", "receivedate": "20180528", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14943465, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180711" }, { "companynumb": "DE-VALIDUS PHARMACEUTICALS LLC-DE-2018VAL000572", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METOPROLOL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "017963", "drugbatchnumb": "UNKNOWN", "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": "METOPROLOL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUPIRTINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "MUSCULOSKELETAL DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUPIRTINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUPIRTINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BACK PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUPIRTINE" } ], "patientagegroup": null, "patientonsetage": "51", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BORLAK J, VAN BOMMEL F, BERG T. N-ACETYLCYSTEINE AND PREDNISOLONE TREATMENT IMPROVED SERUM BIOCHEMISTRIES IN SUSPECTED FLUPIRTINE CASES OF SEVERE IDIOSYNCRATIC LIVER INJURY. LIVER-INT. 2018?38(2):365-376", "literaturereference_normalized": "n acetylcysteine and prednisolone treatment improved serum biochemistries in suspected flupirtine cases of severe idiosyncratic liver injury", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20180330", "receivedate": "20180330", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14699265, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180509" }, { "companynumb": "PHHY2018DE031731", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CELECOXIB" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": "600", "drugcumulativedosageunit": "003", "drugdosageform": "CAPSULE", "drugdosagetext": "DAILY DOSE: 600 MG MILLIGRAM(S) EVERY WEEK", "drugenddate": "20080407", "drugenddateformat": "102", "drugindication": "PAIN", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "20080227", "drugstartdateformat": "102", "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CELEBREX" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CALCIUM\\VITAMIN D" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "NI", "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": "CALCIUM WITH VITAMIN D" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "FLUPIRTINE MALEATE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DAILY DOSE: 400 MG MILLIGRAM(S) EVERY DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "OSTEOPOROSIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUPIRTINE MALEATE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "FLUPIRTINE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": "16400", "drugcumulativedosageunit": "003", "drugdosageform": "TABLET", "drugdosagetext": "DAILY DOSE: 400 MG MILLIGRAM(S) EVERY DAY", "drugenddate": "20080407", "drugenddateformat": "102", "drugindication": "PAIN", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "20080227", "drugstartdateformat": "102", "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KATADOLON" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TRAMADOL HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": "12300", "drugcumulativedosageunit": "003", "drugdosageform": "TABLET", "drugdosagetext": "DAILY DOSE: 300 MG MILLIGRAM(S) EVERY DAY", "drugenddate": "20080407", "drugenddateformat": "102", "drugindication": "PAIN", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "20080227", "drugstartdateformat": "102", "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAMADOLOR ^HEXAL^" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LEVOTHYROXINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "NI", "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": "L?THYROXINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "SIMVASTATIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "NI", "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": "SIMVASTATIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DICLOFENAC" }, "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": "DICLOFENAC" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METAMIZOLE" }, "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": "METAMIZOLE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OMEPRAZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "75757", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "NI", "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": "OMEPRAZOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "POLYETHYLENE GLYCOLS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "NI", "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": "MACROGOL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "IBUPROFEN" }, "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": "IBUPROFEN." } ], "patientagegroup": null, "patientonsetage": "64", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "90", "reaction": [ { "reactionmeddrapt": "Blood alkaline phosphatase increased", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Hepatic necrosis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "4" }, { "reactionmeddrapt": "Aspartate aminotransferase increased", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "International normalised ratio abnormal", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Fatigue", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Alanine aminotransferase increased", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Chromaturia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20080408" } }, "primarysource": { "literaturereference": "BORLAK J, VAN BF, BERG T. N?ACETYLCYSTEINE AND PREDNISOLONE TREATMENT IMPROVED SERUM BIOCHEMISTRIES IN SUSPECTED FLUPIRTINE CASES OF SEVERE IDIOSYNCRATIC LIVER INJURY. LIVER INT.. 2018?38(2):365?76", "literaturereference_normalized": "n acetylcysteine and prednisolone treatment improved serum biochemistries in suspected flupirtine cases of severe idiosyncratic liver injury", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20210203", "receivedate": "20180702", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15096471, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210419" }, { "companynumb": "DE-JNJFOC-20180410583", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "FLUPIRTINE MALEATE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": "100 MG, TID", "drugenddate": "20060307", "drugenddateformat": "102", "drugindication": "SPINAL PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "20060131", "drugstartdateformat": "102", "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUPIRTINE MALEATE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "FLUPIRTINE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": "1 DOSAGE FORMS DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "BACK PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "032", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KATADOLON S" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ETHINYL ESTRADIOL\\LEVONORGESTREL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CONTRACEPTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FEMIGOA" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "IBUPROFEN" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "019012", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IBUPROFEN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TOLPERISONE HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": "50 MG TID", "drugenddate": "20060307", "drugenddateformat": "102", "drugindication": "SPINAL PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "20060222", "drugstartdateformat": "102", "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TOLPERISONE HYDROCHLORIDE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "IBUPROFEN" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "019012", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": "1200 MILLIGRAM DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "BACK PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1200", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IBUPROFEN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ETORICOXIB" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "120 MG, QD", "drugenddate": "20060307", "drugenddateformat": "102", "drugindication": "BACK PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "20060222", "drugstartdateformat": "102", "drugstructuredosagenumb": "120", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ARCOXIA" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": "60", "reaction": [ { "reactionmeddrapt": "Hepatic function abnormal", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Hepatitis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Gamma-glutamyltransferase increased", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Aspartate aminotransferase increased", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Jaundice", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Alanine aminotransferase increased", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20060308" } }, "primarysource": { "literaturereference": "BORLAK J, VAN BOMMEL F, BERG T. N-ACETYLCYSTEINE AND PREDNISOLONE TREATMENT IMPROVED SERUM BIOCHEMISTRIES IN SUSPECTED FLUPIRTINE CASES OF SEVERE IDIOSYNCRATIC LIVER INJURY. LIVER-INT. 2018?38 (2):365-6.", "literaturereference_normalized": "n acetylcysteine and prednisolone treatment improved serum biochemistries in suspected flupirtine cases of severe idiosyncratic liver injury", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20180423", "receivedate": "20180423", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14788353, "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": "DE-JNJFOC-20180322728", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "IBUPROFEN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "019012", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": "400 MILLIGRAM DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "NECK PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IBUPROFEN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TRAMADOL HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "NECK PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAMADOL HYDROCHLORIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "IBUPROFEN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "019012", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "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": "IBUPROFEN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "FLUPIRTINE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": "0.5 DAILY, AS REQUIRED", "drugenddate": null, "drugenddateformat": null, "drugindication": "NECK PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "20090414", "drugstartdateformat": "102", "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUPIRTINE" }, { "actiondrug": "6", "activesubstance": null, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "DROPS", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "GLAUCOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PILOCARPIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "SIMVASTATIN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": "40 MILLIGRAM DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERLIPIDAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "40", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SIMVASTATIN." } ], "patientagegroup": "5", "patientonsetage": "43", "patientonsetageunit": "801", "patientsex": "1", "patientweight": "83", "reaction": [ { "reactionmeddrapt": "Transaminases increased", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hepatitis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20090519" } }, "primarysource": { "literaturereference": "BORLAK J, VAN BOMMEL F, BERG T. N-ACETYLCYSTEINE AND PREDNISOLONE TREATMENT IMPROVED SERUM BIOCHEMISTRIES IN SUSPECTED FLUPIRTINE CASES OF SEVERE IDIOSYNCRATIC LIVER INJURY. LIVER-INT. FEB-2018?38(2):365-376.", "literaturereference_normalized": "n acetylcysteine and prednisolone treatment improved serum biochemistries in suspected flupirtine cases of severe idiosyncratic liver injury", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20180330", "receivedate": "20180329", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14693303, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180509" }, { "companynumb": "DE-JNJFOC-20180222006", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "IBUPROFEN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "019012", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "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": "IBUPROFEN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUPIRTINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BACK PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUPIRTINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DICLOFENAC" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "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": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DICLOFENAC" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "BISOPROLOL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "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": "BISOPROLOL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "IBUPROFEN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "019012", "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": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IBUPROFEN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PANTOPRAZOLE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "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": "PANTOPRAZOLE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "BORLAK J, BOMMEL F, BERG T. N-ACETYLCYSTEINE AND PREDNISOLONE TREATMENT IMPROVED SERUM BIOCHEMISTRIES IN SUSPECTED FLUPIRTINE CASES OF SEVERE IDIOSYNCRATIC LIVER INJURY. LIVER INTERNATIONAL 2018?38 (2):365-376.", "literaturereference_normalized": "n acetylcysteine and prednisolone treatment improved serum biochemistries in suspected flupirtine cases of severe idiosyncratic liver injury", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20180222", "receivedate": "20180222", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14564673, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180509" }, { "companynumb": "DE-JNJFOC-20180341936", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "FLUPIRTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BACK PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUPIRTINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "RAMIPRIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "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": "RAMIPRIL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "HYDROCHLOROTHIAZIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "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": "HYDROCHLOROTHIAZID" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "NEBIVOLOL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, 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"drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACETYLSALICYLIC ACID" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LERCANIDIPINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "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": "LERCANIDIPINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LEVOTHYROXINE SODIUM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "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": "L-THYROXIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "IBUPROFEN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "019012", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLETS", "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": "IBUPROFEN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "IBUPROFEN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "019012", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLETS", "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": "IBUPROFEN." } ], "patientagegroup": "6", "patientonsetage": "71", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "BORLAK J, VAN BOMMEL F, BERG T. N-ACETYLCYSTEINE AND PREDNISOLONE TREATMENT IMPROVED SERUM BIOCHEMISTRIES IN SUSPECTED FLUPIRTINE CASES OF SEVERE IDIOSYNCRATIC LIVER INJURY. LIVER INTERNATIONAL 2017.", "literaturereference_normalized": "n acetylcysteine and prednisolone treatment improved serum biochemistries in suspected flupirtine cases of severe idiosyncratic liver injury", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20180412", "receivedate": "20180412", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14750413, "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": "Elevated concentrations of serum acetaminophen-protein adducts, measured as protein-derived acetaminophen-cysteine (APAP-CYS), have been used to support a diagnosis of APAP-induced liver injury when histories and APAP levels are unhelpful. Adducts have been reported to undergo first-order elimination, with a terminal half-life of about 1.6 days. We wondered whether renal failure would affect APAP-CYS elimination half-life and whether continuous venovenous hemodiafiltration (CVVHDF), commonly used in liver failure patients, would remove adducts to lower their serum concentrations. Terminal elimination half-lives of serum APAP-CYS were compared between subjects with and without renal failure in a prospective cohort study of 168 adults who had ingested excessive doses of APAP. APAP-CYS concentrations were measured in plasma ultrafiltrate during CVVHDF at times of elevated serum adduct concentrations. Paired samples of urine and serum APAP-CYS concentrations were examined to help understand the potential importance of urinary elimination of serum adducts. APAP-CYS elimination half-life was longer in 15 renal failure subjects than in 28 subjects with normal renal function (41.3 ± 2.2 h versus 26.8 ± 1.1 h [mean ± SEM], respectively, p < 0.001). CVVHDF failed to remove detectable amounts of APAP-CYS in any of the nine subjects studied. Sixty-eight percent of 557 urine samples from 168 subjects contained no detectable APAP-CYS, despite levels in serum up to 16.99 μM. Terminal elimination half-life of serum APAP-CYS was prolonged in patients with renal failure for reasons unrelated to renal urinary adduct elimination, and consideration of prolonged elimination needs to be considered if attempting back-extrapolation of adduct concentrations. CVVHDF did not remove detectable APAP-CYS, suggesting approximate APAP-protein adduct molecular weights ≥ 50,000 Da. The presence of urinary APAP-CYS in the minority of instances was most compatible with renal adduct production and protein shedding into urine rather than elimination of serum adducts.", "affiliations": "Department of Medical Toxicology, Banner Good Samaritan Medical Center; Department of Medicine, and Center for Toxicology and Pharmacology Education and Research, University of Arizona College of Medicine-Phoenix, Phoenix, AZ, USA, steven.curry@bannerhealth.com.", "authors": "Curry|Steven C|SC|;Padilla-Jones|Angela|A|;O'Connor|Ayrn D|AD|;Ruha|Anne-Michelle|AM|;Bikin|Dale S|DS|;Wilkins|Diana G|DG|;Rollins|Douglas E|DE|;Slawson|Matthew H|MH|;Gerkin|Richard D|RD|;|||", "chemical_list": "D018712:Analgesics, Non-Narcotic; D011506:Proteins; D000082:Acetaminophen; C069744:acetaminophen cysteine; D003545:Cysteine", "country": "United States", "delete": false, "doi": "10.1007/s13181-014-0431-2", "fulltext": null, "fulltext_license": null, "issn_linking": "1556-9039", "issue": "11(2)", "journal": "Journal of medical toxicology : official journal of the American College of Medical Toxicology", "keywords": null, "medline_ta": "J Med Toxicol", "mesh_terms": "D000082:Acetaminophen; D000328:Adult; D018712:Analgesics, Non-Narcotic; D056486:Chemical and Drug Induced Liver Injury; D015331:Cohort Studies; D003545:Cysteine; D062787:Drug Overdose; D005260:Female; D006207:Half-Life; D017583:Hemodiafiltration; D006801:Humans; D008297:Male; D011446:Prospective Studies; D011506:Proteins; D012079:Renal Circulation; D051437:Renal Insufficiency; D053719:Tandem Mass Spectrometry", "nlm_unique_id": "101284598", "other_id": null, "pages": "169-78", "pmc": null, "pmid": "25288219", "pubdate": "2015-06", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": "21401949;851123;23462933;18958458;21319200;3572810;16317692;18923390;8209379;725953;23571099;3059186;8669426;10773044;19439490;519312;22378043;21652548;9073586;23719681;7229908;21274877", "title": "Prolonged Acetaminophen-Protein Adduct Elimination During Renal Failure, Lack of Adduct Removal by Hemodiafiltration, and Urinary Adduct Concentrations After Acetaminophen Overdose.", "title_normalized": "prolonged acetaminophen protein adduct elimination during renal failure lack of adduct removal by hemodiafiltration and urinary adduct concentrations after acetaminophen overdose" }

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PROLONGED ACETAMINOPHEN-PROTEIN ADDUCT ELIMINATION DURING RENAL FAILURE, LACK OF ADDUCT REMOVAL BY HEMODIAFILTRATION, AND URINARY ADDUCT CONCENTRATIONS AFTER ACETAMINOPHEN OVERDOSE. J. MED. 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{ "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "019872", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Unspecified", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACETAMINOPHEN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, 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"drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LORTAB" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "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": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLONAZEPAM." } ], "patientagegroup": "5", "patientonsetage": "26", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "51.5", "reaction": [ { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "18.0", "reactionoutcome": "4" }, { "reactionmeddrapt": "Intentional self-injury", "reactionmeddraversionpt": "18.0", "reactionoutcome": "4" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Liver function test abnormal", "reactionmeddraversionpt": "18.0", "reactionoutcome": "4" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20120415" } }, "primarysource": { "literaturereference": "CURRY SC, PADILLA-JONES A, O^CONNOR AD, RUHA A, BIKIN DS, WILKINS DG, ET AL. PROLONGED ACETAMINOPHEN-PROTEIN ADDUCT ELIMINATION DURING RENAL FAILURE, LACK OF ADDUCT REMOVAL BY HEMODIAFILTRATION, AND URINARY ADDUCT CONCENTRATIONS AFTER ACETAMINOPHEN OVERDOSE. J. MED. 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PROLONGED ACETAMINOPHEN PROTEIN ADDUCT ELIMINATION DURING RENAL FAILURE, LACK OF ADDUCT REMOVAL BY HEMODIAFILTRATION AND URINARY ADDUCT CONCENTRATIONS AFTER ACETAMINOPHEN OVERDOSE. J. MED. TOXICOL. 2014?OCT: 11:169?178", "literaturereference_normalized": "prolonged acetaminophen protein adduct elimination during renal failure lack of adduct removal by hemodiafiltration and urinary adduct concentrations after acetaminophen overdose", "qualification": null, "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210330", "receivedate": "20210330", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19070537, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210420" }, { "companynumb": "US-JNJFOC-20110411271", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ZOLPIDEM TARTRATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SLEEP DISORDER THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMBIEN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CARISOPRODOL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG WITHDRAWAL SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SOMA" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "HYDROCODONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG 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"drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TYLENOL PM" } ], "patientagegroup": "5", "patientonsetage": "27", "patientonsetageunit": "801", "patientsex": "1", "patientweight": "84.6", "reaction": [ { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute hepatic failure", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Renal failure", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Metabolic acidosis", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Agitation", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20110417" } }, "primarysource": { "literaturereference": "CURRY SC, PADILLA-JONES A, O^ CONNOR AD, RUHA A, BIKIN DS, WILKINS DG, ET AL. PROLONGED ACETAMINOPHEN-PROTEIN ADDUCT ELIMINATION DURING RENAL FAILURE, LACK OF ADDUCT REMOVAL BY HEMODIAFILTRATION, AND URINARY ADDUCT CONCENTRATIONS AFTER ACETAMINOPHEN OVERDOSE. J. MED. TOXICOL. 07-OCT-2014;DOI 10.1007/S13181-0.", "literaturereference_normalized": "prolonged acetaminophen protein adduct elimination during renal failure lack of adduct removal by hemodiafiltration and urinary adduct concentrations after acetaminophen overdose", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20141023", "receivedate": "20110509", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 7937317, "safetyreportversion": 5, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20150529" }, { "companynumb": "US-JNJFOC-20110201393", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "LEVETIRACETAM" }, "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": "LEVETIRACETAM." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "019872", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLETS", "drugdosagetext": null, "drugenddate": "20110123", "drugenddateformat": "102", "drugindication": "BACK PAIN", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "20110123", "drugstartdateformat": "102", "drugstructuredosagenumb": "6", "drugstructuredosageunit": "032", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACETAMINOPHEN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LITHIUM CARBONATE" }, "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": "LITHIUM" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "AMPHETAMINE ASPARTATE\\AMPHETAMINE SULFATE\\DEXTROAMPHETAMINE SACCHARATE\\DEXTROAMPHETAMINE SULFATE" }, "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": "ADDERALL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "QUETIAPINE" }, "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": "QUETIAPINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "019872", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLETS", "drugdosagetext": "40-50 TABLETS ON 24JAN2011", "drugenddate": "20110124", "drugenddateformat": "102", "drugindication": "BACK PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "20110124", "drugstartdateformat": "102", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACETAMINOPHEN." } ], "patientagegroup": "5", "patientonsetage": "23", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "58.6", "reaction": [ { "reactionmeddrapt": "Cerebral haemorrhage", "reactionmeddraversionpt": "18.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "18.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Acute hepatic failure", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Metabolic acidosis", "reactionmeddraversionpt": "18.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Intentional overdose", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "18.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Intracranial pressure increased", "reactionmeddraversionpt": "18.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Pneumonia", "reactionmeddraversionpt": "18.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "18.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Decreased appetite", "reactionmeddraversionpt": "18.0", "reactionoutcome": "3" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20110124" } }, "primarysource": { "literaturereference": "CURRY SC, PADILLA-JONES A, O^ CONNOR AD, RUHA A, BIKIN DS, WILKINS DG, ET AL. PROLONGED ACETAMINOPHEN-PROTEIN ADDUCT ELIMINATION DURING RENAL FAILURE, LACK OF ADDUCT REMOVAL BY HEMODIAFILTRATION, AND URINARY ADDUCT CONCENTRATIONS AFTER ACETAMINOPHEN OVERDOSE. J. MED. TOXICOL 07-OCT-2014;DOI 10.1007/S13181-0.", "literaturereference_normalized": "prolonged acetaminophen protein adduct elimination during renal failure lack of adduct removal by hemodiafiltration and urinary adduct concentrations after acetaminophen overdose", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20141023", "receivedate": "20110211", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 7808517, "safetyreportversion": 5, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20150529" }, { "companynumb": "US-JNJFOC-20121013203", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "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": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201210", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ACETAMINOPHEN\\HYDROCODONE BITARTRATE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Unspecified", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SUBSTANCE USE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201210", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VICODIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "019872", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Unspecified", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APAP" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ACETAMINOPHEN\\OXYCODONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Unspecified", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SUBSTANCE USE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201210", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PERCOCET" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "019872", "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": "201210", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APAP" } ], "patientagegroup": "5", "patientonsetage": "48", "patientonsetageunit": "801", "patientsex": "1", "patientweight": "79", "reaction": [ { "reactionmeddrapt": "Metabolic acidosis", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Encephalopathy", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Anuria", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Shock", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Coma", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Cerebral hypoperfusion", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Multi-organ failure", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Malaise", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201210" } }, "primarysource": { "literaturereference": "CURRY SC, PADILLA-JONES A, O^CONNOR AD, RUHA A, BIKIN DS, WILKINS DG, ET AL. PROLONGED ACETAMINOPHEN-PROTEIN ADDUCT ELIMINATION DURING RENAL FAILURE, LACK OF ADDUCT REMOVAL BY HEMODIAFILTRATION, AND URINARY ADDUCT CONCENTRATIONS AFTER ACETAMINOPHEN OVERDOSE. J. MED. TOXICOL 07-OCT-2014;DOI 10.1007/S13181-0.", "literaturereference_normalized": "prolonged acetaminophen protein adduct elimination during renal failure lack of adduct removal by hemodiafiltration and urinary adduct concentrations after acetaminophen overdose", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20141023", "receivedate": "20121029", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 8876897, "safetyreportversion": 5, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20150529" }, { "companynumb": "US-JNJFOC-20150618820", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "019872", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": "ALL EXCESSIVE INGESTIONS (MORE THAN 4G APAP PER DAY)", "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": "ACETAMINOPHEN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "019872", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "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": "ACETAMINOPHEN." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Renal failure", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hepatic encephalopathy", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute hepatic failure", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Alanine aminotransferase abnormal", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CURRY SC, PADILLA JONES A, O^CONNOR AD, RUHA A, BIKIN DS, WILKINS DG, ET AL. PROLONGED ACETAMINOPHEN PROTEIN ADDUCT ELIMINATION DURING RENAL FAILURE, LACK OF ADDUCT REMOVAL BY HEMODIAFILTRATION, AND URINARY ADDUCT CONCENTRATIONS AFTER ACETAMINOPHEN OVERDOSE. JOURNAL OF MEDICINE TOXICOLOGY 2015;11(2):169-178.", "literaturereference_normalized": "prolonged acetaminophen protein adduct elimination during renal failure lack of adduct removal by hemodiafiltration and urinary adduct concentrations after acetaminophen overdose", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20150709", "receivedate": "20150709", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11254246, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20151125" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-287828", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "76200", "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": "ACETAMINOPHEN." } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Renal failure", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CURRY SC, PADILLA JONES A, O CONNOR AD, RUHA AM, BIKIN DS, WILKINS DG ET AL. PROLONGED ACETAMINOPHEN PROTEIN ADDUCT ELIMINATION DURING RENAL FAILURE, LACK OF ADDUCT REMOVAL BY HEMODIAFILTRATION AND URINARY ADDUCT CONCENTRATIONS AFTER ACETAMINOPHEN OVERDOSE. J. MED. TOXICOL. 2014?OCT: 11:169?178", "literaturereference_normalized": "prolonged acetaminophen protein adduct elimination during renal failure lack of adduct removal by hemodiafiltration and urinary adduct concentrations after acetaminophen overdose", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210330", "receivedate": "20210330", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19070539, "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" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-286748", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "76200", "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": "ACETAMINOPHEN" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Alanine aminotransferase increased", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Curry SC, Padilla Jones A, O Connor AD, Ruha AM, Bikin DS, Wilkins DG et al. Prolonged Acetaminophen Protein Adduct Elimination During Renal Failure, Lack of Adduct Removal by Hemodiafiltration and Urinary Adduct Concentrations After Acetaminophen Overdose. J. Med. Toxicol. 2014;Oct: 11:169-178", "literaturereference_normalized": "prolonged acetaminophen protein adduct elimination during renal failure lack of adduct removal by hemodiafiltration and urinary adduct concentrations after acetaminophen overdose", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20220107", "receivedate": "20210330", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19070640, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220423" }, { "companynumb": "US-JNJFOC-20130207209", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ROSUVASTATIN" }, "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": "ROSUVASTATIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ALLOPURINOL" }, "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": "ALLOPURINOL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SITAGLIPTIN" }, "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": "SITAGLIPTIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CARVEDILOL" }, "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": "CARVEDILOL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "GLIPIZIDE" }, "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": "GLIPIZIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "019872", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLETS", "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": "APAP" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "019872", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLETS", "drugdosagetext": "650MG, APPROXIMATELY 100 TABLETS", "drugenddate": null, "drugenddateformat": null, "drugindication": "PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201302", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APAP" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "GABAPENTIN" }, "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": "GABAPENTIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "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": "METFORMIN" } ], "patientagegroup": "6", "patientonsetage": "79", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "83", "reaction": [ { "reactionmeddrapt": "Acute respiratory failure", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Blood lactic acid increased", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Aspartate aminotransferase increased", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Metabolic acidosis", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Asthenia", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Alanine aminotransferase increased", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Prothrombin time prolonged", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201302" } }, "primarysource": { "literaturereference": "CURRY SC, PADILLA-JONES A, O^ CONNOR AD, RUHA A, BIKIN DS, WILKINS DG, ET AL. PROLONGED ACETAMINOPHEN-PROTEIN ADDUCT ELIMINATION DURING RENAL FAILURE, LACK OF ADDUCT REMOVAL BY HEMODIAFILTRATION, AND URINARY ADDUCT CONCENTRATIONS AFTER ACETAMINOPHEN OVERDOSE. J. MED. TOXICOL 07-OCT-2014;DOI 10.1007/S13181-0.", "literaturereference_normalized": "prolonged acetaminophen protein adduct elimination during renal failure lack of adduct removal by hemodiafiltration and urinary adduct concentrations after acetaminophen overdose", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20141023", "receivedate": "20130219", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 9103871, "safetyreportversion": 6, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20150529" }, { "companynumb": "US-JNJFOC-20130112644", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "PROMETHAZINE\\PROMETHAZINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "048", "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": "PROMETHAZINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "BACLOFEN" }, "drugadditional": null, "drugadministrationroute": "050", "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": "BACLOFEN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "BUPIVACAINE" }, "drugadditional": null, "drugadministrationroute": "050", "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": "BUPIVACAINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "HYDROMORPHONE" }, "drugadditional": null, "drugadministrationroute": "050", "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": "HYDROMORPHONE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TEMAZEPAM" }, "drugadditional": null, "drugadministrationroute": "048", "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": "RESTORIL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "BETHANECHOL CHLORIDE" }, "drugadditional": null, "drugadministrationroute": "048", "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": "URECHOLINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "OXYCODONE" }, "drugadditional": null, "drugadministrationroute": "048", "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": "OXYCODONE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LORAZEPAM" }, "drugadditional": null, "drugadministrationroute": "048", "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": "LORAZEPAM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "019872", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLETS", "drugdosagetext": null, "drugenddate": "20130118", "drugenddateformat": "102", "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": "APAP" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DIPHENHYDRAMINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Unspecified", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SLEEP DISORDER THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DIPHENHYDRAMINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "OXCARBAZEPINE" }, "drugadditional": null, "drugadministrationroute": "048", "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": "OXCARBAZEPINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PROMETHAZINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "048", "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": "PROMETHEGAN" } ], "patientagegroup": "5", "patientonsetage": "59", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "55", "reaction": [ { "reactionmeddrapt": "Brain injury", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Intentional overdose", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Completed suicide", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Respiratory failure", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Anuria", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Haemorrhage intracranial", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Brain oedema", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Coma", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Intracranial pressure increased", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Acute hepatic failure", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201301" } }, "primarysource": { "literaturereference": "CURRY SC, PADILLA-JONES A, O^CONNOR AD, RUHA A, BIKIN DS, WILKINS DG, ET AL. PROLONGED ACETAMINOPHEN-PROTEIN ADDUCT ELIMINATION DURING RENAL FAILURE, LACK OF ADDUCT REMOVAL BY HEMODIAFILTRATION, AND URINARY ADDUCT CONCENTRATIONS AFTER ACETAMINOPHEN OVERDOSE. J. MED. TOXICOL 07-OCT-2014;DOI 10.1007/S13181-0.", "literaturereference_normalized": "prolonged acetaminophen protein adduct elimination during renal failure lack of adduct removal by hemodiafiltration and urinary adduct concentrations after acetaminophen overdose", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20141023", "receivedate": "20130128", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 9064493, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20150529" } ]

{ "abstract": "Tubulointerstitial nephritis is primary injury to renal tubules and interstititum which could be resulting in decreased renal function. The acute and chronic forms are most often due to allergic drug reactions or to infections. Tubulointerstitial nephritis in Crohn's disease has rarely been reported. Imaging findings of a striated nephrogram on enhanced computed tomography (CT) could represent the clinical state of tubulointerstitial nephritis. This is the first report of tubulointerstitial nephritis caused by infliximab, monoclonal antibody against human tumor necrosis factor-α, showing striated nephrograms in Crohn's disease. The case of a 28-year-old man treated with infliximab for Crohn's disease is described. Infliximab was added to his maintenance therapy, and bowel symptoms were stable. The patient presented with a 2-month history of fever and an elevated C-reactive protein after infliximab administration for 4.5 years. Contrast-enhanced CT showed striated nephrograms in both kidneys. Urinalysis showed no abnormal findings. The pathological diagnosis on CT-guided percutaneous renal needle biopsy was drug-induced tubulointerstitial nephritis because of eosinophilic infiltration with neutrophils mainly in the tubulointerstitial areas. The imaging findings of striated nephrogram are important for the diagnosis of tubulointerstitial nephritis. Tubulointerstitial nephritis could be caused by drug-induced inflammation or direct extension of Crohn's disease as an extra-interstitial manifestation. The treatment strategies for these two diseases are contradictory to each other and inappropriate treatment could worsen the renal function. Needle biopsy is therefore indispensable for differential diagnosis.", "affiliations": "Department of Urology, Tohoku University Graduate School of Medicine.;Department of Urology, Tohoku University Graduate School of Medicine.;Department of Urology, Tohoku University Graduate School of Medicine.;Department of Urology, Tohoku University Graduate School of Medicine.;Department of Urology, Tohoku University Graduate School of Medicine.;Department of Urology, Tohoku University Graduate School of Medicine.;Department of Urology, Tohoku University Graduate School of Medicine.;Department of Diagnostic Radiology, Tohoku University Graduate School of Medicine.;Division of Pathology, Tohoku University Hospital.;Department of Urology, Tohoku University Graduate School of Medicine.", "authors": "Sato|Tomonori|T|;Kawasaki|Yoshihide|Y|;Ito|Akihiro|A|;Izumi|Hideaki|H|;Kawamorita|Naoki|N|;Yamashita|Shinichi|S|;Mitsuzuka|Koji|K|;Matsuura|Tomonori|T|;Watanabe|Mika|M|;Arai|Yoichi|Y|", "chemical_list": "D003287:Contrast Media; D000069285:Infliximab", "country": "Japan", "delete": false, "doi": "10.1620/tjem.245.149", "fulltext": null, "fulltext_license": null, "issn_linking": "0040-8727", "issue": "245(3)", "journal": "The Tohoku journal of experimental medicine", "keywords": "Crohn’s disease; infliximab; renal biopsy; striated nephrogram; tubulointerstitial nephritis", "medline_ta": "Tohoku J Exp Med", "mesh_terms": "D000328:Adult; D003287:Contrast Media; D003424:Crohn Disease; D006801:Humans; D000069285:Infliximab; D007668:Kidney; D008297:Male; D009395:Nephritis, Interstitial; D014057:Tomography, X-Ray Computed", "nlm_unique_id": "0417355", "other_id": null, "pages": "149-152", "pmc": null, "pmid": "29973427", "pubdate": "2018-07", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Infliximab-Induced Tubulointerstitial Nephritis with Image Findings of Striated Nephrogram in Crohn's Disease.", "title_normalized": "infliximab induced tubulointerstitial nephritis with image findings of striated nephrogram in crohn s disease" }

[ { "companynumb": "JP-PFIZER INC-2018328198", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "INFLIXIMAB" }, "drugadditional": "1", "drugadministrationroute": null, "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": "2011", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INFLIXIMAB" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MESALAMINE" }, "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": "MESALAZINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "AZATHIOPRINE" }, "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": "AZATHIOPRINE." } ], "patientagegroup": null, "patientonsetage": "28", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Tubulointerstitial nephritis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "SATO, T.. INFLIXIMAB?INDUCED TUBULOINTERSTITIAL NEPHRITIS WITH IMAGE FINDINGS OF STRIATED NEPHROGRAM IN CROHN^S DISEASE. TOHOKU JOURNAL OF EXPERIMENTAL MEDICINE. 2018?245 (3):149?152?10.1620/TJEM.245.149", "literaturereference_normalized": "infliximab induced tubulointerstitial nephritis with image findings of striated nephrogram in crohn s disease", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20180914", "receivedate": "20180820", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15296664, "safetyreportversion": 4, "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-JNJFOC-20170213356", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "AZATHIOPRINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "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": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IMURAN" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "MESALAMINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "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": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PENTASA" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "INFLIXIMAB" }, "drugadditional": "1", "drugadministrationroute": "042", "drugauthorizationnumb": "103772", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "LYOPHILIZED POWDER", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CROHN^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2011", "drugstartdateformat": "602", "drugstructuredosagenumb": "5", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "REMICADE" } ], "patientagegroup": "5", "patientonsetage": "28", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Tubulointerstitial nephritis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201604" } }, "primarysource": { "literaturereference": "SATO T, KAWASAKI Y, ITO A, IZUMI H, KAWAMORITA N, YAMASHITA S, ET AL. INFLIXIMAB?INDUCED TUBULOINTERSTITIAL NEPHRITIS WITH IMAGE FINDINGS OF STRIATED NEPHROGRAM IN CROHN^S DISEASE. THE TOHOKU JOURNAL OF EXPERIMENTAL MEDICINE JUL?2018?245(3):149?152.", "literaturereference_normalized": "infliximab induced tubulointerstitial nephritis with image findings of striated nephrogram in crohn s disease", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20180919", "receivedate": "20170216", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13239572, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20181010" } ]

{ "abstract": "A 45-year-old man presented to our emergency department with disturbance of consciousness; he had mentioned to his family earlier about a drug overdose. When first responders arrived, he suffered cardiac arrest. Cardiac arrest due to drug overdose was diagnosed.The patient was supported with venoarterial extracorporeal membrane oxygenation. Arterial blood gas showed mixed acidosis, and electrocardiogram showed junctional rhythm and complete right bundle branch block.\nThe patient's blood pressure gradually decreased, and he died on the third day of hospitalization. After death, his serum diphenhydramine concentration at the time of arrival was found to be 18.7 μg/mL.\nAlthough diphenhydramine is regarded as a safe medication, it shows dose-dependent toxicity. High intake is associated with death; therefore, caution should be exercised in cases of drug overdose. Developing a procedure for rapid measurement in the emergency department should be a priority.", "affiliations": "Department of Emergency and Critical Care Medicine Tokai University School of Medicine Isehara Kanagawa Japan.;Department of Emergency and Critical Care Medicine Tokai University School of Medicine Isehara Kanagawa Japan.;Department of Emergency and Critical Care Medicine Tokai University School of Medicine Isehara Kanagawa Japan.;Department of Emergency and Critical Care Medicine Tokai University School of Medicine Isehara Kanagawa Japan.", "authors": "Nishino|Tomoya|T|0000-0002-6270-3655;Wakai|Shinjirou|S|;Aoki|Hiromichi|H|;Inokuchi|Sadaki|S|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1002/ams2.351", "fulltext": "\n==== Front\nAcute Med SurgAcute Med Surg10.1002/(ISSN)2052-8817AMS2Acute Medicine & Surgery2052-8817John Wiley and Sons Inc. Hoboken 10.1002/ams2.351AMS2351Case ReportCase ReportsCardiac arrest caused by diphenhydramine overdose T. Nishino et al.Nishino Tomoya http://orcid.org/0000-0002-6270-3655i10ve69@yahoo.co.jp \n1\nWakai Shinjirou \n1\nAoki Hiromichi \n1\nInokuchi Sadaki \n1\n\n1 \nDepartment of Emergency and Critical Care Medicine\nTokai University School of Medicine\nIsehara\nKanagawa\nJapan\n* Corresponding: Tomoya Nishino, MD, Department of Emergency and Critical Care Medicine, Tokai University School of Medicine, Simokasuya143, Isehara, Kanagawa 259‐1193, Japan. E‐mail: i10ve69@yahoo.co.jp.25 6 2018 10 2018 5 4 10.1002/ams2.2018.5.issue-4380 383 12 1 2018 24 5 2018 © 2018 The Authors. Acute Medicine & Surgery published by John Wiley & Sons Australia, Ltd on behalf of Japanese Association for Acute MedicineThis is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ 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.Case\nA 45‐year‐old man presented to our emergency department with disturbance of consciousness; he had mentioned to his family earlier about a drug overdose. When first responders arrived, he suffered cardiac arrest. Cardiac arrest due to drug overdose was diagnosed.The patient was supported with venoarterial extracorporeal membrane oxygenation. Arterial blood gas showed mixed acidosis, and electrocardiogram showed junctional rhythm and complete right bundle branch block.\n\nOutcome\nThe patient's blood pressure gradually decreased, and he died on the third day of hospitalization. After death, his serum diphenhydramine concentration at the time of arrival was found to be 18.7 μg/mL.\n\nConclusion\nAlthough diphenhydramine is regarded as a safe medication, it shows dose‐dependent toxicity. High intake is associated with death; therefore, caution should be exercised in cases of drug overdose. Developing a procedure for rapid measurement in the emergency department should be a priority.\n\nCardiotoxicityH1 histamine receptor antagonistliposolubleover‐the‐counter drugvenoarterial extracorporeal membrane oxygenation source-schema-version-number2.0component-idams2351cover-dateOctober 2018details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:version=5.5.0 mode:remove_FC converted:09.10.2018\nFunding Information No funding information provided.\n==== Body\nBackground\nDiphenhydramine (DPH), a first generation H1 histamine receptor antagonist, is widely used as an over‐the‐counter (OTC) drug; therefore, the frequency of its overdose is high. However, cardiac arrest due to overdose is rare because of its wide therapeutic range. Here, we report the case of a 45‐year‐old man who suffered cardiac arrest and died despite receiving intense venoarterial extracorporeal membrane oxygenation (VA‐ECMO).\n\nCase\nA 45‐year‐old man with no significant medical history or any reported regular medication was transferred to our emergency department in February because of disturbance of consciousness. From the history reported by family members, he had returned home 16 h before being admitted to the hospital and informed his family that he had consumed an overdose of an OTC drug. The details about the drug and its amount could not be known because the patient did not remember the amount ingested and the medication container could not be found. The patient had ingested the drug outside the home then went swimming in the ocean. At 14 h before admission, his family reported that he went to bed and was checked by his parents every hour. Although he was able to speak until 1 h before admission, he was groaning and feeling disturbed. His parents called for an ambulance; however, he suffered cardiac arrest when the ambulance arrived. A helicopter was requested, and evaluation by the ambulance crew revealed pulseless electrical activity. Cardiopulmonary resuscitation (CPR) was initiated, and continued assessment by the doctor and helicopter crew revealed asystole. After the patient received an i.v. line, intubation, continuous CPR, and 2 mg adrenaline by the doctor and helicopter crew, spontaneous circulation returned. They also administered 0.5 mg atropine because his heart rate was approximately 40 beats/min. Initial evaluation at the emergency department revealed a Glasgow Coma Scale (GCS) of E1V1M1, systolic blood pressure of approximately 60 mmHg (only carotid artery was palpable), heart rate of 100 beats/min, axillary temperature of 36.7°C, oxygen saturation (SpO2) of 83% (O2, 10 L/min), and 6‐mm dilation of both pupils without reflex. No injury marks were found. Cardiac arrest due to drug overdose was diagnosed, and VA‐ECMO was initiated 20 min after arrival.\n\nLaboratory tests revealed mixed acidosis, liver and renal dysfunction, elevated creatine kinase levels, and the Triage Panel for Drugs of Abuse (SYSMEX Corporation, Kobe, Japan) was negative (Table 1).\n\nTable 1 Laboratory analyses at admission of a 45‐year‐old man with cardiac arrest caused by diphenhydramine overdose\n\n\nHematology\n\tBlood sugar\t335 mg/dL\t\nWhite blood cells\t11,400/μL\tEthanol\t<3.0 mg/dL\t\nHemoglobin\t12.4 g/dL\tTroponin I\t0.56 ng/mL\t\nHematocrit\t41.6%\tMyoglobin\t>5000 ng/mL\t\nPlatelets\t12.5 × 104/μL\t\n\nCoagulation\n\t\nPT‐INR\t1.15\t\nD‐dimer\t57.3 μg/mL\t\n\nBlood chemistry\n\tFibrinogen\t144 mg/dL\t\nAspartate aminotransferase\t336 IU/L\t\nArterial blood gas analysis (O\n2\n10 L/min)\n\t\nAlanine aminotransferase\t338 IU/L\tpH\t6.773\t\nLactate dehydrogenase\t730 IU/L\tPaCO2\n\t76.4 mmHg\t\nCreatine kinase\t5489 IU/L\tPaO2\n\t407 mmHg\t\nBlood urea nitrogen\t16 mg/dL\tBicarbonate\t10.5 mmol/L\t\nCreatinine\t1.66 mg/dL\tBase excess\t−26.1 mmol/L\t\nC‐reactive protein\t0.71 mg/dL\tLactate\t156 mg/dL\t\nSodium\t143 mEq/L\t\nUrine\n\t\nPotassium\t5.4 mEq/L\tTriage DOA\tNegative\t\nChloride\t98 mEq/L\t\nDOA, Drugs of Abuse; PT‐INR, prothrombin time – international normalized ratio; PaCO2, partial pressure of arterial carbon dioxide; PaO2, partial pressure of arterial oxygen.\n\nJohn Wiley & Sons, LtdNon‐contrast computed tomography (CT) of the head showed loss of gray–white matter differentiation without hemorrhage, and contrast‐enhanced CT of the trunk showed no pulmonary embolism, aortic dissection, or free air. Electrocardiography revealed junctional rhythm, but QTc could not be evaluated because of complete right bundle branch block (Fig. 1). Bedside transthoracic echocardiography showed good wall motion with no asynergy, pericardial effusion, left ventricular hypertrophy, or right ventricular overload.\n\nFigure 1 Electrocardiogram at admission of a 45‐year‐old man with cardiac arrest caused by diphenhydramine overdose. The trace shows junctional rhythm but QTc was unable to be evaluated because of complete right bundle brunch block.\n\nThe patient was treated with VA‐ECMO, given 0.4 μg/kg/min adrenaline, and underwent gastric lavage. His potassium level elevated to 7.2 mEq/L; thus, he was treated with insulin and glucose. Despite treatment, his blood pressure gradually decreased. Bedside transthoracic echocardiography carried out on the second day of hospitalization showed diffuse hypokinesis of wall motion. He was diagnosed with catecholamine‐refractory hypotension. Despite treatment with glucagon, his blood pressure and heart rate gradually decreased, and he died on the third day of hospitalization. After his death, his serum DPH concentration at the time of arrival was found to be 18.7 μg/mL.\n\nDiscussion\nDiphenhydramine overdose can be fatal.1 Peak serum levels of DPH are reached approximately 2–3 h after ingestion, and elimination half‐life is approximately 4 h. Because DPH is liposoluble and its volume of distribution is large (3–7 L/kg),2 its elimination by hemodialysis and hemoperfusion is difficult. Although DPH is considered as a relatively safe drug with a large therapeutic range, it causes dose‐dependent toxicity. Eckes et al.1 have reported serum DPH concentration of >5 μg/mL as fatal.\n\nDiphenhydramine binds to the H1 histamine receptor and suppresses inflammation and respiratory secretion. It also binds to muscarinic and dopamine receptors. The effects of DPH on delayed rectifier potassium channels of the heart include prolongation of the QT interval and flattening of the T‐wave.3 Moreover, DPH inhibits fast sodium channels of the His–Purkinje system. It delays depolarization, which results in the prolongation of QRS time and bundle branch block.3\n\n\nEckes et al.1 reported that pulmonary congestion is frequently seen in autopsies of patients with DPH overdose, which is associated with increased vascular permeability.4\n\n\nThere is a report of pulmonary edema caused by DPH overdose.4 In this case, however, CT scan showed no evidence of pulmonary complication. Therefore, the hypoxemia at initial evaluation in the emergency department was considered to be due to the post‐cardiac arrest status.\n\nIn previous reports, DPH overdose resulted in severe symptoms within several hours.5, 6 Symptoms are dose‐dependent. Severe symptoms (delirium/psychosis, seizures, and coma) can occur with ingestion of >1.0 g DPH. The frequency of coma and seizures may increase with ingestion of >1.5 g DPH, and electrocardiographic disturbances may occur with ingestion of >3.0 g DPH.7 Although the serum DPH concentration was thought to have peaked about 13 h before arriving at the hospital in this case because peak serum DPH concentration is usually reached 2–3 h after ingestion, the patient's serum DPH concentration at the time of arrival was >5 μg/mL, which is considered to be a fatal dose.\n\nAlthough the patient ingested a fatal dose of DPH, it is estimated that it took approximately 16 h for symptoms to appear. Therefore, caution should be exercised when symptoms occur long after DPH ingestion.\n\nTo the best of our knowledge, although immunoassay screening of DPH has been reported,8 there is no procedure for its rapid measurement, such as application of a kit, in the emergency department. Therefore, screening for DPH overdose and judging the toxic range are difficult. In this case, DPH intoxication could not be diagnosed until the patient died, and DPH was detected in his blood. Clearly, a rapid measurement method is needed for DPH.\n\nTreatments for DPH overdose includes general condition management and symptomatic treatments, such as benzodiazepine (diazepam or midazolam) for convulsions, physostigmine for acetylcholinesterase inhibition, sodium bicarbonate for ventricular arrhythmia, and VA‐ECMO for hemodynamic collapse.4, 5, 9, 10 Although the patient died in this case, it is important to treat unstable hemodynamics with invasive auxiliary circulation such as VA‐ECMO.\n\nIntravenous lipid emulsion treatment has been validated for DPH overdose;6, 11 however, its use is controversial.\n\nIn this case, rhabdomyolysis was also detected. Rhabdomyolysis due to DPH overdose is usually caused by secondary consequences (e.g., seizure, agitation, and muscle compression due to coma); however, the influence of DPH overdose in inducing direct myotoxicity is unclear.12 In this case, no hypothermia, hyperthermia, or seizures were observed. Although environmental factors, such as going into the sea in winter, and cardiac arrest and CPR are listed as potential causes of rhabdomyolysis, no such association could be identified.\n\nConclusion\nAlthough DPH is relatively safe for wide use as an OTC drug, it causes dose‐dependent toxicity and may be fatal if overdosed. As fatalities occur despite intensive care, further studies are required to develop early detection systems such as rapid measurement of DPH and specific treatments for DPH overdose.\n\nDisclosure\nApproval of the research protocol: N/A.\n\nInformed consent: Written informed consent was obtained from the patient's family for publication of this case report and accompanying images.\n\nRegistry and the registration no. of the study/trial: N/A.\n\nAnimal studies: N/A.\n\nConflict of interest: None declared.\n==== Refs\nReferences\n1 \n\nEckes \nL \n, \nTsokos \nM \n, \nHerre \nS \n, \nGapert \nR \n, \nHartwig \nS \n. Toxicological identification of diphenhydramine (DPH) in suicide . Forensic Sci. Med. Pathol. \n2013 ; 9 : 145 –53 .23065653 \n2 \n\nPaton \nDM \n, \nWebster \nDR \n. Clinical pharmacokinetics of H1‐receptor antagonists (the antihistamines) . Clin. Pharmacokinet. \n1985 ; 10 : 477 –97 .2866055 \n3 \n\nZareba \nW \n, \nMoss \nAJ \n, \nRosero \nSZ \n, \nHajj‐Ali \nR \n, \nKonecki \nJ \n, \nAndrews \nM \n. Electrocardiographic findings in patients with diphenhydramine overdose . Am. J. Cardiol. \n1997 ; 80 : 1168 –73 .9359544 \n4 \n\nKamijo \nY \n, \nSoma \nK \n, \nSato \nC \n, \nKurihara \nK \n. Fatal diphenhydramine poisoning with increased vascular permeability including late pulmonary congestion refractory to percutaneous cardiovascular support . Clin. Toxicol. \n2008 ; 46 : 864 –8 .\n5 \n\nSharma \nAN \n, \nHexdall \nAH \n, \nChang \nEK \n\net al\nDiphenhydramine‐induced wide complex dysrhythmia responds to treatment with sodium bicarbonate . Am. J. Emerg. Med. \n2003 ; 21 : 212 –5 .12811715 \n6 \n\nAbdi \nA \n, \nRose \nE \n, \nLevine \nM \n. Diphenhydramine overdose with intraventricular conduction delay treated with hypertonic sodium bicarbonate and i.v. lipid emulsion. West . J. Emerg. Med. \n2014 ; 15 : 855 –8 .\n7 \n\nRadovanovic \nD \n, \nMeier \nPJ \n, \nGuirguis \nM \n\net al\nDose‐dependent toxicity of diphenhydramine overdose . Hum. Exp. Toxicol. \n2000 ; 19 : 489 –95 .11204550 \n8 \n\nRodrigues \nWC \n, \nCastro \nC \n, \nCatbagan \nP \n\net al\nImmunoassay screening of diphenhydramine (Benadryl®) in urine and blood using a newly developed assay . J. Anal. Toxicol. \n2012 ; 36 : 123 –9 .22337782 \n9 \n\nBurns \nMJ \n, \nLinden \nCH \n, \nGraudins \nA \n\net al\nA comparison of physostigmine and benzodiazepines for the treatment of anticholinergic poisoning . Ann. Emerg. Med. \n2000 ; 35 : 374 –81 .10736125 \n10 \n\nScharman \nEJ \n, \nErdman \nAR \n, \nWax \nPM \n\net al\nDiphenhydramine and dimenhydrinate poisoning: an evidence‐based consensus guideline for out‐of‐hospital management . Clin. Toxicol. (Phila) \n2006 ; 44 : 205 –23 .16749537 \n11 \n\nYu \nJH \n, \nChen \nDY \n, \nChen \nHY \n\net al\nIntravenous lipid‐emulsion therapy in a patient with cardiac arrest after overdose of diphenhydramine . J. Formos. Med. Assoc. \n2016 ; 115 : 1017 –8 .27421174 \n12 \n\nVearrier \nD \n, \nCurtis \nJA \n. Case files of the medical toxicology fellowship at Drexel University. Rhabdomyolysis and compartment syndrome following acute diphenhydramine overdose . J. Med. Toxicol. \n2011 ; 7 : 213 –9 .21656083\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2052-8817", "issue": "5(4)", "journal": "Acute medicine & surgery", "keywords": "Cardiotoxicity; H1 histamine receptor antagonist; liposoluble; over‐the‐counter drug; venoarterial extracorporeal membrane oxygenation", "medline_ta": "Acute Med Surg", "mesh_terms": null, "nlm_unique_id": "101635464", "other_id": null, "pages": "380-383", "pmc": null, "pmid": "30338086", "pubdate": "2018-10", "publication_types": "D002363:Case Reports", "references": "21656083;11204550;18608279;2866055;16749537;9359544;22337782;23065653;10736125;12811715;27421174;25493135", "title": "Cardiac arrest caused by diphenhydramine overdose.", "title_normalized": "cardiac arrest caused by diphenhydramine overdose" }

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CARDIAC ARREST CAUSED BY DIPHENHYDRAMINE OVERDOSE.. ACUTE MEDICINE + SURGERY. 2018 JUN 25?5 (4):380-383.", "literaturereference_normalized": "cardiac arrest caused by diphenhydramine overdose", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20190514", "receivedate": "20190514", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16308613, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190711" } ]

{ "abstract": "BACKGROUND\nSodium glucose cotransporter 2 (SGLT2) inhibitors use has been associated with toe amputations and non-healing ulcers and gangrene mostly of lower extremities. There are no case reports about association of Empagliflozin with finger ulcers or gangrene. This is the first case report of Empagliflozin (Jardiance) an SGLT2 inhibitor causing gangrene of fingers and second case in literature about any SGLT2 inhibitor causing gangrene of upper extremity.\n\n\nMETHODS\nA 76-year-old man with type 2 diabetes mellitus sustained minimal trauma to both middle fingers, which started healing. He was started on empagliflozin a week later for management of type 2 diabetes mellitus and started developing gangrene to both middle finger tips along with neuropathic pain which worsened over the course of next four months. Investigations were negative for vascular insufficiency, infection and vasculitis and imaging of hand was normal. Discontinuation of empagliflozin slowed progression of gangrene and caused symptomatic improvement with reduction in neuropathic pain.\n\n\nCONCLUSIONS\nThis case report suggests possible association of empagliflozin and finger gangrene and recommends that more research and awareness among clinicians is needed in this area.", "affiliations": "Endocrinology and Metabolism and Internal Medicine, San Francisco VA Medical Center, Santa Rosa, CA 95492, United States. drrajashree.pai@gmail.com.;Infectious Diseases and Internal Medicine, San Francisco VA Medical Center, Santa Rosa, CA 95492, United States.", "authors": "Ramachandra Pai|Rajasree Pai|RP|;Kangath|Raghesh Varot|RV|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.4239/wjd.v10.i2.133", "fulltext": "\n==== Front\nWorld J DiabetesWJDWorld Journal of Diabetes1948-9358Baishideng Publishing Group Inc jWJD.v10.i2.pg13310.4239/wjd.v10.i2.133Case ReportBilateral gangrene of fingers in a patient on empagliflozin: First case report Ramachandra Pai Rajasree Pai Endocrinology and Metabolism and Internal Medicine, San Francisco VA Medical Center, Santa Rosa, CA 95492, United States. drrajashree.pai@gmail.comKangath Raghesh Varot Infectious Diseases and Internal Medicine, San Francisco VA Medical Center, Santa Rosa, CA 95492, United StatesAuthor contributions: Ramachandra Pai RP prepared, reviewed and edited the manuscript; Kangath RV assisted in reviewing and editing the manuscript.\n\nCorresponding author: Rajasree Pai Ramachandra Pai, MD, Staff Physician, Endocrinology and Metabolism and Internal Medicine, San Francisco VA Medical Center, 4150 Clement Street, Santa Rosa, CA 95492, United States. drrajashree.pai@gmail.com\n\nTelephone: +1-415-2214810\n\n15 2 2019 15 2 2019 10 2 133 136 3 1 2019 13 2 2019 13 2 2019 ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.2019This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.BACKGROUND\nSodium glucose cotransporter 2 (SGLT2) inhibitors use has been associated with toe amputations and non-healing ulcers and gangrene mostly of lower extremities. There are no case reports about association of Empagliflozin with finger ulcers or gangrene. This is the first case report of Empagliflozin (Jardiance) an SGLT2 inhibitor causing gangrene of fingers and second case in literature about any SGLT2 inhibitor causing gangrene of upper extremity.\n\nCASE SUMMARY\nA 76-year-old man with type 2 diabetes mellitus sustained minimal trauma to both middle fingers, which started healing. He was started on empagliflozin a week later for management of type 2 diabetes mellitus and started developing gangrene to both middle finger tips along with neuropathic pain which worsened over the course of next four months. Investigations were negative for vascular insufficiency, infection and vasculitis and imaging of hand was normal. Discontinuation of empagliflozin slowed progression of gangrene and caused symptomatic improvement with reduction in neuropathic pain.\n\nCONCLUSION\nThis case report suggests possible association of empagliflozin and finger gangrene and recommends that more research and awareness among clinicians is needed in this area.\n\nEmpagliflozinFinger gangreneNon-healing ulcerType 2 diabetes mellitusSodium glucose cotransporter 2 inhibitorJardianceCase report\n==== Body\nCore tip: Empagliflozin can cause finger gangrene in patients with type 2 diabetes mellitus. Empaglifozin has gained popularity recently as a newer anti diabetic agent with improved cardiovascular outcomes and better glycemic control in addition to lowering blood pressure and helping with weight loss. Lack of proper awareness about this condition can lead to progression of disease if not identified early on and can result in amputations. This medication should be used with caution in patients who have high risk of gangrene such as that on prednisone and in those with diabetic neuropathy.\n\nINTRODUCTION\nThis is the first ever case reported in literature about empaglifozin (Jardiance) as a possible cause of finger gangrene. Sodium glucose cotransporter 2 (SLGT2) inhibitors inhibit sodium and glucose cotransport at proximal renal tubules. SLGT2 inhibitors have been associated with an increased risk of genital infections secondary to increased glycosuria. According to the results of CANVAS trial, Dapagliflozin, another SGLT2 inhibitor of the same class as empagliflozin, has been shown to significantly reduce the risk of cardiovascular events by 14% but it doubled the risk of amputation in patients with type 2 diabetes mellitus[1]. In a similar study conducted on patients with type 2 diabetes mellitus at high risk for cardiovascular events, patients were given empaglifozin vs placebo and those on empagliflozin had lesser adverse cardiovascular events and lower all-cause mortality. Among patients receiving empagliflozin, there was an increased rate of genital infections but there was no increase in lower limb amputations[2]. In another study of over eight million case safety reports, increased risk of lower-limb amputations especially toe amputations were reported with empagliflozin[3].\n\nA data analysis conducted based on data from US Food and Drug Administration adverse event Reporting System showed a total of 66 cases of SGLT2 inhibitor-associated amputations[3]. Among these, there was only one case of hand amputation which was from Dapagliflozin. All others were lower extremity gangrene and ulcers, most commonly of toes[4]. There are two case reports of empagliflozin related Fournier’s gangrene in literature[5,6] which pointed the benefit of keeping a high index of suspicion and early cessation of SGLT2 inhibitors could potentially prevent the progression of these infections requiring surgical debridement later. Empagliflozin has also been associated with vulvovaginal candidiasis along with other SGLT2 inhibitors[7].\n\nSGLT2 inhibitors are used in general, cautiously in patients with vascular insufficiency, neuropathy, risk of amputations and very high hemoglobin A1C over 11. However, there are no case reports to date about an empagliflozin as a possible cause of non-healing finger ulcers or gangrene. Ours is the first reported case of empagliflozin (a SGLT2 inhibitor) as likely cause of gangrene of fingers.\n\nCASE PRESENTATION\nChief complaint\nGangrene both middle fingers.\n\nHistory of present illness\nA 76-year-old man with moderately controlled type 2 diabetes mellitus (hba1c of 8.6) sustained minor injury to the tip of both middle fingers while doing some mechanical work. He had no burns or exposure to heat. Initially, the fingers were healing well with minimal scarring. A week after the injury, he was started on empagliflozin 10 mg for better glycemic control in addition to his other medications. Three weeks after the injury (two weeks after being started on empagliflozin), he started noticing significant pain on tip of both middle fingers which also started changing color to brown and then to black (Figure 1).\n\nFigure 1 Gangrene tip of fingers while on empaglifozin.\n\nHistory of past illness\nNo history of previous vasculitis. He has history of polymyalgia rheumatica and was on prednisone 3 mg daily for the past few years. His other medications included aspirin, atorvastatin, metformin and saxagliptin. No history of diabetic neuropathy.\n\nPersonal and family history\nHe is a nonsmoker with no alcohol use. No family history of diabetes, gangrene or significant illnesses.\n\nPhysical examination upon admission\nHe was seen and evaluated in the emergency room twice in the following four months due to worsening symptoms and investigations were done. On exam during both times, he was afebrile, and physical exam was normal except for gangrenous changes tips of both middle fingers. There was no area of erythema around the region of gangrene on either side. Ankle brachial pressure index was normal and filling pressures were normal in both upper extremities.\n\nLaboratory examinations\nBlood counts, erythrocyte sedimentation rate, C reactive protein were within normal limits. Tests for vasculitis were negative including Anti-nuclear cytoplasmic antibody and anti-nuclear antibody.\n\nImaging examinations\nHand X-rays were normal. Echocardiogram showed no evidence of embolic sources.\n\nFINAL DIAGNOSIS\nPossible etiology was concluded to be from microvascular damage of unclear etiology.\n\nTREATMENT\nPlastic surgery, vascular surgery, dermatology and rheumatology referrals were completed. Biopsy was withheld as there was no surrounding erythema. Patient was seen in endocrinology outpatient for diabetes management and his endocrinologist suspected empagliflozin as a possible cause and discontinued the medication. He was switched to alternate medications for better glycemic control.\n\nOUTCOME AND FOLLOW UP\nAfter a week of stopping empagliflozin, patient started noticing improvement in his pain as well as slowing of blackish discoloration near tip of fingers.\n\nDISCUSSION\nOccurrence of finger gangrene or upper extremity gangrene in individuals with type 2 diabetes on treatment with empaglifozin has not been described previously in the literature. We suggest this adverse event could be under reported due to low index of suspicion.\n\nPatient mentioned in this case presented with gangrene at the same site where he sustained minimal trauma initially, therefore the suspicion was more for vasculitis. But the patient had noticed that the sites were healing well initially. Starting of empagliflozin coincided with onset of symptoms of neuropathic pain and worsening of non-healing ulcers and development of gangrene tip of fingers and vasculitis markers were negative.\n\nEven though this patient has polymyalgia rheumatica and was on prednisone at the time of symptoms, markers for vasculitis were negative and he was on consistent dose of low dose prednisone for few years before onset of symptoms. Addition of empagliflozin again was the only other contributing factor for development of symptoms.\n\nThe timing of empaglifozin and onset of symptoms as well as improvement after stopping empaglifozin point towards a likely association of the medication with finger gangrene.\n\nCONCLUSION\nThis first case report of empaglifozin causing finger gangrene suggests the possibility that upper extremity gangrene with use of empaglifozin could go undiagnosed as occurred initially in this case. Prescribers need to be aware of this association and future studies are warranted to clarify if upper extremity ulcers or gangrene are associated with SGLT2 inhibitor use.\n\nIncreased awareness among primary care physicians and surgeons about this association could prevent progression of non-healing upper extremity ulcers, gangrene and resultant amputations.\n\nInformed consent statement: Written consent from the patient was obtained.\n\nConflict-of-interest statement: The authors disclose no relevant financial conflicts of interest.\n\nCARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).\n\nManuscript source: Unsolicited manuscript\n\nPeer-review started: January 4, 2019\n\nFirst decision: January 12, 2019\n\nArticle in press: February 14, 2019\n\nSpecialty type: Endocrinology and metabolism\n\nCountry of origin: United States\n\nPeer-review report classification\n\nGrade A (Excellent): 0\n\nGrade B (Very good): B\n\nGrade C (Good): C\n\nGrade D (Fair): 0\n\nGrade E (Poor): 0\n\nP- Reviewer: Saisho Y, Koch TR S- Editor: Wang JL L- Editor: A E- Editor: Song H\n==== Refs\n1 Neal B Perkovic V Mahaffey KW de Zeeuw D Fulcher G Erondu N Shaw W Law G Desai M Matthews DR CANVAS Program Collaborative Group Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes N Engl J Med 2017 377 644 657 28605608 \n2 Zinman B Wanner C Lachin JM Fitchett D Bluhmki E Hantel S Mattheus M Devins T Johansen OE Woerle HJ Broedl UC Inzucchi SE EMPA-REG OUTCOME Investigators Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes N Engl J Med 2015 373 2117 2128 26378978 \n3 Khouri C Cracowski JL Roustit M SGLT-2 inhibitors and the risk of lower-limb amputation: Is this a class effect? Diabetes Obes Metab 2018 20 1531 1534 29430814 \n4 Fadini GP Bonora BM Avogaro A SGLT2 inhibitors and diabetic ketoacidosis: data from the FDA Adverse Event Reporting System Diabetologia 2017 60 1385 1389 28500396 \n5 Kumar S Costello AJ Colman PG Fournier’s gangrene in a man on empagliflozin for treatment of Type 2 diabetes Diabetic Medicine 2017 34 1646 1648 28887847 \n6 Voelker R Rare Infection Linked With SGLT-2 Inhibitor Use JAMA 2018 320 1309 \n7 Li D Wang T Shen S Fang Z Dong Y Tang H Urinary tract and genital infections in patients with type 2 diabetes treated with sodium-glucose co-transporter 2 inhibitors: A meta-analysis of randomized controlled trials Diabetes Obes Metab 2017 19 348 355 27862830\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "1948-9358", "issue": "10(2)", "journal": "World journal of diabetes", "keywords": "Case report; Empagliflozin; Finger gangrene; Jardiance; Non-healing ulcer; Sodium glucose cotransporter 2 inhibitor; Type 2 diabetes mellitus", "medline_ta": "World J Diabetes", "mesh_terms": null, "nlm_unique_id": "101547524", "other_id": null, "pages": "133-136", "pmc": null, "pmid": "30788049", "pubdate": "2019-02-15", "publication_types": "D002363:Case Reports", "references": "26378978;27862830;28500396;28605608;28887847;29430814;30285161", "title": "Bilateral gangrene of fingers in a patient on empagliflozin: First case report.", "title_normalized": "bilateral gangrene of fingers in a patient on empagliflozin first case report" }

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{ "abstract": "Ameloblastic carcinoma (AC) is a very rare malignant odontogenic tumor. Although surgical resection is generally performed, treatment approaches have not been established for recurrent cases. Chemotherapy and radiotherapy are positioned as adjunctive therapies, and few studies investigated definitive non-operative therapy. We present the case of a 71-year-old male with recurrent secondary-type AC arising from the right maxilla, who was treated with proton beam therapy (PBT; 71.4 Gy relative biological effectiveness in 32 fractions) combined with continuous intra-arterial infusion of cisplatin (40 mg/m2) and docetaxel (8 mg/m2). The patient experienced acute grade 3 mucositis, dermatitis and neutropenia, which were resolved within 3 months of treatment. Late adverse events were grade 1 skin atrophy, and grade 2 right optic nerve disorder and retinopathy. After ~8 years of treatment, the patient died from another cause but did not experience any relapse or metastasis during the follow-up period of 94 months. To the best of our knowledge, this is the first report of recurrent AC treated with PBT and intra-arterial infusion chemotherapy without any severe late adverse events. This combination therapy approach may be considered as an effective therapeutic option for inoperable AC.", "affiliations": "Department of Radiation Oncology, Southern Tohoku Proton Therapy Center, Koriyama, Fukushima 963-8052, Japan.;Department of Radiation Oncology, Southern Tohoku Proton Therapy Center, Koriyama, Fukushima 963-8052, Japan.;Department of Radiology, Mie University Hospital, Tsu, Mie 514-8507, Japan.;Department of Radiation Oncology, Southern Tohoku Proton Therapy Center, Koriyama, Fukushima 963-8052, Japan.;Department of Pathology, Southern Tohoku General Hospital, Koriyama, Fukushima 963-8563, Japan.;Department of Oral and Maxillofacial Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan.;Department of Radiation Oncology, Ise Red Cross Hospital, Ise, Mie 516-0008, Japan.;Department of Radiation Oncology, Southern Tohoku Proton Therapy Center, Koriyama, Fukushima 963-8052, Japan.", "authors": "Takayama|Kanako|K|;Nakamura|Tatsuya|T|;Takada|Akinori|A|;Kato|Takahiro|T|;Sakuma|Hideo|H|;Mitsudo|Kenji|K|;Fuwa|Nobukazu|N|;Murakami|Masao|M|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.3892/mco.2020.2104", "fulltext": "\n==== Front\nMol Clin Oncol\nMol Clin Oncol\nMCO\nMolecular and Clinical Oncology\n2049-9450 2049-9469 D.A. Spandidos \n\nMCO-0-0-02104\n10.3892/mco.2020.2104\nArticles\nProton beam therapy combined with retrograde intra-arterial infusion chemotherapy for an extremely rapid growing recurrent ameloblastic carcinoma: A case report\nTakayama Kanako 12 Nakamura Tatsuya 1 Takada Akinori 3 Kato Takahiro 1 Sakuma Hideo 4 Mitsudo Kenji 2 Fuwa Nobukazu 5 Murakami Masao 1 1 Department of Radiation Oncology, Southern Tohoku Proton Therapy Center, Koriyama, Fukushima 963-8052, Japan\n2 Department of Oral and Maxillofacial Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan\n3 Department of Radiology, Mie University Hospital, Tsu, Mie 514-8507, Japan\n4 Department of Pathology, Southern Tohoku General Hospital, Koriyama, Fukushima 963-8563, Japan\n5 Department of Radiation Oncology, Ise Red Cross Hospital, Ise, Mie 516-0008, Japan\nCorrespondence to: Dr Kanako Takayama, Department of Radiation Oncology, Southern Tohoku Proton Therapy Center, 7-172 Yatsuyamada, Koriyama, Fukushima 963-8052, Japan kanakotkym@gmail.comAbbreviations: AC, ameloblastic carcinoma; CIT, carbon ion therapy; CT, computed tomography; FDG, 18F-fluorodeoxyglucose; IAIC, intra-arterial infusion chemotherapy; MA, maxillary artery; MRI, magnetic resonance imaging; PBT, proton beam therapy; PET, positron emission tomography; PTV, planning target volume; RBE, relative biological effectiveness; SCC, squamous cell carcinoma; STA, superficial temporal artery\n\n\n10 2020 \n30 7 2020 \n30 7 2020 \n13 4 3409 7 2019 01 7 2020 Copyright: © Takayama et al.2020This is an open access article distributed 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.Ameloblastic carcinoma (AC) is a very rare malignant odontogenic tumor. Although surgical resection is generally performed, treatment approaches have not been established for recurrent cases. Chemotherapy and radiotherapy are positioned as adjunctive therapies, and few studies investigated definitive non-operative therapy. We present the case of a 71-year-old male with recurrent secondary-type AC arising from the right maxilla, who was treated with proton beam therapy (PBT; 71.4 Gy relative biological effectiveness in 32 fractions) combined with continuous intra-arterial infusion of cisplatin (40 mg/m2) and docetaxel (8 mg/m2). The patient experienced acute grade 3 mucositis, dermatitis and neutropenia, which were resolved within 3 months of treatment. Late adverse events were grade 1 skin atrophy, and grade 2 right optic nerve disorder and retinopathy. After ~8 years of treatment, the patient died from another cause but did not experience any relapse or metastasis during the follow-up period of 94 months. To the best of our knowledge, this is the first report of recurrent AC treated with PBT and intra-arterial infusion chemotherapy without any severe late adverse events. This combination therapy approach may be considered as an effective therapeutic option for inoperable AC.\n\nACchemoradiotherapyhead and neck cancerIAICPBTradiotherapy\n==== Body\nIntroduction\nAmeloblastic carcinoma (AC) is a very rare malignant odontogenic tumor, with features of both ameloblastoma and carcinoma. An approximate male-to-female ratio of AC is 2:1 and a mandible-to-maxilla ratio is 1.7:1(1). The common symptoms of AC are pain, swelling, and rapid growth. Clinically, AC is a typically aggressive tumor with extensive local destruction. Lymph node involvement and distant metastasis have also been reported (2-6). AC, first introduced as a distinct entity by Elzay in 1982 (1,2), is defined as a rare odontogenic malignancy that combines the histological features of ameloblastoma with cytological atypia regardless of metastasis, after considerable debate, by the World Health Organization classification of odontogenic tumors in 2005. It is classified into primary- (de novo) and secondary-type (malignant transformation of pre-existing ameloblastoma). Secondary-type AC is further divided into two subtypes: Intraosseous and peripheral. This classification was preserved with the 2017 update of the classification.\n\nNo standard treatment has been established for this rare tumor. Previous reports indicate complete surgical resection with wide local excision and cervical lymph node dissection as a commonly used approach (1-4,7); however, aesthetic failure and dysfunction after surgery, such as dysphagia, dysarthria, and nasopharyngeal closure dysfunction, are severe. The treatment efficacy of systemic chemotherapy and/or radiotherapy seemed poor and limited; local control rate is low and physical strength may decline due to decreased bone marrow function or difficulty in oral intake. These conservative therapies have been used as an adjunctive therapy (1). Strojan et al reported that cumulative dose of cisplatin in concurrent chemoradiation protocols for head and neck squamous cell carcinoma (SCC) has a significant positive correlation with survival (8). Among these non-surgical approaches, intra-arterial infusion chemotherapy (IAIC) combined with radiotherapy has been increasingly performed in recent years for locally advanced head and neck cancers to avoid surgery. Several studies using IAIC reported that the outcomes of this organ-preserving approach were not inferior to those of surgery (9-11). Although AC is considered to be a radioresistant tumor, there are some reports of good treatment results with X-rays, gamma knife, and particle beam therapy, including proton beam therapy (PBT) and carbon ion therapy (CIT) (12-16). Particle beam therapy, which provides several advantages including a rapid dose fall-off at the distal end and the possibility to induce double strand DNA breaks leading to catastrophic damage to cancer cells (17), is an effective approach that provides high-dose irradiation to the tumor without increasing toxicity to the normal tissue (18). Although the therapeutic effect of particle beam therapy has been reported for non-SCC of the head and neck (19), few reports investigated its efficacy in AC (15,16). Here we report a case of recurrent secondary-type AC treated by PBT in combination with IAIC that resulted in a good long-term course.\n\nCase report\nA 71-year-old man was referred to the Southern Tohoku Proton Therapy Center in March 2009 with severe pain and swelling of the right palatal gingiva. In October 2007, he was diagnosed with ameloblastoma of the right maxilla based on the histopathology of biopsy and underwent partial resection several times owing to tumor recurrence. The patient was diagnosed with AC in March 2009 based on pathological assessment after the fourth surgery (Fig. 1).\n\nAt the time of admission, his hard palate on the right was swollen with bony expansion to the oral cavity, and the tumor had invaded the right alveolar ridge. He had paresthesia of the right face. Enhanced magnetic resonance imaging (MRI; Signa HDx, GE Healthcare) revealed a large, heterogeneously enhanced mass extending from the right maxillary sinus to the upper gingiva, measuring ~50x70 mm in dimensions. The medial extension reached the right nasal septum and the right ethmoid sinus. The tumor had destroyed the floor of the right maxillary sinus, perforated the anterior wall of the right maxillary sinus, and extended into the surrounding soft tissue. 18F-fluorodeoxyglucose (synthesized and used in our own facility) positron emission tomography computed tomography (FDG-PET/CT; Discovery ST Elite, GE Healthcare) showed high FDG concentration in the right maxillary sinus (maximum standardized uptake value, 21.6). There were no suspicious lymph nodes or remote metastases.\n\nThe growth speed of the tumor was extremely rapid, and further surgical resection was deemed not to be sufficient for possible tumor control. Therefore, the patient was treated using PBT in combination with IAIC to the artery supplying the tumor. Written informed consent was obtained from the patient. This treatment was approved by the Ethics Committee of Southern Tohoku Research Institute for Neuroscience (approval no. 338). This study was conducted according to the principles of the Declaration of Helsinki.\n\n\nIAIC\nThe treatment schedule is summarized in Fig. 2. The IAIC method described by Fuwa et al (20) was followed. Under local anesthesia (xylocaine injection 1% with epinephrine, Aspen Japan), using fluoroscopy, a guide-wire (GT wire, 0.016 inch diameter, Terumo Corp.) was inserted into the common carotid artery from the superficial temporal artery (STA), and a thin catheter (Anthron P-U catheter; tapering type, 5Fr in outer diameter, Toray, Medical Corp.) was inserted from the STA into the external carotid artery (ECA). As the main feeder of the tumor was the maxillary artery (MA), the tip of the catheter was placed slightly to the central side of the branching section of the MA. The tumor was beyond the median line of the hard palate; therefore, two catheters were inserted bilaterally. After determination of a stable position for the catheter by digital subtraction angiography using a contrast medium (Iopamirn 300), to confirm that the target area was covered, blue dye (Indigocarmine, Daiichi Sankyo) was slowly injected, and MRI was performed with slow injection of a low-dose contrast medium (Gadovist IV, Bayer) via a catheter (21). IAIC was performed after confirming good perfusion (Fig. 3). Based on their reported effect, cisplatin (Maruko, Yakult) in combination with docetaxel (Docetaxel, ELMED) was used (22). Briefly, once a week, 40 mg/m2 cisplatin was infused over 5 h via a catheter, and 8 mg/m2 docetaxel was infused over 2 h. During arterial cisplatin infusion, 8 g/m2 sodium thiosulphate (Detoxol, Nichi-Iko Pharmaceutical Co. Ltd.) as a neutralizing agent for cisplatin was infused intravenously over 7 h. Cisplatin was administered seven times on both sides, for a total dose of 500 mg. Arterial docetaxel infusion was repeated five times for a total dose of 60 mg in the right (affected) side and four times for a total dose of 40 mg in the opposing side. A 5-hydroxytryptamin 3 receptor antagonist and corticosteroids were administered to minimize nausea and vomiting before intra-arterial infusion.\n\nPBT\nThe patient was positioned and immobilized with a thermoplastic head mask to ensure high target repositioning accuracy. CT images with 1-mm scan thickness were obtained using a 16-slice large-bore helical CT scanner (Aquilion LB; Canon). Diagnostic MRI scans with 3-mm thickness were combined with planning CT images for target delineation. A three-dimensional treatment planning system (Xio-M, Elekta; and Hitachi) was used for PBT planning. Gross tumor volume (GTV) 1 was outlined on CT images, and clinical target volume (CTV) 1 was defined as GTV1 with a 4-mm margin in all directions, while avoiding critical organs at risk (brain stem, spinal cord, optic nerves, optic chiasma, and mandible bone). CTV1 was expanded by 3 mm in all directions to create planning target volume (PTV) 1 with the aim to compensate for setup uncertainty. Because of the presence of penumbra and range of the radiation, the following beam-specific margins were set: Proximal, distal, and lateral margins as well as the smearing margin as a margin for bolus (23). The planning CT/MRI images for the boost plan were captured after 15 episodes of irradiation, and GTV2 was outlined. CTV2 was defined by adding a 3-mm margin around GTV2 and modified to exclude organs at risk. PTV2 was created in the same way as that for PTV1. Two portals of 150-MeV noncoplanar beams were arranged at optimal angles to avoid excess-dose exposure to the normal tissue. Doses were calculated based on a pencil-beam algorithm. A spread-out Bragg peak was tuned to the extent that was possible until PTV was exposed to a 90% isodose of the prescribed dose (Fig. 4). The PBT system (Hitachi) at our institution used a synchrotron and a passive scattering method in which a proton beam passed a bar ridge filter, a range shifter, and a bolus before entering the patient. A multileaf collimator, which could be formed into an irregular field shape, was used. Daily X-ray images were used for precise positioning. The patient was prescribed a dose of 45.0 Gy relative biological effectiveness (RBE) in 18 fractions to PTV1 (five fractions per week) as well as a dose of 26.4 Gy (RBE) in 12 fractions to PTV2 for the boost. The total irradiation dose was 71.4 Gy (RBE) in 30 fractions.\n\nFollow-up and outcomes\nThe treatment response was evaluated 3 months after treatment completion by contrast-enhanced MRI and clinical examination. Additional follow-up examination using CT, MRI or FDG-PET/CT was performed every 2-4 months for the first two years and every 4-6 months thereafter. The response was evaluated according to the Response Evaluation Criteria in Solid Tumors guidelines version 1.1, and the Common Terminology Criteria for Adverse Events version 4.0 was used to evaluate adverse effects (24). The patient experienced grade 3 mucositis, dermatitis, and neutropenia as early adverse events, but there was no grade 4 or higher toxicities. Additionally, as late adverse events, the patient developed grade 1 skin atrophy and hardening of the soft tissue on the right cheek after treatment and an oral maxillary fistula at the site of tumor three years after treatment. Furthermore, the patient experienced grade 2 right optic nerve disorder at four years after treatment and grade 2 radiation retinopathy of the right eye at six years after treatment. The patient achieved complete response 3 months after treatment based on the clinical assessment. The patient did not experience recurrence or distant metastases following treatment and died from another cause 94 months after the conclusion of treatment for AC (Figs. 5 and 6).\n\nDiscussion\nSurgical resection is generally performed as an approach for recurrent AC. Chemotherapy and radiotherapy are not efficient and considered as treatment options for inoperable cases, with poor prognostic outcomes (7). Yoon et al reported that 5-year overall survival of 72.9% for AC and recurrence rate after surgical resection was reported as 28.3%, which was 92.3% in patients treated with conservative therapy using chemotherapy and radiotherapy (1). There are over 150 reports of patients treated for AC, with radiotherapy utilized in approximately one-third of the cases, especially in recent years (25-29). In majority of the cases, the therapeutic effects of conventional radiotherapy were inadequate, and high-dose radiation led to severe chronic disorders such as osteoradionecrosis (2).\n\nTo date, a few studies have reported radical radiation therapy for AC (12-14). However, it may not be a desirable treatment from the view of therapeutic effect because AC is resistant to X-ray therapy. PBT is a type of particle therapy, similar to CIT. In comparison with conventional radiotherapy, particle beams are characterized by their unique Bragg peak and can deliver high-dose radiation to the tumor while sparing normal tissues (18). Additionally, compared with conventional X-ray therapy, a higher antitumor effect by direct impairment of cancer cell DNA is expected (17). Importantly, the therapeutic effect of PBT was reported in non-SCC (15,16,19). One difference between proton beams and carbon ion beams is their RBE; the RBE of protons is approximately 1.1, whereas that of carbon ions is approximately 3.0. However, no significant difference in the therapeutic effect between PBT and CIT was reported (30). To date, only two case reports of particle therapy for AC was published, including one patient treated by CIT (15) and one patient treated with PBT (16); however, AC appeared to have arisen de novo in both cases. Most ACs appear to be de novo; however, few cases of secondary-type AC arising from pre-existing ameloblastoma were reported. The current case was diagnosed with secondary-type peripheral AC, which recurred shortly after surgery, advanced extensively, and exhibited high malignancy.\n\nRecent studies assessing IAIC for locally advanced head and neck cancers to avoid surgery reported excellent treatment outcomes. Fuwa et al reported good clinical outcomes of treatment with weekly IAIC and radiotherapy in a series of 92 patients with head and neck cancer, including 84 patients with oral SCC (20). Mitsudo et al assessed treatment results with daily IAIC and conventional radiotherapy in a series of 112 cases with stage III and IV oral SCC and reported that the 5-year local control rate and over-all survival rate were 79.3 and 71.3%, respectively (11). Our previous study in which we used PBT and IAIC in T4 SCC of the maxillary gingiva, the 3-year local control and overall survival rates were 69 and 59%, respectively (31). In the current case, treatment of aggressive AC with a combination of IAIC and PBT achieved a good therapeutic effect. To the best of our knowledge, this is the first report of a good long-term course of 94 months with radical treatment using chemoradiotherapy for postoperative recurrent secondary-type AC. During the follow-up period, the patient had skin atrophy and non-infectious fistula in the right cheek. The cheek fistula had no effect on food and conversation, and the patient did not wish for reconstructive surgery. Although the tumor was close to the right optic nerve, visual acuity was maintained for several years. However, the patient suffered from ischemic syndrome of the right eye and developed grade 2 optic nerve disorder four years after treatment. Blood flow disturbance after radiation therapy have been reported in the past (32,33), and are considered as adverse event of the treatment. It indicates that additional effort to avoid risk organ may be necessary to reduce adverse events with this therapeutic approach. In this study, a passive scattering method, which is difficult to apply for complicated cases, was used to deliver the proton beam. In the future, intensity-modulated proton beam therapy using a pencil bam scanning system can be used to reduce late adverse events.\n\nAlthough case series studies with large samples are necessary for further elucidation of this treatment approach, the current case illustrates the good long-term outcome of recurrent secondary-type AC treated with PBT and IAIC. The beneficial therapeutic effect and organ preservation were achieved without any severe late adverse events, suggesting that PBT in combination with IAIC might be an effective treatment option for inoperable, locally advanced AC.\n\nAcknowledgements\nNot applicable.\n\nFunding\nNo funding was received.\n\nAvailability of data and materials\nThe data used and/or analyzed during this published article are available from the corresponding author on reasonable request.\n\nAuthors' contributions\nKT and NF contributed to the study concept and clinical study design. KT and TN collected data. KT wrote the initial draft of the manuscript. KM and MM conducted the literature search. HS performed histopathological examinations. TN and TK prepared the treatment plans of the case and carried out follow-up. AT evaluated the patient's radiographs. TK established the patient's setup preparation and verifications. KT, AT, NF, TK and HS evaluated the patients and participated in the therapy. KT, KM, NF, and MM prepared the final manuscript. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nThis treatment method was approved by The Ethics Committee of Southern Tohoku Research Institute for Neuroscience. Written consent was obtained from the patient at our institution.\n\nPatient consent for publication\nThe reported case has been approved by the patient for academic use only.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nFigure 1 Histological findings by hematoxylin-eosin staining. (A) Ameloblastoma: Histological specimen of the first biopsy in October 2007. The outer layer comprises several sheets of high columnar cells (white arrows) and, in an inner site, asteroid-shaped cells exhibit a loose and irregular arrangement (black arrows). The diagnosis is follicular-type ameloblastoma. (B) Ameloblastic carcinoma: Histological specimen of the fourth biopsy in March 2009. The specimen shows pleomorphism, nuclear hyperchromatism, increased mitotic ratio, cytologic atypia, foci of keratinization, and presence of several clear cells and tumor cells as seen in ameloblastoma along with marked cytological atypia (white arrows). The diagnosis is ameloblastic carcinoma. Magnification, x100.\n\nFigure 2 Treatment schedule. Concurrent therapy with daily proton beam therapy and weekly intra-arterial infusion chemotherapy. Cisplatin and docetaxel were infused once a week. STS was infused intravenously during the arterial infusion of cisplatin. STS, sodium thiosulphate; RBE, relative biological effectiveness.\n\nFigure 3 Flow check for the delivery of anticancer agents by contrast-enhanced T1-weighted axial magnetic resonance imaging. (A) Flow check by digital subtraction angiography using contrast medium. Flow check by enhanced magnetic resonance imaging via a catheter to cover the whole tumor; (B) the right side of the maxilla is highly enhanced (arrow), whereas (C) the left side is enhanced slightly (arrow).\n\nFigure 4 Dose distribution of proton beam therapy by axial computed tomography. (A) First plan: 45 Gy (RBE) in 18 fractions. (B) Boost plan: 26.4 Gy (RBE) in 12 fractions. Total dose was 71.4 Gy (RBE). Left eye, left optic nerve and optic chiasma were discharged totally in the boost plan. Yellow arrows indicate tumors. RBE, relative biological effectiveness.\n\nFigure 5 Comparison of before and after treatment. (A) Before treatment (FDG-PET/CT, axial, SUVmax=21.6). (B) Before treatment (T2-weighted MRI, axial); MRI shows a large heterogeneous mass occupying the right maxillary sinus and extending from the nasal cavity to sphenoid sinus. (C) After 3 months of treatment (FDG-PET/CT, axial, SUVmax=6.3). (D) After 6 months of treatment (T2-weighted MRI, axial). CT, computed tomography; FDG-PET, 18F-fluorodeoxyglucose positron emission tomography; SUVmax, maximum standardized uptake value. MRI, magnetic resonance imaging.\n\nFigure 6 Comparison of the images of tumors before and after treatment. (A) Before treatment. (B) After 9 months of treatment.\n==== Refs\nReferences\n1 Yoon HJ Hong SP Lee JI Lee SS Hong SD Ameloblastic carcinoma: An analysis of 6 cases with review of the literature Oral Surg Oral Med Oral Pathol Oral Radiol Endod 108 904 913 2009 10.1016/j.tripleo.2009.06.045 19800270 \n2 Benlyazid A Lacroix-Triki M Aziza R Gomez-Brouchet A Guichard M Sarini J Ameloblastic carcinoma of the maxilla: Case report and review of the literature Oral Surg Oral Med Oral Pathol Oral Radiol Endod 104 e17 e24 2007 10.1016/j.tripleo.2007.05.026 17942338 \n3 Kumaran PS Anuradha V Gokkulakrishnan S Thambiah L Jagadish AK Satheesh G Ameloblastic carcinoma: A case series J Pharm Bioallied Sci 6 (Suppl 1) S208 S211 2014 10.4103/0975-7406.137473 25210376 \n4 Fomete B Adebayo ET Ayuba GI Okeke UA Ameloblastic carcinoma of the maxilla: A report of two cases and a review of the literature J Korean Assoc Oral Maxillofac Surg 42 43 46 2016 10.5125/jkaoms.2016.42.1.43 26904494 \n5 Uzawa N Suzuki M Miura C Tomomatsu N Izumo T Harada K Primary ameloblastic carcinoma of the maxilla: A case report and literature review Oncol Lett 9 459 467 2015 10.3892/ol.2014.2654 25436009 \n6 Goldenberg D Sciubba J Koch W Tufano RP Malignant odontogenic tumors: A 22-year experience Laryngoscope 114 1770 1774 2004 10.1097/00005537-200410000-00018 15454770 \n7 Datta R Winston JS Diaz-Reyes G Loree TR Myers L Kuriakose MA Rigual NR Hicks WL Jr Ameloblastic carcinoma: Report of an aggressive case with multiple bony metastases Am J Otolaryngol 24 64 69 2003 10.1053/ajot.2003.15 12579485 \n8 Strojan P Vermorken JB Beitler JJ Saba NF Haigentz M Jr Bossi P Worden FP Langendijk JA Eisbruch A Mendenhall WM Cumulative cisplatin dose in concurrent chemoradiotherapy for head and neck cancer: A systematic review Head Neck 38 e2151 e2158 2016 10.1002/hed.24026 25735803 \n9 Fuwa N Ito Y Matsumoto A Kamata M Kodaira T Furutani K Sasaoka M Kimura Y Morita K A combination therapy of continuous superselective intraarterial carboplatin infusion and radiation therapy for locally advanced head and neck carcinoma. Phase I study Cancer 89 2099 2105 2000 11066051 \n10 Robbins KT Storniolo AM Kerber C Vicario D Seagren S Shea M Hanchett C Los G Howell SB Phase I study of highly selective supradose cisplatin infusions for advanced head and neck cancer J Clin Oncol 12 2113 2120 1994 10.1200/JCO.1994.12.10.2113 7931481 \n11 Mitsudo K Koizumi T Iida M Iwai T Nakashima H Oguri S Kioi M Hirota M Koike I Hata M Tohnai I Retrograde superselective intra-arterial chemotherapy and daily concurrent radiotherapy for stage III and IV oral cancer: Analysis of therapeutic results in 112 cases Radiother Oncol 111 306 310 2014 10.1016/j.radonc.2014.03.005 24746571 \n12 Perera E Lindquist C Hughes C Thomas S The use of Gamma Knife stereotactic radiosurgery in the treatment of ameloblastic carcinoma Int J Oral Maxillofac Surg 42 934 938 2013 10.1016/j.ijom.2013.04.015 23726272 \n13 Koca T Başaran H Arslan D Sezen D Cerkeşli ZA Kılınç O Karaca S Başsorgun CI Okay HO Demirci M Prominent response with helical tomotherapy in recurrent ameloblastic carcinoma of maxillary sinus: A case report Radiat Oncol 9 157 2014 10.1186/1748-717X-9-157 25027948 \n14 Aoki T Akiba T Kondo Y Sasaki M Kajiwara H Ota Y The use of radiation therapy in the definitive management of ameloblastic carcinoma: A case report Oral Surg Oral Med Oral Pathol Oral Radiol 127 e56 e60 2019 10.1016/j.oooo.2018.09.009 30393089 \n15 Jensen AD Ecker S Ellerbrock M Nikoghosyan A Debus J Münter MW Carbon ion therapy for ameloblastic carcinoma Radiat Oncol 6 13 2011 10.1186/1748-717X-6-13 21294917 \n16 Yamagata K Ishikawa H Saito T Bukawa H Proton beam therapy for ameloblastic carcinoma of the maxilla: Report of a rare case J Oral Maxillofac Surg 77 227.e1 227.e5 2019 10.1016/j.joms.2018.08.014 30240599 \n17 Fokas E Kraft G An H Engenhart-Cabillic R Ion beam radiobiology and cancer: Time to update ourselves Biochim Biophys Acta 1796 216 229 2009 10.1016/j.bbcan.2009.07.005 19682551 \n18 Urie MM Sisterson JM Koehler AM Goitein M Zoesman J Proton beam penumbra: Effects of separation between patient and beam modifying devices Med Phys 13 734 741 1986 10.1118/1.595974 3023803 \n19 Patel SH Wang Z Wong WW Murad MH Buckey CR Mohammed K Alahdab F Altayar O Nabhan M Schild SE Foote RL Charged particle therapy versus photon therapy for paranasal sinus and nasal cavity malignant diseases: A systematic review and meta-analysis Lancet Oncol 15 1027 1038 2014 10.1016/S1470-2045(14)70268-2 24980873 \n20 Fuwa N Kodaira T Furutani K Tachibana H Nakamuta T A new method of selective intra-arterial infusion therapy via the superficial temporal artery for head and neck cancer Oral Surg Oral Med Oral Pathol Oral Radiol Endod 105 78378 78379 2008 10.1016/j.tripleo.2007.07.031 18206406 \n21 Nakamura T Fuwa N Takayama K Inokuchi H Tomoda T Takada A Makita C Shiomi M Yokouchi J Watanabe K Phase I study of weekly docetaxel and cisplatin arterial infusion for recurrent head and neck cancer Head Neck 34 1634 1639 2012 10.1002/hed.21983 22179897 \n22 Yabuuchi H Kuroiwa T Tajima T Tomita K Ochiai N Kawamoto K Efficacy of intra-arterial infusion therapy using a combination of cisplatin and docetaxel for recurrent head and neck cancers compared with cisplatin alone Clin Oncol (R Coll Radiol) 15 467 472 2003 10.1016/j.clon.2003.07.003 14690002 \n23 Torres MA Chang EL Mahajan A Lege DG Riley BA Zhang X Lii M Kornguth DG Pelloski CE Woo SY Optimal treatment planning for skull base chordoma: Photons, protons, or a combination of both? 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Accessed July 12, 2019. \n25 Saluja TS Hosalkar R Reconnoitre ameloblastic carcinoma: A prognostic update Oral Oncol 77 118 124 2018 10.1016/j.oraloncology.2017.12.018 29362117 \n26 Simko EJ Brannon RB Eibling DE Ameloblastic carcinoma of the mandible Head Neck 20 654 659 1998 10.1002/(sici)1097-0347(199810)20:7<654::aid-hed14>3.0.co;2-4 9744469 \n27 Infante-Cossio P Hernandez-Guisado JM Fernandez-Machin P Garcia-Perla A Rollon-Mayordomo A Gutierrez-Perez JL Ameloblastic carcinoma of the maxilla: A report of 3 cases J Craniomaxillofac Surg 26 159 162 1998 10.1016/s1010-5182(98)80006-1 9702634 \n28 Philip M Morris CG Werning JW Mendenhall WM Radiotherapy in the treatment of ameloblastoma and ameloblastic carcinoma J HK Coll Radiol 8 157 161 2005 \n29 Atkinson CH Harwood AR Cummings BJ Ameloblastoma of the jaw: A reappraisal of the role of megavoltage irradiation Cancer 53 869 873 1984 10.1002/1097-0142(19840215)53:4<869::aid-cncr2820530409>3.0.co;2-v 6420036 \n30 Demizu Y Fujii O Terashima K Mima M Hashimoto N Niwa Y Akagi T Daimon T Murakami M Fuwa N Particle therapy for mucosal melanoma of the head and neck. A single-institution retrospective comparison of proton and carbon ion therapy Strahlenther Onkol 190 186 191 2014 10.1007/s00066-013-0489-9 24362502 \n31 Endo H Takayama K Mitsudo K Nakamura T Seto I Yamaguchi H Ono T Suzuki M Azami Y Wada H Proton beam therapy in combination with intra-arterial infusion chemotherapy for T4 squamous cell carcinoma of the maxillary gingiva Cancers (Basel) 10 333 2018 10.3390/cancers10090333 30223580 \n32 Tang Y Luo D Peng W Huang F Peng Y Ocular ischemic syndrome secondary to carotid artery occlusion as a late complication of radiotherapy of nasopharyngeal carcinoma J Neuroophthalmol 30 315 320 2010 10.1097/WNO.0b013e3181dee914 20736842 \n33 Gupta A Dhawahir-Scala F Smith A Young L Charles S Radiation retinopathy: Case report and review BMC Ophthalmol 7 6 2007 10.1186/1471-2415-7-6 17411428\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2049-9450", "issue": "13(4)", "journal": "Molecular and clinical oncology", "keywords": "AC; IAIC; PBT; chemoradiotherapy; head and neck cancer; radiotherapy", "medline_ta": "Mol Clin Oncol", "mesh_terms": null, "nlm_unique_id": "101613422", "other_id": null, "pages": "34", "pmc": null, "pmid": "32802330", "pubdate": "2020-10", "publication_types": "D016428:Journal Article", "references": "23726272;20736842;26904494;24362502;14690002;9744469;30223580;17411428;25210376;30393089;3023803;25436009;19356861;25027948;7931481;19800270;24746571;29362117;6420036;30240599;11066051;17942338;19682551;22179897;12579485;18206406;9702634;21294917;24980873;25735803;15454770", "title": "Proton beam therapy combined with retrograde intra-arterial infusion chemotherapy for an extremely rapid growing recurrent ameloblastic carcinoma: A case report.", "title_normalized": "proton beam therapy combined with retrograde intra arterial infusion chemotherapy for an extremely rapid growing recurrent ameloblastic carcinoma a case report" }

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"drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "40", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOCETAXEL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CISPLATIN" }, "drugadditional": "3", "drugadministrationroute": "013", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "40 MG/M2, CONTINUOUS INTRA?ARTERIAL INFUSION", "drugenddate": null, "drugenddateformat": null, "drugindication": "AMELOBLASTIC CARCINOMA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "40", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CISPLATIN." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Skin atrophy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dermatitis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Optic nerve disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Retinopathy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neutropenia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Mucosal inflammation", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "TAKAYAMA K.? NAKAMURA T.? TAKADA A.? KATO T.? SAKUMA H.? MITSUDO K.? ET AL.. PROTON BEAM THERAPY COMBINED WITH RETROGRADE INTRA?ARTERIAL INFUSION CHEMOTHERAPY FOR AN EXTREMELY RAPID GROWING RECURRENT AMELOBLASTIC CARCINOMA: A CASE REPORT. MOLECULAR AND CLINICAL ONCOLOGY.. 2020?13(4):1?7", "literaturereference_normalized": "proton beam therapy combined with retrograde intra arterial infusion chemotherapy for an extremely rapid growing recurrent ameloblastic carcinoma a case report", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20200922", "receivedate": "20200827", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18203606, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "JP-PFIZER INC-2020332805", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DOCETAXEL" }, "drugadditional": "3", "drugadministrationroute": "013", "drugauthorizationnumb": "022234", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "8 MG/M2, (INFUSED OVER 2 H)REPEATED FIVE TIMES FOR A TOTAL DOSE OF 60 MG IN THE RIGHT (AFFECTED) SI", "drugenddate": null, "drugenddateformat": null, "drugindication": "AMELOBLASTIC CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "8", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOCETAXEL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CISPLATIN" }, "drugadditional": "3", "drugadministrationroute": "013", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "40 MG/M2, CYCLIC (ONCE A WEEK; INFUSED OVER 5 H VIA A CATHETER; ADMINISTERED SEVEN TIMES ON BOTH SID", "drugenddate": null, "drugenddateformat": null, "drugindication": "AMELOBLASTIC CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "40", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CISPLATIN." }, { "actiondrug": null, "activesubstance": null, "drugadditional": null, "drugadministrationroute": "040", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK (8 G/M2 OVER 7 H)", "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": "DETOXOL" } ], "patientagegroup": null, "patientonsetage": "71", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Optic nerve disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neutropenia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Retinopathy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Mucosal inflammation", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Skin atrophy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dermatitis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "TAKAYAMA, K.. PROTON BEAM THERAPY COMBINED WITH RETROGRADE INTRA?ARTERIAL INFUSION CHEMOTHERAPY FOR AN EXTREMELY RAPID GROWING RECURRENT AMELOBLASTIC CARCINOMA: A CASE REPORT. MOLECULAR AND CLINICAL ONCOLOGY. 2020?13 (4):1?7", "literaturereference_normalized": "proton beam therapy combined with retrograde intra arterial infusion chemotherapy for an extremely rapid growing recurrent ameloblastic carcinoma a case report", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20200904", "receivedate": "20200831", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18214275, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" } ]

{ "abstract": "Ovarian tissue cryopreservation (OTC) is an option to preserve fertility. This article describes the effect of cycle monitoring on the chances of pregnancy following orthotopic ovarian tissue autotransplantation.\nA 32-year-old woman diagnosed with breast cancer underwent right-sided oophorectomy and OTC prior to chemotherapy. Three years later she was diagnosed with premature ovarian insufficiency and ovarian tissue chips were transplanted in the remaining ovary and a peritoneal window. Eight months after transplantation, activity was seen in the tissue placed in the peritoneal window. With a low natural chance of conception, modified natural-cycle (MNC) IVF was started by administration of a GnRH antagonist. Ovulation was triggered with hCG. One oocyte was retrieved by transvaginal ovum pick-up. After fertilization, a six-cell-stage embryo of good quality was transferred. This resulted in pregnancy and a healthy girl was born at 41 weeks. In the second monitored cycle after her delivery, a follicle was seen in the remaining ovary. Two weeks later a pregnancy test was positive and after an uncomplicated pregnancy a healthy boy was delivered spontaneously at 41 weeks.\nThis case reports shows that MNC IVF conception after OTC is successful in patients with tissue partially placed in a peritoneal window. If the tissue placed in the peritoneal window becomes active, MNC IVF can be performed. If the tissue placed in the remaining ovary becomes active, natural conception should be pursued.", "affiliations": "Department of Obstetrics & Gynaecology, Leiden University Medical Center, Albinusdreef 2, 2333, ZA, Leiden, The Netherlands.;Department of Obstetrics & Gynaecology, Leiden University Medical Center, Albinusdreef 2, 2333, ZA, Leiden, The Netherlands.;Department of Obstetrics & Gynaecology, Leiden University Medical Center, Albinusdreef 2, 2333, ZA, Leiden, The Netherlands.;Department of Obstetrics & Gynaecology, Leiden University Medical Center, Albinusdreef 2, 2333, ZA, Leiden, The Netherlands.", "authors": "Klijn|Nicole Francisca|NF|;Louwé|Leoni Albertine|LA|;Pilgram|Gonneke Saskia Kirsten|GSK|;van der Westerlaken|Lucia Alida Johanna|LAJ|", "chemical_list": null, "country": "Netherlands", "delete": false, "doi": "10.1016/j.crwh.2019.e00143", "fulltext": "\n==== Front\nCase Rep Womens HealthCase Rep Womens HealthCase Reports in Women's Health2214-9112Elsevier S2214-9112(19)30124-910.1016/j.crwh.2019.e00143e00143ArticleTwo live births following orthotopic ovarian tissue autotransplantation: A case report of cycle monitoring and (modified) natural-cycle IVF in one patient Klijn Nicole Francisca n.f.klijn@lumc.nl⁎Louwé Leoni Albertine Pilgram Gonneke Saskia Kirsten van der Westerlaken Lucia Alida Johanna Department of Obstetrics & Gynaecology, Leiden University Medical Center, Albinusdreef 2, 2333, ZA, Leiden, The Netherlands⁎ Corresponding author at: Leiden University Medical Center (H3-P), Postbus 9600, 2300 RC Leiden, The Netherlands. n.f.klijn@lumc.nl05 9 2019 10 2019 05 9 2019 24 e0014327 7 2019 26 8 2019 3 9 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/).Highlights\n• Ovarian tissue cryopreservation is a successful fertility preservation treatment.\n\n• Ovarian tissue placed in a peritoneal window leads to reactivation of the tissue.\n\n• Cycle monitoring after transplantation is necessary to confirm follicular activity.\n\n• In women with low antral follicle count cycle monitoring optimizes pregnancy chances.\n\n• In case of activity in peritoneal placed tissue, MNC IVF is of added value.\n\n\n\nIntroduction\nOvarian tissue cryopreservation (OTC) is an option to preserve fertility. This article describes the effect of cycle monitoring on the chances of pregnancy following orthotopic ovarian tissue autotransplantation.\n\nCase presentation\nA 32-year-old woman diagnosed with breast cancer underwent right-sided oophorectomy and OTC prior to chemotherapy. Three years later she was diagnosed with premature ovarian insufficiency and ovarian tissue chips were transplanted in the remaining ovary and a peritoneal window. Eight months after transplantation, activity was seen in the tissue placed in the peritoneal window. With a low natural chance of conception, modified natural-cycle (MNC) IVF was started by administration of a GnRH antagonist. Ovulation was triggered with hCG. One oocyte was retrieved by transvaginal ovum pick-up. After fertilization, a six-cell-stage embryo of good quality was transferred. This resulted in pregnancy and a healthy girl was born at 41 weeks. In the second monitored cycle after her delivery, a follicle was seen in the remaining ovary. Two weeks later a pregnancy test was positive and after an uncomplicated pregnancy a healthy boy was delivered spontaneously at 41 weeks.\n\nConclusions\nThis case reports shows that MNC IVF conception after OTC is successful in patients with tissue partially placed in a peritoneal window. If the tissue placed in the peritoneal window becomes active, MNC IVF can be performed. If the tissue placed in the remaining ovary becomes active, natural conception should be pursued.\n\nKeywords\nFertility preservationOvarian tissue cryopreservationPregnancyCycle monitoringIVF\n==== Body\n1 Introduction\nPremature ovarian insufficiency is one of the most common long-term adverse effects of the treatment of malignant diseases with alkylating agents or radiotherapy [1]. This results in loss of both endocrine and reproductive function of the ovary. Several options are available to preserve fertility. These include cryopreservation of oocytes, embryos and ovarian tissue. Only ovarian tissue cryopreservation (OTC) can start without delaying the gonadotoxic treatment, as no hormonal stimulation is needed.\n\nWhen the patient is disease free and premature ovarian insufficiency has been diagnosed, the cryopreserved ovarian tissue can be thawed and transplanted into an orthotopic site (i.e. the remaining ovary or a peritoneal window) or a heterotopic site (i.e. the forearm) [2].\n\nIn 2004, the first child born after autotransplantation was documented [3]. Since then, the number of live births has exceeded 130 [4]. Naturally conceived pregnancies and pregnancies after in vitro fertilization are described in case reports and case series [5,6].\n\nThis case report concerns a woman who gave birth to two children after ovarian tissue autotransplantation. This unique case shows that after ovarian tissue autotransplantation, cycle monitoring is crucial, especially when tissue is placed in a peritoneal window.\n\n2 Case Presentation\n2.1 Patient History\nThe patient was diagnosed with ductal carcinoma of the right breast, stage T2N1M0, triple negative, at age 32. Genetic testing for BRCA mutations was negative. Her oncologist advised her not to postpone the cancer treatment for an ovarian stimulation to obtain oocytes. Therefore, before neoadjuvant chemotherapy, and after the patient gave signed written informed consent, the right-side ovary was removed by laparoscopy for ovarian tissue cryopreservation.\n\nAfter oophorectomy, she was treated with four cycles of dense adriamycin cyclophosphamide (AC) and two cycles of intermediate high-dose chemotherapy with cyclophosphamide, carboplatin and thiotepa. This treatment was followed by right-sided mastectomy and post-operative local radiation therapy (64 Gy).\n\nThree years after this treatment she was considered disease-free. There was a desire to conceive and because of secondary amenorrhoea, with less than one hot flush a day, hormonal tests were performed. Post-menopausal status was confirmed (FSH 185.8 U/L, estradiol 22,5 pmol/L, AMH < 0.1 μg/L).\n\nAutotransplantation was decided on at a multidisciplinary team meeting. The patient was counselled by a fertility specialist about the procedure. The oncologist had no objections to transplantation and potential pregnancies, as there was a low estimated risk of recurrence of the breast cancer, based on the tumour characteristics, cancer treatment and disease-free interval. Semen analysis of her partner showed normospermia.\n\n2.2 Procedure of Ovarian Tissue Cryopreservation and Autotransplantation\nImmediately after the oophorectomy, the cortex of the ovary was isolated, whereas the medulla was discarded. Freezing of ovarian tissue was undertaken according to the protocol described by Radford et al. [7]. The frozen ovarian tissue chips were stored in cryovials in liquid nitrogen.\n\nBefore autotransplantation, the first vial was thawed and the tissue tested negative for malignant cells by negative keratin AE1/AE3 colouring. Primordial follicles were seen in this tissue.\n\nFor autotransplantation, five cryovials, each containing one ovarian cortical strip, were thawed according to the protocol of the Andersen group [8]. They were transferred to a container containing PBS and transported to the operating theatre, where it arrived within 30 min after starting the thawing process. Four of the five pieces were transplanted; one was discarded because of abnormal colouring of the tissue and sent for further examination to the pathology department. There, only ovarian stromal cells were seen, and no malignancy.\n\nThe transfer of the tissue was performed by laparoscopy. Two cortical chips were placed on the medullar incision of the remaining ovary with the cortical side positioned to the surface. Due to lack of space for the other two chips, a peritoneal window was made at the right side of the uterus.\n\nAntibiotic prophylaxis was (due to allergy) clindamycin 600 mg and ciproflocaxin 400 mg intravenous administered 30 min before surgery.\n\n2.3 Ethical Approval\nThe Medical Ethical Committee of the LUMC approved all the procedures. In the Netherlands, there is consensus for OTC and autotransplantation by the Dutch Society of Obstetrics and Gynaecology (NVOG) and the Society of Clinical Embryology (KLEM).\n\n2.4 Results\nIn follow-up after transplantation, first follicular activity was seen on ultrasound in the remaining ovary after four months. This was confirmed by a drop in FSH level to 23 U/L and a rise in estradiol level (245 pmol/L). The patient mentioned disappearance of hot flushes and an increase of vaginal discharge. Cycle monitoring showed continuing follicle growth (17 mm) and increasing estradiol levels (up to 502 pmol/L). Unfortunately, luteinisation could not be confirmed. One month later, recovery of the menstrual cycle was observed. This was followed by another menstrual bleed after 22 days, but cycle monitoring thereafter did not show any follicular activity and higher FSH levels were measured (FSH 62 U/L).\n\nAt a follow-up appointment, eight months after the autotransplantation, activity was seen in the ovarian tissue placed in the peritoneal window. With a low chance of natural conception from this side and low ovarian reserve, the cycle was converted to a MNC IVF cycle with the start of a GnRH-antagonist (Cetrotide®) to prevent a spontaneous LH surge. One day later, the follicle diameter was 17 mm, estradiol 515 pmol/L and ovulation triggered with choriongonadotropin alpha (Ovitrelle®) 250 μg. The transvaginal ovum pick-up 36 h later retrieved one oocyte. After conventional IVF, the oocyte was fertilised and two days later a six-cell-stage embryo of good quality (see Fig. 1) was transferred under abdominal ultrasound guidance. Luteal phase was supported with vaginal progesterone capsules (Utrogestan®) three times a day 200 mg. Two weeks later the pregnancy test was positive.Fig. 1 The 6-cell-stage embryo on day 2 just before transfer.\n\nFig. 1\n\nUltrasound at 6 weeks and 4 days of gestational age confirmed a viable pregnancy. The pregnancy was uncomplicated and at 41 weeks she delivered spontaneously a healthy girl of 3850 g.\n\nFive months after delivery she returned to our clinic with recovery of her menstrual cycle. Transvaginal ultrasound showed a follicle in the tissue in the peritoneal window with a confirmatory estradiol level (1300 pmol/L). The patient and her partner were not ready to pursue another ART treatment, but would welcome a spontaneous conception. The next cycle, monitoring was performed and for the first time a follicle was seen in the remaining ovary with an estradiol level of 1000 pmol/L and a starting LH surge (15 U/L). In all other monitored cycles in this patient, activity in this ovary had never been observed. Two weeks later a pregnancy test was positive.\n\nUltrasound at 7 weeks and 1 day of gestational age confirmed a viable pregnancy. The pregnancy was uncomplicated and at 41 weeks she delivered spontaneously a healthy boy of 3800 g.\n\n3 Discussion and Conclusions\nThis article describes two successful pregnancies after ovarian tissue autotransplantation in one woman. The first pregnancy is the result of MNC IVF, the second the result of natural conception. The conversion to MNC IVF was started when cycle monitoring showed follicular activity in the tissue placed in the peritoneal window. With absence of a fallopian tube on the right side and follicle growth in this tissue, it was argued that the chance of natural conception from this side was low. It could be argued that there was a chance of natural conception and that conversion to MNC-IVF was not necessary. However, the antral follicle count in this patient after autotransplantation was low and together with the location of the growing follicle, the overall chances of natural conception were estimated as low. This information was discussed with the patient and her partner and in mutual agreement conversion to MNC IVF was undertaken.\n\nAlthough other articles describe pregnancies after ovarian tissue autotransplantation with a complete IVF stimulation, this is not always the optimal treatment. The benefit of stimulation can be argued in patients with a low antral follicle count. Furthermore, in patients with a history of estrogen receptor-positive breast cancer, stimulation might be harmful. In these situations, cycle monitoring without added hormonal stimulation and with selected MNC IVF might give higher chances of pregnancy than would attempts at natural conception.\n\nThis case reports shows that follow-up by cycle monitoring increases the chances of pregnancy after OTC in patients with ovarian tissue partially placed in a peritoneal window. Follicular activity can be detected during cycle monitoring. When there is follicular growth in the tissue placed in the peritoneal window, MNC IVF can start. If the ovarian tissue placed in the remaining ovary is active, natural conception can be pursued.\n\nContributors\nNicole Francisca Klijn performed the embryo transfer and wrote the first manuscript draft.\n\nLeoni Albertine Louwé performed the oophorectomy and autotransplantation of the ovarian tissue.\n\nGonneke Saskia Kirsten Pilgram performed the cryopreservation procedure of the ovarian tissue and the laboratory phase of the natural cycle IVF treatment.\n\nLucia Alida Johanna van der Westerlaken performed the cryopreservation procedure of the ovarian tissue and the laboratory phase of the natural cycle IVF treatment.\n\nAll authors contributed substantially to the interpretation of the procedures in this case. They all critically reviewed and approved the manuscript.\n\nFunding\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nEthical Approval\nThe Medical Ethical Committee of the LUMC approved all the procedures. In the Netherlands, there is consensus for OTC and autotransplantation by The Dutch Society of Obstetrics and Gynaecology (NVOG) and the Society of Clinical Embryology (KLEM).\n\nPatient Consent\nObtained.\n\nProvenance and Peer Review\nThis case report was peer reviewed.\n\nDeclaration of Competing Interest\nThe authors declare that they have no conflict of interest regarding the publication of this case report.\n==== Refs\nReferences\n1 Meirow D. Reproduction post-chemotherapy in young cancer patients Mol. Cell. Endocrinol. 169 2000 123 131 11155944 \n2 Oktay K. Economos K. Kan M. Rucinski J. Veeck L. Rosenwaks Z. Endocrine function and oocyte retrieval after autologous transplantation of ovarian cortical strips to the forearm JAMA. 286 2001 1490 1493 11572742 \n3 Donnez J. Dolmans M.M. Demylle D. Jadoul P. Pirard C. Squifflet J. Martinez-Madrid B. Van Langendonckt A. Livebirth after orthotopic transplantation of cryopreserved ovarian tissue Lancet 364 2004 1405 1410 15488215 \n4 Donnez J. Dolmans M.M. Fertility preservation in women N. Engl. J. Med. 377 2017 1657 1665 29069558 \n5 Pacheco F. Oktay K. Current success and efficiency of autologous ovarian transplantation: a meta-analysis Reprod. Sci. 24 2017 1111 1120 28701069 \n6 Jensen A.K. Macklon K.T. Fedder J. Ernst E. Humaidan P. Andersen C.Y. 86 successful births and 9 ongoing pregnancies worldwide in women transplanted with frozen-thawed ovarian tissue: focus on birth and perinatal outcome in 40 of these children J. Assist. Reprod. Genet. 34 Mar 2017 325 336 28028773 \n7 Radford J.A. Lieberman B.A. Brison D.R. Smith A.R.B. Critchlow J.D. Russell S.A. Watson A.J. Clayton J.A. Harris M. Gosden R.G. Orthotopic reimplantation of cryopreserved ovarian cortical strips after high-dose chemotherapy for Hodgkin's lymphoma Lancet. 357 2001 1172 1175 11323045 \n8 Rosendahl M. Schmidt K.T. Ernst E. Rasmussen P.E. Loft A. Byskov A.G. Andersen A.N. Andersen C.Y. Cryopreservation of ovarian tissue for a decade in Denmark: a view of the technique Reprod. BioMed. Online 22 2011 162 171 21239230\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2214-9112", "issue": "24()", "journal": "Case reports in women's health", "keywords": "Cycle monitoring; Fertility preservation; IVF; Ovarian tissue cryopreservation; Pregnancy", "medline_ta": "Case Rep Womens Health", "mesh_terms": null, "nlm_unique_id": "101682122", "other_id": null, "pages": "e00143", "pmc": null, "pmid": "31709155", "pubdate": "2019-10", "publication_types": "D002363:Case Reports", "references": "15488215;11323045;28028773;29069558;11155944;11572742;28701069;21239230", "title": "Two live births following orthotopic ovarian tissue autotransplantation: A case report of cycle monitoring and (modified) natural-cycle IVF in one patient.", "title_normalized": "two live births following orthotopic ovarian tissue autotransplantation a case report of cycle monitoring and modified natural cycle ivf in one patient" }

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TWO LIVE BIRTHS FOLLOWING ORTHOTOPIC OVARIAN TISSUE AUTOTRANSPLANTATION: A CASE REPORT OF CYCLE MONITORING AND (MODIFIED) NATURAL-CYCLE IVF IN ONE PATIENT. 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TWO LIVE BIRTHS FOLLOWING ORTHOTOPIC OVARIAN TISSUE AUTOTRANSPLANTATION: A CASE REPORT OF CYCLE MONITORING AND (MODIFIED) NATURAL-CYCLE IVF IN ONE PATIENT. CASE REPORTS IN WOMEN^S HEALTH 24. 2019 OCT?.", "literaturereference_normalized": "two live births following orthotopic ovarian tissue autotransplantation a case report of cycle monitoring and modified natural cycle ivf in one patient", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20191202", "receivedate": "20191202", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17100113, "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": "BACKGROUND\nThere has been no study investigating nonsteroidal anti-inflammatory drugs (NSAIDs)-exacerbated respiratory disease (NERD) exclusively in childhood. Therefore, in the current study, the authors aimed to evaluate the diagnostic features, clinical characteristics, and follow-up of adolescents diagnosed with NERD.\n\n\nMETHODS\nThe patients who were consecutively diagnosed with NERD between January 2011, and November 2013, included in the study. Oral provocation test (OPT) with at least 2 different NSAIDs was used to confirm NSAID hypersensitivity in patients with underlying asthma/chronic rhinosinusitis/nasal polyps. All patients were followed regularly in 3-month intervals by the Pediatric Allergy and Otorhinolaryngology Department for asthma, allergic rhinitis, or chronic rhinosinusitis with or without nasal polyps.\n\n\nRESULTS\nA total of 10 adolescents with NERD were included in the study. The mean age of the patients at the time of diagnosis was 14.9 ± 1.5 years. Hives or angioedema accompanied respiratory complaints induced by NSAIDs. The mean duration of follow-up was 28.9 ± 12.4 months. All patients had asthma except 1 with asymptomatic bronchial hyperreactivity. Asthma of patients was well-controlled with moderate dose of inhaled corticosteroids. Chronic rhinosinusitis with or without nasal polyps developed in 2 patients. Aspirin desensitization was required in these 2 patients with recurrent nasal polyps.\n\n\nCONCLUSIONS\nNERD in childhood has much more favorable clinical characteristics and course than in adulthood. Few adolescents with NERD refer with typical chronic upper respiratory tract complaints. The asthma component seems to be mild and is well controlled in the short-term follow-up.", "affiliations": "Department of Pediatric Allergy and Asthma, Gazi University School of Medicine, Ankara, Turkey.;Department of Pediatric Allergy and Asthma, Gazi University School of Medicine, Ankara, Turkey.;Department of Pediatric Allergy and Asthma, Gazi University School of Medicine, Ankara, Turkey.;Department of Otorhinolaryngology-Head and Neck Surgery, Gazi University School of Medicine, Ankara, Turkey.;Department of Pediatric Allergy and Asthma, Gazi University School of Medicine, Ankara, Turkey.", "authors": "Ertoy Karagol|Hacer Ilbilge|HI|;Yilmaz|Ozlem|O|;Topal|Erdem|E|;Ceylan|Alper|A|;Bakirtas|Arzu|A|", "chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal", "country": "United States", "delete": false, "doi": "10.1002/alr.21494", "fulltext": null, "fulltext_license": null, "issn_linking": "2042-6976", "issue": "5(5)", "journal": "International forum of allergy & rhinology", "keywords": "NERD; NSAIDs-exacerbated respiratory disease; adolescents; follow-up; nonsteroidal anti-inflammatory drug", "medline_ta": "Int Forum Allergy Rhinol", "mesh_terms": "D000293:Adolescent; D000894:Anti-Inflammatory Agents, Non-Steroidal; D055963:Asthma, Aspirin-Induced; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D009298:Nasal Polyps; D012189:Retrospective Studies; D012220:Rhinitis; D012852:Sinusitis", "nlm_unique_id": "101550261", "other_id": null, "pages": "392-8", "pmc": null, "pmid": "25755210", "pubdate": "2015-05", "publication_types": "D016428:Journal Article; D064888:Observational Study", "references": null, "title": "Nonsteroidal anti-inflammatory drugs-exacerbated respiratory disease in adolescents.", "title_normalized": "nonsteroidal anti inflammatory drugs exacerbated respiratory disease in adolescents" }

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NONSTEROIDAL ANTI-INFLAMMATORY DRUGS-EXACERBATED RESPIRATORY DISEASE IN ADOLESCENTS.. INT-FORUM-ALLERGY-RHINOL. 2015?5(5):392-398", "literaturereference_normalized": "nonsteroidal anti inflammatory drugs exacerbated respiratory disease in adolescents", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20151229", "receivedate": "20151229", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 11874264, "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": "TR-BAYER-2015-064822", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "BUDESONIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "320 MCG", "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": "BUDESONIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "NAPROXEN SODIUM" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "020204", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG PROVOCATION TEST", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NAPROXEN SODIUM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "FLURBIPROFEN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG PROVOCATION TEST", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLURBIPROFEN." } ], "patientagegroup": "4", "patientonsetage": "14", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Nasal congestion", "reactionmeddraversionpt": "18.0", "reactionoutcome": null }, { "reactionmeddrapt": "Rhinorrhoea", "reactionmeddraversionpt": "18.0", "reactionoutcome": null }, { "reactionmeddrapt": "Allergic respiratory disease", "reactionmeddraversionpt": "18.0", "reactionoutcome": null }, { "reactionmeddrapt": "Drug hypersensitivity", "reactionmeddraversionpt": "18.0", "reactionoutcome": null }, { "reactionmeddrapt": "Dyspnoea", "reactionmeddraversionpt": "18.0", "reactionoutcome": null }, { "reactionmeddrapt": "Angioedema", "reactionmeddraversionpt": "18.0", "reactionoutcome": null }, { "reactionmeddrapt": "Wheezing", "reactionmeddraversionpt": "18.0", "reactionoutcome": null }, { "reactionmeddrapt": "Sneezing", "reactionmeddraversionpt": "18.0", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "ERTOY KARAGOL HI; YILMAZ O; TOPAL E; CEYLAN A; BAKIRTAS A. NONSTEROIDAL ANTI-INFLAMMATORY DRUGS-EXACERBATED RESPIRATORY DISEASE IN ADOLESCENTS. 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NONSTEROIDAL ANTI-INFLAMMATORY DRUGS-EXACERBATED RESPIRATORY DISEASE IN ADOLESCENTS.. INT-FORUM-ALLERGY-RHINOL. 2015?5(5):392-8", "literaturereference_normalized": "nonsteroidal anti inflammatory drugs exacerbated respiratory disease in adolescents", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20151211", "receivedate": "20151211", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11827427, "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": "PHHY2015TR161671", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": "048", "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": "ACETYLSALICYLIC ACID" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLURBIPROFEN" }, "drugadditional": null, "drugadministrationroute": "048", "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": "FLURBIPROFEN." } ], "patientagegroup": null, "patientonsetage": "17", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Aspirin-exacerbated respiratory disease", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ERTOY KARAGOL HI, YILMAZ O, TOPAL E, CEYLAN A, BAKIRTAS A.. NONSTEROIDAL ANTI-INFLAMMATORY DRUGS-EXACERBATED RESPIRATORY DISEASE IN ADOLESCENTS.. INT-FORUM-ALLERGY-RHINOL. 2015?5(5):392-8", "literaturereference_normalized": "nonsteroidal anti inflammatory drugs exacerbated respiratory disease in adolescents", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20151211", "receivedate": "20151211", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11827547, "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": "PHHY2015TR161669", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "NAPROXEN" }, "drugadditional": null, "drugadministrationroute": "048", "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": "NAPROXEN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "IBUPROFEN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "70733", "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": "IBUPROFEN." } ], "patientagegroup": null, "patientonsetage": "16", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Flushing", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Forced expiratory volume decreased", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Angioedema", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dyspnoea", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rhinorrhoea", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Wheezing", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ERTOY KARAGOL HI, YILMAZ O, TOPAL E, CEYLAN A, BAKIRTAS A.. NONSTEROIDAL ANTI-INFLAMMATORY DRUGS-EXACERBATED RESPIRATORY DISEASE IN ADOLESCENTS.. INT-FORUM-ALLERGY-RHINOL. 2015?5(5):392-8", "literaturereference_normalized": "nonsteroidal anti inflammatory drugs exacerbated respiratory disease in adolescents", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20151211", "receivedate": "20151211", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11827417, "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": "TR-SUN PHARMACEUTICAL INDUSTRIES LTD-2015RR-108440", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUDESONIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "160 ?G, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ASTHMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "160", "drugstructuredosageunit": "004", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUDESONIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "NAPROXEN" }, "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": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NAPROXEN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "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": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Urticaria", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Angioedema", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Forced expiratory volume decreased", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dyspnoea", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Wheezing", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rhinorrhoea", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nasal congestion", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cough", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Flushing", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ERTOY KARAGOL HI, YILMAZ O, TOPAL E, CEYLAN A, BAKIRTAS A.. NONSTEROIDAL ANTI-INFLAMMATORY DRUGS-EXACERBATED RESPIRATORY DISEASE IN ADOLESCENTS.. INT-FORUM-ALLERGY-RHINOL. 2015?5(5):392-398", "literaturereference_normalized": "nonsteroidal anti inflammatory drugs exacerbated respiratory disease in adolescents", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20151229", "receivedate": "20151229", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 11874266, "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": "TR-SUN PHARMACEUTICAL INDUSTRIES LTD-2015RR-108438", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "NAPROXEN" }, "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": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NAPROXEN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLURBIPROFEN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "75058", "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": "FLURBIPROFEN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUDESONIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "320 ?G, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ASTHMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "320", "drugstructuredosageunit": "004", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUDESONIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Forced expiratory volume decreased", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Angioedema", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nasal congestion", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sneezing", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rhinorrhoea", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Wheezing", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dyspnoea", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ERTOY KARAGOL HI, YILMAZ O, TOPAL E, CEYLAN A, BAKIRTAS A.. NONSTEROIDAL ANTI-INFLAMMATORY DRUGS-EXACERBATED RESPIRATORY DISEASE IN ADOLESCENTS.. INT-FORUM-ALLERGY-RHINOL. 2015?5(5):392-398", "literaturereference_normalized": "nonsteroidal anti inflammatory drugs exacerbated respiratory disease in adolescents", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20151229", "receivedate": "20151229", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 11874376, "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": "TR-PFIZER INC-2015201006", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "IBUPROFEN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "018989", "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": "IBUPROFEN." } ], "patientagegroup": null, "patientonsetage": "16", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Dyspnoea", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Forced expiratory volume decreased", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Angioedema", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rhinorrhoea", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Wheezing", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Flushing", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KARAGOL, H I E. NONSTEROIDAL ANTI-INFLAMMATORY DRUGS-EXACERBATED RESPIRATORY DISEASE IN ADOLESCENTS. INTERNATIONAL FORUM OF ALLERGY AND RHINOLOGY. 2015;5 (5):392-398", "literaturereference_normalized": "nonsteroidal anti inflammatory drugs exacerbated respiratory disease in adolescents", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20150622", "receivedate": "20150622", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 11208996, "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" }, { "companynumb": "PHHY2015TR159930", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLURBIPROFEN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "74448", "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": "FLURBIPROFEN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "NIMESULIDE" }, "drugadditional": null, "drugadministrationroute": "048", "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": "NIMESULIDE" } ], "patientagegroup": null, "patientonsetage": "16", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Dyspnoea", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Angioedema", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Forced expiratory volume decreased", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rhinorrhoea", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Wheezing", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Urticaria", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ERTOY KARAGOL HI, YILMAZ O, TOPAL E, CEYLAN A, BAKIRTAS A.. NONSTEROIDAL ANTI-INFLAMMATORY DRUGS-EXACERBATED RESPIRATORY DISEASE IN ADOLESCENTS.. INT-FORUM-ALLERGY-RHINOL. 2015?5(5):392-8", "literaturereference_normalized": "nonsteroidal anti inflammatory drugs exacerbated respiratory disease in adolescents", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20151211", "receivedate": "20151211", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11827419, "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": "PHHY2015TR161011", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": "048", "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": "ACETYLSALICYLIC ACID" } ], "patientagegroup": null, "patientonsetage": "14", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Aspirin-exacerbated respiratory disease", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ERTOY KARAGOL HI, YILMAZ O, TOPAL E, CEYLAN A, BAKIRTAS A.. NONSTEROIDAL ANTI-INFLAMMATORY DRUGS-EXACERBATED RESPIRATORY DISEASE IN ADOLESCENTS.. INT-FORUM-ALLERGY-RHINOL. 2015?5(5):392-8", "literaturereference_normalized": "nonsteroidal anti inflammatory drugs exacerbated respiratory disease in adolescents", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20151211", "receivedate": "20151211", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11827529, "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": "TR-SUN PHARMACEUTICAL INDUSTRIES LTD-2015RR-108432", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "NAPROXEN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "91183", "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": "NAPROXEN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DICLOFENAC" }, "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": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DICLOFENAC" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Dyspnoea", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nasal congestion", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Flushing", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rhinorrhoea", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Chest discomfort", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ERTOY KARAGOL HI, YILMAZ O, TOPAL E, CEYLAN A, BAKIRTAS A.. NONSTEROIDAL ANTI-INFLAMMATORY DRUGS-EXACERBATED RESPIRATORY DISEASE IN ADOLESCENTS.. INT-FORUM-ALLERGY-RHINOL. 2015?5(5):392-398", "literaturereference_normalized": "nonsteroidal anti inflammatory drugs exacerbated respiratory disease in adolescents", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20151229", "receivedate": "20151229", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 11874282, "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": "PHHY2015TR161012", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "NAPROXEN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "74140", "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": "NAPROXEN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "IBUPROFEN" }, "drugadditional": null, "drugadministrationroute": "048", "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": "IBUPROFEN." } ], "patientagegroup": null, "patientonsetage": "16", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Urticaria", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Wheezing", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Angioedema", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dyspnoea", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Forced expiratory volume decreased", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rhinorrhoea", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cough", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ERTOY KARAGOL HI, YILMAZ O, TOPAL E, CEYLAN A, BAKIRTAS A.. NONSTEROIDAL ANTI-INFLAMMATORY DRUGS-EXACERBATED RESPIRATORY DISEASE IN ADOLESCENTS.. INT-FORUM-ALLERGY-RHINOL. 2015?5(5):392-8", "literaturereference_normalized": "nonsteroidal anti inflammatory drugs exacerbated respiratory disease in adolescents", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20151211", "receivedate": "20151211", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11827422, "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": "TR-MYLANLABS-2015M1044577", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "NAPROXEN" }, "drugadditional": null, "drugadministrationroute": "048", "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": "NAPROXEN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "IBUPROFEN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "070045", "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": "IBUPROFEN." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypersensitivity", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Angioedema", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ERTOY KARAGOL HI, YILMAZ O, TOPAL E, CEYLAN A, BAKIRTAS A. NONSTEROIDAL ANTI-INFLAMMATORY DRUGS-EXACERBATED RESPIRATORY DISEASE IN ADOLESCENTS. INT-FORUM-ALLERGY-RHINOL 2015? 5(5):392-398.", "literaturereference_normalized": "nonsteroidal anti inflammatory drugs exacerbated respiratory disease in adolescents", "qualification": "1", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20151215", "receivedate": "20151215", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11835722, "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": "TR-PFIZER INC-2015201002", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "NAPROXEN" }, "drugadditional": null, "drugadministrationroute": null, "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": "NAPROXEN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "BUDESONIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "320 ?G, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ASTHMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "320", "drugstructuredosageunit": "004", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUDESONIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "IBUPROFEN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "018989", "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": "IBUPROFEN." } ], "patientagegroup": null, "patientonsetage": "13", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Urticaria", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rhinorrhoea", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Angioedema", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nasal congestion", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ERTOY KARAGOL, H.I.. NONSTEROIDAL ANTI-INFLAMMATORY DRUGS-EXACERBATED RESPIRATORY DISEASE IN ADOLESCENTS. INTERNATIONAL FORUM OF ALLERGY AND RHINOLOGY. 2015;5 (5):392-398", "literaturereference_normalized": "nonsteroidal anti inflammatory drugs exacerbated respiratory disease in adolescents", "qualification": "1", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20150619", "receivedate": "20150619", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 11202212, "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" }, { "companynumb": "TR-MYLANLABS-2015M1044576", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "IBUPROFEN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "070045", "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": "IBUPROFEN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DIPYRONE" }, "drugadditional": null, "drugadministrationroute": "048", "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": "DIPYRONE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypersensitivity", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Angioedema", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ERTOY KARAGOL HI, YILMAZ O, TOPAL E, CEYLAN A, BAKIRTAS A. NONSTEROIDAL ANTI-INFLAMMATORY DRUGS-EXACERBATED RESPIRATORY DISEASE IN ADOLESCENTS. INT-FORUM-ALLERGY-RHINOL 2015? 5(5):392-398.", "literaturereference_normalized": "nonsteroidal anti inflammatory drugs exacerbated respiratory disease in adolescents", "qualification": "1", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20151215", "receivedate": "20151215", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11835730, "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": "TR-BAYER-2015-064302", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "BUDESONIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "320 MCG", "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": "BUDESONIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "IBUPROFEN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG PROVOCATION TEST", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IBUPROFEN [IBUPROFEN]" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "NAPROXEN SODIUM" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "020204", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG PROVOCATION TEST", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NAPROXEN SODIUM." } ], "patientagegroup": "4", "patientonsetage": "13", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug hypersensitivity", "reactionmeddraversionpt": "18.0", "reactionoutcome": null }, { "reactionmeddrapt": "Nasal congestion", "reactionmeddraversionpt": "18.0", "reactionoutcome": null }, { "reactionmeddrapt": "Urticaria", "reactionmeddraversionpt": "18.0", "reactionoutcome": null }, { "reactionmeddrapt": "Allergic respiratory disease", "reactionmeddraversionpt": "18.0", "reactionoutcome": null }, { "reactionmeddrapt": "Rhinorrhoea", "reactionmeddraversionpt": "18.0", "reactionoutcome": null }, { "reactionmeddrapt": "Angioedema", "reactionmeddraversionpt": "18.0", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "ERTOY KARAGOL HI; YILMAZ O; TOPAL E; CEYLAN A; BAKIRTAS A. NONSTEROIDAL ANTI-INFLAMMATORY DRUGS-EXACERBATED RESPIRATORY DISEASE IN ADOLESCENTS. INT FORUM ALLERGY RHINOL. 2015;XX:XX", "literaturereference_normalized": "nonsteroidal anti inflammatory drugs exacerbated respiratory disease in adolescents", "qualification": "1", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20150331", "receivedate": "20150331", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 10971100, "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": "PHHY2015TR161016", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "NAPROXEN" }, "drugadditional": null, "drugadministrationroute": "048", "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": "NAPROXEN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": "048", "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": "ACETYLSALICYLIC ACID" } ], "patientagegroup": null, "patientonsetage": "17", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Angioedema", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Flushing", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Urticaria", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Forced expiratory volume decreased", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rhinorrhoea", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cough", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Wheezing", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nasal congestion", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dyspnoea", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ERTOY KARAGOL HI, YILMAZ O, TOPAL E, CEYLAN A, BAKIRTAS A.. NONSTEROIDAL ANTI-INFLAMMATORY DRUGS-EXACERBATED RESPIRATORY DISEASE IN ADOLESCENTS.. INT-FORUM-ALLERGY-RHINOL. 2015?5(5):392-8", "literaturereference_normalized": "nonsteroidal anti inflammatory drugs exacerbated respiratory disease in adolescents", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20151211", "receivedate": "20151211", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11827475, "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" }, { "companynumb": "TR-SUN PHARMACEUTICAL INDUSTRIES LTD-2015RR-108435", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUDESONIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "160 ?G, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ASTHMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "160", "drugstructuredosageunit": "004", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUDESONIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "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": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Angioedema", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rhinorrhoea", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sneezing", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nasal congestion", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ERTOY KARAGOL HI, YILMAZ O, TOPAL E, CEYLAN A, BAKIRTAS A.. NONSTEROIDAL ANTI-INFLAMMATORY DRUGS-EXACERBATED RESPIRATORY DISEASE IN ADOLESCENTS.. INT-FORUM-ALLERGY-RHINOL. 2015?5(5):392-398", "literaturereference_normalized": "nonsteroidal anti inflammatory drugs exacerbated respiratory disease in adolescents", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20151229", "receivedate": "20151229", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 11874265, "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": "TR-LUPIN PHARMACEUTICALS INC.-2015-04252", "fulfillexpeditecriteria": "2", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "DICLOFENAC" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "204132", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "4 OR 5 ESCALATING DOSES", "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": "DICLOFENAC" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "NAPROXEN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "4 OR 5 ESCALATING DOSES", "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": "NAPROXEN." } ], "patientagegroup": null, "patientonsetage": "14", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Chest discomfort", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rhinorrhoea", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nasal congestion", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sneezing", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Flushing", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dyspnoea", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KARAGOL H, YILMAZ O, TOPAL E, CEYLAN A, BAKIRTAS A. NONSTEROIDAL ANTI-INFLAMMATORY DRUGS-EXACERBATED RESPIRATORY DISEASE IN ADOLESCENTS. INTERNATIONAL FORUM OF ALLERGY AND RHINOLOGY. 2015 MAY?5(5):392-398.", "literaturereference_normalized": "nonsteroidal anti inflammatory drugs exacerbated respiratory disease in adolescents", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "TR", "receiptdate": "20160303", "receivedate": "20160303", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 12139515, "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": "TR-SUN PHARMACEUTICAL INDUSTRIES LTD-2015RR-108439", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "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": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLURBIPROFEN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "75058", "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": "FLURBIPROFEN." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Chest discomfort", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nasal congestion", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rhinorrhoea", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Angioedema", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ERTOY KARAGOL HI, YILMAZ O, TOPAL E, CEYLAN A, BAKIRTAS A.. NONSTEROIDAL ANTI-INFLAMMATORY DRUGS-EXACERBATED RESPIRATORY DISEASE IN ADOLESCENTS.. INT-FORUM-ALLERGY-RHINOL. 2015?5(5):392-398", "literaturereference_normalized": "nonsteroidal anti inflammatory drugs exacerbated respiratory disease in adolescents", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20151229", "receivedate": "20151229", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 11874375, "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": "TR-PFIZER INC-2015201007", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "IBUPROFEN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "018989", "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": "IBUPROFEN." } ], "patientagegroup": null, "patientonsetage": "13", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Angioedema", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dyspnoea", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rhinorrhoea", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cough", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Forced expiratory volume decreased", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Wheezing", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ERTOY KRAGOL H.I.. NONSTEROIDAL ANTI-INFLAMMATORY DRUGS-EXACERBATED RESPIRATORY DISEASE IN ADOLESCENTS. INTERNATIONAL FORUM OF ALLERGY AND RHINOLOGY. 2015;5 (5):392-398", "literaturereference_normalized": "nonsteroidal anti inflammatory drugs exacerbated respiratory disease in adolescents", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20150622", "receivedate": "20150622", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 11208991, "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" }, { "companynumb": "TR-BAYER-2015-064457", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "FLURBIPROFEN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG PROVOCATION TEST", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLURBIPROFEN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "NAPROXEN SODIUM" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "020204", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG PROVOCATION TEST", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NAPROXEN SODIUM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "BUDESONIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "160 MCG", "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": "BUDESONIDE." } ], "patientagegroup": "4", "patientonsetage": "15", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug hypersensitivity", "reactionmeddraversionpt": "18.0", "reactionoutcome": null }, { "reactionmeddrapt": "Cough", "reactionmeddraversionpt": "18.0", "reactionoutcome": null }, { "reactionmeddrapt": "Nasal congestion", "reactionmeddraversionpt": "18.0", "reactionoutcome": null }, { "reactionmeddrapt": "Angioedema", "reactionmeddraversionpt": "18.0", "reactionoutcome": null }, { "reactionmeddrapt": "Allergic respiratory disease", "reactionmeddraversionpt": "18.0", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "ERTOY KARAGOL HI; YILMAZ O; TOPAL E; CEYLAN A; BAKIRTAS A. NONSTEROIDAL ANTI-INFLAMMATORY DRUGS-EXACERBATED RESPIRATORY DISEASE IN ADOLESCENTS. INT FORUM ALLERGY RHINOL. 2015;00:XX", "literaturereference_normalized": "nonsteroidal anti inflammatory drugs exacerbated respiratory disease in adolescents", "qualification": "1", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20150331", "receivedate": "20150331", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 10971171, "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": "TR-SUN PHARMACEUTICAL INDUSTRIES LTD-2015RR-108434", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "NAPROXEN" }, "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": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NAPROXEN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUDESONIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "160 ?G, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ASTHMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "160", "drugstructuredosageunit": "004", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUDESONIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLURBIPROFEN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "75058", "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": "FLURBIPROFEN." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cough", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Angioedema", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nasal congestion", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ERTOY KARAGOL HI, YILMAZ O, TOPAL E, CEYLAN A, BAKIRTAS A.. NONSTEROIDAL ANTI-INFLAMMATORY DRUGS-EXACERBATED RESPIRATORY DISEASE IN ADOLESCENTS.. INT-FORUM-ALLERGY-RHINOL. 2015?5(5):392-398", "literaturereference_normalized": "nonsteroidal anti inflammatory drugs exacerbated respiratory disease in adolescents", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20151229", "receivedate": "20151229", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 11874273, "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": "TR-BAYER-2015-064758", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "IBUPROFEN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG PROVOCATION TEST", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IBUPROFEN [IBUPROFEN]" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "NAPROXEN SODIUM" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "020204", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DRUG PROVOCATION TEST", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NAPROXEN SODIUM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "BUDESONIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "200 MCG", "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": "BUDESONIDE." } ], "patientagegroup": "4", "patientonsetage": "16", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug hypersensitivity", "reactionmeddraversionpt": "18.0", "reactionoutcome": null }, { "reactionmeddrapt": "Rhinorrhoea", "reactionmeddraversionpt": "18.0", "reactionoutcome": null }, { "reactionmeddrapt": "Cough", "reactionmeddraversionpt": "18.0", "reactionoutcome": null }, { "reactionmeddrapt": "Allergic respiratory disease", "reactionmeddraversionpt": "18.0", "reactionoutcome": null }, { "reactionmeddrapt": "Angioedema", "reactionmeddraversionpt": "18.0", "reactionoutcome": null }, { "reactionmeddrapt": "Dyspnoea", "reactionmeddraversionpt": "18.0", "reactionoutcome": null }, { "reactionmeddrapt": "Wheezing", "reactionmeddraversionpt": "18.0", "reactionoutcome": null }, { "reactionmeddrapt": "Flushing", "reactionmeddraversionpt": "18.0", "reactionoutcome": null }, { "reactionmeddrapt": "Urticaria", "reactionmeddraversionpt": "18.0", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "ERTOY KARAGOL HI; YILMAZ O; TOPAL E; CEYLAN A; BAKIRTAS A. NONSTEROIDAL ANTI-INFLAMMATORY DRUGS-EXACERBATED RESPIRATORY DISEASE IN ADOLESCENTS. INT FORUM ALLERGY RHINOL. 2015;00:XX", "literaturereference_normalized": "nonsteroidal anti inflammatory drugs exacerbated respiratory disease in adolescents", "qualification": "1", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20150331", "receivedate": "20150331", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 10971183, "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": "PHHY2015TR161014", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "NAPROXEN" }, "drugadditional": null, "drugadministrationroute": "048", "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": "NAPROXEN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLURBIPROFEN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "74448", "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": "FLURBIPROFEN." } ], "patientagegroup": null, "patientonsetage": "14", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Sneezing", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Angioedema", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Forced expiratory volume decreased", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dyspnoea", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nasal congestion", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rhinorrhoea", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Wheezing", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ERTOY KARAGOL HI, YILMAZ O, TOPAL E, CEYLAN A, BAKIRTAS A.. NONSTEROIDAL ANTI-INFLAMMATORY DRUGS-EXACERBATED RESPIRATORY DISEASE IN ADOLESCENTS.. INT-FORUM-ALLERGY-RHINOL. 2015?5(5):392-8", "literaturereference_normalized": "nonsteroidal anti inflammatory drugs exacerbated respiratory disease in adolescents", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20151211", "receivedate": "20151211", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11827473, "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": "Trials of adjuvant high-dose chemotherapy (HDCT) have failed to show a survival benefit in unselected patients with breast cancer, but long-term follow-up is lacking.\n\n\n\nTo determine 20-year efficacy and safety outcomes of a large trial of adjuvant HDCT vs conventional-dose chemotherapy (CDCT) for patients with stage III breast cancer.\n\n\n\nThis secondary analysis used data from a randomized phase 3 multicenter clinical trial of 885 women younger than 56 years with breast cancer and 4 or more involved axillary lymph nodes conducted from August 1, 1993, to July 31, 1999. Additional follow-up data were collected between June 1, 2016, and December 31, 2017, from medical records, general practitioners, the Dutch national statistical office, and nationwide cancer registries. Analysis was performed on an intention-to-treat basis. Statistical analysis was performed from February 1, 2018, to October 14, 2019.\n\n\n\nParticipants were randomized 1:1 to receive 5 cycles of CDCT consisting of fluorouracil, 500 mg/m2, epirubicin, 90 mg/m2, and cyclophosphamide, 500 mg/m2, or HDCT in which the first 4 cycles were identical to CDCT and the fifth cycle was replaced by cyclophosphamide, 6000 mg/m2, thiotepa, 480 mg/m2, and carboplatin, 1600 mg/m2, followed by hematopoietic stem cell transplant.\n\n\n\nMain end points were overall survival and safety and cumulative incidence risk of a second malignant neoplasm or cardiovascular events.\n\n\n\nOf the 885 women in the study (mean [SD] age, 44.5 [6.6] years), 442 were randomized to receive HDCT, and 443 were randomized to receive CDCT. With 20.4 years median follow-up (interquartile range, 19.2-22.0 years), the 20-year overall survival was 45.3% with HDCT and 41.5% with CDCT (hazard ratio, 0.89; 95% CI, 0.75-1.06). The absolute improvement in 20-year overall survival was 14.6% (hazard ratio, 0.72; 95% CI, 0.54-0.95) for patients with 10 or more invoved axillary lymph nodes and 15.4% (hazard ratio, 0.67; 95% CI, 0.42-1.05) for patients with triple-negative breast cancer. The cumulative incidence risk of a second malignant neoplasm at 20 years or major cardiovascular events was similar in both treatment groups (20-year cumulative incidence risk for second malignant neoplasm was 12.1% in the HDCT group vs 16.2% in the CDCT group, P = .10), although patients in the HDCT group more often had hypertension (21.7% vs 14.3%, P = .02), hypercholesterolemia (15.7% vs 10.6%, P = .04), and dysrhythmias (8.6% vs 4.6%, P = .005).\n\n\n\nHigh-dose chemotherapy provided no long-term survival benefit in unselected patients with stage III breast cancer but did provide improved overall survival in very high-risk patients (ie, with ≥10 involved axillary lymph nodes). High-dose chemotherapy did not affect long-term risk of a second malignant neoplasm or major cardiovascular events.\n\n\n\nClinicalTrials.gov Identifier: NCT03087409.", "affiliations": "Department of Medical Oncology, Netherlands Cancer Institute, Antoni van Leeuwenhoek, Amsterdam, the Netherlands.;Department of Medical Oncology, University Medical Center Groningen, Groningen, the Netherlands.;Department of Medical Oncology, Erasmus MC University Medical Center, Rotterdam, the Netherlands.;Department of Medical Oncology, Radboud University Medical Center, Nijmegen, the Netherlands.;Department of Medical Oncology, Erasmus MC University Medical Center, Rotterdam, the Netherlands.;Department of Medical Oncology, Erasmus MC University Medical Center, Rotterdam, the Netherlands.;Department of Medical Oncology, Amsterdam UMC, location VUmc, Cancer Center Amsterdam, Amsterdam, the Netherlands.;Department of Medical Oncology, Leiden University Medical Center, Leiden, the Netherlands.;Department of Internal Medicine/Medical Oncology, Medisch Spectrum Twente, Enschede, the Netherlands.;Department of Medical Oncology, Maastricht University Medical Center, Maastricht, the Netherlands.;Department of Medical Oncology, University Medical Center Utrecht, Utrecht, the Netherlands.;Department of Medical Oncology, Amsterdam UMC, location AMC, Amsterdam, the Netherlands.;Department of Medical Oncology, Netherlands Cancer Institute, Antoni van Leeuwenhoek, Amsterdam, the Netherlands.;Department of Psychosocial Research and Epidemiology, Netherlands Cancer Institute, Antoni van Leeuwenhoek, Amsterdam, the Netherlands.;Department of Psychosocial Research and Epidemiology, Netherlands Cancer Institute, Antoni van Leeuwenhoek, Amsterdam, the Netherlands.;Department of Psychosocial Research and Epidemiology, Netherlands Cancer Institute, Antoni van Leeuwenhoek, Amsterdam, the Netherlands.;Department of Medical Oncology, University Medical Center Groningen, Groningen, the Netherlands.;Department of Biostatistics, the Netherlands Cancer Institute, Antoni van Leeuwenhoek, Amsterdam, the Netherlands.;Department of Medical Oncology, University Medical Center Groningen, Groningen, the Netherlands.;Department of Medical Oncology, Netherlands Cancer Institute, Antoni van Leeuwenhoek, Amsterdam, the Netherlands.;Department of Medical Oncology, University Medical Center Groningen, Groningen, the Netherlands.", "authors": "Steenbruggen|Tessa G|TG|;Steggink|Lars C|LC|;Seynaeve|Caroline M|CM|;van der Hoeven|Jacobus J M|JJM|;Hooning|Maartje J|MJ|;Jager|Agnes|A|;Konings|Inge R|IR|;Kroep|Judith R|JR|;Smit|Wim M|WM|;Tjan-Heijnen|Vivianne C G|VCG|;van der Wall|Elsken|E|;Bins|Adriaan D|AD|;Linn|Sabine C|SC|;Schaapveld|Michael|M|;Jacobse|Judy N|JN|;van Leeuwen|Flora E|FE|;Schröder|Carolien P|CP|;van Tinteren|Harm|H|;de Vries|Elisabeth G E|EGE|;Sonke|Gabe S|GS|;Gietema|Jourik A|JA|", "chemical_list": "D015251:Epirubicin; D003520:Cyclophosphamide; D005472:Fluorouracil", "country": "United States", "delete": false, "doi": "10.1001/jamaoncol.2019.6276", "fulltext": null, "fulltext_license": null, "issn_linking": "2374-2437", "issue": "6(4)", "journal": "JAMA oncology", "keywords": null, "medline_ta": "JAMA Oncol", "mesh_terms": "D000328:Adult; D001365:Axilla; D001940:Breast; D001943:Breast Neoplasms; D018376:Cardiovascular Abnormalities; D002648:Child; D003520:Cyclophosphamide; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D015251:Epirubicin; D005260:Female; D005472:Fluorouracil; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008198:Lymph Nodes; D008207:Lymphatic Metastasis; D008875:Middle Aged", "nlm_unique_id": "101652861", "other_id": null, "pages": "528-534", "pmc": null, "pmid": "31999296", "pubdate": "2020-04-01", "publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D016449:Randomized Controlled Trial", "references": "17513820;21768471;12598854;10655439;11352968;26968393;15265969;9605801;28945867;15817602;24887359;16639731;15767638;17301072;10076722;12075738;12840087;26946057;26786933;29117498;16325695;21135055;16446318;12840088;11052580;19468030", "title": "High-Dose Chemotherapy With Hematopoietic Stem Cell Transplant in Patients With High-Risk Breast Cancer and 4 or More Involved Axillary Lymph Nodes: 20-Year Follow-up of a Phase 3 Randomized Clinical Trial.", "title_normalized": "high dose chemotherapy with hematopoietic stem cell transplant in patients with high risk breast cancer and 4 or more involved axillary lymph nodes 20 year follow up of a phase 3 randomized clinical trial" }

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"reactionmeddraversionpt": "23.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "STEENBRUGGEN, T.. HIGH?DOSE CHEMOTHERAPY WITH HEMATOPOIETIC STEM CELL TRANSPLANT IN PATIENTS WITH HIGH?RISK BREAST CANCER AND 4 OR MORE INVOLVED AXILLARY LYMPH NODES: 20?YEAR FOLLOW?UP OF A PHASE 3 RANDOMIZED CLINICAL TRIAL. JAMA ONCOLOGY. 2020?6(4):528?534", "literaturereference_normalized": "high dose chemotherapy with hematopoietic stem cell transplant in patients with high risk breast cancer and 4 or more involved axillary lymph nodes 20 year follow up of a phase 3 randomized clinical trial", "qualification": "1", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20210120", "receivedate": "20210120", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18761813, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210419" } ]

{ "abstract": "Biliary hamartomas (BH) are rare benign lesions of the liver characterized by a dilation of a variable number of small biliary ducts, usually surrounded by abundant fibrotic tissue. These malformations are due to an aberrant remodelling of the ductal plate, that is the embryonic structure generating the normal biliary tree. BH are usually asymptomatic, but in rare cases they can be associated with jaundice, heartburn and fever. Evidences for a sharing of similar pathological pathways between BH and adult dominant polycystic kidney disease (ADPKD) are widely reported. These similarities induce an increased neoplastic risk transformation in both conditions. This risk is even greater in immunosuppressed patients. The diagnosis of BH by imaging is not easy, especially in the context of ADPKD. We present a clinical case of a 54-year-old kidney transplant recipient affected by ADPKD in which BH, previously undetected, was for the first time suspected on routine ultrasound scan and confirmed with MRI 4 years after renal transplantation. Demodulation of proliferative signals induced by immunosuppressive therapy, and particularly by calcineurin inhibitors, could cause an enlargement of AB and increase the risk of neoplastic transformation. Our case-report suggests a close imaging follow-up may be needed in ADPKD patients with BH, especially if transplanted. High sensitivity techniques, such as CEUS and MRI, should be preferred to conventional ultrasound.", "affiliations": "UO Nefrologia e Dialisi, Policlinico Germaneto, Catanzaro.;UO Nefrologia e Dialisi, Policlinico Germaneto, Catanzaro.;UO Nefrologia e Dialisi, Policlinico Germaneto, Catanzaro.;UO Nefrologia e Dialisi, Policlinico Germaneto, Catanzaro.;UO Nefrologia e Dialisi, Policlinico Germaneto, Catanzaro.", "authors": "Leonardi|Giuseppe|G|;Simeoni|Mariadelina|M|;Bozzo|Michele|M|;Caglioti|Alfredo|A|;Fuiano|Giorgio|G|", "chemical_list": "D003287:Contrast Media", "country": "Italy", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0393-5590", "issue": "36(1)", "journal": "Giornale italiano di nefrologia : organo ufficiale della Societa italiana di nefrologia", "keywords": "ADPKD; biliary hamartomatosis; kidney transplant", "medline_ta": "G Ital Nefrol", "mesh_terms": "D001660:Biliary Tract Diseases; D002471:Cell Transformation, Neoplastic; D003287:Contrast Media; D006222:Hamartoma; D006801:Humans; D016867:Immunocompromised Host; D007668:Kidney; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D016891:Polycystic Kidney, Autosomal Dominant; D013997:Time Factors; D066027:Transplant Recipients; D014463:Ultrasonography", "nlm_unique_id": "9426434", "other_id": null, "pages": null, "pmc": null, "pmid": "30758151", "pubdate": "2019-02", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Diagnosis of Biliary Hamartomatosis in Kidney Transplant Recipient affected by ADPKD.", "title_normalized": "diagnosis of biliary hamartomatosis in kidney transplant recipient affected by adpkd" }

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"drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MILLIGRAM, PER DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." } ], "patientagegroup": null, "patientonsetage": "6", "patientonsetageunit": "800", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Glomerular filtration rate increased", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hyponatraemia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Abdominal pain upper", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dehydration", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Blood creatinine increased", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Biliary hamartoma", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Abdominal tenderness", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Flatulence", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Functional gastrointestinal disorder", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Fatigue", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Metabolic alkalosis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LEONARDI G, SIMEONI M, BOZZO M, CAGLIOTI A, FUIANO G.. DIAGNOSIS OF BILIARY HAMARTOMATOSIS IN KIDNEY TRANSPLANT RECIPIENT AFFECTED BY ADPKD.. GIORNALE ITALIANO DI NEFROLOGIA. 2019?36(1)", "literaturereference_normalized": "diagnosis of biliary hamartomatosis in kidney transplant recipient affected by adpkd", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20200311", "receivedate": "20191125", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17070312, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200409" }, { "companynumb": "IT-MYLANLABS-2020M1011398", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CICLOSPORIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "065520", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "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": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." } ], "patientagegroup": null, "patientonsetage": "54", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Unmasking of previously unidentified disease", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acquired gene mutation", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LEONARDI G, SIMEONI M, BOZZO M, CAGLIOTI A, FUIANO G.. DIAGNOSIS OF BILIARY HAMARTOMATOSIS IN KIDNEY TRANSPLANT RECIPIENT AFFECTED BY ADPKD.. 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"drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DELTACORTENE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "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": "CICLOSPORIN" } ], "patientagegroup": null, "patientonsetage": "54", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "22.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Abdominal pain upper", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Unmasking of previously unidentified disease", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "22.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Metabolic alkalosis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "22.1", "reactionoutcome": "2" } ], "summary": null }, 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DIAGNOSIS OF BILIARY HAMARTOMATOSIS IN KIDNEY TRANSPLANT RECIPIENT AFFECTED BY ADPKD. G ITAL NEFROL 2019?36 (1):-.", "literaturereference_normalized": "diagnosis of biliary hamartomatosis in kidney transplant recipient affected by adpkd", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20200107", "receivedate": "20191220", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17181991, "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": "IT-SUN PHARMACEUTICAL INDUSTRIES LTD-2019R1-228701", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "360 MILLIGRAM, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "Immunosuppression", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "360", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "089247", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "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": "PREDNISONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MILLIGRAM, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "Immunosuppression", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOSPORINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MILLIGRAM, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "Immunosuppression", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE" } ], "patientagegroup": null, "patientonsetage": "54", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Biliary hamartoma", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Unmasking of previously unidentified disease", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Leonardi G, Simeoni M, Bozzo M, Caglioti A, Fuiano G. Diagnosis of Biliary Hamartomatosis in Kidney Transplant Recipient affected by ADPKD. G Ital Nefrol. 2019;Feb; 36No. 1:1-7", "literaturereference_normalized": "diagnosis of biliary hamartomatosis in kidney transplant recipient affected by adpkd", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20220118", "receivedate": "20191129", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17091721, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220423" } ]

{ "abstract": "Vasodilators, specifically calcium-channel modulators, are currently in widespread use for the treatment of essential hypertension. Several reports of toxicity from immediate-release verapamil have appeared in the literature. We present a case of sustained-release verapamil overdose as a consequence of an attempted suicide. The treatment measures used in a verapamil toxicity are discussed, as well as a review of the current literature on verapamil overdose.", "affiliations": "Medical College of Virginia.", "authors": "Krick|S E|SE|;Gums|J G|JG|;Grauer|K|K|;Cooper|G R|GR|", "chemical_list": "D003692:Delayed-Action Preparations; D014700:Verapamil", "country": "United States", "delete": false, "doi": "10.1177/106002809002400711", "fulltext": null, "fulltext_license": null, "issn_linking": "1042-9611", "issue": "24(7-8)", "journal": "DICP : the annals of pharmacotherapy", "keywords": null, "medline_ta": "DICP", "mesh_terms": "D000328:Adult; D003692:Delayed-Action Preparations; D006801:Humans; D008297:Male; D013405:Suicide; D014700:Verapamil", "nlm_unique_id": "8904338", "other_id": null, "pages": "705-6", "pmc": null, "pmid": "2375141", "pubdate": "1990", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Severe verapamil (sustained-release) overdose.", "title_normalized": "severe verapamil sustained release overdose" }

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{ "abstract": "To describe a fatal case of influenza A pneumonia in a patient with severe lymphopenia after receiving subcutaneous cladribine to treat her multiple sclerosis (MS).\nCase report.\nA 53-year-old woman developed fatal influenza pneumonia associated with grade 4 lymphopenia two months after receiving a total dose of 60mg subcutaneous cladribine. Despite treatment with oseltamivir, her condition deteriorated and the patient passed away after developing respiratory failure.\nCladribine-related lymphopenia is usually mild to moderate, however severe lymphopenia may occur. People with MS, especially those who are immunosuppressed, should be offered the inactivated influenza vaccine annually.", "affiliations": "Department of Neurology, Hospital General Universitario de Castellón, Castellón de la Plana, Spain.;Clinical Board Medicine (Neuroscience), The Royal London Hospital, Barts Health NHS Trust, London, UK.;Clinical Board Medicine (Neuroscience), The Royal London Hospital, Barts Health NHS Trust, London, UK.;Clinical Board Medicine (Neuroscience), The Royal London Hospital, Barts Health NHS Trust, London, UK.;Clinical Board Medicine (Neuroscience), The Royal London Hospital, Barts Health NHS Trust, London, UK.;Clinical Board Medicine (Neuroscience), The Royal London Hospital, Barts Health NHS Trust, London, UK.;Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK.;Clinical Board Medicine (Neuroscience), The Royal London Hospital, Barts Health NHS Trust, London, UK.;Clinical Board Medicine (Neuroscience), The Royal London Hospital, Barts Health NHS Trust, London, UK.", "authors": "Mateo-Casas|M|M|;Reyes|S|S|;De Trane|S|S|;Edwards|F|F|;Espasandin|M|M|;Anjorin|G|G|;Baker|D|D|;Schmierer|K|K|;Giovannoni|G|G|", "chemical_list": null, "country": "Netherlands", "delete": false, "doi": "10.1016/j.ensci.2020.100279", "fulltext": "\n==== Front\neNeurologicalSci\neNeurologicalSci\neNeurologicalSci\n2405-6502 Elsevier \n\nS2405-6502(20)30058-7\n10.1016/j.ensci.2020.100279\n100279\nCase Report\nSevere lymphopenia after subcutaneous cladribine in a patient with multiple sclerosis: To vaccinate or not?\nMateo-Casas M. mateo_marcas1@gva.esac⁎1 Reyes S. bc1 De Trane S. bc Edwards F. b Espasandin M. b Anjorin G. b Baker D. c Schmierer K. bc Giovannoni G. bc a Department of Neurology, Hospital General Universitario de Castellón, Castellón de la Plana, Spain\nb Clinical Board Medicine (Neuroscience), The Royal London Hospital, Barts Health NHS Trust, London, UK\nc Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK\n⁎ Corresponding author at: Department of Neurology, Royal London Hospital, Barts Health NHS Trust, 7000 Whitechapel Road, Whitechapel, London E1 1FR, UK. mateo_marcas1@gva.es1 These authors contributed equally to the manuscript.\n\n\n09 10 2020 \n12 2020 \n09 10 2020 \n21 1002792 6 2020 7 9 2020 30 9 2020 © 2020 Published by Elsevier B.V.2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Objective\nTo describe a fatal case of influenza A pneumonia in a patient with severe lymphopenia after receiving subcutaneous cladribine to treat her multiple sclerosis (MS).\n\nMethods\nCase report.\n\nResults\nA 53-year-old woman developed fatal influenza pneumonia associated with grade 4 lymphopenia two months after receiving a total dose of 60mg subcutaneous cladribine. Despite treatment with oseltamivir, her condition deteriorated and the patient passed away after developing respiratory failure.\n\nConclusion\nCladribine-related lymphopenia is usually mild to moderate, however severe lymphopenia may occur. People with MS, especially those who are immunosuppressed, should be offered the inactivated influenza vaccine annually.\n\nHighlights\n• We report a case of lethal influenza A infection with severe lymphopenia in an MS patient receiving s.c. cladribine.\n\n• Cladribine-related lymphopenia is usually mild to moderate, however severe lymphopenia may occur.\n\n• Annual influenza immunisation should be recommended for people with MS, especially those who are immunosuppressed.\n\n\n\nKeywords\nCladribineDisease-modifying treatmentLymphopeniaAdverse eventInfluenza A virusMultiple Sclerosis\n==== Body\n1 Introduction\nCladribine is a synthetic purine nucleoside analogue originally developed as a treatment for haematologic malignancies. More recently, an oral formulation of cladribine (Mavenclad®) has been licensed for treating people with relapsing multiple sclerosis (pwRMS) [1]. We have been using subcutaneously administered (s.c.) cladribine (Litak®) to treat over 210 people with MS (pwMS) since November 2014 [2]. Whilst semi-selective lymphocyte depletion is considered key to the efficacy of cladribine in controlling MS, lymphopenia also leads to adverse risk, mainly of viral infections [3]. Although lymphopenia is usually mild to moderate, a small number of pwMS develop severe lymphopenia [4,5]. We report the case of a woman who developed grade 4 lymphopenia in the context of cladribine treatment for her MS, and died of influenza A pneumonia.\n\n2 Case report\nA 53-year-old woman with a 21-year history of RMS, was first diagnosed after an attack of lower limb weakness and numbness. Her only other significant medical history was hypothyroidism. She initially had a relatively mild course of the disease with no restriction in mobility. However, 15 years after disease onset she suffered a severe relapse associated with a new cervical lesion that left her with an Expanded Disability Status Scale (EDSS) score of 9.5. Treatment with natalizumab was started and although she gradually recovered over the following month, her new baseline EDSS score stabilised at 8.5. Eight months into the treatment she became seropositive for JC virus. Whilst her antibody titre remained below 0.9 for 5 years, it then increased up to 1.34. After discussing the risks of no treatment, for example rebound disease activity on natalizumab withdrawal, a decision was made to switch onto a different immunotherapy. Safety checks were successfully addressed and she was started on s.c. cladribine using a treatment schedule developed in-house [6]. At baseline, white blood cell count (WBC) was 8.5x109/L (normal, 4-11x109/L) and total lymphocyte count (TLC) was 3.6x109/L (normal, 1-4.8x109/L). In week 1 she received cladribine 10mg s.c. on three consecutive days. TLC at week 4 was 1.9x109/L, and she was given another 10mg of s.c. cladribine on three consecutive days in week 5. At week 6 her TLC was 1.1x109/L. At week 13, she presented to the emergency room with new onset dyspnoea. Her blood pressure was 96/57 mm Hg, pulse rate 81 bpm, respiratory rate 21/min and temperature 35,7°C. Peripheral oxygen saturation was 95% with a FiO2 of 0.5. Crackles were noted in both lower lung fields. Neurological examination showed no new findings compared to her baseline. Blood tests revealed grade 4 lymphopenia with a TLC of 0.2x109/L. WBC was 4.2x109/L with 0.1x109/L monocytes and 3.9x109/L neutrophils. The time course of her WBC and TLC is shown in Fig.1. Her haemoglobin concentration was 88g/L and platelet count 120x109/L. Her C-reactive protein was 182 mg/L. Chest X-ray revealed patchy opacification within the right lower zone suggesting pneumonia, and treatment with amoxicillin and clarithromycin was started. Influenza A virus target RNA was detected from a nose swab and treatment with oseltamivir was initiated. However, she gradually deteriorated and five days after admission she developed progressive respiratory failure and died. Since influenza vaccination would have coincided with the start of her immunotherapy, she did not receive her seasonal influenza vaccine.Fig. 1 White blood cells and lymphocytes counts.\n\nBaseline white blood cells (1A) and lymphocytes (1B) counts at week 6 of treatment with cladribine and its course after hospital admission in week 13. LC: lymphocyte count. WBC: white blood cell. W6: week 6. W13: week 13.\n\nFig. 1\n\n3 Discussion\nCladribine has been shown to be a relatively safe and effective form of therapy for RMS [4]. Its mechanism of benefit is not fully understood but the most striking effect appears to be semi-selective, and relatively long-lasting, depletion of B and T lymphocytes with a particularly significant and long-lasting reduction for memory B cells [3]. Hence, lymphopenia is a regular observation in people treated with cladribine that relates to both its therapeutic mechanism of action as well as the potential associated risk, particularly viral infections or reactivations, such as shingles [3].\n\nA previous study on pwRMS receiving s.c. cladribine reported a decrease of the mean TLC of approximately 40–45% compared to baseline [7]. The medication was administered monthly for six months, and an additional injection was given three months later. TLC reached a nadir approximately six months after treatment initiation with counts recovering thereafter, and no cases of grade 3 or grade 4 lymphopenia occurred [7]. Bearing in mind differences in the dosing schedule between studies, these results are comparable with data from our centre where only 2% of patients developed grade 3 lymphopenia [2]. However, the case presented here is a cautionary tale that grade 4 lymphopenia can occur even after following a personalised dosing protocol designed to prevent severe lymphopenia [6]. Another factor that could have contributed to lymphopenia in our patient is the influenza virus infection. However, grade 4 lymphopenia such as the one experienced by our patient is rare in otherwise immunocompetent patients with influenza virus infection [8,9].\n\nTwo large trials of oral cladribine in pwRMS and patients with a first clinical demyelinating event (CLARITY and ORACLE MS, respectively) evaluated the clinical effectiveness and safety profile of oral cladribine tablets [4,5]. In both studies, most of the lymphopenia events were classified as mild or moderate and occurred more frequently with higher doses. The CLARITY extension study confirmed these findings [10]. Additionally, a post-hoc analysis of the CLARITY and CLARITY extension studies showed no cases of grade 4 lymphopenia in pwRMS treated with cladribine tablets 3.5 mg/kg using a dosing schedule that took into account the TLC (i.e. Grade 0 lymphocyte count at the start of treatment and a maximum of grade 1 at the start of the second cycle) [10].\n\nThe WHO recommends that people who are most at risk of developing serious complications from influenza infection be vaccinated every year before the season begins. Clinical risk groups who should receive the influenza immunisation include adults with chronic neurological conditions, such as MS, and/or those who are immunosuppressed due to disease or treatment [11]. The patient reported here started immune reconstitution treatment with cladribine at a time when her seasonal influenza vaccination was due, and a decision was made to delay her immunisation. Whilst the inactivated influenza vaccine can generally be considered safe at any point of treatment, it will remain unclear whether this patient would have mounted an effective immune response during TLC depletion. Recent data suggest that the inactivated influenza vaccine will still provide some protection in patients already receiving B cell depletion therapy [12]. However, the vaccination response during lymphocyte depletion in pwMS treated with cladribine is uncertain and should be studied in a formal research protocol. The live attenuated influenza vaccine is given as a nasal spray and is contraindicated in people who are clinically severely immunocompromised and in their close contacts [11,13]. Cladribine treatment should not be initiated within four weeks after vaccination with an attenuated live vaccine and pwMS treated with cladribine should not receive live vaccines until their WBC and TLC have returned to within their normal reference ranges [14]. In line with WHO guidance and the UK national influenza immunisation programme [11,13], we recommend annual influenza vaccination with inactivated, but not live vaccines, in pwMS who have received cladribine and whose immune system is compromised. Nevertheless, inactivated vaccines should ideally be administered at least two weeks before commencing immunosuppressive treatments [13]. Influenza immunisation should also be recommended for household members and carers of pwMS, as well as healthcare and social care workers in direct contact with pwMS [13].\n\n4 Conclusion\nWe report a case of lethal influenza A infection associated with grade 4 lymphopenia in an MS patient receiving s.c. cladribine. This incident occurred despite using a personalised dosing schedule that was adapted to both body weight and individual TLC. Influenza vaccination may de-risk the use of cladribine further. As some immunocompromised patients may have a suboptimal immunological response to the vaccine, the inactivated influenza vaccine should ideally be administered prior to treatment initiation with cladribine.\n\nDeclaration of Competing Interest\nMM-C has received presentation fees or grants from Sanofi-Genzyme and UCB Pharma. DB has received consultancy or presentation fees from Canbex Therapeutics, Japan Tobacco, Merck Roche and Sanofi Genzyme. KS has received presentation fees, meeting support or scientific advisory fees from Biogen, Lipomed, Merck Serono, Novartis, Roche and Teva. GG has received consultancy, presentation fees or grants from AbbVie Biotherapeutics, Bayer Healthcare, Biogen, Canbex, Celgene, Ironwood, Japan Tobacco, Novartis, Roche, Sanofi-Genzyme, Synthon, Takeda, Teva and Vertex. No other disclosures were reported.\n\nAcknowledgements\nWe wish to thank ECTRIMS (10.13039/100008659European Committee for Treatment and Research in Multiple Sclerosis) for supporting SR through their MS clinical training fellowship programme.\n==== Refs\nReferences\n1 Giovannoni G. Comi G. Cook S. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis N. Engl. J. Med. 362 2010 416 426 20089960 \n2 De Trane S. Mao Z. Álvarez-González C. Cladribine personalised dosing in people with MS (n>200) four years experience in clinical care Mult. Scler. J. 24 S2 2018 42 43 \n3 Jacobs B.M. Ammoscato F. Giovannoni G. Cladribine: mechanisms and mysteries in multiple sclerosis J. Neurol. Neurosurg. Psychiatry 89 2018 1266 1271 29991490 \n4 Cook S. Vermersch P. Comi G. Safety and tolerability of cladribine tablets in multiple sclerosis: the CLARITY (CLAdRIbine Tablets treating multiple sclerosis orallY) study Mult. Scler. J. 17 2011 578 593 \n5 Leist T.P. Comi G. Cree B.A.C. Effect of oral cladribine on time to conversion to clinically definite multiple sclerosis in patients with a first demyelinating event (ORACLE MS): a phase 3 randomised trial Lancet Neurol. 13 2014 257 267 24502830 \n6 Mao Z. Álvarez-González C. Allen-Philbey K. Treating the ineligible: disease modification in people with multiple sclerosis beyond NHS England commissioning policies Mult. Scler. Relat. Disord. 27 2019 247 253 30419510 \n7 S Z. S J. N J. Effect of parenteral cladribine on relapse rates in patients with relapsing forms of multiple sclerosis: results of a 2-year, double-blind, placebo-controlled, crossover study Mult. Scler. 15 2009 767 770 19482866 \n8 Cheng Y. Zhao H. Song P. Dynamic changes of lymphocyte counts in adult patients with severe pandemic H1N1 influenza A J. Infect. Pub. Health 12 2019 878 883 31202719 \n9 Lalueza A. Folgueira D. Díaz-Pedroche C. Severe lymphopenia in hospitalized patients with influenza virus infection as a marker of a poor outcome Infect. Dis. Ther. 51 2019 543 546 \n10 Giovannoni G. Soelberg Sorensen P. Cook S. Safety and efficacy of cladribine tablets in patients with relapsing–remitting multiple sclerosis: results from the randomized extension trial of the CLARITY study Mult. Scler. J. 24 2018 1594 1604 \n11 World Health Organization (WHO) Vaccines Against Influenza WHO Position Paper - November 2012 vol. 87 2012 Wkly Epidemiol Rec/Heal Sect Secr Leag Nations 461 476 \n12 Stokmaier D. Winthrop K. Chognot C. Effect of ocrelizumab on vaccine responses in patients with multiple sclerosis Neurology 90 2018 (S36.002) \n13 Public Health England Immunisation Against Infectious Disease (The Green Book) 2017 The Stationery Office London \n14 Compendium electronic medicines MAVENCLAD 10 mg tablets Summary of Product Characteristics (SmPC) (emc) https://www.medicines.org.uk/emc/product/8435/smpc (accessed 26 October 2019)\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2405-6502", "issue": "21()", "journal": "eNeurologicalSci", "keywords": "Adverse event; Cladribine; Disease-modifying treatment; Influenza A virus; Lymphopenia; Multiple Sclerosis", "medline_ta": "eNeurologicalSci", "mesh_terms": null, "nlm_unique_id": "101667077", "other_id": null, "pages": "100279", "pmc": null, "pmid": "33163633", "pubdate": "2020-12", "publication_types": "D002363:Case Reports", "references": "31202719;23210147;24502830;31012776;20089960;28870107;30419510;29991490;32727835;19482866;21228029", "title": "Severe lymphopenia after subcutaneous cladribine in a patient with multiple sclerosis: To vaccinate or not?", "title_normalized": "severe lymphopenia after subcutaneous cladribine in a patient with multiple sclerosis to vaccinate or not" }

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SEVERE LYMPHOPENIA AFTER SUBCUTANEOUS CLADRIBINE IN A PATIENT WITH MULTIPLE SCLEROSIS: TO VACCINATE OR NOT?. ENEUROLOGICALSCI 2020?21:100279.", "literaturereference_normalized": "severe lymphopenia after subcutaneous cladribine in a patient with multiple sclerosis to vaccinate or not", "qualification": "3", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20210805", "receivedate": "20210805", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19660187, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20211014" } ]

{ "abstract": "To report a postmenopausal patient with keratoconus who experienced significant progression after using hormone replacement therapy.\nA 51-year-old woman with previously stable keratoconus presented with acute disease progression following hormone replacement therapy in the context of prophylactic hysterectomy and bilateral ovariosalpingectomy. Over a 14-month period after starting hormone therapy, the steepest K increased from 63.7D to 71.5D in the right eye and from 65.8D to 78.1D in the left eye.\nHormone replacement therapy may amplify progression of keratoconus.", "affiliations": "Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.;Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.;Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.;Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.;Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.", "authors": "Coco|Giulia|G|;Kheirkhah|Ahmad|A|;Foulsham|William|W|;Dana|Reza|R|;Ciolino|Joseph B|JB|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1016/j.ajoc.2019.100519", "fulltext": "\n==== Front\nAm J Ophthalmol Case RepAm J Ophthalmol Case RepAmerican Journal of Ophthalmology Case Reports2451-9936Elsevier S2451-9936(18)30440-710.1016/j.ajoc.2019.100519100519Case ReportKeratoconus progression associated with hormone replacement therapy Coco Giulia abKheirkhah Ahmad aFoulsham William aDana Reza aCiolino Joseph B. joseph_ciolino@meei.harvard.edua∗a Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA, USAb Department of Clinical Science and Translational Medicine, University of Rome Tor Vergata, Rome, Italy∗ Corresponding author. Massachusetts Eye and Ear Infirmary, 243 Charles Street, Boston, MA, 02114, USA. joseph_ciolino@meei.harvard.edu16 7 2019 9 2019 16 7 2019 15 10051921 10 2018 13 1 2019 15 7 2019 © 2019 Published by Elsevier Inc.2019This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Purpose\nTo report a postmenopausal patient with keratoconus who experienced significant progression after using hormone replacement therapy.\n\nObservations\nA 51-year-old woman with previously stable keratoconus presented with acute disease progression following hormone replacement therapy in the context of prophylactic hysterectomy and bilateral ovariosalpingectomy. Over a 14-month period after starting hormone therapy, the steepest K increased from 63.7D to 71.5D in the right eye and from 65.8D to 78.1D in the left eye.\n\nConclusions\nHormone replacement therapy may amplify progression of keratoconus.\n\nKeywords\nKeratoconusKeratoconus progressionHormone replacement therapy\n==== Body\n1 Introduction\nKeratoconus is a progressive, non-inflammatory corneal ectasia that can lead to severe impairment of vision.1 Keratoconus is one of the most common indications for keratoplasty in the United States.2 Individuals with this condition most commonly present during adolescence, after which there is a period of progression for approximately 10–20 years.1 The etiology of the disease has not been fully delineated.1 In recent years, there has been considerable interest in the influence of hormones on keratoconus progression.3, 4, 5 Previous reports have implicated estrogens, progesterone, and thyroid hormones in the alteration of corneal biomechanics.5, 6, 7 Case reports detailing keratoconus progression following pregnancy3,8 and in vitro fertilization (IVF)9 have been published. To further support the effects of sex hormones on this condition, herein we report a case of keratoconus progression in a postmenopausal patient treated with hormone replacement therapy (HRT).\n\n2 Case report\nA 51-year-old woman with a history of keratoconus presented to our facility with a subacute reduction of visual acuity in both eyes.\n\nPrior to age 28 the patient reported having uncorrected vision of 20/20 in both eyes. At the age of 29, the patient received hormone therapy related to IVF and was diagnosed with keratoconus shortly after the birth of her child. Although we were unable to obtain medical records prior to her pregnancy, we reviewed the medical records following her initial diagnosis. For the next 20 years, the patient was managed with rigid gas permeable (RGP) contact lenses. Her annual keratometry and topography during the next 17 years exhibited minimal disease progression (Fig. 1).Fig. 1 Keratoconus progression over the course of 20 years in the right eye (A) and in the left eye (B) with its association with in vitro fertilization (IVF) treatment and hysterectomy. Pr = progression rate.\n\nFig. 1\n\nTwo years prior to presentation at our clinic, the patient underwent a prophylactic hysterectomy and ovariosalpingectomy in the context of BRCA gene mutation. HRT with estrogens and progesterone was commenced postoperatively. After experiencing fluctuations in vision for two years she attended our facility for ophthalmic evaluation. Associated symptoms included ocular itching and intermittent burning sensation, yet despite these symptoms the patient denied rubbing her eyes. The patient's previously well-tolerated RGP contact lenses were causing her significant discomfort, and the patient noted recent onset of copious mucus discharge.\n\nOn examination, the best spectacle corrected visual acuity was 20/50 in the right eye and 20/100 in the left eye. With RGP contact lenses, the vision improved to 20/40 in both eyes. Slit lamp examination revealed conjunctival follicles, keratoconus, and inferior punctate epithelial erosions in both eyes, as well as a Fleischer ring and apical opacity in the left eye. Anterior segment tomography with Pentacam demonstrated inferior steepening in both eyes, with progression relative to her previous exams (Table 1).Table 1 Tomography (Pentacam) of both eyes.\n\nTable 1Tomography (Pentacam) Right Eye\t\nOD\tVA cc\tVA contacts\tSteep K\tAnterior Elevation\tPosterior Elevation\tThinnest point\tKmax\tKm front\tKm back\t\nBaseline\t20/50\t20/40\t63.7D\t+30μm\t+81μm\t432μm\t56.4D\t56.2D\t−8.3D\t\n6 months\t20/30 + 2\t\t69.2D\t+49μm\t+101μm\t447μm\t59.1D\t58.2D\t−8.8D\t\n10 months\t20/30\t20/30\t67.2D\t+41μm\t+79μm\t457μm\t59.7D\t58.8D\t−8.7D\t\n14 months\t20/40\t20/30\t71.5D\t+48μm\t+89μm\t490μm\t60.7D\t59.7D\t−8.8D\t\nTomography (Pentacam) Left Eye\t\nOS\tVA cc\tVA contacts\tSteep K\tAnterior elevation\tPosterior Elevation\tThinnest point\tKmax\tKm front\tKm back\t\nBaseline\t20/100\t20/40\t65.8D\t+69μm\t+137μm\t401μm\t59.9D\t55.0D\t−6.6D\t\n6 months\t20/50\t\t74.5D\t+78μm\t+158μm\t427μm\t63.1D\t60.1D\t−8.0D\t\n10 months\t20/40\t20/25-1\t79.0D\t+88μm\t+172μm\t369μm\t62.1D\t61.3D\t−7.9D\t\n14 months\t20/300\t20/20-1\t78.1D\t+81μm\t+143μm\t410μm\t65.5D\t60.7D\t−8.8D\t\nVA cc = BCVA with spectacles; VA contacts = BCVA with contact lenses; μm = micron.\n\n\n\nDue to concerns about further progression, a close follow-up was scheduled. Furthermore, the patient was prescribed hybrid contact lenses rather than RGP lenses. The patient was highly satisfied with her hybrid contact lenses at the six-month follow-up, and best-corrected visual acuity with spectacles at this time was 20/30 in the right eye and 20/50 in the left eye. Nevertheless, corneal tomography demonstrated further progression (Table 1). Clinic notes from this encounter acknowledged that these alterations in corneal tomography might have resulted from the recent change to the patient's contact lenses; nevertheless, regular follow-up was continued given the concerns regarding keratoconus progression. These concerns were realized when further progression was noted at two subsequent follow-up exams (Table 1 and Fig. 2).Fig. 2 Tomograpy exam (Pentacam) comparing the progression in the Axial/Sagittal Curvature (Front) and in the Posterior Elevation observed over 14 months (first and last exams shown). (A) Right eye and (B) left eye.\n\nFig. 2\n\nIn summary, after many years of very slowly progressive keratoconus, over a 14-month period the patient displayed remarkable changes in her corneal tomography. The steepest K changed from 63.7D to 71.5D in the right eye and from 65.8D to 78.1D in the left eye. Corresponding changes were noted in the Kmax values as well as in the anterior and, less dramatically, the posterior elevation (Table 1). After discussing the risks and benefits of corneal collagen crosslinking, the patient opted in favor of the procedure.\n\n3 Discussion\nProgression of keratoconus after menopause is generally uncommon.1 Age-related differences in human corneal biomechanical properties have previously been reported,10,11 and it has been proposed that the resistance to keratoconus progression observed with aging may be due to physiological collagen crosslinking that is similar to the age-related changes in corneal stromal collagen biomechanics.12,13 Given the relative resistance of the aged human cornea to keratoconus progression, our case of a 51-year-old postmenopausal patient exhibiting rapid disease progression following HRT is particularly intriguing.\n\nEstrogen levels in the blood have previously been implicated in alterations to corneal anatomy. Specifically, the fluctuation of estrogen levels during the menstrual cycle, pregnancy, and abortion has been associated with changes in corneal thickness.14, 15, 16 Corneal curvature has been reported to increase in pregnancy.17 Moreover, case reports describe keratoconus progression or post-Laser-assisted in situ keratomileusis (LASIK) ectasia during pregnancy3,18 and after IVF treatment.9\n\nThe extensive clinical data linking both endogenous and exogenous estrogens with altered corneal structure have prompted investigators to evaluate the effect of estrogens on corneal tissue in vitro. Spoerl and colleagues evaluated the changes in corneal biomechanical parameters induced by incubation of 12 fresh porcine corneas with β-estradiol for seven days.6 The investigators reported that the incubation of porcine corneas with β-estradiol resulted in increased corneal thickness and, importantly, to a reduction in corneal stiffness compared to the control. These findings corroborate the role of estrogen as a modulating factor for corneal biomechanical stability.\n\nHormone receptors for estrogens, progesterone, and androgens are located in the nuclei of various human corneal cells such as stromal keratocytes, and epithelial and endothelial cells.19,20 After the hormone binds its respective receptor, the newly-formed complex hormone-receptor acts as a transcription factor to regulate gene expression. The modulation of the synthesis of proteins, which are subsequently released into the extracellular matrix, changes the mechanical properties of the cornea.21 Estrogens increase corneal distensibility as a result of their action on collagens through (i) the production of matrix metalloproteinases (MMP) and (ii) the direct or indirect (via prostaglandins) activation of collagenases.22,23 These proteinases, acting on proteoglycans, change the viscoelasticity of the cornea by reducing the cohesion among collagen fibers.6 Furthermore, proteinases modify corneal flexibility via stimulation of the synthesis of glycosaminoglycans that augment the tissue water binding capacity.24,25\n\nInterestingly, the Collaborative Longitudinal Evaluation of Keratoconus Study (CLEK) reported no difference in the progression of keratoconus in relation to the hormone status of the patients aged 49–58 years.4 Key limitations of the CLEK study, however, included the fact that the slow progression of keratoconus, commonly seen in this age group, may have compromised the detection of changes linked to sex and hormones. Furthermore, the findings may have been confounded by the fact that the study population defined as “hormone-active” represented a heterogeneous grouping of naturally hormone active patients, patients at <1 year following cessation of menstruation, and patients taking HRT. Finally, a subset of patients transitioned from being “hormone-active” to “hormone-inactive” during the study period.4\n\nPrevious studies have established that keratoconus may continue to progress beyond the age of 30,26 yet the rate of progression observed in our 51-year-old patient is exceptionally high. It is important to acknowledge that atopy, and eye rubbing in particular, has been associated with keratoconus progression.27 Although our patient was experiencing symptoms of allergic conjunctivitis, this is unlikely to be the primary cause of her disease progression given that she denied having rubbed her eyes.\n\n4 Conclusion\nHRT is an extremely common therapeutic approach for alleviating the symptoms of menopause. The case reported herein implicates HRT in driving keratoconus progression, at least in this patient, and highlights the potential of estrogen levels in the blood to influence corneal biomechanics. Further studies are certainly required to fully delineate the effect of estrogen on keratoconus progression.\n\nPatient consent\nWritten informed consent was obtained from the patient to publish case details.\n\nFunding\nNone.\n\nConflicts of interest\nThe authors have no financial interest to disclose.\n\nAuthorship\nAll authors attest that they meet the current ICMJE criteria for Authorship.\n\nAcknowledgements\nNone.\n==== Refs\nReferences\n1 Rabinowitz Y.S. Keratoconus. Surv Ophthalmol 42 1998 297 319 9493273 \n2 Park C.Y. Lee J.K. Gore P.K. Lim C.-Y. Chuck R.S. Keratoplasty in the United States Ophthalmology 122 2015 2432 2442 26386848 \n3 Bilgihan K. Hondur A. Sul S. Ozturk S. Pregnancy-induced progression of keratoconus Cornea 30 2011 991 994 21705880 \n4 Fink B.A. Sinnott L.T. Wagner H. Friedman C. Zadnik K. CLEK Study Group The influence of gender and hormone status on the severity and progression of keratoconus Cornea 29 2010 65 72 19907298 \n5 Gatzioufas Z. Thanos S. Acute keratoconus induced by hypothyroxinemia during pregnancy J Endocrinol Investig 31 2008 262 266 18401210 \n6 Spoerl E. Zubaty V. Raiskup-Wolf F. Pillunat L.E. Oestrogen-induced changes in biomechanics in the cornea as a possible reason for keratectasia Br J Ophthalmol 91 2007 1547 1550 17591666 \n7 Thanos S. Oellers P. Meyer zu Hörste M. Role of thyroxine in the development of keratoconus Cornea 35 2016 1338 1346 27560028 \n8 Soeters N. Tahzib N.G. Bakker L. Van der Lelij A. Two cases of keratoconus diagnosed after pregnancy Optom Vis Sci 89 2012 112 116 22051781 \n9 Yuksel E. Yalinbas D. Aydin B. Bilgihan K. Keratoconus progression induced by in vitro fertilization treatment J Refract Surg 32 2016 60 63 26812716 \n10 Elsheikh A. Geraghty B. Rama P. Campanelli M. Meek K.M. Characterization of age-related variation in corneal biomechanical properties J R Soc Interface 7 2010 1475 1485 20392712 \n11 Knox Cartwright N.E. Tyrer J.R. Marshall J. Age-related differences in the elasticity of the human cornea Investig Opthalmology Vis Sci 52 2011 4324 \n12 Millodot M. Ortenberg I. Lahav-Yacouel K. Behrman S. Effect of ageing on keratoconic corneas J Opt 9 2016 72 77 \n13 Daxer A. Misof K. Grabner B. Ettl A. Fratzl P. Collagen fibrils in the human corneal stroma: structure and aging Investig Ophthalmol Vis Sci 39 1998 644 648 9501878 \n14 Soni P.S. Effects of oral contraceptive steroids on the thickness of human cornea Am J Optom Physiol Opt 57 1980 825 834 6778217 \n15 Weinreb R.N. Lu A. Beeson C. Maternal corneal thickness during pregnancy Am J Ophthalmol 105 1988 258 260 3344782 \n16 Kiely P.M. Carney L.G. Smith G. Menstrual cycle variations of corneal topography and thickness Am J Optom Physiol Opt 60 1983 822 829 6650653 \n17 Goldich Y. Cooper M. Barkana Y. Ocular anterior segment changes in pregnancy J Cataract Refract Surg 40 2014 1868 1871 25217070 \n18 Hafezi F. Iseli H.P. Pregnancy-related exacerbation of iatrogenic keratectasia despite corneal collagen crosslinking J Cataract Refract Surg 34 2008 1219 1221 18571094 \n19 Gupta P.D. Johar K. Nagpal K. Vasavada A.R. Sex hormone receptors in the human eye Surv Ophthalmol 50 2005 274 284 15850816 \n20 Suzuki T. Kinoshita Y. Tachibana M. Expression of sex steroid hormone receptors in human cornea Curr Eye Res 22 2001 28 33 11402376 \n21 Meek K.M. Boote C. The organization of collagen in the corneal stroma Exp Eye Res 78 2004 503 512 15106929 \n22 Suzuki T. Sullivan D.A. Estrogen stimulation of proinflammatory cytokine and matrix metalloproteinase gene expression in human corneal epithelial cells Cornea 24 2005 1004 1009 16227852 \n23 Harris E.D. Krane S.M. Collagenases. N Engl J Med 291 1974 557 563 4368514 \n24 Mogilner I.G. Ruderman G. Grigera J.R. Collagen stability, hydration and native state J Mol Graph Model 21 2002 209 213 12463639 \n25 Soergel F. Jean B. Seiler T. Dynamic mechanical spectroscopy of the cornea for measurement of its viscoelastic properties in vitro Ger J Ophthalmol 4 1995 151 156 7663327 \n26 Gokul A. Patel D.V. Watters G.A. McGhee C.N.J. The natural history of corneal topographic progression of keratoconus after age 30 years in non-contact lens wearers Br J Ophthalmol 101 2017 839 844 27729309 \n27 Bawazeer A.M. Hodge W.G. Lorimer B. Atopy and keratoconus: a multivariate analysis Br J Ophthalmol 84 2000 834 836 10906086\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2451-9936", "issue": "15()", "journal": "American journal of ophthalmology case reports", "keywords": "Hormone replacement therapy; Keratoconus; Keratoconus progression", "medline_ta": "Am J Ophthalmol Case Rep", "mesh_terms": null, "nlm_unique_id": "101679941", "other_id": null, "pages": "100519", "pmc": null, "pmid": "31372581", "pubdate": "2019-09", "publication_types": "D002363:Case Reports", "references": "10906086;11402376;12463639;15106929;15850816;16227852;17591666;18401210;18571094;19907298;20392712;20847118;21705880;22051781;25217070;26142151;26386848;26812716;27560028;27729309;3344782;4368514;6650653;6778217;7663327;9493273;9501878", "title": "Keratoconus progression associated with hormone replacement therapy.", "title_normalized": "keratoconus progression associated with hormone replacement therapy" }

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HTTPS://DOI.ORG/10.1016/J.AJOC.2019.100519. 2019?.", "literaturereference_normalized": "keratoconus progression associated with hormone replacement therapy", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190821", "receivedate": "20190821", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16723588, "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" }, { "companynumb": "US-TEVA-2019-US-1098644", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ESTROGENS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HORMONE REPLACEMENT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ESTROGEN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PROGESTERONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "017362", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HORMONE REPLACEMENT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROGESTERONE." } ], "patientagegroup": null, "patientonsetage": "51", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Keratoconus", "reactionmeddraversionpt": "22.0", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "COCO G, KHEIRKHAH A, FOULSHAM W, DANA R, CIOLINO JB. KERATOCONUS PROGRESSION ASSOCIATED WITH HORMONE REPLACEMENT THERAPY. AM-J-OPHTHALMOL-CASE-REP 2019?15:100519.", "literaturereference_normalized": "keratoconus progression associated with hormone replacement therapy", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190827", "receivedate": "20190827", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16743968, "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": "Rivastigmine is an acetylcholine esterase inhibitor which is commonly used as therapy for dementia in Alzheimer's disease and Parkinson's disease (PD). Recently, a randomized controlled trial demonstrated a positive effect of rivastigmine on gait function in nondemented PD patients. Disturbed gait is a shared hallmark of PD and ataxias.\n\n\n\nWe hypothesized that the effect of rivastigmine could be translated to spinocerebellar ataxia (SCA) improving gait function.\n\n\n\nFive patients with SCA type 3 were treated with transdermal rivastigmine for 8 weeks. The patients were monitored using the Scale for the Assessment and Rating of Ataxia (SARA) and an electronic walkway system (GAITRite®).\n\n\n\nGait function was not changed by treatment, but 4 patients who continued treatment for 8 weeks showed improved coordination of extremities. The SARA sum score, which was 7.6 ± 2.2 at baseline, had dropped by 1.5 ± 1.9 after 4 weeks and by 2.1 ± 1.4 after 8 weeks.\n\n\n\nContrary to our hypothesis, we observed no improvement of gait parameters as assessed by SARA and GAIT-Rite®, but coordination abilities were improved. Rivastigmine was well tolerated, but known side effects of rivastigmine, such as deterioration of asthma, may appear. Further trials in larger cohorts are needed to confirm our findings.", "affiliations": "Department of Neurology, University of Bonn, Bonn, Germany, Marcus.Grobe-Einsler@dzne.de.;Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Bonn, Germany.;Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Bonn, Germany.;Department of Psychiatry, School of Medicine and Health Sciences, and Research Center for Neurosensory Science, University of Oldenburg, Oldenburg, Germany.;Department of Neurology, University of Bonn, Bonn, Germany.;Department of Neurology, University of Bonn, Bonn, Germany.", "authors": "Grobe-Einsler|Marcus|M|;Vogt|Ina Rosemarie|IR|;Schaprian|Tamara|T|;Hurlemann|Rene|R|;Klockgether|Thomas|T|;Kaut|Oliver|O|", "chemical_list": "D002800:Cholinesterase Inhibitors; D000068836:Rivastigmine", "country": "Switzerland", "delete": false, "doi": "10.1159/000510057", "fulltext": null, "fulltext_license": null, "issn_linking": "1660-2854", "issue": "20(2-3)", "journal": "Neuro-degenerative diseases", "keywords": "Ataxia; Neurodegenerative disease; Rivastigmine; Spinocerebellar ataxia type 3", "medline_ta": "Neurodegener Dis", "mesh_terms": "D000328:Adult; D002800:Cholinesterase Inhibitors; D005260:Female; D005684:Gait; D006801:Humans; D017827:Machado-Joseph Disease; D008297:Male; D008875:Middle Aged; D000068836:Rivastigmine", "nlm_unique_id": "101189034", "other_id": null, "pages": "104-109", "pmc": null, "pmid": "32992315", "pubdate": "2020", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Effects of Rivastigmine on Patients with Spinocerebellar Ataxia Type 3: A Case Series of Five Patients.", "title_normalized": "effects of rivastigmine on patients with spinocerebellar ataxia type 3 a case series of five patients" }

[ { "companynumb": "DE-MYLANLABS-2020M1093946", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "RIVASTIGMINE" }, "drugadditional": null, "drugadministrationroute": "062", "drugauthorizationnumb": "205622", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TRANSDERMAL PATCH", "drugdosagetext": "4.6 MILLIGRAM, QD(4.6 MG, Q24H)", "drugenddate": null, "drugenddateformat": null, "drugindication": "HEREDITARY ATAXIA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4.6", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIVASTIGMINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "RIVASTIGMINE" }, "drugadditional": null, "drugadministrationroute": "062", "drugauthorizationnumb": "205622", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TRANSDERMAL PATCH", "drugdosagetext": "9.6 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "9.6", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIVASTIGMINE." } ], "patientagegroup": null, "patientonsetage": "61", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Condition aggravated", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Asthma", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "GROBE?EINSLER M, VOGT IR, SCHAPRIAN T, HURLEMANN R, KLOCKGETHER T, KAUT O.. EFFECTS OF RIVASTIGMINE ON PATIENTS WITH SPINOCEREBELLAR ATAXIA TYPE 3: A CASE SERIES OF FIVE PATIENTS.. J. NEURODEGENERATIVE DIS.. 2020?20:104?109", "literaturereference_normalized": "effects of rivastigmine on patients with spinocerebellar ataxia type 3 a case series of five patients", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20210420", "receivedate": "20201123", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18534516, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" } ]

{ "abstract": "Methotrexate is one of the most used drugs in the treatment of psoriasis with indication of systemic therapy. Cutaneous and mucous side effects are described by pharmacological characteristics of the drug itself or due to overdose. We report the case of a patient with ulcerations in oral mucosa and psoriatic plaques after incorrect use of Methotrexate. Prescribed in a weekly dose, it was used continuously for 10 days and without simultaneous intake of folic acid. It is important to ensure correct comprehension of the prescription.", "affiliations": "Instituto de Dermatologia Professor Rubem David Azulay da Santa Casa da Misericórdia do Rio de Janeiro (IDPRDA/SCMRJ) - Rio de Janeiro (RJ), Brazil.;Instituto de Dermatologia Professor Rubem David Azulay da Santa Casa da Misericórdia do Rio de Janeiro (IDPRDA/SCMRJ) - Rio de Janeiro (RJ), Brazil.;Instituto de Dermatologia Professor Rubem David Azulay da Santa Casa da Misericórdia do Rio de Janeiro (IDPRDA/SCMRJ) - Rio de Janeiro (RJ), Brazil.;Instituto de Dermatologia Professor Rubem David Azulay da Santa Casa da Misericórdia do Rio de Janeiro (IDPRDA/SCMRJ) - Rio de Janeiro (RJ), Brazil.;Instituto de Dermatologia Professor Rubem David Azulay da Santa Casa da Misericórdia do Rio de Janeiro (IDPRDA/SCMRJ) - Rio de Janeiro (RJ), Brazil.;Instituto de Dermatologia Professor Rubem David Azulay da Santa Casa da Misericórdia do Rio de Janeiro (IDPRDA/SCMRJ) - Rio de Janeiro (RJ), Brazil.", "authors": "Souza|Claudia Fernanda Dias|CF|;Suarez|Olga Milena Zarco|OM|;Silva|Talita Fonseca Medeiros da|TF|;Gorenstein|Ana Carolina Lourenço Araújo|AC|;Quintella|Leonardo Pereira|LP|;Avelleira|João Carlos Regazzi|JC|", "chemical_list": "D005493:Folic Acid Antagonists; D008727:Methotrexate", "country": "Spain", "delete": false, "doi": null, "fulltext": "\n==== Front\nAn Bras DermatolAn Bras DermatolabdAnais Brasileiros de Dermatologia0365-05961806-4841Sociedade Brasileira de Dermatologia 10.1590/abd1806-4841.20163960Case ReportUlcerations due to methotrexate toxicity in a psoriasis patient* Souza Claudia Fernanda Dias 1Suarez Olga Milena Zarco 1da Silva Talita Fonseca Medeiros 1Gorenstein Ana Carolina Lourenço Araújo 1Quintella Leonardo Pereira 12Avelleira João Carlos Regazzi 11 Instituto de Dermatologia Professor Rubem David Azulay\nda Santa Casa da Misericórdia do Rio de Janeiro (IDPRDA/SCMRJ) - Rio de\nJaneiro (RJ), Brazil.2 Fundação Oswaldo Cruz (FIOCRUZ) - Rio de\nJaneiro (RJ), Brazil. Mailing address: Claudia Fernanda Dias Souza, R. Santa Luzia, 206,\nCentro, 20020-020 - Rio de Janeiro - RJ, Brazi, E-mail:\ncfdsouza.rj@gmail.comConflict of Interest: None.\n\nMay-Jun 2016 May-Jun 2016 91 3 375 377 18 8 2014 03 12 2014 © 2016 by Anais Brasileiros de\nDermatologia2016This is an Open Access article distributed under the terms of the\nCreative Commons Attribution Non-Commercial License which permits\nunrestricted non-commercial use, distribution, and reproduction in any\nmedium provided the original work is properly cited.Methotrexate is one of the most used drugs in the treatment of psoriasis with\nindication of systemic therapy. Cutaneous and mucous side effects are described\nby pharmacological characteristics of the drug itself or due to overdose. We\nreport the case of a patient with ulcerations in oral mucosa and psoriatic\nplaques after incorrect use of Methotrexate. Prescribed in a weekly dose, it was\nused continuously for 10 days and without simultaneous intake of folic acid. It\nis important to ensure correct comprehension of the prescription.\n\nMethotrexatePsoriasisTherapeuticsToxicity\n==== Body\nINTRODUCTION\nMethotrexate (MTX) was introduced as antipsoriatic agent in 1951 and approved by FDA\n(Food and Drug Administration) with this indication in 1972.\nStructurally similar to folic acid, MTX is irreversibly linked to dihydrofolate\nreductase, exerting antiproliferative activity. It induces apoptosis and increases\nthe concentration of adenosine, resulting also in anti-inflammatory and\nimmunoregulation action.1\n\nPsoriasis is a frequent dermatosis that may progress to severe forms that require\nsystemic medication.2 In these\ncases, MTX is one of the most used drugs, due to its efficiency, safety (in\nprescribed doses) and low cost. However, overdose of MTX may cause important\ncutaneous, oral mucosa and systemic side effects.\n\nThe most common skin/mucosa alterations related to its toxicity are ulcerations on\nthe oral mucosa, while reports of such alterations in preexisting psoriatic lesions\nor even on healthy skin are rare.3\n\nCASE REPORT\nA female patient, 58 years old, of mixed race, diagnosed with psoriasis 3 years\nbefore presented generalized lesions in the form of plaques and with poor response\nto topical treatment. The PASI (Psoriasis Area Severity Index) test\nhad a result of 10.6. MTX was prescribed in a weekly dose of 10 mg orally,\naccompanied by 5 mg of folic acid 3 times a week. Ten days later she returned with\nintense dysphagia for solids and liquids, diarrhea and myalgia. She was dysphonic,\nwith multiple erosions on the oral mucosa, hard and soft palate and ulcerations\nlocated mainly on the periphery of preexisting plaque psoriasis (Figures 1, 2\nand 3). The histopathological examination\nrevealed an ulcerated area covered by regenerating exudate and epithelium, ectasia\nin proliferated vessels and neutrophils at the bottom of the lesion (Figure 4). After denying irregular use of\nmedication at first, the patient then admitted having ingested 10 mg of MTX daily\nand that she had not used folic acid as originally recommended. She was hospitalized\nfor evaluation of possible hematological and hepatic alterations and started\nreceiving folinic acid 25mg/day intravenously.\n\n\nFigure 1 Ulcerated lesion on oral mu cosa\n\n\n\n\n\nFigure 2 Ulcerated areas in the a periphery of psoriatic plaques on upper\nlimbs\n\n\n\n\n\nFigure 3 In closer de tail, on left knee\n\n\n\n\n\nFigure 4 Histopathology: Ulcerated area covered by exudate and regenerating\nepithelium. Proliferating vessels and neutrophils\n\n\n\n\nThe laboratory tests revealed leukopenia (2.780 mil/mm3) with\nhypersegmentation of neutrophils, decrease in total red blood cells, hematocrits and\nhemoglobin (3.860.000 u/l, HT: 31.7%, Hb: 10g/dl) with absence of alterations in\nliver and kidney function. The patient progressed with rapid improvement and was\ndischarged on the 8th day of hospitalization. Thirty days later,\nfollow-up showed complete reepithelization of lesions. The tests demonstrated\nnormalization of leukocytes (8.600 mil/mm3) and slower recuperation of\nthe red series (HT: 31.9%, Hb: 10.1g/dl). After being oriented again, the patient\ncontinued to use MTX, keeping the disease under control (PASI: 2.4) for 18 months of\nfollow-up.\n\nDISCUSSION\nMethotrexate is a relatively safe drug in the dosage used in dermatology (7.5 mg to\n25 mg/week), with side effects and toxicity associated with idiosyncratic or\ndose-dependent mechanisms. The latter will occur mainly in cells that proliferate\nfaster, like hematopoietic bone marrow cells, epithelial gastrointestinal tube and\nepidermal cells. As MTX is excreted by the kidneys and circulates in the blood flow\nconjugated with albumin, its administration to nephropathic patients or those with\nhypoalbuminemia should be done carefully or avoided. Furthermore, drug interaction\n(drugs that diminish renal excretion of MTX, that inhibit folate synthesis, or that\ndecrease MTX binding to proteins) and errors in administration of the drug may\ntrigger adverse effects through the increased drug level in the body.\n\nOn the skin, the adverse affects are more rare. Not related to the methotrexate dose\nhave been described: erythematous eruptions, blisters, toxic epidermal necrolysis,\nexacerbation of photosensitivity reactions, purpuric lesions due to vasculitis,\nhives and formation of nodules that may involve internal organs also, first reported\nin rheumatoid arthritis and later found in psoriasis and psoriatic\narthritis.3-6\n\nCutaneous manifestations in patients with MTX dose-dependent psoriasis are more\nfrequent due to acute intoxication. Ulcerations and ulcerative processes are\nobserved on oral mucosa (more precocious), on psoriatic plaques, in other\npreexisting dermatoses or, more rarely, on healthy skin.3 They may be similar to a \"flare-up\" of psoriasis or\nto pustular psoriasis.3,7,8\n\nPearce and Wilson6 reviewed 47 cases\nin the period of 1951 to 1996 and found simultaneous use of non-hormonal\nanti-inflammatories and advanced age as risk factors. Many of these cases occurred\nin the first weeks after introduction of MTX or reintroduction of medication in\npatients with relapsing disease, suggesting the hypothesis of higher susceptibility\nto MTX of phase S cells, that are found in larger numbers when there is acceleration\nof the epidermal turn over.3,6-8\n\nThe histopathological study of eroded cutaneous lesions shows a microscopic image\nsimilar to that observed after intradermal administration of the drug, suggesting\nthat the reaction is caused by a direct cytotoxic effect.9 Therefore, the alterations observed would be derived\nfrom inhibition of keratinocytes by direct MTX toxicity, leading to epidermal\nnecrosis.\n\nIn case of acute intoxication by MTX, skin signs and symptoms are a toxicity alert\nsign and may precede more serious hematologic alterations. The treatment is made\nwith immediate suspension of the drug and administration of parenteral folinic acid\nin the dose of 10 mg/m2 of body surface; the earlier the treatment, the\nhigher the success rate, mainly regarding the attempt to avoid or interrupt\nmyelosuppressive effects.7 As\nregards skin lesions, reepithelization takes place between 1 and 2 weeks after\ninterruption of medication and beginning of the new treatment.10\n\nMethotrexate is an option of great therapeutic value for psoriasis, and its use\nshould be well guided by the physician. The patient should be totally aware of the\nrisks and side effects. More safety is achieved by means of a rigorous selection of\npatients (considering absolute and relative contraindications) and periodical\nclinical-laboratorial follow-up. In case of elderly patients or those with cognitive\ndifficulties it is of fundamental importance for a companion to be present to ensure\nmore safety to the offered treatment.\n\nFinancial Support: None.\n\n* Work carried out at the Instituto de Dermatologia Professor Rubem David Azulay da\nSanta Casa da Misericórdia do Rio de Janeiro (IDPRDA/SCMRJ) - Rio de Janeiro\n(RJ), Brazil.\n==== Refs\nREFERENCES\n1 Alencar M Avelleira JC Metotrexate Consenso Brasileiro de Psoríase 2012: guias de\navaliação e tratamento Sociedade Brasileira de\nDermatologia 2 ed Rio de Janeiro Sociedade Brasileira de Dermatologia 2012 67p \n2 Ataíde DST Esmanhoto LDK Helmer KA Guerra IRC Guimarãesn CCG Moritz S Ulceração das placas psoriáticas - efeito\nadverso do metotrexate em altas doses no tratamento da psoríase:\nrelato de três casos An Bras Dermatol 2003 78 749 753 \n3 Kerstens PJ Boerbooms AM Jeurissen ME Fast JH Assmann KJ van de Putte LB Accelerated nodulosis during low dose methotrexate therapy for\nrheumatoid arthritis. An analysis of ten cases J Rheumatol 1992 19 867 871 1404122 \n4 Lebwohl M Ting PT Koo JYM Psoriasis treatment: traditional therapy Ann Rheum Dis 2005 64 ii83 ii86 15708945 \n5 Lee HJ Hong SK Seo JK Lee D Sung HS A Case of Cutaneous Side Effect of Methotrexate Mimicking\nBehçet's Disease Ann Dermatol 2011 23 412 414 21909222 \n6 Pearce HP Wilson BB Erosion of psoriatic plaques: An early sign of methotrexate\ntoxicity J Am Acad Dermatol 1996 35 835 838 8912599 \n7 KishanKumar A AmiyaKumar N DevinderMohan T Methotrexate toxicity presenting as ulceration of psoriatic\nplaques: A report of two cases Indian J Dermatol Venereol Leprol 2008 74 481 484 19052409 \n8 Truchuelo T Alcántara J Moreno C Vano-Galván S Jaén P Focal skin toxicity related to methotrexate sparing psoriatic\nplaques Dermatol Online J 2010 16 16 20579471 \n9 López AA Toxicidad aguda por metotrexate en psoriasis Gac Méd Méx 1999 135 513 516 10596492 \n10 Fridlington JL Tripple JW Reichenberg JS Hall CS Diven DG Acute methotrexate toxicity seen as plaque psoriasis ulceration\nand necrosis: A diagnostic clue Dermatol Online J 2011 17 2 22136858\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "0365-0596", "issue": "91(3)", "journal": "Anais brasileiros de dermatologia", "keywords": null, "medline_ta": "An Bras Dermatol", "mesh_terms": "D000284:Administration, Oral; D003875:Drug Eruptions; D005260:Female; D005493:Folic Acid Antagonists; D006801:Humans; D007970:Leukopenia; D008508:Medication Errors; D008727:Methotrexate; D008875:Middle Aged; D019226:Oral Ulcer; D000067490:Prescription Drug Overuse; D011565:Psoriasis; D012883:Skin Ulcer", "nlm_unique_id": "0067662", "other_id": null, "pages": "375-7", "pmc": null, "pmid": "27438211", "pubdate": "2016", "publication_types": "D002363:Case Reports", "references": "20579471;1404122;10596492;21909222;22136858;8912599;15708945;19052409", "title": "Ulcerations due to methotrexate toxicity in a psoriasis patient.", "title_normalized": "ulcerations due to methotrexate toxicity in a psoriasis patient" }

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ULCERATIONS DUE TO METHOTREXATE TOXICITY IN A PSORIASIS PATIENT.. 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{ "abstract": "Serous choroidal detachment that is caused by rhegmatogenous retinal detachment (RRD) may present a significant diagnostic challenge as delayed recognition and repair of the underlying RRD can severely impact the final anatomical and visual outcome. We report 2 consecutive patients with atypical choroidal detachments who were later found to have underlying RRDs. A 71-year-old female presented with a 1-week history of painful vision loss and floaters in the left eye. Examination revealed choroidal detachments in the nasal and temporal periphery and an overlying retinal detachment with shifting subretinal fluid. However, no retinal breaks were identified. An extensive laboratory workup and imaging of the orbits were unrevealing. She was treated with 80 mg oral prednisone daily for 2 weeks with subsequent resolution of the choroidals but persistence of the retinal detachment. Similarly, a 52-year-old male presented with a 3-week history of flashes and floaters followed by painful vision loss in the left eye 1 day prior to presentation. He had hand motion vision OS and the intraocular pressure was undetectable by hand-held tonometry OS. Dense brunescent cataract prevented adequate viewing of the posterior pole. B-scan ultrasonography revealed a funnel retinal detachment, with homogenous choroidal echogenicities suggestive of hemorrhagic choroidal detachment. Extensive laboratory workup was unrevealing. The patient was started on 60 mg oral prednisone and re-evaluated every 2 days, but ultrasonography revealed persistence of the choroidal detachment after 1 week. The diagnosis of RRD with an associated choroidal detachment should be considered, even in the absence of an identifiable causative retinal break.", "affiliations": "Department of Ophthalmology, Jones Eye Institute, University of Arkansas for Medical Sciences (UAMS), Little Rock, Arkansas, USA.;Department of Ophthalmology, Jones Eye Institute, University of Arkansas for Medical Sciences (UAMS), Little Rock, Arkansas, USA.;Department of Ophthalmology, Jones Eye Institute, University of Arkansas for Medical Sciences (UAMS), Little Rock, Arkansas, USA.;Department of Ophthalmology, Jones Eye Institute, University of Arkansas for Medical Sciences (UAMS), Little Rock, Arkansas, USA.;Department of Ophthalmology, Jones Eye Institute, University of Arkansas for Medical Sciences (UAMS), Little Rock, Arkansas, USA.", "authors": "Fong|Joseph W|JW|;Broyles|Heather V|HV|;Atassi|Nour Y|NY|;Sallam|Ahmed B|AB|;Uwaydat|Sami H|SH|", "chemical_list": null, "country": "Switzerland", "delete": false, "doi": "10.1159/000513220", "fulltext": "\n==== Front\nCase Rep Ophthalmol\nCase Rep Ophthalmol\nCOP\nCase Reports in Ophthalmology\n1663-2699\nS. 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.com\n\n10.1159/000513220\ncop-0012-0315\nCase Report\nTwo Patients with Atypical Choroidal Detachment\nFong Joseph W.\nBroyles Heather V.\nAtassi Nour Y.\nSallam Ahmed B.\nUwaydat Sami H. *\nDepartment of Ophthalmology, Jones Eye Institute, University of Arkansas for Medical Sciences (UAMS), Little Rock, Arkansas, USA\n*Sami H. Uwaydat, shuwaydat@uams.edu\nMay-Aug 2021\n3 5 2021\n3 5 2021\n12 2 315319\n7 10 2020\n19 11 2020\n2021\nCopyright © 2021 by S. Karger AG, Basel\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.\nSerous choroidal detachment that is caused by rhegmatogenous retinal detachment (RRD) may present a significant diagnostic challenge as delayed recognition and repair of the underlying RRD can severely impact the final anatomical and visual outcome. We report 2 consecutive patients with atypical choroidal detachments who were later found to have underlying RRDs. A 71-year-old female presented with a 1-week history of painful vision loss and floaters in the left eye. Examination revealed choroidal detachments in the nasal and temporal periphery and an overlying retinal detachment with shifting subretinal fluid. However, no retinal breaks were identified. An extensive laboratory workup and imaging of the orbits were unrevealing. She was treated with 80 mg oral prednisone daily for 2 weeks with subsequent resolution of the choroidals but persistence of the retinal detachment. Similarly, a 52-year-old male presented with a 3-week history of flashes and floaters followed by painful vision loss in the left eye 1 day prior to presentation. He had hand motion vision OS and the intraocular pressure was undetectable by hand-held tonometry OS. Dense brunescent cataract prevented adequate viewing of the posterior pole. B-scan ultrasonography revealed a funnel retinal detachment, with homogenous choroidal echogenicities suggestive of hemorrhagic choroidal detachment. Extensive laboratory workup was unrevealing. The patient was started on 60 mg oral prednisone and re-evaluated every 2 days, but ultrasonography revealed persistence of the choroidal detachment after 1 week. The diagnosis of RRD with an associated choroidal detachment should be considered, even in the absence of an identifiable causative retinal break.\n\nKeywords\n\nRhegmatogenous retinal detachment with choroidal detachment\nSerous choroidal detachment\nChoroidal detachment\n==== Body\nIntroduction\n\nAn unexplained serous choroidal detachment may present a significant diagnostic challenge. The differential diagnosis of choroidal detachment with overlying retinal detachment includes inflammatory conditions (posterior scleritis), neoplastic etiologies (choroidal melanoma and choroidal metastatic lesions), and idiopathic etiologies such as uveal effusion syndrome [1, 2, 3]. However, when resolution of the choroidal detachment occurs with persistence of the retinal detachment following steroid therapy, the diagnosis of rhegmatogenous retinal detachment (RRD) with an associated choroidal detachment (RRDCD) should be considered, even in the absence of an identifiable causative retinal break. We present 2 consecutive patients with RRDCD and their outcomes.\n\nCase Presentation 1\n\nA 71-year-old female presented with a 1-week history of painful vision loss and floaters in the left eye. She had no history of myopia, previous ocular trauma, or surgery. On initial examination, her visual acuity was 20/30-2 OD and 20/80 OS with intraocular pressures of 21 mm Hg OD and 17 mm Hg OS. Examination of the unaffected right eye was within normal limits, with a mild nuclear sclerotic cataract, and no evidence of intraocular inflammation. Examination of the left eye revealed rare anterior chamber cells, 1+ vitreous cells, choroidal detachments in the nasal and temporal periphery, and an overlying retinal detachment with shifting subretinal fluid as shown in Figure 1a. No retinal breaks were identified. Her medical history was nonrevealing for underlying medical conditions, specifically hypertension, autoimmune diseases, and systemic malignancy. Complete blood count, basic metabolic panel, HIV, T-spot, syphilis screen, and antinuclear cytoplasmic antibody panel were all normal. MRI of the brain and orbits revealed mild enhancement of the posterior sclera but no intraocular mass. Fluorescein angiography showed late leakage in the temporal periphery, fundus autofluorescence image showed the normal autofluorescent pattern of retinal pigment epithelium (Fig. 1b), and optical coherence tomography of the macula showed shallow subretinal fluid and a posterior vitreous detachment (Fig. 1c). The patient was started on 80 mg oral prednisone for a presumed diagnosis of serous retinal detachment secondary to posterior scleritis. Two weeks later, the choroidal detachments resolved but the retinal detachment persisted, exhibiting a more corrugated appearance as shown in Figure 1d, yet no retinal breaks were identified. Intraocular pressures remained normal.\n\nAfter 4 weeks of observation and treatment with oral steroids, the retinal detachment extended to involve the superior quadrants with development of fixed retinal folds in the inferior quadrants. No retinal breaks could be identified on serial fundus examinations. At this point, the patient underwent pars plana vitrectomy combined with phacoemulsification with intraocular lens implantation and placement of an encircling band. Intraoperatively, a small peripheral break was identified at the 11 o'clock meridian. An inferior retinectomy was performed to mobilize and flatten the retina, and the vitreous cavity was filled with silicone oil. At the 6-week visit, the retina remained reattached and the patient's vision had improved to 20/400.\n\nCase Presentation 2\n\nA 52-year-old male presented with a 3-week history of flashes and floaters followed by painful vision loss in the left eye 1 day prior to presentation. He had no history of myopia, previous ocular trauma, or surgery but reported a family history of retinal detachment in 2 immediate family members. On initial examination, his visual acuity was 20/200 OD and hand motion OS with intraocular pressures of 24 mm Hg OD and undetectable by hand-held tonometry OS. Examination of the unaffected right eye was within normal limits, with a 3+ brunescent nuclear sclerotic cataract, no evidence of intraocular inflammation, and an attached retina. Examination of the left eye revealed rare anterior chamber cells and 4+ brunescent nuclear sclerotic cataract which prevented adequate viewing of the posterior pole. B-scan ultrasonography revealed a funnel retinal detachment, with homogenous choroidal echogenicities suggestive of hemorrhagic choroidal detachment as shown in Figure 2a. His medical history was significant for type 2 diabetes and hypertension but negative for autoimmune diseases and systemic malignancy. Complete blood count, basic metabolic panel, HIV, T-spot, syphilis screen, and antinuclear cytoplasmic antibody panel were all normal. Computed tomography of the brain and maxillofacial structures did not reveal any intraocular mass but demonstrated prominent choroidal detachment as shown in Figure 2b. Chest X-ray was within normal limits. The patient was started on 60 mg oral prednisone and re-evaluated every 2 days. Serial ultrasonography revealed persistence of the choroidal detachment. One week after initial presentation, the patient underwent pars plana vitrectomy combined with phacoemulsification, drainage of serous and hemorrhagic choroidals, placement of an encircling band, and injection of a C3F8 gas bubble. Intraoperatively, inspection of the retina revealed a total retinal detachment with retinal breaks in the inferior and superior periphery. At the 1-month visit, the retina remained attached (Fig. 2c) and the patient's vision had improved to counting fingers near face.\n\nDiscussion and Conclusions\n\nThe reported rate of RRDCD is 2.0–4.5% of all primary RRDs in Western countries, and it is reported as high as 18.1% of primary RRDs in China [4, 5, 6]. Risk factors for RRDCD include high myopia, history of ocular trauma, older age, and pseudophakia or aphakia [5]. RRDCD has a poor prognosis, primarily due to poor visualization and difficult identification of causative breaks that may cause delay in treatment, difficult application of retinopexy, and rates of proliferative vitreoretinopathy reported to be as high as 35.4–52.4% after initial surgery [7, 8].\n\nThe etiology of RRDCD is unknown. It is believed that in a RRD, liquefied syneretic vitreous containing inflammatory cytokines accesses the subretinal space, inducing choroidal vessel hyperpermeability. This hyperpermeability leads to exudation of fluid into the supraciliary and suprachoroidal spaces and subsequently results in ciliary body edema. Ciliary body edema reduces aqueous production which results in hypotony and the development of a choroidal detachment [8]. Our first patient did not have hypotony in the affected eye, but her IOP was 3–9 mm Hg lower in the affected eye than in the unaffected eye on serial exams. This is consistent with Seelenfreund's report that in 48 RRDCD patients who had IOP recording, all but 1 had a lower IOP in the affected eye compared to the fellow eye [5]. Our second patient, on the other hand, demonstrated frank hypotony.\n\nEarly diagnosis of RRDCD is crucial as delay in surgical intervention to repair the underlying RRD can negatively impact the final anatomical and visual outcome. RRDCD should be suspected when resolution of the choroidal detachment is noted with persistence of the retinal detachment. When this is observed, the diagnosis of RRDCD should be entertained despite the absence of an identifiable causative retinal break in the clinic setting, and prompt surgical intervention should be strongly considered to locate an occult retinal break. Despite clear visualization of the fundus, definite retinal breaks may not be found in 2.2–4% of phakic retinal detachments [1, 2, 3]. Other differential diagnoses of choroidal detachment with overlying retinal detachment include inflammatory conditions (posterior scleritis), neoplastic etiologies (choroidal melanoma and choroidal metastatic lesions), and idiopathic etiologies such as uveal effusion syndrome. The complaint of pain associated with vision loss, especially in case 1, initially led us to strongly suspect an inflammatory etiology, but in retrospect, the pain may be due to the presence of blood in the suprachoroidal space.\n\nIn case 1, although treatment with oral steroids or observation would have been appropriate for the management of a serous choroidal detachment alone, the progression of the patient's retinal detachment over the course of 1 month, despite the resolution of the choroidal detachment, warranted surgical intervention to identify and manage the causative retinal break. The retinal break that was identified intraoperatively explains the inferior retinal detachment seen on presentation, based on Lincoff's rules. We had an increased index of suspicion for the possibility of RRDCD with our second patient and elected to pursue aggressive surgical management much earlier in his clinical course especially considering the inability to identify a causative retinal break due to the dense cataract. Early recognition and surgical management of RRDCD decreases the likelihood of vision-threatening sequelae such as proliferative vitreoretinopathy and re-detachment. In summary, in patients who present with choroidal detachment, the possibility of a RRDCD should always be entertained, even when no retinal breaks can be identified or media opacities preclude adequate visualization of the peripheral retina.\n\nStatement of Ethics\n\nWritten informed consent for this case report was obtained from the patient.\n\nConflict of Interest Statement\n\nThe authors declare that there are no conflicts of interest to disclose.\n\nFunding Sources\n\nThis research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\n\nAuthor Contributions\n\nJ.W.F.: writing and reviewing. H.V.B.: writing and reviewing. N.Y.A.: writing and reviewing. A.A.S.: reviewing. S.H.U: reviewing.\n\nFig. 1. a Optos color fundus photography showing choroidal detachments in the nasal and temporal periphery with an overlying retinal detachment. b Fundus autofluorescence image showing the normal autofluorescent pattern of retinal pigment epithelium. c OCT of the macula showed shallow subretinal fluid. d Optos color fundus photography showing resolution of choroidal detachments with persistent retinal detachment 2 weeks after starting oral steroids. OCT, optical coherence tomography.\n\nFig. 2. a B-scan ultrasonography revealed a funnel retinal detachment, with homogenous choroidal echogenicities suggestive of hemorrhagic choroidal detachment. b Computed tomography of the brain and maxillofacial structures did not reveal any intraocular mass but demonstrated prominent choroidals. c Optos color fundus photography at the 1-month visit showing the retina remained attached.\n==== Refs\nReferences\n\n1 Ashrafzadeh MT Schepens CL Elzeneiny II Aphakic and phakic retinal detachment. I. Preoperative findings Arch Ophthalmol 1973 89 (6) 476 83 4706445\n2 Norton EW Retinal detachment in aphakia Am J Ophthalmol 1964 58 (1) 111 24 14177964\n3 Everett WG Katzin D Meridional distribution of retinal breaks in aphakic retinal detachment Am J Ophthalmol 1968 66 (5) 928 32 5686927\n4 Zhu J Xu X Zhang X Surgical therapeutic results of rhegmatogenous retinal detachment associated with choroidal detachment Zhonghua Yan Ke Za Zhi 2002 38 135 9 11955315\n5 Seelenfreund MH Kraushar MF Schepens CL Freilich DB Choroidal detachment associated with. Choroidal detachment associated with primary retinal detachment Arch Ophthalmol 1974 91 (4) 254 8 4621149\n6 Gottlieb F Combined choroidal and retinal detachment Arch Ophthalmol 1972 88 (5) 481 6 4634785\n7 Yu Y An M Mo B Yang Z Liu W. Risk factors for choroidal detachment following rhegmatogenous retinal detachment in a chinese population. BMC Ophthalmol 2016 16 140 Published 2016 Aug 9. doi 27507568\n8 Sharma T Gopal L Reddy RK Kasinathan N Shah NA Sulochana KN Primary vitrectomy for combined rhegmatogenous retinal detachment and choroidal detachment with or without oral corticosteroids: a pilot study Retina 2005 25 (2) 152 7 15689804\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "1663-2699", "issue": "12(2)", "journal": "Case reports in ophthalmology", "keywords": "Choroidal detachment; Rhegmatogenous retinal detachment with choroidal detachment; Serous choroidal detachment", "medline_ta": "Case Rep Ophthalmol", "mesh_terms": null, "nlm_unique_id": "101532006", "other_id": null, "pages": "315-319", "pmc": null, "pmid": "34054477", "pubdate": "2021", "publication_types": "D002363:Case Reports", "references": "4706445;4621149;14177964;11955315;4634785;5686927;15689804;27507568", "title": "Two Patients with Atypical Choroidal Detachment.", "title_normalized": "two patients with atypical choroidal detachment" }

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{ "abstract": "Hyperkalemic renal tubular acidosis is a non-anion gap metabolic acidosis that invariably indicates an abnormality in potassium, ammonium, and hydrogen ion secretion. In clinical practice, it is usually attributed to real or apparent hypoaldosteronism caused by diseases or drug toxicity. We describe a 54-year-old liver transplant patient that was admitted with flaccid muscle weakness associated with plasma potassium level of 9.25 mEq/L. Additional investigation revealed type 4 renal tubular acidosis and marked hypomagnesemia with high fractional excretion of magnesium. Relevant past medical history included a recent diagnosis of Paracoccidioidomycosis, a systemic fungal infection that is endemic in some parts of South America, and his outpatient medications contained trimethoprim-sulfamethoxazole, tacrolimus, and propranolol. In the present acid-base and electrolyte case study, we discuss a clinical approach for the diagnosis of hyperkalemic renal tubular acidosis and review the pathophysiology of this disorder.", "affiliations": "Universidade Federal do Espírito Santo, Vitória, ES, Brasil.;Universidade Federal do Espírito Santo, Vitória, ES, Brasil.;Universidade Federal do Espírito Santo, Vitória, ES, Brasil.;Universidade de São Paulo, Faculdade de Medicina, Departamento de Nefrologia, Laboratório de Pesquisa Médica - LIM12, São Paulo, SP, Brasil.;Universidade Federal do Espírito Santo, Departamento de Clínica Médica, Divisão de Nefrologia, Vitória, ES, Brasil.", "authors": "Menegussi|Juliana|J|;Tatagiba|Luiza Sarmento|LS|;Vianna|Júlia Guasti P|JGP|;Seguro|Antonio Carlos|AC|;Luchi|Weverton Machado|WM|", "chemical_list": null, "country": "Brazil", "delete": false, "doi": "10.1590/2175-8239-JBN-3821", "fulltext": "\n==== Front\nJ Bras NefrolJ Bras NefroljbnJornal Brasileiro de Nefrologia0101-28002175-8239Sociedade Brasileira de Nefrologia 3004856310.1590/2175-8239-JBN-3821Case ReportsA physiology-based approach to a patient with hyperkalemic renal tubular acidosis Abordagem diagnóstica de um paciente com acidose tubular renal hipercalêmica Menegussi Juliana 1Tatagiba Luiza Sarmento 1Vianna Júlia Guasti P. 1Seguro Antonio Carlos 2Luchi Weverton Machado 3\n1 Universidade Federal do Espírito Santo, Vitória, ES, Brasil.\n2 Universidade de São Paulo, Faculdade de Medicina, Departamento de Nefrologia, Laboratório de Pesquisa Médica - LIM12, São Paulo, SP, Brasil.\n3 Universidade Federal do Espírito Santo, Departamento de Clínica Médica, Divisão de Nefrologia, Vitória, ES, Brasil.Correspondence to: Weverton Machado Luchi. E-mail: wmluchi@hotmail.com.br23 7 2018 Oct-Dec 2018 40 4 410 417 31 5 2017 04 9 2017 This is an Open Access article distributed under the terms of the\nCreative Commons Attribution License, which permits unrestricted use,\ndistribution, and reproduction in any medium, provided the original work is\nproperly cited.ABSTRACT\nHyperkalemic renal tubular acidosis is a non-anion gap metabolic acidosis that\ninvariably indicates an abnormality in potassium, ammonium, and hydrogen ion\nsecretion. In clinical practice, it is usually attributed to real or apparent\nhypoaldosteronism caused by diseases or drug toxicity. We describe a 54-year-old\nliver transplant patient that was admitted with flaccid muscle weakness\nassociated with plasma potassium level of 9.25 mEq/L. Additional investigation\nrevealed type 4 renal tubular acidosis and marked hypomagnesemia with high\nfractional excretion of magnesium. Relevant past medical history included a\nrecent diagnosis of Paracoccidioidomycosis, a systemic fungal infection that is\nendemic in some parts of South America, and his outpatient medications contained\ntrimethoprim-sulfamethoxazole, tacrolimus, and propranolol. In the present\nacid-base and electrolyte case study, we discuss a clinical approach for the\ndiagnosis of hyperkalemic renal tubular acidosis and review the pathophysiology\nof this disorder.\n\nRESUMO\nA acidose tubular renal hipercalêmica é uma acidose metabólica de ânion gap\nnormal que invariavelmente indica anormalidade na secreção de íons potássio,\namônio e hidrogênio. Na prática clínica, está geralmente atribuída a um estado\nde hipoaldosteronismo real ou aparente, causado por doenças ou toxicidade por\ndrogas. Descrevemos um paciente de 54 anos, transplantado hepático, que foi\nadmitido com fraqueza muscular associada à hipercalemia, potássio plasmático de\n9,25 mEq/L. A investigação adicional revelou acidose tubular renal tipo 4 e\nimportante hipomagnesemia com elevada fração de excreção de magnésio. A história\npatológica pregressa incluía um diagnóstico recente de Paracoccidioidomicose -\numa infecção sistêmica fúngica endêmica que ocorre em algumas partes da América\ndo Sul -, e as medicações de uso habitual continham sulfametoxazol-trimetoprim,\ntacrolimus e propranolol. No presente relato de caso, discutiremos uma abordagem\nclínico-laboratorial para o diagnóstico da acidose tubular renal hipercalêmica,\nassim como da hipomagnesemia, revisando a fisiopatologia desses transtornos.\n\nKeywords:\nHyperkalemiaCalcineurinHypoaldosteronismAcidosis, Renal TubularMagnesiumPalavras-chave:\nHipercalemiaCalcineurinaHipoaldosteronismoAcidose Tubular RenalMagnésio\n==== Body\nINTRODUCTION\nRenal tubular acidosis (RTA) is a group of syndromes arising from different transport\ndefects in bicarbonate reabsorption or hydrogen excretion. Despite the presence of\nrenal tubular dysfunction, the glomerular filtration rate (GFR) is relatively\npreserved in RTA. The condition is characterized by non-anion gap or hyperchloremic\nmetabolic acidosis associated with positive urinary anion gap (AG) and can be\naccompanied by low, normal or high serum potassium concentration. Hyperkalemic RTA,\nalso called type 4 RTA, invariably implies an abnormal potassium, ammonium, and\nproton secretion. It is linked to conditions affecting lumen-negative voltage\ngradient generated by sodium reabsorption in the collecting duct (CD) and the\nammoniagenesis within proximal tubular cells, usually attributed to real or apparent\nhypoaldosteronism. With the following case study, we describe our approach to a\npatient with severe hyperkalemic RTA and hypomagnesemia, highlighting\npathophysiologic mechanisms and important key points to the diagnosis.\n\nCASE REPORT\nCLINICAL HISTORY AND INITIAL LABORATORY DATA\nA 54-year-old man, who underwent a liver transplant two years ago as a treatment\nfor end-stage liver disease caused by alcoholic cirrhosis, was admitted because\nof a 4-week progressive muscle weakness involving the lower and upper\nextremities. He was unable to walk alone at presentation and physical\nexamination revealed flaccid weakness of proximal muscles (2/5 strength grade)\nwithout hypotrophy or sensory deficit. He was hydrated, had regular heart rhythm\n(60 bpm), blood pressure of 120/80 mmHg, and unremarkable pulmonary and\nabdominal examinations. The man had no previous medical history of hypertension,\ndiabetes mellitus or kidney disease. He also described that six months earlier,\nhe started treatment with trimethoprim-sulfamethoxazole due to the appearance of\ndiffuse nodules in the skin and subcutaneous, the biopsy of which was consistent\nwith paracoccidioidomycosis (PCM). Other outpatient medications were propranolol\nfor prevention of esophageal variceal bleeding and tacrolimus for prophylaxis\nagainst graft rejection.\n\nInitial laboratory tests (Table 1) showed\nsevere hyperkalemia (9.25 mEq/L) and the electrocardiogram revealed \"peaked\" T\nwaves, widened and flattened P waves, prolonged PR interval, and widened QRS\ncomplex, as illustrated in Figure 1A.\nImmediate stabilization of the myocardial cell membrane with iv injection of 10\nmL of 10% calcium gluconate over two minutes and rapid shifting of potassium to\nthe intracellular space by iv injection of insulin with glucose (10 units of\nregular insulin plus 100 mL of 50% glucose in 30 minutes), 8.4% sodium\nbicarbonate (150 mEq IV in 30 minutes), and beta-agonists inhalation (fenoterol\n20 drops = 5 mg) were the initial priorities. After these interventions, the\nelectrocardiogram normalized (Figure 1B).\nVolume expansion with 0.9% saline solution (2 L in 2 hours) followed by iv\ninjection of 40 mg furosemide generated a high urinary volume that contributed\nfor body potassium elimination. Due to the persistence of severe acidosis,\nanother infusion with 100 mEq of bicarbonate was performed. Calcium polystyrene\nsulfonate, a chelating agent, was subsequently given (30 g orally three times a\nday) because of its delayed action.\n\nTable 1 Laboratory Parameters\nBlood\tOn Admission\tDay 2 --> Day 5\tReference Range\t\nCreatinine (mg/dL)\t1.8\t1.5 --> 0.8\t0.7-1.2\t\nUrea (mg/dL)\t115\t84 --> 32\t10-50\t\nCalcium (mg/dL)\t9.79\t \t8.8-10.5\t\nChloride (mEq/L)\t113\t \t98-106\t\nMagnesium (mg/dL)\t1.4\t1.2 --> 1.6\t1.8-2.4\t\nPotassium (mEq/L\t9.25\t5.8 --> 4\t3.5-5.1\t\nSodium (mEq/L)\t137\t \t135-145\t\nGlycated hemoglobin (%)\t5.5\t \t< 6\t\nArterial Blood Gas\t \t \t \t\npH\t7.247\t \t7.35-7.45\t\npCO2 (mmHg)\t23.7\t \t35-40\t\nHCO3 (mEq/L)\t12.7\t19 --> 21\t22-26\t\nAnion Gap (mEq/L)\t11.3\t \t10±2\t\nRenin Activity (ng/mL/h)\t9.2\t \t0.2-3.3\t\nAldosterone (ng/dL)\t13.8\t \t2.5-39.2\t\nBasal Cortisol (µg/dL)\t \t7.8\t6.2-19.4\t\nACTH (pg/dL)\t \t10\t< 46\t\nTacrolimus level (ng/dL)\t27.8\t \t5-7\t\nUrine (spot)\t \t \t \t\npH\t5.0\t \t4.5-8\t\nSodium (mEq/L)\t117\t \t20-110\t\nChloride (mEq/L)\t130\t \t55-125\t\nPotassium (mEq/L)\t31\t \t12-62\t\nTTKG\t2.3\t \t~ 4-6\t\nFE Mg (%)\t9\t \t2-4\t\nAnion Gap (mEq/L)\t+ 18\t \tnegative\t\n\nFigure 1 (A) Pretreatment electrocardiogram with peaked T-waves,\nflattening of the P-wave, prolonged PR interval, and widening of the\nQRS complex. (B) Post-treatment electrocardiogram with normalization\nof T-waves, PR, and QRS intervals.\n\n\n\nADDITIONAL INVESTIGATIONS\nOnce hyperkalemia was identified and therapeutic interventions initiated, a urine\nsample was promptly collected. It is important to emphasize that when an\nelectrolytic disturbance is detected, a urine sample must be immediately\ncollected, since therapeutic interventions may alter pH and electrolyte\nconcentrations in the urine, possibly distorting correct interpretations and\ndiagnosis. Urine tests in the emergency department have short turnaround time,\nusually within one hour, and can be helpful to guide the correct diagnosis and\ntreatment.\n\nAs depicted in Table 1, arterial blood gas\nrevealed marked metabolic acidosis with normal serum anion-gap (plasma\n[Na+] - [HCO3-] - [Cl-]), and an isolated\nurine sample showed apparent noraml urinary acidification (urine pH: 5.0).\nUrinary AG (urine [Na+] + [K+] - [Cl-]) was +18\nand calculated transtubular potassium gradient was 2.3 (TTKG = [K+\nurine\n* Osmplasma] / [K+\nplasma\n* Osmurine]). Urine osmolality can be estimated using the\nfollowing formula: Osmurine = (2 * [Na+\nmEq/L + K+\nmEq/L]) + (Glucosemg/dL/18) + (Ureamg/dL/6).\nFractional excretion of magnesium was 9%, calculated by FEMg% =\n100* [Mg+2\nurine x Crplasma] / [0.7 * Mg+2\nplasma x Crurine]. Serum magnesium concentration is\nmultiplied by 0.7 in order to adjust for magnesium filtered by the kidney.\n\nBecause of renal hyperkalemia without advanced decreased of GFR, plasma\naldosterone and plasma renin activity analysis were required. Serum cortisol,\nplasma ACTH, and abdominal computed tomography (CT) were indicated since PCM is\nknown to involve the adrenal gland. Drug-induced nephrotoxicity was also evoked\nas a possible diagnosis and the above-mentioned medications were temporarily\nsuspended and tacrolimus was replaced by mycophenolate.\n\nDIAGNOSIS\nHYPERKALEMIC RTA AND RENAL MAGNESIUM WASTING\nCLINICAL FOLLOW-UP\nAs shown in Table 1, a significant\ndecrease in plasma potassium levels was progressively observed and there was\nno need for dialysis therapy. Renal function returned to the previous\nbaseline after five days. Further evaluation excluded the hypothesis of\nadrenal insufficiency associated with PCM despite the identification of an\nadrenal nodule in the CT. Aldosterone level was inappropriate for\nhyperkalemia and the main causal factor was very high level of tacrolimus\n(Table 1). During follow-up,\ntrimethoprim and propranolol were reintroduced, followed by tacrolimus (dose\nreduction from 4 to 1 mg per day) without new disorders in plasma potassium,\nbicarbonate or tacrolimus levels. Below, we discuss the differential\ndiagnoses for the case, dissecting the understanding of hyperkalemic RTA and\nhypomagnesemia.\n\nDISCUSSION\nThe presented case illustrates a typical non-anion gap or hyperchloremic metabolic\nacidosis. Renal or extrarenal causes for this disturbance can be differentiated by\nurine AG. It indirectly represents the excretion of unmeasured ammonium cation\n(NH4+) that constitutes the most import urinary buffer system to\nexcrete H+ during acid overload. If the kidneys do not excrete\nNH4+ properly, the urine AG turns positive, suggesting RTA as the\ncause of hyperchloremic metabolic acidosis1.\n\nAmong the RTA types, only type 4 leads to hyperkalemia. Conversely, proximal (type 2)\nand distal (type 1) occur with normal or low plasma potassium levels. TTKG is a\nclinically useful tool for estimating the potassium concentration \"gradient\" between\nthe peritubular capillary and the tubular lumen at the level of cortical CD. A TTKG\nlower than 8 in the hyperkalemic patient implies that the kidney is not responding\nappropriately to the prevailing hyperkalemia and that potassium secretion is\nimpaired2\n,\n3.\n\nIn normal circumstances, the reabsorption of sodium in the CD, driven by aldosterone,\ngenerates transepithelial voltage gradient that is lumen-negative, creating a\ndriving force for the secretion of potassium and hydrogen, by principal and\nα-intercalated cells, respectively (Figure 2).\nBesides, the proton secretion requires the parallel movement of NH3, and its\nprotonation to NH4+, in order to provide sufficient buffering. The\nammonia is produced in proximal tubules by glutamine deamidation, reaching the renal\nmedulla through NKCC transporter in the Henle loop. After, it is secreted in urine\nin the distal nephron. Apart from stimulating Na+/K+-ATPase,\nENaC, and H-ATPase transporters, aldosterone plays a pivotal role in\nammoniagenesis2\n,\n4\n,\n5. Any interference in these pathways may lead\nto hyperkalemic RTA. The etiologies and pathophysiological mechanisms of\nhyperkalemic RTA are briefly reviewed in Figure\n3.\n\n\nFigure 2 Interaction between potassium and proton excretion and\nammoniagenesis. Sodium reabsorption by ENAC transporter in principal\ncells, driven by Na+/K+-ATPase, creates a\nlumen-negative transepithelial voltage that is critical for potassium\n(by ROMK) and proton (By H-ATPase) excretion in the collecting duct\n(CD). The excretion of H+ also requires the ammonia buffer\nthat prevents a marked drop in urinary pH. Ammonia is produced in the\nproximal cells from glutamine and reaches tubular fluid as\nNH4\n+. After, it is reabsorbed in the thick ascending limb to the\ninterstitium and then is secreted as NH3 into the CD by\nα-intercalated cells in parallel with the H+. Aldosterone\n(ALDO) is a pivot in these processes, stimulating both sodium\nreabsorption and ammoniagenesis. Impairment of the ENAC activity and/or\nNa+/K+-ATPase transporters, reduction of the\namount of sodium delivered in CD, and the reduction in ammonia\nproduction are the main mechanisms involved in the pathogenesis of type\n4 renal tubular acidosis. MR: mineralocorticoid receptor.\n\n\n\n\nFigure 3 Pathophysiologic classification and etiologies of disorders\nassociated with hyperkalemic hyperchloremic renal tubular acidosis. PHA:\npseudohypoaldosteronism; CD: collecting duct; MR: mineralocorticoid\nreceptor. a = The voltage defect causes a relative\n\"resistance\" to aldosterone in the CD, but does not interfere with its\naction on ammoniagenesis in the proximal cells; b = Others:\nHyperkalemia due to these causes may be related to hyporeninemic\nhypoaldosteronism and/or a direct defect in voltage gradient generation\nin CD.\n\n\n\nUrine pH depends on both the concentration of H+ and the amount of\nammonium buffer. A normal renal response to acidemia includes an ability to produce\nurine with pH as low as 5.0. Thus, a deficit of proton secretion tends to leave the\nurine with an inappropriate high pH (>5.5) despite systemic acidosis. However,\neven with a reduction in H+ secretion, the urine pH may remain below 5.5\nif an ample reduction the ammonium buffer occurs simultaneously. In this\ncircumstance, the interpretation of adequate urinary acidification will be\nmisleading6.\n\nIt is well known that hyperkalemia raises intracellular pH by exchange with protons,\nimpairing enzymes involved in ammoniagenesis and thus can per se\nlead to acidosis, but it usually does not reduce urine pH below 5.5. However, when\nanother factor besides hyperkalemia reduces ammonia production and excretion during\nacidosis, as observed in real or apparent hypoaldosteronism, urine pH is reduced\nbelow 5.5. Therefore, patients with aldosterone deficiency/resistance can lower\nurine pH \"normally\" during acidemia, and this capacity is extremely useful in\ndistinguishing this syndrome from the so-called voltage-dependent hyperkalemic RTA\n(Figure 4)1\n,\n2\n,\n6.\n\n\nFigure 4 Clinical approach to the diagnosis of hyperkalemic RTA based on urine\npH. Adapted from reference 1. *Antagonism, reduction or mutation in\nmineralocorticoid receptor.\n\n\n\nInterestingly, in our case, the first urine collected presented pH of 5.0, suggesting\nthe presence of aldosterone deficiency/resistance as shown in Figure 4. Plasma renin activity was increased while plasma\naldosterone concentration was within the reference values (Table 1). When potassium is elevated, plasma aldosterone\nconcentration should be at least three times higher6. Thus, an aldosterone of 13.8 ng/dL is a suboptimal hormonal response\nconsidering plasma potassium level of 9.25 mEq/L. Additionally, three months after\nthe resolution of acidosis, when plasma potassium level was normal, plasma\naldosterone was 39.1 ng/dL. These data support the existence of a relative and\ntransient hypoaldosteronism.\n\nPCM is the main systemic mycosis in Brazil caused by the dimorphic fungus\nParacoccidioides brasiliensis, which predominantly involves the\nlungs but can disseminate to the mucous membranes, skin, lymph nodes, and adrenal\nglands. The frequency of adrenal involvement in PCM varies from 2.9% to 48% among\nthe different clinical studies, but in necropsy reports, the adrenal invasion is as\nhigh as 85%-90% of the cases7. Severe\nhyperkalemia in a patient with previous diagnosis of PCM could be explained by\nAddison's disease. Although abdominal CT showed a poorly defined nodule in the left\nadrenal gland (3.1×1.9mm), there were no symptoms like hypotension, abdominal pain,\nhypoglycemia or hyperpigmentation of the skin. In addition, serum cortisol and ACTH\nlevels were normal and aldosterone level became normal after withdrawal of the\ndrugs. Thus, the hypothesis of hypoaldosteronism associated with PCM became\nunlikely.\n\nHyperkalemia and RTA are common complications that affect transplant recipients\nreceiving immunosuppressive therapy with calcineurin inhibitors (CNIs) as\ncyclosporine and tacrolimus8\n,\n9. The mechanism of these adverse effects is\nmultifactorial and related to CNIs serum levels. The most important one appears to\nbe the inhibition of basolateral Na+/K+-ATPase at the CD10, which blocks sodium uptake by ENaC and\ncauses the loss of lumen-negative potential difference, the so-called\nvoltage-dependent mechanism, leading to reduced potassium and hydrogen secretion\n(Figure 2). NCC cotransporter stimulation,\nincreased paracellular chloride reabsorption, and inhibition of ROMK channel in the\ndistal nephron, via alteration of WNK kinases, can aggravate this effect11. It is suggested that CNIs-induced\nhyperkalemia is in part caused by cellular K+ leakage since erythrocyte\nmembrane Na+/K+-ATPase activity is decreased and K secretory\nchannels upregulated when these cells are incubated with CNIs12. Moreover, CNIs may reduce aldosterone production/secretion\nby direct action on the adrenal gland or associated hyporeninemia. Also, CNIs can\ncreate resistance to aldosterone's action by reducing mineralocorticoid receptor\nexpression13\n-\n15. Finally, CNIs inhibit the polymerization\nof the hensin protein, which is responsible for converting bicarbonate-secreting\nb-intercalated cells into the acid secreting a-intercalated cells during metabolic\nacidosis11.\n\nFrom the above, the marked increase in serum level of tacrolimus in this case (Table 1) can explain the hyperkalemic RTA by\ninterfering with the voltage-dependent mechanism, hydrogen ion pump defect and by\nreduction of ammoniagenesis (Figure 3). The\nlatter is caused by unappropriated level or resistance to aldosterone and by\nhyperkalemia itself, which together are responsible for the low urine pH at\npresentation. Delivery of Na+ did not seem to be the problem because\nthere was an abundant excretion of this cation (UNa=117mmol/L), and the\nprompt response of hyperkalemia to bicarbonate infusion may point to a defect in\ngenerating a favorable electrochemical gradient in cortical CD as the cause of this\nsyndrome. These findings are in line with a previous study in which TTKG\nsignificantly increased after bicarbonaturia induced by bicarbonate or acetazolamide\nadministration, but did not normalize after mineralocorticoid administration,\nindicating tubular insensitivity to aldosterone16.\n\nThe reversible renal dysfunction related to acute CNIs nephrotoxicity occurs due to\nvasoconstriction of the afferent arterioles. It results from an increase in\nvasoconstrictor factors that include endothelin and thromboxane and activation of\nthe renin-angiotensin system, as well as a reduction of vasodilator factors like\nprostacyclin, prostaglandin E2, and nitric oxide10. The process can explain the high urea/creatinine ratio suggestive of\npre-renal injury and the high levels of renin as depicted in Table 1. Also, it demonstrates the different patterns of\nresponse in plasma renin activity with CNI, since hyporeninemic hypoaldosteronism is\nalso found with these drugs. Thus, under certain conditions, dosage, and duration,\nthe renin profile can change17. Elevated\nrenin strengthens the hypothesis of a direct impairment of aldosterone\nproduction/secretion by the high level of tacrolimus. Furthermore, it is important\nto emphasize that RTA syndromes are characterized by a relatively normal GFR, and\nthe degree of renal dysfunction found in the present case cannot be imputed as a\ncausal factor for hyperkalemia.\n\nHypomagnesemia is an often neglected complication of CNIs in the post-transplantation\nperiod. These drugs induce renal loss of magnesium by reducing the expression of\nparacellin-1(claudin-16) in thick ascending limb cells and TRPM6 transporter in the\ndistal convoluted tubule10\n,\n18. Interestingly, in clinical practice, the\nhypomagnesemia usually runs in parallel to hypokalemia since magnesium deficiency\nreleases the magnesium-mediated inhibition of ROMK channels and increases potassium\nsecretion19. However, the apparent\nparadox of concomitant hyperkalemia and hypomagnesemia can be detected in renal\ntoxicity by CNIs. Another relevant fact is that ENaC and aldosterone blockers\nprevent renal Mg wasting by increasing membrane negative potential in distal\nnephrons and hypoaldosteronism tends to occur with hypermagnesemia20. Thus, the presence of hypomagnesemia\nassociated to high FEMg (>4%) on admission was a key finding that indicated\ntacrolimus as the possible cause of hyperkalemia/hypoaldosteronism rather than the\nsupposed adrenal insufficiency by PCM. Furthermore, hypomagnesemia may have\ncontributed to acute nephrotoxicity of CNIs by aggravating renal\nvasoconstriction10\n,\n21.\n\nBeta blockers have been described as a potential cause of type 4 acidosis, mediated\nby hyporeninemic hypoaldosteronism22.\nHowever, the high levels of renin in this case, eliminate the possibility of\npropranolol involvement as a causative factor.\n\nTrimethoprim is a bacteriostatic antibiotic that has been related to the induction of\nhyperkalemia through the competitive inhibition of ENaC transporter, identically to\nthe potassium-sparing diuretic amiloride. In addition, this drug also decreases\nNa+/K+-ATPase activity in the cortical CD23. Thus, trimethoprim limits the formation of\na voltage gradient in the CD necessary to transepithelial excretion of potassium and\nhydrogen similar to tacrolimus. A previous case report also speculated that\ntrimethoprim might have a direct effect on the adrenal axis, possibly inhibiting\naldosterone synthesis/release, as the level of aldosterone was inappropriate for the\nhyperkalemia condition24. Thus, trimethoprim\nmight play an adjuvant role in the induction of hyperkalemia in this case.\n\nIn summary, drug-nephrotoxicity and diseases such as diabetes and other conditions\nassociated with underproduction of renin or aldosterone are the main causes of\nhyperkalemic RTA in clinical practice. It should be pointed out that urine pH is a\ncornerstone to the differential diagnosis of this disorder, suggesting aldosterone\ndeficit/resistance as a causal factor when < 5.5. Clinicians must remain alerted\nto severe hyperkalemia, acidosis, and hypomagnesemia that might develop in patients\nundergoing therapy with CNIs. Besides, we emphasize that the CNIs combination with\nother drugs such as trimethoprim can aggravate hyperkalemia dangerously.\n==== Refs\nREFERENCES\n1 Kurtzman NA Renal tubular acidosis syndromes South Med J 2000 93 1042 1052 11095551 \n2 DuBose TD Jr Hyperkalemic hyperchloremic metabolic acidosis: pathophysiologic\ninsights Kidney Int 1997 51 591 602 9027745 \n3 Choi MJ Ziyadeh FN The utility of the transtubular potassium gradient in the\nevaluation of hyperkalemia J Am Soc Nephrol 2008 19 424 426 18216310 \n4 Karet FE Mechanisms in hyperkalemic renal tubular acidosis J Am Soc Nephrol 2009 20 251 254 19193780 \n5 Palmer BF Clegg DJ Electrolyte and Acid-Base Disturbances in Patients with Diabetes\nMellitus N Engl J Med 2015 373 548 559 26244308 \n6 Kurtzman NA Disorders of distal acidification Kidney Int 1990 38 720 727 2232509 \n7 Tobón AM Agudelo CA Restrepo CA Villa CA Quiceno W Estrada S Adrenal function status in patients with paracoccidioidomycosis\nafter prolonged post-therapy follow-up Am J Trop Med Hyg 2010 83 111 114 20595488 \n8 Kaplan B Wang Z Abecassis MM Fryer JP Stuart FP Kaufman DB Frequency of hyperkalemia in recipients of simultaneous pancreas\nand kidney transplants with bladder drainage Transplantation 1996 62 1174 1175 8900321 \n9 Keven K Ozturk R Sengul S Kutlay S Ergun I Erturk S Renal tubular acidosis after kidney transplantation--incidence,\nrisk factors and clinical implications Nephrol Dial Transplant 2007 22 906 910 17210594 \n10 Naesens M Kuypers DR Sarwal M Calcineurin inhibitor nephrotoxicity Clin J Am Soc Nephrol 2009 4 481 508 19218475 \n11 Lee CH Kim GH Electrolyte and Acid-base disturbances induced by clacineurin\ninhibitors Electrolyte Blood Press 2007 5 126 130 24459511 \n12 Laine J Holmberg C Renal and adrenal mechanisms in cyclosporine-induced\nhyperkalaemia after renal transplantation Eur J Clin Invest 1995 25 670 676 7498241 \n13 Deppe CE Heering PJ Viengchareun S Grabensee B Farman N Lombès M Cyclosporine a and FK506 inhibit transcriptional activity of the\nhuman mineralocorticoid receptor: a cell-based model to investigate partial\naldosterone resistance in kidney transplantation Endocrinology 2002 143 1932 1941 11956176 \n14 Bantle JP Nath KA Sutherland DE Najarian JS Ferris TF Effects of cyclosporine on the renin-angiotensin-aldosterone\nsystem and potassium excretion in renal transplant\nrecipients Arch Intern Med 1985 145 505 508 3883934 \n15 Heering PJ Kurschat C Vo DT Klein-Vehne N Fehsel K Ivens K Aldosterone resistance in kidney transplantation is in part\ninduced by a down-regulation of mineralocorticoid receptor\nexpression Clin Transplant 2004 18 186 192 15016134 \n16 Kamel KS Ethier JH Quaggin S Levin A Albert S Carlisle EJ Studies to determine the basis for hyperkalemia in recipients of\na renal transplant who are treated with cyclosporine J Am Soc Nephrol 1992 2 1279 1284 1627752 \n17 Lee DB Cyclosporine and the renin-angiotensin axis Kidney Int 1997 52 248 260 9211371 \n18 Nijenhuis T Hoenderop JG Bindels RJ Downregulation of Ca(2+) and Mg(2+) transport proteins in the\nkidney explains tacrolimus (FK506)-induced hypercalciuria and\nhypomagnesemia J Am Soc Nephrol 2004 15 549 557 14978156 \n19 Huang CL Kuo E Mechanism of hypokalemia in magnesium deficiency J Am Soc Nephrol 2007 18 2649 2652 17804670 \n20 de Baaij JH Hoenderop JG Bindels RJ Magnesium in man: implications for health and\ndisease Physiol Rev 2015 95 1 46 25540137 \n21 Miura K Nakatani T Asai T Yamanaka S Tamada S Tashiro K Role of hypomagnesemia in chronic cyclosporine\nnephropathy Transplantation 2002 73 340 347 11884928 \n22 Johnson JA Davis JO Gotshall RW Lohmeier TE Davis JL Braverman B Evidence for an intrarenal beta receptor in control of renin\nrelease Am J Physiol 1976 230 410 418 1259022 \n23 Perazella MA Trimethoprim-induced hyperkalaemia: clinical data, mechanism,\nprevention and management Drug Saf 2000 22 227 236 10738846 \n24 Eiam-Ong S Kurtzman NA Sabatini S Studies on the mechanism of trimethoprim-induced\nhyperkalemia Kidney Int 1996 49 1372 1378 8731102\n\n", "fulltext_license": "CC BY", "issn_linking": "0101-2800", "issue": "40(4)", "journal": "Jornal brasileiro de nefrologia : 'orgao oficial de Sociedades Brasileira e Latino-Americana de Nefrologia", "keywords": null, "medline_ta": "J Bras Nefrol", "mesh_terms": "D000141:Acidosis, Renal Tubular; D006801:Humans; D006947:Hyperkalemia; D008297:Male; D008875:Middle Aged", "nlm_unique_id": "9426946", "other_id": null, "pages": "410-417", "pmc": null, "pmid": "30048563", "pubdate": "2018", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "10738846;11095551;11884928;11956176;1259022;14978156;15016134;1627752;17210594;17804670;18216310;19193780;19218475;20595488;2232509;24459511;25540137;26244308;3883934;7498241;8731102;8900321;9027745;9211371", "title": "A physiology-based approach to a patient with hyperkalemic renal tubular acidosis.", "title_normalized": "a physiology based approach to a patient with hyperkalemic renal tubular acidosis" }

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A PHYSIOLOGY-BASED APPROACH TO A PATIENT WITH HYPERKALEMIC RENAL TUBULAR ACIDOSIS. J BRAS NEFROL. 2018 OCT-DEC?40(4):410-417. 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A PHYSIOLOGY-BASED ?APPROACH TO A PATIENT WITH HYPERKALEMIC RENAL TUBULAR ACIDOSIS. J BRAS NEFROL.?2018 JUL 23. PII: S0101-28002018005021101. DOI: 10.1590/2175-8239-JBN-3821", "literaturereference_normalized": "a physiology based approach to a patient with hyperkalemic renal tubular acidosis", "qualification": "3", "reportercountry": "BR" }, "primarysourcecountry": "BR", "receiptdate": "20180814", "receivedate": "20180813", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15269831, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190204" } ]

{ "abstract": "BACKGROUND\nAutologous hematopoietic stem cell transplantation (aHSCT) is used in aggressive relapsing and progressive multiple sclerosis (MS). The multicentre studies and case series reported have relatively short follow-up.\n\n\nOBJECTIVE\nTo evaluate long-term effect and safety of HSCT in MS.\n\n\nMETHODS\nPatients referred to the MS centre of Cagliari and undergoing HSCT were included. Variations in relapses and EDSS before and after HSCT were evaluated by Wilcoxon test. A descriptive analysis was made for other clinical data.\n\n\nRESULTS\nNine patients (female 6, males 3; 5 relapsing-remitting, 2 secondary progressive, 1 primary progressive, and 1 progressive relapsing) performed HSCT (1999-2006). The median follow-up was 11 years (11-18). Eight patients underwent aHSCT, seven using a low intensity conditioning regimen, and one an intermediate intensity. The primary progressive underwent allogeneic HSCT, due to onco hematological disease. The relapses number decreased in the 2 years following the procedure compared to the two preceding years (p = 0.041). New relapses or disease progressions were observed after a range of 7 (low intensity regimen)-118 (intermediate intensity) months. At last follow-up, the EDSS was stable in two patients, improved in two, and worse in five (maximum 2 EDSS in one patient). Six patients showed new lesions, and seven gadolinium-enhancing on brain MRI after a mean of 23.3 and 19.8 months, respectively. Two serious adverse events were reported: melanoma, and progressive multifocal leukoencephalopathy.\n\n\nCONCLUSIONS\nOur results confirm in a long follow-up the efficacy of HSCT in reducing relapses and disability progression. The risk/benefit profile is better for intermediate intensity regimens.", "affiliations": "Department of Medical Sciences and Public Health, Multiple Sclerosis Center, ATS Sardegna, Ospedale Binaghi, University of Cagliari, Via Is Guadazzonis 2, 09126, Cagliari, Italy. jessicafrau@hotmail.it.;Department of Medical Sciences and Public Health, Multiple Sclerosis Center, ATS Sardegna, Ospedale Binaghi, University of Cagliari, Via Is Guadazzonis 2, 09126, Cagliari, Italy.;Department of Medical Sciences and Public Health, Multiple Sclerosis Center, ATS Sardegna, Ospedale Binaghi, University of Cagliari, Via Is Guadazzonis 2, 09126, Cagliari, Italy.;Department of Medical Sciences and Public Health, Multiple Sclerosis Center, ATS Sardegna, Ospedale Binaghi, University of Cagliari, Via Is Guadazzonis 2, 09126, Cagliari, Italy.;Department of Medical Sciences and Public Health, Multiple Sclerosis Center, ATS Sardegna, Ospedale Binaghi, University of Cagliari, Via Is Guadazzonis 2, 09126, Cagliari, Italy.;Department of Medical Sciences and Public Health, Bone Marrow Transplant Center, University of Cagliari, Via Is Guadazzonis 2, 09126, Cagliari, Italy.;Department of Medical Sciences and Public Health, Multiple Sclerosis Center, ATS Sardegna, Ospedale Binaghi, University of Cagliari, Via Is Guadazzonis 2, 09126, Cagliari, Italy.;Department of Medical Sciences and Public Health, Bone Marrow Transplant Center, University of Cagliari, Via Is Guadazzonis 2, 09126, Cagliari, Italy.;Department of Medical Sciences and Public Health, Multiple Sclerosis Center, ATS Sardegna, Ospedale Binaghi, University of Cagliari, Via Is Guadazzonis 2, 09126, Cagliari, Italy.;Department of Medical Sciences and Public Health, Multiple Sclerosis Center, ATS Sardegna, Ospedale Binaghi, University of Cagliari, Via Is Guadazzonis 2, 09126, Cagliari, Italy.", "authors": "Frau|Jessica|J|;Carai|Margherita|M|;Coghe|Giancarlo|G|;Fenu|Giuseppe|G|;Lorefice|Lorena|L|;La Nasa|Giorgio|G|;Mamusa|Elena|E|;Vacca|Adriana|A|;Marrosu|Maria Giovanna|MG|;Cocco|Eleonora|E|", "chemical_list": null, "country": "Germany", "delete": false, "doi": "10.1007/s00415-017-8718-2", "fulltext": null, "fulltext_license": null, "issn_linking": "0340-5354", "issue": "265(2)", "journal": "Journal of neurology", "keywords": "Conditioning regimens; Disease progression; Hematopoietic stem cell transplantation; Multiple sclerosis", "medline_ta": "J Neurol", "mesh_terms": "D000328:Adult; D004185:Disability Evaluation; D005260:Female; D005500:Follow-Up Studies; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting; D012189:Retrospective Studies; D018709:Statistics, Nonparametric; D014182:Transplantation, Autologous; D016896:Treatment Outcome", "nlm_unique_id": "0423161", "other_id": null, "pages": "410-416", "pmc": null, "pmid": "29270686", "pubdate": "2018-02", "publication_types": "D016428:Journal Article", "references": "25938688;28455383;9383225;11456302;28277827;20019096;20921236;28396953;28283109;20350962;22056644;27657737;21422458;25583838;16283615;28241268;26843383;22127896;28148635;24554104;22116203;25546364;6847134;25672923;27071689;25602998;10798604;24759080;14648027", "title": "Long-term follow-up more than 10 years after HSCT: a monocentric experience.", "title_normalized": "long term follow up more than 10 years after hsct a monocentric experience" }

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LONG-TERM FOLLOW-UP MORE THAN 10 YEARS AFTER HSCT: A MONOCENTRIC EXPERIENCE. DOI: 10.1007/S00415-017-8718-2. JOURNAL OF NEUROLOGY. 265:410-416.", "literaturereference_normalized": "long term follow up more than 10 years after hsct a monocentric experience", "qualification": "1", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20180530", "receivedate": "20180516", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14904248, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180711" }, { "companynumb": "IT-TEVA-2018-IT-897864", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": "3", "drugadministrationroute": "065", 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"drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cytomegalovirus infection", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "FRAU J, CARAI M, COGHE G, FENU G, LOREFICE L, LA NASA G, ET AL. LONG-TERM FOLLOW-UP MORE THAN 10 YEARS AFTER HSCT: A MONOCENTRIC EXPERIENCE. J-NEUROL 2018?265(2):410-416.", "literaturereference_normalized": "long term follow up more than 10 years after hsct a monocentric experience", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20180531", "receivedate": "20180525", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14937192, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180711" }, { "companynumb": "IT-BIOGEN-2017BI00346503", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "NATALIZUMAB" }, "drugadditional": "2", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CONCENTRATE FOR SOLUTION FOR INFUSION", "drugdosagetext": null, "drugenddate": "201701", "drugenddateformat": "610", "drugindication": "PRIMARY PROGRESSIVE MULTIPLE SCLEROSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "20131001", "drugstartdateformat": "102", "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TYSABRI" } ], "patientagegroup": null, "patientonsetage": "51", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Progressive multifocal leukoencephalopathy", "reactionmeddraversionpt": "21.0", "reactionoutcome": "3" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20170116" } }, "primarysource": { "literaturereference": "FRAU J, CARAI M, COGHE G, FENU G, LOREFICE L, LA NASA G, MAMUSA E, VACCA A, MARROSU M, COCCO E. LONG-TERM FOLLOW-UP MORE THAN 10 YEARS AFTER HSCT: A MONOCENTRIC EXPERIENCE. JOURNAL OF NEUROLOGY. 2017 DEC 21?265:410-416.", "literaturereference_normalized": "long term follow up more than 10 years after hsct a monocentric experience", "qualification": null, "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20180517", "receivedate": "20170207", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13192462, "safetyreportversion": 5, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180711" } ]

{ "abstract": "BACKGROUND\nProvocative growth hormone (GH) stimulation testing is used to evaluate short stature and growth failure in children. Agents commonly used for testing include clonidine, arginine and glucagon. While stimulation testing is generally considered safe, gross hematuria has been described as a rare idiopathic complication of GH stimulation testing. This study was designed to estimate the incidence of both microscopic and macroscopic hematuria following GH testing with different provocative agents.\n\n\nMETHODS\nSubjects undergoing GH stimulation testing were invited to participate in the study. Prior to testing, vital signs were measured and baseline point-of-care (POC) urinalysis was done. The subjects performed urine testing at home on days 1, 2, 3 and 7 following GH stimulation studies. Families notified the study team with any positive findings and returned the data collection tool by mail.\n\n\nRESULTS\nIn total, 34 subjects aged 11.14±2.71 years (91.2% male) completed the study. Agents used in provocative testing included arginine (73.5%), clonidine (94.1%) and glucagon (32.4%). Three subjects developed hematuria after GH stimulation testing (clonidine/arginine). The hematuria resolved by 7 days after testing. Additional adverse effects included nausea, vomiting and hypotension.\n\n\nCONCLUSIONS\nIn this study of children undergoing GH testing, hematuria was identified in three subjects. This study demonstrates that side effects to agents used for GH testing are self-limited, yet not rare, and should be discussed with patients and families prior to stimulation testing.", "affiliations": "Division of Pediatric Endocrinology, Children's Hospital of Michigan, Detroit, MI, USA.;Division of Pediatric Endocrinology, UBMD Pediatrics, Buffalo, NY, USA.;Division of Pediatric Endocrinology, UBMD Pediatrics, Buffalo, NY, USA.;Division of Pediatric Endocrinology, Children's Hospital of Michigan, Detroit, MI, USA.", "authors": "Thirunagari|Rajeev|R|;Marrone|Alexandra|A|;Elsinghorst|Hannah|H|;Mastrandrea|Lucy D|LD|", "chemical_list": "D019382:Human Growth Hormone", "country": "Germany", "delete": false, "doi": "10.1515/jpem-2017-0458", "fulltext": null, "fulltext_license": null, "issn_linking": "0334-018X", "issue": "31(5)", "journal": "Journal of pediatric endocrinology & metabolism : JPEM", "keywords": "arginine; clonidine; growth hormone deficiency; hematuria; pediatric; short stature", "medline_ta": "J Pediatr Endocrinol Metab", "mesh_terms": "D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D003430:Cross-Sectional Studies; D003940:Diagnostic Techniques, Endocrine; D005260:Female; D005500:Follow-Up Studies; D006130:Growth Disorders; D006417:Hematuria; D019382:Human Growth Hormone; D006801:Humans; D008297:Male; D011379:Prognosis; D013268:Stimulation, Chemical", "nlm_unique_id": "9508900", "other_id": null, "pages": "539-543", "pmc": null, "pmid": "29688887", "pubdate": "2018-04-25", "publication_types": "D016428:Journal Article; D064888:Observational Study", "references": null, "title": "Hematuria as an adverse outcome following provocative growth hormone stimulation testing in children.", "title_normalized": "hematuria as an adverse outcome following provocative growth hormone stimulation testing in children" }

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{ "abstract": "Metronidazole induced encephalopathy (MIE), an encephalopathy brought by an antibiotic, is characterized with cerebellar dysfunction, altered mental status and extrapyramidal symptoms. MIE can result in an acute manifestation, but MIE has not been reported as a stroke mimic. An 86-year-old patient undergoing metronidazole therapy for Clostridium difficile enteritis presented to our hospital with sudden disoriented status and motor weakness of the left extremities. Computed tomography (CT) was unrevealing of intracranial hemorrhagic change, and CT angiography did not show any apparent major occlusion or stenosis of the intracranial vessels. However, CT perfusion (CTP) revealed a decrease in peripheral blood flow in the right cerebral hemisphere, and tissue plasminogen activator was administrated for a possible acute ischemic stroke. The findings of follow-up magnetic resonance imaging (MRI) were typical for MIE, revealing areas of hyperintensity on fluid attenuated inversion recovery (FLAIR) signal intensity in the dentate nuclei, the splenium of the corpus callosum, and in the dorsal midbrain. The degree of hyperintensity was stronger in the left dentate nucleus than in the right left dentate on FLAIR and the apparent diffusion coefficient map. The asymmetric findings of the left dentate nucleus on MRI were considered to be responsible for the clinical symptoms and the findings of CTP. We report a rare case of MIE mimicking an acute ischemic stroke, and hypothesize the relationship between the findings of CTP and that of MRI based on the anatomical connection of the dentate nucleus and the cerebral hemisphere.", "affiliations": "Department of Neurosurgery, Kurashiki Central Hospital.;Department of Neurosurgery, Kurashiki Central Hospital.;Department of Neurosurgery, Kurashiki Central Hospital.;Department of Neurosurgery, Kurashiki Central Hospital.;Department of Neurosurgery, Kurashiki Central Hospital.;Department of Neurosurgery, Kurashiki Central Hospital.", "authors": "Takada|Kensuke|K|;Maki|Yoshinori|Y|;Kinosada|Masanori|M|;Ishibashi|Ryota|R|;Chin|Masaki|M|;Yamagata|Sen|S|", "chemical_list": "D000900:Anti-Bacterial Agents; D008795:Metronidazole", "country": "Japan", "delete": false, "doi": "10.2176/nmc.cr.2018-0107", "fulltext": "\n==== Front\nNeurol Med Chir (Tokyo)Neurol. Med. Chir. (Tokyo)NMCNeurologia medico-chirurgica0470-81051349-8029The Japan Neurosurgical Society 3007882010.2176/nmc.cr.2018-0107nmc-58-400Case ReportMetronidazole Induced Encephalopathy Mimicking an Acute Ischemic Stroke Event TAKADA Kensuke 1MAKI Yoshinori 1KINOSADA Masanori 1ISHIBASHI Ryota 1CHIN Masaki 1YAMAGATA Sen 11 Department of Neurosurgery, Kurashiki Central Hospital, Kurashiki, Okayama, JapanAddress reprint requests to: Yoshinori Maki, MD, Department of Neurosurgery, Kurashiki Central Hospital, 1-1-1 Miwa, Kurashiki, Okayama 710-0052, Japan. e-mail: maki0427@kuhp.kyoto-u.ac.jp9 2018 03 8 2018 58 9 400 403 16 4 2018 29 5 2018 © 2018 The Japan Neurosurgical Society2018This 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/Metronidazole induced encephalopathy (MIE), an encephalopathy brought by an antibiotic, is characterized with cerebellar dysfunction, altered mental status and extrapyramidal symptoms. MIE can result in an acute manifestation, but MIE has not been reported as a stroke mimic. An 86-year-old patient undergoing metronidazole therapy for Clostridium difficile enteritis presented to our hospital with sudden disoriented status and motor weakness of the left extremities. Computed tomography (CT) was unrevealing of intracranial hemorrhagic change, and CT angiography did not show any apparent major occlusion or stenosis of the intracranial vessels. However, CT perfusion (CTP) revealed a decrease in peripheral blood flow in the right cerebral hemisphere, and tissue plasminogen activator was administrated for a possible acute ischemic stroke. The findings of follow-up magnetic resonance imaging (MRI) were typical for MIE, revealing areas of hyperintensity on fluid attenuated inversion recovery (FLAIR) signal intensity in the dentate nuclei, the splenium of the corpus callosum, and in the dorsal midbrain. The degree of hyperintensity was stronger in the left dentate nucleus than in the right left dentate on FLAIR and the apparent diffusion coefficient map. The asymmetric findings of the left dentate nucleus on MRI were considered to be responsible for the clinical symptoms and the findings of CTP. We report a rare case of MIE mimicking an acute ischemic stroke, and hypothesize the relationship between the findings of CTP and that of MRI based on the anatomical connection of the dentate nucleus and the cerebral hemisphere.\n\nmetronidazole induced encephalopathycomputed tomography perfusionstroke mimicmagnetic resonance imagingtissue plasminogen activator\n==== Body\nIntroduction\nMetronidazole induced encephalopathy (MIE), an encephalopathy brought by an antibiotic for Clostridium difficile, Helicobacter Pylori, trichomobal infection and amoebiasis, can show clinical manifestations such as cerebellar dysfunction, altered mental status and extrapyramidal symptoms.1) MIE has been reported mostly in adult cases without sex predisposition.1) The mechanism of neurotoxicity in MIE remains unclear though several mechanisms have been proposed.1,2) Hyperintensities of the dentate nuclei, the splenium of the corpus callosum and the midbrain on fluid attenuated inversion recovery (FLAIR) are considered to be typical for MIE.1,2) The signals of the lesions related to MIE are mostly symmetric but can be asymmetric on magnetic resonance imaging (MRI),1,3) and can show regions of hypointensity or hyperintensity on apparent diffusion coefficient (ADC) mapping.1,2) The onset of symptoms in MIE can be acute,4) but there has been no description in the literature of MIE mimicking an acute ischemic stroke.1,4)\n\nStroke mimic is an entity in which presentation mimicking acute ischemic stroke within the appropriate time-window from symptom onset can result in the erroneous administration of tissue plasminogen activator (t-PA), and can include cases of hypoglycemia, seizure, migraine, conversion disorder and drug intoxication.5) Here, we describe the first report of MIE mimicking an acute ischemic event in which t-PA was administrated.\n\nCase Report\nAn 86-year-old woman on her fourth week of metronidazole therapy for C. difficile enteritis was introduced to our department. The patient was at usual status at 18:40, but a nurse confirmed motor weakness of the left extremities and right conjugate deviation in the patient about 21:30. The patient was then transferred in our hospital at 22:18. On arrival, her Glasgow Coma Scale (GCS) was E1V2M5. We observed motor weakness predominantly in the left extremities, and in the right extremities to a lesser extent. Dysarthria was also confirmed, and an acute stroke event was suspected. National Institutes of Health Stroke Scale assessment was 23. Blood of the patient was collected on arrival for the examination. After we confirmed that apparent kidney failure did not exist with venous blood gas, the patient was soon moved for the examination of computed tomography (CT). CT did not show any apparent hemorrhagic lesions or early ischemic signs. The Alberta Stroke Program CT (ASPECT) Score was 10. CT angiography (CTA) did not demonstrate any major intracranial vascular stenosis or occlusion (Figs. 1A and 1B), and CT perfusion (CTP) showed a decreased cerebral blood flow in the right cerebral hemisphere. The blood flow seemed to decrease also in the left frontal and occipital regions (Fig. 1C). As diffuse peripheral embolic event was strongly suspected with the findings of CTP, t-PA was administrated at 22:58 after any contraindication was not confirmed with past medical history and blood examination. The neurological symptoms did not change after the administration of t-PA.\n\nMagnetic resonance imaging on FLAIR images signal intensity performed 20 hours after the onset revealed areas of hyperintensity in the splenium of the corpus callosum and the bilateral dentate nuclei, with the hyperintensity more prominent in the left dentate nucleus than in the right dentate nucleus (Figs. 2A and 2B). Diffusion weighted images (DWI) revealed bilateral areas of hyperintensity in the deep white matter, but did not reveal any remarkable change in the dentate nuclei. The hyperintensity in the left white matter was seen especially in the frontal and the parieto-occipital regions (Figs. 2C and 2D). The splenium of the corpus callosum and left dentate nucleus showed respectively isointensity and hyperintensity on ADC map. The deep white matter showed hypointensity corresponding to hyperintensity on DWI (Figs. 2E and 2F).\n\nAs the findings of MRIs were typical for MIE and atypical for acute ischemic stroke, we considered that the symptoms resulted from MIE, and subsequently ceased metronidazole therapy.\n\nHemorrhagic complications related to t-PA did not occur, but an epileptic seizure occurred on admission day 3. Levetiracetam of 2,000 mg was initiated. MRI on admission day 10 showed a decrease of hyperintensity on FLAIR, except in the splenium of the corpus callosum. The patient recovered gradually to the status of GCS E3V1M4, but the bilateral motor weakness remained. Tubal feeding was required, and she was transported to another hospital for rehabilitation therapy.\n\nDiscussion\nWe report a case of MIE mimicking an acute ischemic stroke for which t-PA was administrated. MIE was diagnosed in our case with typical findings on MRI performed 20 hours after the onset.\n\nThe administration of t-PA within 4.5 hours has become standard therapy for the treatment of acute ischemic stroke, and endovascular therapy is also strongly recommended, with CTA and CTP considered useful in determining the indications of t-PA and endovascular therapy.6) In our case, CTA did not show any apparent intracranial occlusion or stenosis, and we decided that endovascular therapy was not needed. However, due to the decrease of the blood flow in the right cerebral hemisphere detected on CTP, we were unable to completely eliminate an acute ischemic event from the differential diagnosis. In addition, transfer to our hospital was undertaken about 4 hours after the onset of the initial symptoms, and thus we did not have time to examine the patient with MRI. As a result, we administered t-PA. Among the cases where a t-PA was administrated for a stroke mimic, hypoglycemia, seizure, migraine, conversion disorder and drug intoxication have been reported. In our case, an epileptic seizure happened after the admission. The first symptom in our case could be also seizure related to MIE. To clarify the pathology of the first symptoms in our case under emergency situation, MRI during the administration of t-PA could be considered. Electroencephalography could be also effective to detect seizure. The erroneous administration of t-PA even for the stroke mimics is not considered to be contraindicative, and instead seen as preferable to missing a true acute ischemic stroke.5) Because the administration of t-PA in cases of stroke mimic has been reported to result in a low occurrence of symptomatic intracranial hemorrhage,5) t-PA should be administrated without hesitation when no contraindication of t-PA is confirmed in possible stroke patients like our case.\n\nThe relation of the radiological findings and the clinical symptoms in our case was interesting. MRI performed 20 hours after the onset showed typical findings for MIE. The lesions of the deep white matter shown as hyperintensity on DWI and hypointensity on ADC could result from cytotoxic edema related to MIE.2) These findings can be observed on CTP as the decrease of the blood flow in the bilateral cerebral hemispheres.\n\nEspecially in the left hemisphere, the lesions of the decrease of blood flow on CTP almost corresponded to the lesions of the deep white matter confirmed on MRI. In addition, hyperintensity on FLAIR was dominantly observed in the left dentate nucleus in our case. As the left dentate nucleus did not show hypointensity on ADC map, vasogenic edema or inflammation due to MIE was considered.1,2) As the right cerebral hemisphere is anatomically connected to the left dentate nucleus,7) the cell dysfunction due to vasogenic edema or inflammation of the left dentate nucleus demonstrated on ADC mapping might have caused right cerebral dysfunction as a remote effect. The right cerebral dysfunction could be then projected on CTP as a decrease of CBF (cerebral blood flow). The laterality of the findings of CTP in our case was possibly due to the remote effect existing only in the right hemisphere. Our hypothesis can be applied to explain the laterality of motor weakness in our case. However, our speculated mechanism requires further validation, as the findings of CTP concerning MIE are still lacking.\n\nAs a rapid assessment for the administration t-PA and endovascular therapy are strongly recommended based on the findings of CTA and CTP,6) metabolic diseases including MIE can also result in a presentation mimicking stroke. Our experience should be shared as a rare case of MIE mimicking an acute stroke event.\n\nConclusion\nWe reported a case of MIE mimicking an acute ischemic stroke. The findings of CTP resulting in our suspicion of an acute ischemic stroke could be related to the pathology of MIE. Although the administration of t-PA in cases MIE mimicking stroke is not contraindicative, our experience should be shared as the first report of MIE mimicking an acute ischemic event.\n\nAcknowledgment\nWe thank Paul Williams (Kurashiki Central Hospital) for his extensive proofreading of this article.\n\nConflicts of Interest Disclosure\n\nNone.\n\nFig. 1. CT images before the administration of t-PA. (A) No apparent hemorrhagic lesion was detected on computed tomography (CT). CTA (B) and CTP (C). (B) CTA demonstrating no apparent cerebral artery stenosis or occlusion. (C) CTP showing the decrease of the blood flow in the right cerebral hemisphere. The decrease of the blood flow was also seen in the frontal and occipital regions.\n\nFig. 2. MRIs 20 hours after the onset. MRI Axial fluid attenuated inversion recovery (FLAIR) (A and B), diffusion weighted image (DWI) (C and D), apparent diffusion coefficient (ADC) map (E and F). (A) FLAIR image demonstrating the hyperintensity in the splenium of the corpus callosum (arrow). (B) FLAIR image showing the hyperintensities in the bilateral dentate nuclei. Stronger hyperintensity revealed in the left dentate nucleus (arrow) than in the right dentate nucleus. (C) DWI showing the hyperintensity areas in the bilateral deep white matter. The hyperintensity in the left white matter was seen especially in the frontal and the parieto-occipital regions. (D) DWI showing no remarkable change in the dentate nuclei. (E) ADC map demonstrating the isointensity area in the splenium of the corpus callosum. (F) ADC map demonstrating dominantly the hyperintensity area in the left dentate nucleus (arrow).\n==== Refs\nReferences\n1) Roy U Panwar A Pandit A Das SK Joshi B : Clinical and neuroradiological spectrum of metronidazole induced encephalopathy: our experience and the review of literature . J Clin Diagn Res \n10 : OE01 –OE09 , 2016 \n2) Kim E Na DG Kim EY Kim JH Son KR Chang KH : MR imaging of metronidazole-induced encephalopathy: lesion distribution and diffusion-weighted imaging findings . AJNR Am J Neuroradiol \n28 : 1652 –1658 , 2007 17885234 \n3) Bahn Y Kim E Park C Park HC : Metronidazole induced encephalopathy in a patient with brain abscess . J Korean Neurosurg Soc \n48 : 301 –304 , 2010 21082066 \n4) Demel SL Jovin TG Jadhav AP : Metronidazole toxicity presenting with acute onset of aphasia and right sided weakness . J Clin Neurosci \n22 : 1199 –1200 , 2015 25796956 \n5) Tsivgoulis G Alexandrov AV Chang J : Safety and outcomes of intravenous thrombolysis in stroke mimics: a 6-year, single-care center study and a pooled analysis of reported series . Stroke \n42 : 1771 –1774 , 2011 21493900 \n6) Powers WJ Derdeyn CP Biller J American Heart Association Stroke Council : 2015 American Heart Association/American Stroke Association Focused Update of the 2013 Guidelines for the Early Management of Patients With Acute Ischemic Stroke Regarding Endovascular Treatment: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association . Stroke \n46 : 3020 –3035 , 2015 26123479 \n7) Milosević NT Ristanović D Marić DL Rajković K : Morphology and cell classification of large neurons in the adult human dentate nucleus: a quantitative study . Neurosci Lett \n468 : 59 –63 , 2010 19857549\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "0470-8105", "issue": "58(9)", "journal": "Neurologia medico-chirurgica", "keywords": "computed tomography perfusion; magnetic resonance imaging; metronidazole induced encephalopathy; stroke mimic; tissue plasminogen activator", "medline_ta": "Neurol Med Chir (Tokyo)", "mesh_terms": "D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D002545:Brain Ischemia; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D008795:Metronidazole; D020521:Stroke", "nlm_unique_id": "0400775", "other_id": null, "pages": "400-403", "pmc": null, "pmid": "30078820", "pubdate": "2018-09-15", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "26123479;17885234;25796956;21493900;19857549;21082066;27504340", "title": "Metronidazole Induced Encephalopathy Mimicking an Acute Ischemic Stroke Event.", "title_normalized": "metronidazole induced encephalopathy mimicking an acute ischemic stroke event" }

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NEUROL MED CHIR ?(TOKYO). 2018 AUG 3.", "literaturereference_normalized": "metronidazole induced encephalopathy mimicking an acute ischemic stroke event", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20180823", "receivedate": "20180823", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15310047, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20181010" }, { "companynumb": "JP-CHARTWELL PHARMA-2053921", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METRONIDAZOLE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "018845", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CLOSTRIDIUM DIFFICILE COLITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METRONIDAZOLE." } ], "patientagegroup": null, "patientonsetage": "86", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Encephalopathy", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "TAKADA K, MAKI Y, KINOSADA M, ISHIBASHI R, CHIN M, YAMAGATA S. METRONIDAZOLE INDUCED ENCEPHALOPATHY MIMICKING AN ACUTE ISCHEMIC STROKE EVENT. NEUROL MED CHIR (TOKYO). 2018 AUG 3. PMID: 30078820.", "literaturereference_normalized": "metronidazole induced encephalopathy mimicking an acute ischemic stroke event", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20180820", "receivedate": "20180820", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15293098, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20181010" }, { "companynumb": "JP-FLAMINGO-002083", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METRONIDAZOLE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "207309", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CLOSTRIDIUM DIFFICILE INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METRONIDAZOLE." } ], "patientagegroup": null, "patientonsetage": "86", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Ischaemic stroke", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Encephalopathy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "TAKADA K, MAKI Y, KINOSADA M, ISHIBASHI R, CHIN M, YAMAGATA S. METRONIDAZOLE INDUCED ENCEPHALOPATHY MIMICKING AN ACUTE ISCHEMIC STROKE EVENT. NEUROL MED CHIR ?(TOKYO). 2018 AUG 3.", "literaturereference_normalized": "metronidazole induced encephalopathy mimicking an acute ischemic stroke event", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20190212", "receivedate": "20180823", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15310048, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20190417" }, { "companynumb": "JP-ALEMBIC PHARMACUETICALS LIMITED-2019SCAL000084", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METRONIDAZOLE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "079067", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CLOSTRIDIUM DIFFICILE COLITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METRONIDAZOLE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Disorientation", "reactionmeddraversionpt": "21.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Dysarthria", "reactionmeddraversionpt": "21.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Coma scale abnormal", "reactionmeddraversionpt": "21.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Gaze palsy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Epilepsy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Muscular weakness", "reactionmeddraversionpt": "21.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Toxic encephalopathy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "TAKADA K, MAKI Y, KINOSADA M, ISHIBASHI R, CHIN M, YAMAGATA S. METRONIDAZOLE INDUCED ENCEPHALOPATHY MIMICKING AN ACUTE ISCHEMIC STROKE EVENT. NEUROLOGIA MEDICO-CHIRURGICA. 2018?58 (9):400-403", "literaturereference_normalized": "metronidazole induced encephalopathy mimicking an acute ischemic stroke event", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20190218", "receivedate": "20190218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15974610, "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" }, { "companynumb": "JP-TOLMAR, INC.-TOLG20180458", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METRONIDAZOLE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "090903", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": "UNKNOWN", "drugenddate": null, "drugenddateformat": null, "drugindication": "CLOSTRIDIUM DIFFICILE COLITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METRONIDAZOLE." } ], "patientagegroup": null, "patientonsetage": "86", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Eye movement disorder", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Toxic encephalopathy", "reactionmeddraversionpt": "21.0", "reactionoutcome": "4" }, { "reactionmeddrapt": "Muscular weakness", "reactionmeddraversionpt": "21.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Epilepsy", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dysarthria", "reactionmeddraversionpt": "21.0", "reactionoutcome": "4" }, { "reactionmeddrapt": "Disorientation", "reactionmeddraversionpt": "21.0", "reactionoutcome": "4" } ], "summary": null }, "primarysource": { "literaturereference": "TAKADA K, MAKI Y, KINOSADA M, ISHIBASHI R, CHIN M, YAMAGATA S. METRONIDAZOLE INDUCED ENCEPHALOPATHY MIMICKING AN ACUTE ISCHEMIC STROKE EVENT. NEUROL MED CHIR (TOKYO). 2018 AUG 03?.", "literaturereference_normalized": "metronidazole induced encephalopathy mimicking an acute ischemic stroke event", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20180819", "receivedate": "20180819", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15292711, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20181010" } ]

{ "abstract": "Limited information is available on the efficacy of post-transplantation cyclophosphamide (PTcy) or thymoglobulin for graft-versus-host disease (GVHD) prophylaxis in mismatched unrelated donor (MMUD) transplants. We retrospectively compared outcomes of 76 adult patients with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) who underwent 7/8 HLA-MMUD transplantation and received either PTcy (50 mg/kg on day 3 and 4) or thymoglobulin (total dose 4.5 mg/kg) for GVHD prophylaxis. In addition, tacrolimus and mycophenolate were used in both groups. Propensity score-based multivariable analyses (PSCA) were performed to adjust confounding effects of patient characteristics between both groups. Between January 2006 and June 2019, 25 patients received PTcy, and 51 received thymoglobulin. Median age of the population was 57 years, 78% of patients had AML, most common graft source was peripheral blood (96%), and 46% received myeloablative conditioning regimens. Median time to neutrophil (15 versus 11 days, P < .001) and platelet engraftment (21 versus 15 days, P = .002) was prolonged in the PTcy group. The cumulative incidence of grade III-IV acute GVHD at day 100 was similar (12% versus 19.6%, P = .38), whereas chronic GVHD at 1 year was lower with PTcy compared to thymoglobulin (16% versus 49%, P = .006). Using PSCA, no difference in survival, relapse, relapse-free survival, and GVHD-free relapse-free survival was seen between groups. However, thymoglobulin was associated with higher incidence of acute (hazard ratio [HR] = 2.63, P = .01) and chronic GVHD (HR = 4.43, P = .03), and non-relapse mortality (HR 3.38, P = .04) compared to PTcy. Our study demonstrated that PTcy resulted in significantly lower rates of acute and chronic GVHD and non-relapse mortality compared to thymoglobulin in 7/8 HLA-MMUD transplants for AML and MDS.", "affiliations": "Department of Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, Michigan. Electronic address: drdipen228@gmail.com.;Department of Internal Medicine and Pediatrics, DMC and Children's Hospital of Michigan, Detroit, Michigan.;Biostatistics Core, Barbara Ann Karmanos Cancer Institute, Department of Oncology, Wayne State University, Detroit, Michigan.;Department of Oncology, Blood and Marrow Stem Cell Transplant Program, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, Michigan.;Department of Oncology, Blood and Marrow Stem Cell Transplant Program, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, Michigan.;Department of Oncology, Blood and Marrow Stem Cell Transplant Program, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, Michigan.;Department of Oncology, Blood and Marrow Stem Cell Transplant Program, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, Michigan.", "authors": "Modi|Dipenkumar|D|;Kondrat|Kyle|K|;Kim|Seongho|S|;Deol|Abhinav|A|;Ayash|Lois|L|;Ratanatharathorn|Voravit|V|;Uberti|Joseph P|JP|", "chemical_list": "D000961:Antilymphocyte Serum; D003520:Cyclophosphamide; C512542:thymoglobulin", "country": "United States", "delete": false, "doi": "10.1016/j.jtct.2021.06.018", "fulltext": null, "fulltext_license": null, "issn_linking": "2666-6367", "issue": "27(9)", "journal": "Transplantation and cellular therapy", "keywords": "Acute myeloid leukemia; Allogeneic stem cell transplant; Antithymocyte globulin (thymoglobulin); Cytokine release syndrome; Mismatched unrelated donor; Myelodysplastic syndrome; Post-transplantation cyclophosphamide", "medline_ta": "Transplant Cell Ther", "mesh_terms": "D000328:Adult; D000961:Antilymphocyte Serum; D003520:Cyclophosphamide; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008875:Middle Aged; D009190:Myelodysplastic Syndromes; D012189:Retrospective Studies; D061349:Unrelated Donors", "nlm_unique_id": "101774629", "other_id": null, "pages": "760-767", "pmc": null, "pmid": "34174469", "pubdate": "2021-09", "publication_types": "D016428:Journal Article", "references": null, "title": "Post-transplant Cyclophosphamide Versus Thymoglobulin in HLA-Mismatched Unrelated Donor Transplant for Acute Myelogenous Leukemia and Myelodysplastic Syndrome.", "title_normalized": "post transplant cyclophosphamide versus thymoglobulin in hla mismatched unrelated donor transplant for acute myelogenous leukemia and myelodysplastic syndrome" }

[ { "companynumb": "US-MYLANLABS-2022M1032958", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": "090596", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.03 MILLIGRAM/KILOGRAM, QD, FROM DAY 5", "drugenddate": null, "drugenddateformat": null, "drugindication": "Prophylaxis against graft versus host disease", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "0.03", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": "203859", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Injection", "drugdosagetext": "15 MILLIGRAM/KILOGRAM, BID, FROM DAY 5 THROUGH DAY 30", "drugenddate": null, "drugenddateformat": null, "drugindication": "Prophylaxis against graft versus host disease", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "15", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MILLIGRAM/KILOGRAM, ON DAY 3 AND 4", "drugenddate": null, "drugenddateformat": null, "drugindication": "Prophylaxis against graft versus host disease", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Transplant failure", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Modi D, Kondrat K, Kim S, Deol A, Ayash L, Ratanatharathorn V, et al. Post-transplant Cyclophosphamide Versus Thymoglobulin in HLA-Mismatched Unrelated Donor Transplant for Acute Myelogenous Leukemia and Myelodysplastic Syndrome. Transplant-Cell-Ther 2021;27(9):760-767.", "literaturereference_normalized": "post transplant cyclophosphamide versus thymoglobulin in hla mismatched unrelated donor transplant for acute myelogenous leukemia and myelodysplastic syndrome", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20220506", "receivedate": "20220506", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 20794470, "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" } ]

{ "abstract": "We present the case of a 25-year-old woman who, although normotensive on presentation, had a severe hypotensive episode more than 12 h after initial ingestion of sustained release verapamil. Management of asymptomatic patients who have overdosed on a sustained release preparation of a calcium channel blocker is discussed.", "affiliations": "Department of Emergency Medicine, Stanford University Medical Center, California 94305.", "authors": "Tom|P A|PA|;Morrow|C T|CT|;Kelen|G D|GD|", "chemical_list": "D003692:Delayed-Action Preparations; D014700:Verapamil", "country": "United States", "delete": false, "doi": "10.1016/0736-4679(94)90414-6", "fulltext": null, "fulltext_license": null, "issn_linking": "0736-4679", "issue": "12(5)", "journal": "The Journal of emergency medicine", "keywords": null, "medline_ta": "J Emerg Med", "mesh_terms": "D000328:Adult; D003692:Delayed-Action Preparations; D004562:Electrocardiography; D005260:Female; D006327:Heart Block; D006801:Humans; D007022:Hypotension; D011041:Poisoning; D013997:Time Factors; D014700:Verapamil", "nlm_unique_id": "8412174", "other_id": null, "pages": "621-5", "pmc": null, "pmid": "7989689", "pubdate": "1994", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Delayed hypotension after overdose of sustained release verapamil.", "title_normalized": "delayed hypotension after overdose of sustained release verapamil" }

[ { "companynumb": "US-RECRO GAINESVILLE LLC-REPH-2018-000037", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "VERAPAMIL HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "019614", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "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": "VERAPAMIL HYDROCHLORIDE SUSTAINED RELEASE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Arrhythmia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOM, PRENTICE A., MORROW, CHRISTOPHER T., KELEN, GABOR D.. DELAYED HYPOTENSION AFTER OVERDOSE OF SUSTAINED RELEASE VERAPAMIL. THE JOURNAL OF EMERGENCY MEDICINE. 1994?12:5:621?25", "literaturereference_normalized": "delayed hypotension after overdose of sustained release verapamil", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20180717", "receivedate": "20180717", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15156251, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20181010" }, { "companynumb": "US-PFIZER INC-2018331688", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "VERAPAMIL HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "019152", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "MODIFIED-RELEASE TABLET", "drugdosagetext": "UNK (INGESTING FIVE TO TEN 240MG CALAN SR TABLETS)", "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": "CALAN SR" } ], "patientagegroup": null, "patientonsetage": "25", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "50", "reaction": [ { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Atrioventricular block first degree", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anuria", "reactionmeddraversionpt": "21.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Electrocardiogram QRS complex prolonged", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Atrioventricular block second degree", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dizziness", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Asthenia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOM, P.. DELAYED HYPOTENSION AFTER OVERDOSE OF SUSTAINED RELEASE VERAPAMIL. THE JOURNAL OF EMERGENCY MEDICINE.. 1994?12?5:621?625", "literaturereference_normalized": "delayed hypotension after overdose of sustained release verapamil", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20180828", "receivedate": "20180820", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15296991, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20181010" } ]

{ "abstract": "Preclinical research and prior clinical observations demonstrated reduced toxicity and suggested enhanced efficacy of cisplatin due to folic acid and vitamin B12 suppletion. In this randomized phase 2 trial, we evaluated the addition of folic acid and vitamin B12 to first-line palliative cisplatin and gemcitabine in patients with advanced esophagogastric cancer (AEGC).\n\n\n\nPatients with AEGC were randomized to gemcitabine 1250 mg/m2 (i.v. days 1, 8) and cisplatin 80 mg/m2 (i.v. day 1) q 3 weeks with or without folic acid (450 µg/day p.o.) and vitamin B12 (1000 µg i.m. q 9 weeks). The primary endpoint was response rate (RR). Secondary endpoints included overall survival (OS), time to progression (TTP), toxicity, and exploratory biomarker analyses. Cisplatin sensitivity and intracellular platinum levels were determined in adenocarcinoma cell lines cultured under high and low folate conditions in vitro.\n\n\n\nAdenocarcinoma cells cultured in medium with high folate levels were more sensitive to cisplatin and this was associated with increased intracellular platinum levels. In the randomized phase 2 clinical trial, which ran from October 2004 to September 2013, treatment was initiated in 78 of 82 randomized pts, 39 in each study arm. The RR was similar; 42.1% for supplemented patients vs. 32.4% for unsupplemented patients; p = 0.4. Median OS and TTP were 10.0 and 5.9 months for supplemented vs. 7.7 and 5.4 months for unsupplemented patients (OS, p = 0.9; TTP, p = 0.9). Plasma homocysteine was lower in the supplemented group [n = 20, 6.9 ± 1.6 (mean ± standard error of mean, SEM) µM; vs. 12.5 ± 4.0 µM; p < 0.001]. There was no significant difference in the Cmax of gemcitabine and cisplatin in the two treatment groups.\n\n\n\nFolic acid and vitamin B12 supplementation do not improve the RR, PFS, or OS of cisplatin and gemcitabine in patients with AEGC.", "affiliations": "Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.;Department of Internal Medicine, Amstelland Hospital, Amstelveen, The Netherlands.;Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.;Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.;Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.;Department of Internal Medicine, Noordwest Ziekenhuisgroep Alkmaar, Alkmaar, The Netherlands.;Department of Medical Oncology, Georgetown University Medical Center, Washington, DC, USA.;Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.;Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.;Department of Medical Oncology, VU University Medical Center, Room 3A38, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. jj.vandervliet@vumc.nl.", "authors": "van Zweeden|A A|AA|;van Groeningen|C J|CJ|;Honeywell|R J|RJ|;Giovannetti|E|E|;Ruijter|R|R|;Smorenburg|C H|CH|;Giaccone|G|G|;Verheul|H M W|HMW|;Peters|G J|GJ|;van der Vliet|Hans J|HJ|", "chemical_list": "D003841:Deoxycytidine; D005492:Folic Acid; C056507:gemcitabine; D014805:Vitamin B 12; D002945:Cisplatin", "country": "Germany", "delete": false, "doi": "10.1007/s00280-018-3588-6", "fulltext": "\n==== Front\nCancer Chemother PharmacolCancer Chemother. PharmacolCancer Chemotherapy and Pharmacology0344-57041432-0843Springer Berlin Heidelberg Berlin/Heidelberg 358810.1007/s00280-018-3588-6Original ArticleRandomized phase 2 study of gemcitabine and cisplatin with or without vitamin supplementation in patients with advanced esophagogastric cancer van Zweeden A. A. 12van Groeningen C. J. 2Honeywell R. J. 1Giovannetti E. 1Ruijter R. 1Smorenburg C. H. 3Giaccone G. 4Verheul H. M. W. 1Peters G. J. 1van der Vliet Hans J. 31-20-4445152jj.vandervliet@vumc.nl 51 0000 0004 0435 165Xgrid.16872.3aDepartment of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands 2 Department of Internal Medicine, Amstelland Hospital, Amstelveen, The Netherlands 3 Department of Internal Medicine, Noordwest Ziekenhuisgroep Alkmaar, Alkmaar, The Netherlands 4 0000 0001 2186 0438grid.411667.3Department of Medical Oncology, Georgetown University Medical Center, Washington, DC USA 5 0000 0004 0435 165Xgrid.16872.3aDepartment of Medical Oncology, VU University Medical Center, Room 3A38, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands 25 4 2018 25 4 2018 2018 82 1 39 48 5 1 2018 20 4 2018 © The Author(s) 2018\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.Purpose\nPreclinical research and prior clinical observations demonstrated reduced toxicity and suggested enhanced efficacy of cisplatin due to folic acid and vitamin B12 suppletion. In this randomized phase 2 trial, we evaluated the addition of folic acid and vitamin B12 to first-line palliative cisplatin and gemcitabine in patients with advanced esophagogastric cancer (AEGC).\n\nMethods\nPatients with AEGC were randomized to gemcitabine 1250 mg/m2 (i.v. days 1, 8) and cisplatin 80 mg/m2 (i.v. day 1) q 3 weeks with or without folic acid (450 µg/day p.o.) and vitamin B12 (1000 µg i.m. q 9 weeks). The primary endpoint was response rate (RR). Secondary endpoints included overall survival (OS), time to progression (TTP), toxicity, and exploratory biomarker analyses. Cisplatin sensitivity and intracellular platinum levels were determined in adenocarcinoma cell lines cultured under high and low folate conditions in vitro.\n\nResults\nAdenocarcinoma cells cultured in medium with high folate levels were more sensitive to cisplatin and this was associated with increased intracellular platinum levels. In the randomized phase 2 clinical trial, which ran from October 2004 to September 2013, treatment was initiated in 78 of 82 randomized pts, 39 in each study arm. The RR was similar; 42.1% for supplemented patients vs. 32.4% for unsupplemented patients; p = 0.4. Median OS and TTP were 10.0 and 5.9 months for supplemented vs. 7.7 and 5.4 months for unsupplemented patients (OS, p = 0.9; TTP, p = 0.9). Plasma homocysteine was lower in the supplemented group [n = 20, 6.9 ± 1.6 (mean ± standard error of mean, SEM) µM; vs. 12.5 ± 4.0 µM; p < 0.001]. There was no significant difference in the Cmax of gemcitabine and cisplatin in the two treatment groups.\n\nConclusion\nFolic acid and vitamin B12 supplementation do not improve the RR, PFS, or OS of cisplatin and gemcitabine in patients with AEGC.\n\nKeywords\nEsophagogastric cancerCisplatinGemcitabineVitamin B12Folic acidhttp://dx.doi.org/10.13039/100010806Amgen Nederlandhttp://dx.doi.org/10.13039/100004312Eli Lilly and Companyissue-copyright-statement© Springer-Verlag GmbH Germany, part of Springer Nature 2018\n==== Body\nIntroduction\nEsophagogastric cancer is one of the most common malignancies of the gastrointestinal tract worldwide. These cancers encompass malignant epithelial neoplasms located in all regions of the esophagus and stomach irrespective of the histological type. In the majority of cases, the malignancies are adenocarcinomas (AC) or squamous cell carcinomas (SCC). The incidence of SCC has largely remained constant over time, while the incidence of AC has increased [1]. Treatment for metastatic disease is palliative and frequently consists of combination chemotherapy and/or radiotherapy. The goals of palliative systemic chemotherapy are survival benefit and palliation of symptoms [2, 3]. Cisplatin has been considered a key substance in combination regimens for metastatic gastro-esophageal cancer [4]. Results from a phase 2 study at our institute showed a response rate (RR) of 41% using the combination of cisplatin and gemcitabine, with manageable toxicity [5]. Treatment with pemetrexed plus cisplatin and vitamin supplementation resulted in superior survival time, time to progression, and response rates compared with treatment with cisplatin alone in patients with malignant mesothelioma in the EMPHACIS trial [6]. The majority of patients in this study received folic acid and vitamin B12. Vitamin suppletion significantly reduced toxicity of the chemotherapy and did not decrease efficacy parameters. Vitamin suppletion was found to be predictive of increased overall survival in a multivariate regression analysis of prognostic factors derived from this trial [7]. Preclinical evidence demonstrated that differences in the folate environment resulted in a different sensitivity of human cancer cell lines to cisplatin [8, 9]. Tumor cells that are relatively cisplatin resistant require lower intracellular folate concentrations for growth [10]. In line, low tumor cell expression levels of the folate receptor (FR), which is a major influx transporter for folates in normal tissues and certain tumors [11], are associated with cisplatin resistance [12, 13]. In this paper, we first investigated the cisplatin sensitivity of adenocarcinoma cell lines grown under high or low folate conditions. Adenocarcinoma cells grown under high folate conditions were more sensitive to cisplatin and this was associated with higher intracellular platinum accumulation, providing a rationale for supplementation of patients with folates. Based on these in vitro data and the clinical suggestion of increased efficacy in mesothelioma patients we hypothesized that folate supplementation to patients would increase the sensitivity to cisplatin-based treatment. We designed a randomized phase 2 trial to determine whether supplementation of folic acid and vitamin B12 could increase the efficacy of gemcitabine and cisplatin in advanced esophagogastric cancer.\n\nPatients and methods\nEffect of folic acid supplementation on intratumoral accumulation of cisplatin and tumor cell sensitivity to cisplatin\nTo determine whether and how folic acid supplementation would affect sensitivity to cisplatin we tested the cisplatin sensitivity of two pairs of adenocarcinoma cell lines WiDr and CaCo-2 and their sublines (WiDr/LF, CaCo-2/LF/LV and CaCo-2/LF/FA) adapted to grow under low folate conditions [13, 14]. Due to the unavailability of modified esophageal adenocarcinoma cell lines, adenocarcinoma cell lines of colorectal origin were used for this purpose. Standard mycoplasma testing was performed. Wild type WiDr and CaCo-2 are cultured in standard DMEM medium containing 8 µM folic acid, WiDr/LF and CaCo-2/LF/LV have been selected to grow in folate-free RPMI medium supplemented with 2.5 and 1 nM leucovorin, respectively, while CaCo-2/LF/FA is adapted to grow in RPMI medium supplemented with 1 nM folic acid. Sensitivity of these cells to cisplatin was determined by a 72 h exposure to cisplatin alone or in combination with gemcitabine using the sulforodamide B (SRB) assay [15]. We also determined whether folate supplementation would affect the accumulation of cisplatin into these cells. Intracellular platinum concentrations were determined as described earlier [16].\n\nClinical study design and study population\nThe clinical study was a multicenter randomized open label phase 2 study comparing therapy with gemcitabine and cisplatin with or without vitamin B12 and folic acid supplementation. From October 2004 to August 2013, 82 patients were included in the study. The study recruited patients in the VU University medical center (VUmc) in Amsterdam, The Netherlands and the Noordwest Ziekenhuisgroep in Alkmaar, The Netherlands. Main inclusion criteria included histologically or cytologically confirmed metastatic or locally advanced unresectable advanced esophagogastric carcinoma (AEGC), squamous cell or adenocarcinoma, not amenable to curative treatment, measurable disease according to RECIST [17], age of at least 18 years, ECOG performance score of 0–2, life expectancy of at least 12 weeks, adequate bone marrow function, adequate renal function, and adequate hepatic function. Prior surgery, chemotherapy and/or radiotherapy in the neo-adjuvant or adjuvant setting was allowed as long as the chemotherapy was completed at least 6 months prior to entry of the study. Written informed consent was obtained from all patients prior to inclusion into the study. Patients with known symptomatic metastasis in the central nervous system (CNS) or suffering from any serious concomitant systemic disorders incompatible with study treatment were not eligible. Other exclusion criteria were treatment with any investigational agent in the month prior to inclusion or prior diagnosis of other malignant disease (excluding adequately treated in situ carcinoma of the cervix and non-melanoma skin cancer, low grade prostate carcinoma or any other non-relapsed malignancy that was treated more than 5 years before diagnosis). Randomization was performed by the data management center of the Integraal Kanker Center Amsterdam (IKA) using a computerized randomization system. The institutional Medical Ethical board of the VUmc and Noordwest Ziekenhuisgroep approved the trial, which was in accordance with the Declaration of Helsinki and Good Clinical Practice.\n\nStudy treatment\nPatients were randomized to receive treatment with gemcitabine 1250 mg/m2 intravenously (i.v.) on days 1 and 8 in combination with cisplatin 80 mg/m2 i.v. on day 1 in a 3 weekly cycle with or without vitamin supplementation, further described as supplemented vs. unsupplemented patients, respectively.\n\nVitamin supplementation consisted of folic acid 450 µg/24 h per os (p.o.), starting at least 1 week prior to chemotherapy and finishing at least 3 weeks after the last treatment dose, and vitamin B12 1000 µg (1 vial intramuscularly, i.m.) every 9 weeks, starting 1 week before chemotherapy and finishing at least 3 weeks after the last treatment dose.\n\nPatients were treated with up to six cycles of chemotherapy. Study treatment was discontinued in case of progressive disease, unacceptable toxicity or upon patient request.\n\nEndpoints\nThe primary endpoint of this study was to determine whether supplementation of folic acid and vitamin B12 could increase the response rate (RR) of patients with advanced esophagogastric cancer treated with the combination of gemcitabine and cisplatin. Secondary endpoints were assessment of time to progression (TTP), defined as the time from randomization to progression and overall survival (OS), defined as the time from randomization to death. Further secondary objectives included the assessment of plasma homocysteine concentrations as an indication for plasma folic acid homeostasis. Moreover, we investigated the effect of folate supplementation on plasma pharmacokinetics of cisplatin (total and free unbound), gemcitabine, the gemcitabine degradation product 2′,2′-difluoro-2′-deoxyuridine (dFdU) and, in white blood cells (WBC), its active metabolite gemcitabine–triphosphate (dFdCTP). We also determined polymorphisms in the genes encoding methylenetetrahydrofolate reductase (MTHFR), which may affect folate homeostasis [11], and cytidine deaminase (CDA), that catalyzes the deamination of gemcitabine to dFdU [18].\n\nToxicity evaluation, dose adjustments and response assessment\nTreatment toxicity was rated according to CTC version 2.0 (CTCAE v2.0 Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events, Version 2.0, DCTD, NCI, NIH, DHHS) (http://ctep.cancer.gov). All serious adverse events (SAE) were collected from registration until 30 days after the last protocol treatment administration. Criteria for chemotherapy administration on day 1 of each cycle was delayed 1 week in case of neutropenia (absolute neutrophil count (ANC) of < 1.5 × 109/L) or thrombopenia (platelets < 100 × 109/L), renal toxicity (creatinine > 120 µmol/L, and/or creatinine clearance < 60 mL/min) or any non-haematological toxicity above CTC grade 1 or baseline. Gemcitabine was reduced on day 8 with 25 or 50% in case of grade 2 or 3 neutropenia or grade 1 or 2 thrombopenia, respectively. Platelets < 50 × 109/L or neutrophils < 0.5 × 109/L were reason to omit gemcitabine on day 8. The dose of gemcitabine was reduced 50% in case of grade 3 non-haematological toxicity (except emesis) and discontinued in case of grade 4 AE’s. The doses of gemcitabine and cisplatin were reduced with 25% after a 2 week treatment delay due to toxicity, neutropenic fever, grade 4 neutropenia and/or thrombopenia lasting over 1 week or thrombopenia associated with bleeding. Cisplatin was reduced or discontinued in case of grade ≥ 2 peripheral neuropathy or grade ≥ 2 renal toxicity or other grade ≥ 3 non-haematological toxicity (except emesis). No dose escalations were allowed. Unacceptable toxicity was defined as failure to recover from side effects after a treatment delay of a maximum of 3 weeks, requirement of a third dose reduction, the repeated occurrence of grade 3 or 4 non-haematological toxicity or drug-induced pneumonitis ≥ grade 2 or according to investigator’s judgement. Tumor assessments by CT scan of chest and abdomen were performed every 6 weeks until disease progression according to RECIST [17]. A baseline scan was done within 4 weeks before initiation of study therapy. Disease status, date of progression, date of death and subsequent lines of therapy were collected during regular follow-up visits. TTP was defined as the time from randomization to progression. OS was defined as the time from randomization to death.\n\nAssessment of potential predictive parameters\nPlasma pharmacokinetics of gemcitabine, its metabolite dFdU and cisplatin were measured during treatment in the first 20 patients to assess whether vitamin supplementation would affect either gemcitabine or cisplatin pharmacokinetics. We also determined the concentration of dFdCTP in WBC and the homocysteine concentration in these 20 patients. The other patients were monitored for homocysteine before randomization and at the beginning of each 3rd chemotherapy cycle (1 week after vitamin B12 administration). To assess these parameters, blood was collected in heparinized tubes containing tetrahydrouridine to prevent conversion of gemcitabine to dFdU. After centrifugation the plasma was taken off and stored at − 20 °C until analysis. The intermediate layer between plasma and red blood cells containing the WBC was layered on Ficoll–Hypaque, centrifuged and the buffy coat with the WBC was washed, counted and the pellet was frozen in liquid nitrogen until analysis for dFdCTP. Gemcitabine, dFdU and dFdCTP were measured with validated HPLC assays [16]. Homocysteine was measured as described earlier [19]. To determine the amount of total and free (non-protein) bound platinum species, one part was immediately frozen at − 20 °C until analysis (total platinum), and the other part was mixed with ethanol, incubated overnight at − 20 °C, and centrifuged. The supernatant contained free platinum [20]. Free plasma platinum and total plasma platinum (free and protein-bound platinum) were determined using flameless atomic absorption spectroscopy [16, 20].\n\nThe 79A > C (rs2072671) CDA and 667C > T MTHFR polymorphism were analyzed in, respectively, 37 and 20 patients in this study to asses a possible association with response, survival and toxicity.\n\nStatistical analysis\nBased on a hypothesized 1.5-fold improvement in the RR from an anticipated 33% in the non-supplemented arm to 50% in the vitamin supplemented arm, a sample size of 82 patients (41 per study arm) was required. If the true RR difference between the study regimens would be ≥ 15%, there would be an approximate 90% probability of selecting the true superior arm. The unpaired t test was used to compare RR and the stratified log-rank test was used to compare survival rates between treatment groups. An intention to treat analysis was used for TTP and OS. OS and TTP were calculated using Kaplan–Meier estimates. The correlation between homocysteine levels in both treatment groups was determined with a 2-tailed t test. p values < 0.05 were considered statistically significant.\n\nResults\nHigh folate status increases sensitivity to cisplatin\nUnder normal (high folate) cell culture conditions CaCo-2 cells were more sensitive to cisplatin than WiDr cells (IC50 1.2 ± 0.2 µM for CaCo-2 vs. 6.4 ± 0.5 µM for WiDr, means ± SEM, p < 0.001). However, when cultured under low folate (LF) conditions these cell lines were two to five fold less sensitive to cisplatin (IC50 for CaCo-2-LF sublines CaCo-2-LF/LV, 5.6 ± 0.5 µM; p < 0.01 and CaCo-2-LF/FA 3.4 ± 0.3 µM; p < 0.02, and for WiDr/LF 10.1 ± 0.1 µM; p < 0.02), as shown in Fig. 1. The addition of gemcitabine to cisplatin resulted in a slight increase in cisplatin sensitivity, but the difference in IC50 between high and low folate containing medium remained the same.\n\n\nFig. 1 High folate conditions can increase sensitivity of adenocarcinoma cells to cisplatin. CaCo-2 and WiDr adenocarcinoma cell lines were treated with cisplatin and gemcitabine under high folate or low folate conditions. a CaCo-2 and sublines CaCo-2/LF/LV and CaCo-2/LF/FA; b WiDr. CaCo-2-LF sublines CaCo-2-LF/LV (IC50 5.6 ± 0.5 µM; p < 0.01), CaCo-2-LF/FA (IC50 3.4 ± 0.3 µM; p < 0.02), and WiDr/LF (IC50 10.1 ± 0.1 µM; p < 0.02) under low folate (LF) conditions were two to five fold less sensitive to cisplatin compared to culture under high folate conditions. LF low folate, FA folic acid reduced into the nM range, LV leucovorin reduced into the nM range\n\n\n\n\nTo investigate the mechanism behind the observed difference in cisplatin sensitivity of tumor cells cultured in medium containing different folate concentrations, tumor cells were exposed to 20 µM cisplatin for 24 h. WiDr cells accumulated more platinum than WiDr-LF cells (50 ± 0.5 vs. 28 ± 3 pmol/106 cells, respectively; p < 0.0001), while CaCo-2 cells (96 ± 16 pmol/106 cells) accumulated more platinum than CaCo-2-LF/LV (58 ± 8 pmol/106 cells; p < 0.05) or CaCo-2-LF/FA (44 ± 6 pmol/106 cells; p < 0.02). Co-incubation with gemcitabine resulted in a slight increase in cisplatin accumulation, especially under LF conditions (not shown). Overall, these data demonstrate that high folate conditions can increase sensitivity of adenocarcinoma cells to cisplatin, and that this is associated with higher intratumoral platinum accumulation, providing a rationale for supplementation of patients with folates.\n\nPatient characteristics\nA total of 82 patients were randomly assigned to each treatment arm (41 patients in each arm). Baseline characteristics were generally well matched between the two treatment arms (Table 1). The mean age of patients was 61 years (range 35–83). The majority of patients were male, and most (72%) suffered from advanced esophageal cancer. In 85–90% of patients the ECOG performance score was 0–1. Less than 10% of the supplemented patients and none of the unsupplemented patients had undergone prior treatment for esophagogastric carcinoma (two patients received palliative radiotherapy of the primary tumor, one patient received neo-adjuvant chemotherapy and one patient received prior chemoradiation). Treatment was initiated in 78 patients. Four patients did not receive chemotherapy after randomization. One patient, allocated to the vitamin group, deceased unexpectedly before the first chemotherapy, while another patient in the same treatment group was not eligible due to neutropenia. Two patients allocated to the treatment arm without vitamin suppletion were not eligible due to increasing renal impairment. These four patients could not be monitored for response but were included in the intention to treat analysis for TTP and OS.\n\n\nTable 1 Baseline patient and disease characteristics\n\n\tSupplemented patients\nN = 41\tUnsupplemented patients\nN = 41\t\nCharacteristic\t\n Mean age (range)\t61 year (50–78)\t61 (35–82)\t\n Gender (female/male)\t8/33\t8/33\t\n Primary tumor (stomach/esophagus)\t11/30\t12/29\t\n Tumor type (SCC/AC)\t8/33\t8/33\t\nPerformance status\t\n PS 0\t14 (34%)\t12 (29%)\t\n PS 1\t23 (56%)\t23 (56%)\t\n PS 2\t2 (5%)\t4 (10%)\t\n PS unknown\t2 (5%)\t2 (5%)\t\n Prior therapy\t4 (10%)\t0\t\n\n\n\nSafety and tolerability\nThe overall incidence of grade 3–5 AEs was comparable between the two treatment groups and probably caused by the chemotherapy (Table 2). Grade 3 leukopenia was the most common severe toxicity in supplemented patients (22%), while fatigue was the most common severe toxicity (24%) in unsupplemented patients. Three supplemented patients suffered from grade 4 thrombopenia. Grade 4 thrombopenia was reported in one unsupplemented patient. Two supplemented patients were diagnosed with an ischemic cerebrovascular accident (CVA) after two treatment cycles (grade 4 neurologic toxicity) and one patient was diagnosed with a hemorrhagic CVA three days after day 1 of the first chemotherapy cycle (grade 4 hemorrhage) and received no further study treatment. Two unsupplemented patients deceased shortly after the first chemotherapy cycle, in 1 case probably due to cardiac arrhythmias likely caused by cardiac metastases and in the other case due to the occurrence of cardiac failure. These events were considered to be most likely related to cisplatin chemotherapy and underlying predisposing conditions of the patients. These three patients could not be monitored for response but were included in the intention to treat analysis for PFS and OS.\n\n\nTable 2 Treatment related grade 3–5 AEs per study arm\n\nAdverse event\tSupplemented patients (n = 41), n (%)\tNon-supplemented patients (n = 41), n (%)\t\nGrade\tGrade\t\n3\t4\t5\t3\t4\t5\t\nFebrile neutropenia\t2 (5)\t\t\t1 (2)\t\t\t\nLeukopenia\t9 (22)\t\t\t4 (10)\t\t\t\nTrombopenia\t4 (10)\t3 (7)\t\t4 (10)\t1 (2)\t\t\nAnemia\t6(15)\t\t\t2 (5)\t\t\t\nFatigue\t4 (10)\t\t\t10 (24)\t\t\t\nCardiac\t1 (2)\t\t\t1 (2)\t\t2 (5)\t\nNeurologic\t1 (2)\t2 (5)\t\t5 (12)\t\t\t\nOtotoxicity\t\t\t\t1 (2)\t\t\t\nPulmonary\t\t\t\t1 (2)\t\t\t\nNausea\t4 (10)\t\t\t3 (7)\t\t\t\nVomiting\t2 (5)\t\t\t2 (5)\t\t\t\nAnorexia\t2 (5)\t\t\t5 (12)\t\t\t\nLiver\t1 (2)\t\t\t\t\t\t\nDiarrhea\t\t\t\t1 (2)\t\t\t\nPain\t\t\t\t1 (2)\t\t\t\nSkin\t1 (2)\t\t\t\t\t\t\nRenal/bladder\t5 (12)\t\t\t\t\t\t\nHemorrhage\t1 (2)\t1 (2)\t\t2 (5)\t\t\t\nInfection\t1 (2)\t\t\t1 (2)\t\t\t\nPercentages are rounded to whole numbers. For each grade 3/4/5 adverse event the maximum toxicity was noted per patient\n\n\n\n\nTwenty patients (in both treatment groups) were treated with darbepoetin alfa for chemotherapy induced anemia [21] with a hemoglobin response in 15 of these 20 patients. Darbepoetin did not increase toxicity.\n\nResponse rate, overall survival and time to progression\nResponse rate\nThirty-eight supplemented patients and 37 unsupplemented patients were evaluable for response. The RR was 42.1% (n = 16) for supplemented patients, all partial responses (PR). The RR for unsupplemented patients was 32.4% (n = 12), and consisted of PR in 29.7% (n = 11) and a complete response (CR) in 2.7% (n = 1) of patients. The RR was not significantly different between the two treatment groups, p = 0.4.\n\nOverall survival and time to progression\nThe median OS in this study was 10.0 months (range 0.3–42.6) for the supplemented arm vs. 7.7 months (range 0.03–46.7) for the unsupplemented arm. This difference was not statistically significant (p = 0.9). One patient was lost to follow-up and was censored for the OS analysis. According to the prespecified intention to treat analysis all other randomized patients were included in the survival analysis, including one patient who deceased between randomization and the start of study treatment and one patient who was treated with epirubicin and oxaliplatin instead of cisplatin–gemcitabine due to renal impairment. This patient was not included in the TTP analysis. Vitamin supplementation did not lead to a significantly different median TTP, 5.9 months (range 1.4–33.5) for supplemented patients vs. 5.4 months (range 1.4–30.9) for unsupplemented patients (p = 0.9). The Kaplan–Meier curves for OS and TTP are shown in Fig. 2.\n\n\nFig. 2 Kaplan–Meier curve for OS and TTP. The dotted line represents the supplemented arm, while the black line represents the unsupplemented arm. OS and TTP were not significantly different between the supplemented vs. the unsupplemented patients (median OS 10.0 months; range 0.3–42.6 vs. 7.7 months; range 0.03–46.7; p = 0.9; median TTP 5.9 months; range 1.4–33.5 vs. 5.4 months; range 1.4–30.9; p = 0.9)\n\n\n\n\nPharmacokinetic monitoring and assessment of potential prognostic parameters\nFollowing vitamin supplementation, homocysteine levels were lower in supplemented patients vs. unsupplemented patients (mean 6.9 ± 1.6 µM; range 6.2–7.2 vs. 12.5 ± 4.0 µM; range 11.7–13.4; p < 0.001), as shown in Fig. 3. This difference was expected, since homocysteine levels are inversely related to folate and vitamin B12 consumption. Compared to pre-randomization levels, vitamin supplementation decreased homocysteine levels in supplemented patients, while homocysteine increased when patients were randomized to the unsupplemented arm. This illustrates compliance to the allocated treatment arm. The maximum concentration (Cmax) of gemcitabine was identical for patients in both treatment groups (n = 20; Cmax 53.4 ± 18.6 (mean ± SEM) µM for supplemented vs. 53.2 ± 15.0 µM for unsupplemented pts). However, vitamin supplementation did change gemcitabine pharmacokinetics. For example, supplementation resulted in increased levels of the gemcitabine metabolite dFdU (Fig. 3; p < 0.05), and in addition also resulted in an increase in the formation of the active metabolite of gemcitabine dFdCTP (peak levels at 30 min 255 ± 190 vs. 133 ± 93 pmol/106 cells and at 90 min 298 ± 245 vs. 226 ± 101 pmol/106 cells; p > 0.1), though these results were not statistically significant. Vitamin supplementation led to a small, but not statistically significant, increase in total cisplatin levels (total platinum 15.7 ± 2.7 µM in the vitamin group vs. 14.8 ± 1.4 µM for patients without vitamin supplementation), and a significant increase in free (non-protein bound) platinum levels: 4.7 ± 1.7 µM in the vitamin group vs. 3.6 ± 0.7 µM without vitamin supplementation (p < 0.05). Genetic polymorphisms in the folate metabolizing enzyme MTHFR 677C > T were measured in 20 patients, while polymorphisms in the gemcitabine metabolizing enzyme CDA 79A > C were measured in 37 patients. For the CDA gene, neither the OS (p = 0.56; Log-rank; Mantel–Cox test), TTP (p = 0.61; Log-rank; Mantel–Cox test) nor the RR (p = 0.46, ANOVA test) differed significantly between the patients with the AA, CC or AC variant, although analyzed patient numbers may be too small to formally rule out smaller differences (Table 3). Similarly, the incidence of grade 3 toxicity of any cause was not statistically significantly different between patients with either of the three polymorphisms (p = 0.9).The OS (p = 0.90 Log-rank; Mantel–Cox test), TTP (p = 0.89 Log-rank; Mantel–Cox test) and RR (p = 0.42 ANOVA test) were not significantly different for patients with a TT, CC or CT MTHFR 677. Again numbers may be considered too small for a reliable comparison. Grade 3 toxicity of any cause was equally distributed between the different polymorphisms.\n\n\nFig. 3 Plasma concentrations of homocysteine and dFdU in vitamin supplemented and unsupplemented the patients from the pharmacokinetics cohort. a The black line represents the supplemented arm, while the dotted line represents the unsupplemented arm. Values are means ± SEM from ten patients in each cohort. Homocysteine levels were lower in supplemented patients vs. unsupplemented patients (mean 6.9 ± 1.6 µM; range 6.2–7.2 vs. 12.5 ± 4.0 µM; range 11.7–13.4; p < 0.001); b The black line represents the supplemented arm, while the dotted line represents the unsupplemented arm. Supplementation resulted in increased levels of the gemcitabine metabolite dFdU (p < 0.05). Values are means ± SEM from 10 to 7 patients, respectively\n\n\n\n\n\nTable 3 CDA and MTHFR gene polymorphisms in relation to outcome and toxicity\n\n\tAA\nn = 22\tCC\nn = 7\tAC\nn = 8\tTT\nn = 2\tCC\nn = 6\tCT\nn = 12\t\nClinical parameter\t\n OS (months)\t7.8 (SD 9.1)\t17.3 (SD 13.7)\t10.1 (SD 3.1)\t11.0 (SD 12.4)\t5.0 (SD 19.3)\t9.8 (SD 11.0)\t\n TTP (months)\t5.5 (SD 12.9)\t9.0 (SD 8.6)\t6.8 (SD 2.0)\t10.5 (−)\t1.9 (SD 12.8)\t6.4 (SD 9.0)\t\n PR/CR\tn = 8\tn = 3\tn = 5\tn = 1\tn = 1\tn = 6\t\n RR (%)\t36\t43\t63\t50\t17\t50\t\n Grade 3 toxicity\tn = 12 (55%)\tn = 4 (57%)\tn = 5 (63%)\tn = 1 (50%)\tn = 3 (50%)\tn = 6 (50%)\t\n Grade 4 toxicity\t–\t–\tN = 1 (13%)\t–\t–\t–\t\nPolymorphisms in the gene for CDA were measured in 37 patients. The AA variant was found in 22 patients, the CC variant in 7 patients and AC variant in 8 patients. Polymorphisms in the gene for MTHFR were measured in 20 patients. The TT variant was found in 2 patients, the CC variant in 6 patients and CT variant in 12 patients\n\nOS overall survival (median months), TTP time to progression (median months), RR response rate (%), PR partial response, CR complete response, SD standard deviation\n\n\n\n\nDiscussion\nIn this study we demonstrate that the combination of gemcitabine and cisplatin can be considered an effective palliative chemotherapeutic regime in patients with AEGC. The median combined OS of 9.2 months and TTP of 5.4 months in our study is comparable with the currently commonly used first-line palliative chemotherapy regimens for AEGC. The current standard first-line palliative chemotherapy for AEGC consists of triplet chemotherapy regimens such as EOX (epirubicin, oxaliplatin and capecitabine, OS/PFS 11.2/7.0 months), ECX (epirubicin, cisplatin, capecitabine, OS/PFS 9.9/6.7 months) or EOF (epirubicin, oxaliplatin and fluorouracil, OS/PFS 9.3/6.5 months) [22] or doublet therapies (fluorouracil, leucovorin in combination with oxaliplatin or cisplatin, OS/PFS resp. 10.7/5.8 vs. 8.8/3.9 months) [23], or capecitabine and oxaliplatin, OS 8 months [24]. A recent meta-analysis showed a limited survival benefit of triplet chemotherapy with an increased risk of toxicity when compared to doublet chemotherapy [25]. Cisplatin and gemcitabine have a different side effect profile compared with oxaliplatin-based chemotherapy regimens. Cisplatin is associated with a higher incidence of grade 3–4 neutropenia, alopecia, thromboembolism, and renal dysfunction, while peripheral neuropathy and diarrhea is a more frequent side effect of oxaliplatin [26, 27]. The intravenous administration route of cisplatin and gemcitabine can be a relevant consideration for patients with AEGC and problems with the passage of food (and oral medication such as, e.g., capecitabine) as a result of obstruction caused by the primary tumor. Therefore, the here employed cisplatin and gemcitabine treatment combination can be considered a reasonable or perhaps even preferred palliative treatment option for AEGC patients with, e.g., signs of dysphagia or preexistent neuropathy.\n\nThis multicenter randomized phase 2 trial was designed to investigate whether supplementation of folic acid and vitamin B12 resulted in an improved clinical outcome in AEGC patients treated with the combination of cisplatin and gemcitabine chemotherapy. The addition of folic acid and vitamin B12 to this chemotherapy backbone did not significantly increase the RR which was 42.1% (n = 16) in the vitamin group vs. 32.4% (n = 12) in the chemotherapy alone group. The difference in RR between the study arms did not meet the prespecified target RR of 50% nor a 15% difference in RR between the two treatment groups. The median OS was not significantly different with or without vitamin suppletion (10.0 vs. 7.7 months). The median TTP was similar in both treatment groups (5.9 months for supplemented patients vs. 5.4 months for unsupplemented patients). Baseline characteristics of the patients in both study arms were well balanced. Vitamin supplementation did not result in an apparent decrease in the incidence of grade 3–5 adverse events.\n\nAs homocysteine levels are inversely related to folate and vitamin B12 consumption, the measured lower concentration of homocysteine in patients receiving concomitant vitamin supplementation is indicative of the biological activity of the employed vitamin supplementation and is in support of adequate patient compliance [28]. Though the use of second line chemotherapy or experimental therapy was not specifically documented in this trial, its use could potentially affect differences in OS between the two study groups. The impact of second line chemotherapy in AEGC was very limited if at all present and is unlikely to substantially confound our data.\n\nOur study results contrast with the previously reported beneficial effects observed when folic acid and vitamin B12 were added to the combination of cisplatin and pemetrexed and cisplatin monotherapy [6]. Apart from the fact that a different patient group was studied, both studies also differed in their design as our study was randomized for the addition of vitamins, while the study of Vogelzang et al. was not randomized for vitamin suppletion. The discrepancy could also be related to specific effects of folate and vitamin B12 on the efficacy of pemetrexed that do not occur with the cisplatin and gemcitabine combination used in this study [29]. Indeed, in the phase 3 study of Vogelzang et al. the benefit of adding vitamin suppletion was predominantly observed in the group of patients treated with pemetrexed and cisplatin. Moreover, as in our study cisplatin was combined with gemcitabine a potential positive effect of folate suppletion on cisplatin sensitivity (e.g., an increased exposure to free platinum) might have been masked by effects on gemcitabine metabolism as, e.g., degradation of gemcitabine to dFdU was increased in supplemented patients. In earlier studies an association between increased gemcitabine deamination and a lower response rate and survival were reported [18]. The formation of the active metabolite of gemcitabine dFdCTP in white blood cells, included as a surrogate biomarker for tissue accumulation, was initially increased. The levels of dFdCTP and the effect of cisplatin are in line with other studies of gemcitabine–cisplatin combination therapy [30]. However, this difference did not persist and may, therefore, preclude a clinically relevant increase of dFdCTP levels in tissues, which is necessary for an optimal effect of gemcitabine [31]. One can also not exclude that the potentiating effects of vitamin supplementation, as found in patients with mesothelioma, differ between tumor types. The 79A > C polymorphism in the CDA gene and the 667C > T polymorphism in the MTHFR gene were measured in a subgroup of patients. We found no correlation with RR, OS, TTP or severe toxicity although numbers were small and the study was not powered for this analysis.\n\nThe results of this trial are important for daily practice, since vitamin supplement use is very common among patients with cancer [32, 33]. Reasons for vitamin suppletion include an expected reduced toxicity of chemotherapy, an expected enhanced efficacy of cancer treatment in combination with vitamin use and an expected improvement in general well-being. Complementary medicine is very often not evidence based [34], but in this randomized trial no efficacy benefit was found of vitamin suppletion. In recent years, clinical trials for advanced esophagogastric cancer have focused more on triple-drug regimens. These consist of chemotherapy with tumor-specific targeted therapies, e.g., therapies targeting Her2, c-Met or VEGFR [35–37]. These approaches are likely to be further developed and expanded in an effort to improve the still dismal perspectives of patients suffering from metastatic esophagogastric cancer.\n\nIn conclusion this phase 2 trial has demonstrated that folic acid and vitamin B12 supplementation does not improve the RR, PFS or OS of cisplatin and gemcitabine in patients with AEGC. We here show that the combination of gemcitabine/cisplatin is a reasonable alternative treatment schedule for patients with AEGC in case of dysphagia or preexistent neuropathy.\n\nFunding\nAmgen and Lilly provided financial support for this study.\n\nCompliance with ethical standards\nConflict of interest\nThe authors declare that they have no conflict of interest.\n\nEthical approval\nAll procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.\n\nInformed consent\nInformed consent was obtained from all individual participants included in the study.\n==== Refs\nReferences\n1. Pohl H Sirovich B Welch HG Esophageal adenocarcinoma incidence: are we reaching the peak? Cancer Epidemiol Biomark Prev 2010 19 6 1468 1470 10.1158/1055-9965.EPI-10-0012 \n2. 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Velicer CM Ulrich CM Vitamin and mineral supplement use among US adults after cancer diagnosis: a systematic review J Clin Oncol 2008 26 4 665 673 10.1200/JCO.2007.13.5905 18235127 \n34. Ernst E How much of CAM is based on research evidence? Evid Based Complement Altern Med 2011 2011 676490 10.1093/ecam/nep044 \n35. Zhang L Ma J Han Y Liu J Zhou W Hong L Fan D Targeted therapy in esophageal cancer Expert Rev Gastroenterol Hepatol 2016 10 5 595 604 10.1586/17474124.2016.1140036 26895097 \n36. Shah MA Update on metastatic gastric and esophageal cancers J Clin Oncol 2015 33 16 1760 1769 10.1200/JCO.2014.60.1799 25918288 \n37. Fuchs CS Tomasek J Yong CJ Dumitru F Passalacqua R Goswami C Safran H dos Santos LV Aprile G Ferry DR Melichar B Tehfe M Topuzov E Zalcberg JR Chau I Campbell W Sivanandan C Pikiel J Koshiji M Hsu Y Liepa AM Gao L Schwartz JD Tabernero J Investigators RT Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial Lancet 2014 383 9911 31 39 10.1016/S0140-6736(13)61719-5 24094768\n\n", "fulltext_license": "CC BY", "issn_linking": "0344-5704", "issue": "82(1)", "journal": "Cancer chemotherapy and pharmacology", "keywords": "Cisplatin; Esophagogastric cancer; Folic acid; Gemcitabine; Vitamin B12", "medline_ta": "Cancer Chemother Pharmacol", "mesh_terms": "D000230:Adenocarcinoma; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D002945:Cisplatin; D003841:Deoxycytidine; D019587:Dietary Supplements; D004357:Drug Synergism; D004938:Esophageal Neoplasms; D005260:Female; D005492:Folic Acid; D006801:Humans; D008297:Male; D008875:Middle Aged; D013274:Stomach Neoplasms; D014805:Vitamin B 12", "nlm_unique_id": "7806519", "other_id": null, "pages": "39-48", "pmc": null, "pmid": "29696360", "pubdate": "2018-07", "publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't", "references": "2686531;18172173;10655437;12479273;11379400;17259744;3258308;28594276;24094768;19465405;25918288;21276754;28648400;20501776;26267802;15111354;1834124;12422304;12127861;8133587;10370787;12616253;18235127;18623116;27007129;18349393;1820582;10956384;26895097;17437008;14760114;17054195;9218736;12860938", "title": "Randomized phase 2 study of gemcitabine and cisplatin with or without vitamin supplementation in patients with advanced esophagogastric cancer.", "title_normalized": "randomized phase 2 study of gemcitabine and cisplatin with or without vitamin supplementation in patients with advanced esophagogastric cancer" }

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{ "abstract": "BACKGROUND\nNocardiosis is a rare and life-threatening opportunistic infection in immunocompromised patients. Myasthenia gravis (MG) patients are potentially at risk of nocardia infection because of the use of immunosuppressive agents. To date, only 7 patients with MG have been reported to have nocardiosis. Disseminated nocardiosis with ocular involvement has not been reported in MG patients.\n\n\nMETHODS\nA 66-year-old man with MG who was receiving treatment with methylprednisolone and azathioprine was found to have a respiratory infection. He also had heterogeneous symptoms with skin, brain and ocular manifestations. Nocardia bacteria verified by the culture of puncture fluid, and a diagnosis of disseminated nocardiosis was made. Except for left eye blindness, the patient completely recovered from the disease with combination antibiotic therapy. To further understand nocardiosis in patients with MG, we reviewed the previous relevant literature. According to the literature, this is the first report of disseminated nocardiosis with ocular involvement in an MG patient.\n\n\nCONCLUSIONS\nMG patients with immunosuppressant treatments are potentially at risk of a rare nocardia infection, and a favourable prognosis can be achieved through early diagnosis and appropriate antibiotic therapy.", "affiliations": "Department of Neurology, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China. drwangshuhui@163.com.;Department of Neurology, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China.;Department of Neurology, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China.;Department of Geriatric Neurology, Chinese People's Liberation Army General Hospital, National Clinical Research Center for Geriatric Diseases, Beijing, 100853, China.;Department of Neurology and Center for Translational Neuromedicine, University of Rochester Medical Center, New York, NY, USA.;Department of Neurology, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China.", "authors": "Wang|Shuhui|S|http://orcid.org/0000-0002-9496-0963;Jiang|Bin|B|;Li|Yao|Y|;Shang|Yanchang|Y|;Liu|Zhengshan|Z|;Zhang|Yongbo|Y|", "chemical_list": "D000900:Anti-Bacterial Agents; D007166:Immunosuppressive Agents", "country": "England", "delete": false, "doi": "10.1186/s12883-019-1482-4", "fulltext": "\n==== Front\nBMC NeurolBMC NeurolBMC Neurology1471-2377BioMed Central London 148210.1186/s12883-019-1482-4Case ReportA case report of disseminated nocardiosis with ocular involvement in a myasthenia gravis patient and literature review http://orcid.org/0000-0002-9496-0963Wang Shuhui drwangshuhui@163.com 1Jiang Bin 1Li Yao 1Shang Yanchang 2Liu Zhengshan 3Zhang Yongbo 11 0000 0004 0369 153Xgrid.24696.3fDepartment of Neurology, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050 China 2 Department of Geriatric Neurology, Chinese People’s Liberation Army General Hospital, National Clinical Research Center for Geriatric Diseases, Beijing, 100853 China 3 0000 0004 1936 9166grid.412750.5Department of Neurology and Center for Translational Neuromedicine, University of Rochester Medical Center, New York, NY USA 21 10 2019 21 10 2019 2019 19 24326 3 2019 9 10 2019 © The Author(s). 2019Open 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\nNocardiosis is a rare and life-threatening opportunistic infection in immunocompromised patients. Myasthenia gravis (MG) patients are potentially at risk of nocardia infection because of the use of immunosuppressive agents. To date, only 7 patients with MG have been reported to have nocardiosis. Disseminated nocardiosis with ocular involvement has not been reported in MG patients.\n\nCase presentation\nA 66-year-old man with MG who was receiving treatment with methylprednisolone and azathioprine was found to have a respiratory infection. He also had heterogeneous symptoms with skin, brain and ocular manifestations. Nocardia bacteria verified by the culture of puncture fluid, and a diagnosis of disseminated nocardiosis was made. Except for left eye blindness, the patient completely recovered from the disease with combination antibiotic therapy. To further understand nocardiosis in patients with MG, we reviewed the previous relevant literature. According to the literature, this is the first report of disseminated nocardiosis with ocular involvement in an MG patient.\n\nConclusions\nMG patients with immunosuppressant treatments are potentially at risk of a rare nocardia infection, and a favourable prognosis can be achieved through early diagnosis and appropriate antibiotic therapy.\n\nKeywords\nDisseminated nocardiosisMyasthenia gravisOpportunistic infectionCase reportResearch Foundation of Beijing Friendship Hospital, Capital Medical Universityyyqdkt2018-30issue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nNocardiosis is an acute purulent or chronic granulomatous disease caused by infection of nocardia bacteria, a gram-positive branching rod-shaped aerobic bacterium from the genus Actinomyces [1, 2]. Nocardia is an opportunistic pathogen with a relatively low incidence, and it is usually infectious in immunocompromised patients, such as those with autoimmune disease or those receiving immunosuppressive treatments. They can cause local or disseminated nocardiosis in humans. Patients with myasthenia gravis (MG) are commonly treated with immunosuppressive agents for a long time and are potentially at risk of nocardia infection.\n\nNocardiosis is a life-threatening infectious disease, especially in patients who cannot be treated appropriately in the early stage of the disease. However, the heterogeneous clinical presentations of affected patients and laboratory test limitations make the diagnosis of nocardiosis very difficult. Therefore, it is important for physicians to diagnose the disease and treat the patients in a timely manner. Here, we present a case of disseminated nocardiosis in an MG patient in whom multiple systems were involved. Based on our findings, we also conducted a literature review.\n\nCase presentation\nA 66-year-old Chinese man presented with fever, cough, dyspnoea and lumbodynia after falling from exercise equipment on July 6, 2015. He had a medical history of blood hypertension and diabetes mellitus. In 2014, he was hospitalized because of fluctuating ptosis and dysphagia. The fatigue test and neostigmine test were positive. Slow frequency repetitive nerve stimulation (3 Hz) on the bilateral facial nerves showed that the compound muscle action potential (CAMP) decrement was more than 15%. An immunological serum test showed that the patient was negative for the acetylcholine receptor (AChR) and muscle-specific kinase (MusK) antibodies but positive for Titin and ryanodine receptor (RyR) antibodies. Thoracic enhanced computed tomography (CT) did not find an abnormal thymus. The patient was diagnosed with generalized MG and received glucocorticoids and pyridostigmine therapy. The maximum dose of methylprednisolone was 56 mg per day, which was subsequently tapered to 20 mg per day. In addition, he took 100 mg azathioprine daily for MG therapy.\n\nA physical examination revealed that the patient had a temperature of 38 degrees centigrade. Other vital signs were in the normal range. There were multiple rales in the bilateral lungs on auscultation. Multiple, irregular, and tender masses were found on the patient’s chest, back, neck, and right limbs. These masses had a high temperature and were red in colour. There was an infectious ulcer mass on the right lower limb. Except for weakness in the right lower limb (5−/5), there were no other abnormal findings on a neurological examination.\n\nRoutine laboratory investigations, including routine blood tests, hepatic and renal functions, electrolyte and coagulation function, were in the normal range. Antinuclear antibody (ANA), extractable nuclear antibody (ENA), and neoplastic marker tests were in the normal range. Immunoglobulin (Ig) and complement (C) levels were checked twice. The patient’s levels of IgG/IgA/C3/C4 were normal, but his levels of IgM were 25 mg/dL and 25.7 mg/dL (normal limit, 40–230 mg/dL). The proportions of lymphocyte subgroups (CD3, CD4, CD8, CD4/CD8, CD19, and CD16 + CD56) were normal. Respiratory virus screening was negative. His level of C reactive protein (CRP) was 37 mg/L (normal range < 5 mg/L). Tuberculosis infection T lymphocytes and anti-tuberculosis antibody were not positive. Antibodies against hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV) and syphilis were negative.\n\nA lumbar spine X-ray scan showed compression fractures in the L1 and L2 vertebral bodies. A neck CT scan found a mass on the left, and a diagnosis of swollen lymph node, abscess or tumour was considered (Fig. 1a). A chest CT scan revealed multiple nodular and patchy shadows in the bilateral lungs and pleural as well as pericardial effusion (Fig. 1b-c). An abdominal CT scan revealed gallstones and a small cyst on the right kidney.\nFig. 1 CT images of the neck and chest on the day of admission to hospital (a, b, c): a CT scan showing a mass on the left of the neck, arrow shown in (a). CT of the chest showing the subcutaneous nodes, with the arrow shown in (b). There were multiple nodular or patchy shadows in the bilateral lungs and pleural and pericardial effusion (c). One month after treatment with SMZ-TMP, a repeated chest CT (d) showed pleural effusion and that the lesions in the left lung had disappeared while the lesions in the right lung had become more apparent\n\n\n\nThe patient was diagnosed with pneumonia and received moxifloxacin treatment. The patient’s body temperature gradually returned to the normal range, and cough and dyspnoea were also relieved after treatment. However, he had a fever with chill, heavy dyspnoea, headache, and pain in the right leg after 20 days of treatment. He also felt great pain in the left eye, and his vision became blurred and rapidly aggravated to blindness. For differential diagnoses, both brain CT scan and magnetic resonance imaging (MRI) were performed. The CT scan showed multiple low-intensity lesions in different brain areas, and MRI revealed marked multiple abnormalities in the bilateral cerebrum and cerebellum with low signal intensity on T1-weighted images as well as high signal intensity on T2-weighted images. After administration of gadolinium contrast material, these lesions demonstrated ring enhancement (Fig. 2a-d). Accordingly, a diagnosis of abscess or multiple brain metastases was considered. Importantly, MRI of the orbit showed an abnormal enhanced lesion behind the left eyeball and retinal detachment (Fig. 3a-c). To identify the characteristics of these lesions, we performed percutaneous drainage from the mass on the left neck guided by ultrasound. Nocardia bacteria were found in a culture of puncture fluid, confirming the diagnosis of disseminated nocardiosis.\nFig. 2 Magnetic resonance imaging of the brain. Gadolinium contrast T1 images, with sagittal reformat (a) and axial reformat (b, c, d) images of the brain showing ring-enhancing lesions in the bilateral brain and cerebellum. e-h: Reviewed MRI scan of the brain showing that some lesions had decreased and some had disappeared after one and half months of SMZ treatment\n\n\nFig. 3 Magnetic resonance imaging of the orbit. An abnormal lesion was noted behind the left eye (shown on arrow) with a high-intensity signal on T2-weighted images (a), low signal intensity on T1-weighted images (b) and high signal intensity on gadolinium contrast T1-weighted images (c)\n\n\n\nAfter the diagnosis of nocardiosis, the patient was treated with trimethoprim-sulfamethoxazole (TMP-SMX) tablets (TMP0.08 g + SMX0.4 g/per tablet, 2 pills every 8 h). Moreover, imipenem/meropenem/ceftriaxone and sporanox were also given for the bacteria and fungus infection. Two weeks later, the patient was found to have leukocytopenia and underwent a bone marrow puncture examination. The results indicated a suspected diagnosis of myelodysplastic syndrome (MDS). Therapy with TMP-SMX tablets was adjusted to 1 pill every 12 h plus injection with etimicin sulfate. Azathioprine therapy was replaced with berbamine to treat the leukocytopenia. Three weeks later, the patient was treated with TMP-SMX tablets alone (1 pill every 12 h). After this treatment, except for the left eye blindness, all of his symptoms, including fever, dyspnoea, headache, and pain in the leg and left eye, gradually remitted. In addition, 1 month of TMP-SMX treatment also reduced pleural effusion and bilateral lung lesions based on repeat chest CT results (Fig. 1d). After one and a half months of TMP-SMX treatment, multiple brain lesions had decreased or even disappeared based on a repeat brain MRI (Fig. 2 e-h). The patient was continuously treated on an out-patient basis with TMP-SMX tablets (1 pill every 12 h) for one and a half years. His blood cells were monitored every 2 weeks. Six months after discharge, the subcutaneous masses had disappeared, and a repeat brain MRI showed that the encephalic lesions had also disappeared. At that point, the dosage of methylprednisolone was tapered slowly until it was stopped because of the improvement observed in his MG, and there were no recurrent syndromes at the 2-year follow-up.\n\nDiscussion and conclusions\nIn general, nocardia bacteria are opportunistic bacteria that mainly infect immunocompromised patients. Although MG is an autoimmune disease that requires immunosuppressive treatment, nocardia infection is rarely observed in these patients. We performed the literature review by searching the MEDLINE database using the key words “nocardia,” “nocardiosis, “and “myasthenia gravis.” We found that up until our search, only 7 case reports of MG patients with nocardiosis had been reported [3–9]. To improve understanding of the disease process, we summarized the clinical characteristics of these patients, and these are listed in Table 1. Seven out of 8 patients had a good prognosis. All patients were treated with glucocorticoids and other immunosuppressants. Three patients had thymoma, and 1 patient had Good’s syndrome. There was no clear relationship between nocardia infection and MG or thymoma. However, patients with Good’s syndrome, who usually have thymoma and immunodeficiency, easily acquire opportunistic infections. Although our patient had low IgM levels, he had no thymoma and normal levels of lymphocyte subgroups, and a diagnosis of Good’s syndrome was therefore not considered. Repeated immunoglobulin tests showed that he had low levels of IgM and normal levels of IgG, IgA and lymphocyte subgroups. Selective immunoglobulin M deficiency (sIgMD) was considered in our patient and is a rare primary immunodeficiency disease characterized by low levels of IgM (below two standard deviations of the mean) in association with infection and normal levels of IgG and IgA [10]. In addition, our patient had the history of diabetes for many years. Therefore, immunosuppressant use, sIgMD and diabetes were the predisposing factors for nocardia infection in our patient. We concluded the data in Table 1. The following factors may be preconditions for nocardia infection in MG patients. The primary factor was the use of immunomodulator and/or immunosuppressive agents, consistent with numerous previous studies [11, 12]. The second factor was age. We found that MG patients with nocardia infection were 49–79 years old, indicating that older patients with MG might be more susceptible to nocardiosis. This is consistent with the fact that older MG patients have a higher incidence of tumours, such as thymoma, and low immunity. The last factor is gender, as supported by our finding that 7 out of 8 MG patients with nocardia infection were male patients. In summary, older male MG patients being treated with immunomodulator and/or immunosuppressive agents might represent a population that is susceptible to nocardia infection.\nTable 1 Clinical characteristics of MG patients with disseminated nocardiosis\n\nCase\tAge /sex\tAuthor/year\tSymptoms\tUnderlying disease\tImmune suppression\tOperation\tSites of disease\tTreatments\tOutcome\t\n1\t59/male\tKim 2002\tskin lesions, fever, cough\tMG, thymoma\tprednisolone\tthymectomy\tskin, lung\tTMP-SMX\tresolution\t\n2\t49/male\tEl-Herte 2012\tFever, chills, chest pain, weight loss\tMG, thymoma\tprednisone\tthymectomy\tlung, brain, heart\timipenem, amikacin, TMP-SMX\tresolution\t\n3\t59/female\tTanioka 2012\tMalaise, cough\tMG\tprednisolone, tacrolimus, cyclosporine\tNA\tlung, kidney, brain\timipenem-cilastatin, TMP-SMX, minocycline, meropenem, amikacin, linezolid\tresolution\t\n4\t79/male\tPatel 2013\tleft leg pain, cough\tMG\tprednisone\tNA\tleg, lung\tmoxifloxacin\tNA\t\n5\t77/male\tGarcia 2015\tnight sweats, cough\tMG, TB\tprednisone, plasmapheresis\tthymectomy\tlung, brain\tTMP-SMX, meropenem, linezolid\tresolution\t\n6\t79/male\tVeerappan 2015\tleg abscesses\tMG\tsteroid\tNA\tlung, muscle\tvancomycin, piperacillin-tazobactam, ampicillin, ceftriaxone, doxycycline, moxifloxacin, linezolid\tresolution\t\n7\t52/male\tWargo 2015\tcough, dyspnoea, weight loss, subcutaneous nodules, fatigue\tMG, thymoma, Good’s syndrome\tprednisone, chemotherapy, radiation\tNA\tlung, skin, brain\tmeropenem, TMP-SMX, imipenem, linezolid\tresolution\t\n8\t66/male\tWang 2019\tfever, dyspnoea, headache, pain on left eye and right leg, skin ulcer, blindness, muscle strength decreased\tMG, hypertension, diabetes\tmethylprednisolone, azathioprine\tNone\tLung, brain, skin, ocular\tTMP-SMX, etimicin sulfate, moxifloxacin, ceftriaxone, imipenem, meropenem\tresolution\t\nAbbreviations: MG myasthenia gravis, TMP-SMX trimethoprim-sulfamethoxazole, TB tuberculosis, NA not available\n\n\n\nThe clinical manifestations of nocardia infections are very heterogeneous and nonspecific. Lung, brain and skin are the most commonly affected sites [13]. All 8 patients had lung lesions. The infection also involved the muscles, heart, and kidneys. In addition to lung, brain and skin lesions, our patient also had ocular lesions. To the best of our knowledge, this is the first case report of an MG patient with disseminated nocardiosis with ocular lesions.\n\nOcular tissue is an unusual site for disseminated nocardiosis, and ocular infection is generally diagnosed as local nocardiosis, with presents a keratitis or endophthalmitis resulting from ocular trauma or surgery [14]. Occasionally, ocular infection might also be caused by haematogenous dissemination via the choroidal circulation [15]. The ocular nocardia infection that occurred in our patient may have been caused by haematogenous spread because the patient did not have eye trauma or a history of surgery and he had no abnormal signs in his eyeball. The prognosis of ocular nocardiosis is generally poor. Blindness is a common consequence, and ophthalmectomy is performed in approximately 30% of these patients. For these reasons, regular ophthalmologic screening should be performed in patients with suspected disseminated nocardiosis [15, 16]. In our patient, the ocular lesion was located behind the left eyeball, which finally led to retinal detachment. After he received suitable treatment, the ocular lesion completely vanished, but his vision was not restored.\n\nDue to the paucity of trials, there are no formal guidelines to direct drug choice and treatment duration in nocardiosis. Most clinicians agree that CNS nocardiosis warrants a long course of treatment, with 12 months commonly recommended [17]. Empirical treatment of disseminated nocardiosis usually involves three antibiotics, including imipenem or ceftriaxone, TMP-SMX, and amikacin. TMP-SMX is thought to be the cornerstone of treatment for nocardia infections and is also the drug of choice for cerebral nocardiosis due to its good penetration into the CNS. Other drugs, including meropenem, cefotaxime, minocycline, moxifloxacin, levofloxacin, linezolid, tigecycline, and amoxicillin/clavulanic acid, are also used for the treatment of these patients [12]. MG patients should be treated with the proper antibiotics because some antibiotics can aggravate the disease. Patients with nocardiosis often have an underlying autoimmune disease or are receiving immunosuppressive treatment. Therefore, a combination of antibiotics is recommended in the beginning, and a single drug can be maintained after the clinical symptoms are relieved [12]. Immunosuppressive therapy will increase the risk of infection and the difficulty of treating infection in patients with MG. The use of immunosuppressants in MG patients with infections is an important issue. By reviewing the literature [18] and combining our findings with our own clinical practice experience, we cautiously suggest that if the infection can be controlled, immunosuppressive therapy can be continued in MG patients. However, when an infection is hard to control with administration of the proper antibiotics and becomes life-threatening, physicians should reduce the dose of immunosuppressants or even stop it. We stopped the use of azathioprine and continued a tapered dose of methylprednisolone in our patient when he developed leukocytopenia.\n\nBecause of the nonspecific manifestations of nocardiosis, most patients with nocardia infection are not diagnosed in the early stage of the disease, and it normally takes from 42 days to 12 months after the appearance of symptoms to achieve a clear diagnosis [19, 20]; this causes a substantial physical and emotional burden in these patients. The prognosis of nocardiosis depends on the location and severity of the infection as well as the overall condition of the patient. The curable rate of pulmonary nocardiosis is approximately 90% with timely treatment, while the one-year mortality rate is high in patients with CNS involvement. The mortality rate is 10-fold higher in patients with solid organ transplantation from nocardiosis than in those without [11, 12]. None of the eight patients included in Table 1 had a history of organ transplantation. Although 4 of the 8 patients had CNS lesions, these lesions were relatively small, the symptoms were mild, and the diagnosis and treatment were timely, and this may have been the reasons for their good prognosis.\n\nIn conclusion, nocardiosis is a life-threatening infectious disease, and diagnosis in the early stage and appropriate antibiotic therapy are crucial to prognosis. Ocular involvement is rare in disseminated nocardiosis, and patients who are suspected to have disseminated nocardiosis should receive ophthalmologic screening. Neurological physicians should be aware of nocardia infection in MG patients.\n\nAbbreviations\nAChRAcetylcholine receptor\n\nANAAntinuclear antibody\n\nCComplement\n\nCAMPCompound muscle action potential\n\nCNSCentral nervous system\n\nCRPC reactive protein\n\nCTComputed tomography\n\nENAExtractable nuclear antibody\n\nHBVHepatitis B virus\n\nHCVHepatitis C virus\n\nHIVHuman immunodeficiency virus\n\nIgImmunoglobulin\n\nMDSMyelodysplastic syndrome\n\nMGMyasthenia gravis\n\nMRIMagnetic resonance imaging\n\nMusKMuscle-specific kinase\n\nNANot available\n\nRyRRyanodine receptor\n\nsIgMDselective immunoglobulin M deficiency\n\nTBTuberculosis\n\nTMP-SMXTrimethoprim-sulfamethoxazole\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nWe thank Prof. Henry Kaminski (The George Washington University) for his valuable suggestions regarding the writing of the paper.\n\nAuthors’ contributions\nSHW: patient examination, medical data collection, and article preparation; BJ and YL: patient examination and medical data collection; YCS and ZSL: medical data analysis, article preparation, and correction and translation; YBZ: medical and scientific consultation and article preparation. All authors read and approved the final manuscript.\n\nFunding\nThis work was supported by the Research Foundation of Beijing Friendship Hospital, Capital Medical University (No. yyqdkt2018–30).\n\nAvailability of data and materials\nThe datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.\n\nEthics approval and consent to participate\nThe institutional review board of Beijing Friendship Hospital approved this case report. Written informed consent was obtained from the patient for the publication of the present case report.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n==== Refs\nReferences\n1. McNeil MM Brown JM The medically important aerobic actinomycetes: epidemiology and microbiology Clin Microbiol Rev 1994 7 3 357 417 10.1128/cmr.7.3.357 7923055 \n2. Takayanagi N Kagiyama N Ishiguro T Tokunaga D Sugita Y Etiology and outcome of community-acquired lung abscess Respiration 2010 80 2 98 105 10.1159/000312404 20389050 \n3. Kim CY Kim TH Lee WS Lee AY Reactive cutaneous cytophagocytosis in nocardiosis J Korean Med Sci 2002 17 2 279 282 10.3346/jkms.2002.17.2.279 11961320 \n4. El-Herte RI Kanj SS Araj GF Chami H Gharzuddine W First report of Nocardia asiatica presenting as an anterior Mediastinal mass in a patient with myasthenia gravis: a case report and review of the literature Case Rep Infect Dis 2012 2012 325767 10.1155/2012/325767 22844621 \n5. Tanioka K Nagao M Yamamoto M Matsumura Y Tabu H Matsushima A Disseminated Nocardia farcinica infection in a patient with myasthenia gravis successfully treated by linezolid: a case report and literature review J Infect Chemother 2012 18 3 390 394 10.1007/s10156-011-0315-1 21997125 \n6. Patel Nachiket Baker Sarah M. Filho J. Americo Fernandes Leg Pain in a Patient with Myasthenia Gravis Journal of General Internal Medicine 2013 28 11 1523 1523 10.1007/s11606-013-2445-x 23613264 \n7. Garcia RR, Bhanot N, Min Z. A mimic’s imitator: a cavitary pneumonia in a myasthenic patient with history of tuberculosis. BMJ Case Rep. 2015;2015. 10.1136/bcr-2015-210264.\n8. Veerappan Kandasamy V. Nagabandi A. Horowitz E. A. Vivekanandan R. Multidrug-resistant Nocardia pseudobrasiliensis presenting as multiple muscle abscesses Case Reports 2015 2015 may06 1 bcr2014205262 bcr2014205262 \n9. Wargo JJ Kim AH Hart A Berg A It took a village: Good's syndrome Am J Med 2015 128 7 699 701 10.1016/j.amjmed.2015.03.002 25796418 \n10. Gupta S Gupta A Selective IgM deficiency-an underestimated primary immunodeficiency Front Immunol 2017 8 1056 10.3389/fimmu.2017.01056 28928736 \n11. Lebeaux D Freund R van Delden C Guillot H Marbus SD Matignon M Outcome and treatment of Nocardiosis after solid organ transplantation: new insights from a European study Clin Infect Dis 2017 64 10 1396 1405 10.1093/cid/cix124 28329348 \n12. Wilson JW Nocardiosis: updates and clinical overview Mayo Clin Proc 2012 87 4 403 407 10.1016/j.mayocp.2011.11.016 22469352 \n13. Beaman BL Beaman L Nocardia species: host-parasite relationships Clin Microbiol Rev 1994 7 2 213 264 10.1128/cmr.7.2.213 8055469 \n14. Sharma D Mathur U Gour A Acharya M Gupta N Sapra N Nocardia infection following intraocular surgery: report of seven cases from a tertiary eye hospital Indian J Ophthalmol 2017 65 5 371 375 10.4103/ijo.IJO_564_16 28573992 \n15. Nishizawa A Hirose M Nagata Y Takeuchi M Satoh T Disseminated cutaneous nocardiosis with ocular involvement J Eur Acad Dermatol Venereol 2017 31 11 e488 e4e9 10.1111/jdv.14328 28500674 \n16. Eisenberg MA Wilker SC Nocardia asteroides subretinal abscess in patient with acute myelogenous leukemia after allogeneic stem cell transplant Retin Cases Brief Rep 2014 8 2 113 115 10.1097/ICB.0000000000000017 25372323 \n17. Ambrosioni J Lew D Garbino J Nocardiosis: updated clinical review and experience at a tertiary center Infection. 2010 38 2 89 97 10.1007/s15010-009-9193-9 20306281 \n18. Gilhus NE Romi F Hong Y Skeie GO Myasthenia gravis and infectious disease J Neurol 2018 265 6 1251 1258 10.1007/s00415-018-8751-9 29372387 \n19. Martinez R Reyes S Menendez R Pulmonary nocardiosis: risk factors, clinical features, diagnosis and prognosis Curr Opin Pulm Med 2008 14 3 219 227 10.1097/MCP.0b013e3282f85dd3 18427245 \n20. Rafiei Nastaran Peri Anna Maria Righi Elda Harris Patrick Paterson David L. Central nervous system nocardiosis in Queensland Medicine 2016 95 46 e5255 10.1097/MD.0000000000005255 27861348\n\n", "fulltext_license": "CC BY", "issn_linking": "1471-2377", "issue": "19(1)", "journal": "BMC neurology", "keywords": "Case report; Disseminated nocardiosis; Myasthenia gravis; Opportunistic infection", "medline_ta": "BMC Neurol", "mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D005128:Eye Diseases; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D008297:Male; D009157:Myasthenia Gravis; D009615:Nocardia; D009617:Nocardia Infections", "nlm_unique_id": "100968555", "other_id": null, "pages": "243", "pmc": null, "pmid": "31638926", "pubdate": "2019-10-21", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": "21997125;28573992;20306281;25948839;25372323;28329348;20389050;22469352;25796418;27861348;22844621;26150643;7923055;29372387;18427245;23613264;28928736;8055469;11961320;28500674", "title": "A case report of disseminated nocardiosis with ocular involvement in a myasthenia gravis patient and literature review.", "title_normalized": "a case report of disseminated nocardiosis with ocular involvement in a myasthenia gravis patient and literature review" }

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A CASE REPORT OF DISSEMINATED NOCARDIOSIS WITH OCULAR INVOLVEMENT IN A MYASTHENIA GRAVIS PATIENT AND LITERATURE REVIEW. 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{ "abstract": "The localized activation of coagulation in vascular malformations can lead to a consumptive coagulopathy characterized by elevated D-dimers and a consumption of fibrinogen and platelets, eventually giving rise to a bleeding tendency. By reducing coagulation activation, anticoagulant treatment with heparin is able to limit this haemostatic dysregulation and the associated bleeding diathesis. Here, we present a case of a consumptive coagulopathy due to a large venous malformation with a sustained correction of the fibrinogen depletion and associated bleeding tendency both with subcutaneous enoxaparin and with the oral factor Xa inhibitor rivaroxaban.", "affiliations": "Vascular Medicine and Haemostasis, Department of Cardiovascular Diseases, University Hospitals Leuven, Herestraat 49, Bus 911, 3000, Leuven, Belgium, christophe.vandenbriele@med.kuleuven.be.", "authors": "Vandenbriele|Christophe|C|;Vanassche|Thomas|T|;Peetermans|Marijke|M|;Verhamme|Peter|P|;Peerlinck|Kathelijne|K|", "chemical_list": "D065427:Factor Xa Inhibitors; D005338:Fibrin Fibrinogen Degradation Products; D009025:Morpholines; D013876:Thiophenes; C036309:fibrin fragment D; D000069552:Rivaroxaban", "country": "Netherlands", "delete": false, "doi": "10.1007/s11239-013-1024-7", "fulltext": null, "fulltext_license": null, "issn_linking": "0929-5305", "issue": "38(1)", "journal": "Journal of thrombosis and thrombolysis", "keywords": null, "medline_ta": "J Thromb Thrombolysis", "mesh_terms": "D000284:Administration, Oral; D000328:Adult; D004211:Disseminated Intravascular Coagulation; D065427:Factor Xa Inhibitors; D005338:Fibrin Fibrinogen Degradation Products; D006801:Humans; D008297:Male; D009025:Morpholines; D000069552:Rivaroxaban; D013876:Thiophenes; D054079:Vascular Malformations", "nlm_unique_id": "9502018", "other_id": null, "pages": "121-3", "pmc": null, "pmid": "24202701", "pubdate": "2014-07", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "21128814;11435349;18645137;7046845;19916972;9039172;13996896;17367610;22449293;21830957;15543326;18645138;17005308;12181029;6973947", "title": "Rivaroxaban for the treatment of consumptive coagulopathy associated with a vascular malformation.", "title_normalized": "rivaroxaban for the treatment of consumptive coagulopathy associated with a vascular malformation" }

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"drugstartdateformat": "610", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIVAROXABAN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RIVAROXABAN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": null, "drugenddate": "201302", "drugenddateformat": "610", "drugindication": "DISSEMINATED INTRAVASCULAR COAGULATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "201209", "drugstartdateformat": "610", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIVAROXABAN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RIVAROXABAN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DISSEMINATED INTRAVASCULAR COAGULATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "201306", "drugstartdateformat": "610", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIVAROXABAN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RIVAROXABAN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": null, "drugenddate": "201302", "drugenddateformat": "610", "drugindication": "BLOOD FIBRINOGEN DECREASED", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "201209", "drugstartdateformat": "610", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIVAROXABAN" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Spontaneous haemorrhage", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Blood fibrinogen decreased", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "VANDENBRIELE C, VANASSCHE T, PEETERMANS M, VERHAMME P, PEERLINCK K. RIVAROXABAN FOR THE TREATMENT OF CONSUMPTIVE COAGULOPATHY ASSOCIATED WITH A VASCULAR MALFORMATION. J THROMB THROMBOLYSIS 2014;38(1):121-123.", "literaturereference_normalized": "rivaroxaban for the treatment of consumptive coagulopathy associated with a vascular malformation", "qualification": "3", "reportercountry": "BE" }, "primarysourcecountry": "BE", "receiptdate": "20140707", "receivedate": "20140707", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10279710, "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": "Rhabdomyosarcoma (RMS) is a highly malignant soft tissue sarcoma (STS), usually of adults, displaying skeletal muscle differentiation. STS principally metastasize to the lungs with more than 50% of metastatic patients presenting with isolated pulmonary metastasis. Paradoxically, the majority of drugs prescribed to treat RMS are associated with multidrug resistance.\n\n\n\nWe report the case of a 53 year-old patient who developed three synchronous chemoresistant lung metastasis from pleomorphic RMS. Considering the poor prognosis, the patient's preference and the chemoresistance of her lung metastasis, we decided to perform two consecutive stereotactic body radiotherapy (SBRT) on two of these three lesions.\n\n\n\nInitially, the patient was referred to our institute with a painful mass in the anterior part of the left thigh increasing in volume for 3 months. Biopsy revealed a high-grade pleomorphic RMS. The cancer being staged IB, she had neoadjuvant radiotherapy. After complete surgical excision, pathology examination revealed a 6 cm Grade II pleomorphic RMS, with clear margins. Six months later, she developed three synchronous lung metastases. She got 4 courses of doxorubicin-ifosfamide which were poorly supported. After two courses, a heterogeneous (morphological and metabolic) response was observed, hence SBRT was delivered with a Biologically Equivalent Dose (α/β10)> 100 Gray on the two more chemoresistant lesions. This SBRT was very well tolerated, no side effects were reported. The patient remained alive and achieved a complete response of these three metastases, which sustains after more than 3 years.\n\n\n\nEarly recognition and proper management of these oligometastatic patients may lead to motivating results in a poor prognosis disease.", "affiliations": "Institut Jules Bordet-Université Libre de Bruxelles, Department of Radiation-Oncology, Brussels, Belgium. Electronic address: Sofian.benkhaled@bordet.be.;Cancer Institute of Dakar Department of Radiation-Oncology, Dakar, Senegal.;Institut Jules Bordet-Université Libre de Bruxelles, Department of Medical Oncology, Brussels, Belgium.;Institut Jules Bordet-Université Libre de Bruxelles, Department of Surgery, Brussels, Belgium.;Institut Jules Bordet-Université Libre de Bruxelles, Department of Pathology, Brussels, Belgium.;Institut Jules Bordet-Université Libre de Bruxelles, Department of Radiation-Oncology, Brussels, Belgium.", "authors": "Benkhaled|Sofian|S|;Mané|Maïmouna|M|;Jungels|Christiane|C|;Shumelinsky|Felix|F|;Aubain|Nicolas De Saint|NS|;Van Gestel|Dirk|D|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1016/j.ctarc.2020.100282", "fulltext": null, "fulltext_license": null, "issn_linking": "2468-2942", "issue": "26()", "journal": "Cancer treatment and research communications", "keywords": "Chemoresistance; Lung metastasis; Pleomorphic Rhabdomyosarcoma; Stereotaxic body radiation therapy; Synchronous metastasis", "medline_ta": "Cancer Treat Res Commun", "mesh_terms": null, "nlm_unique_id": "101694651", "other_id": null, "pages": "100282", "pmc": null, "pmid": "33360328", "pubdate": "2021", "publication_types": "D016428:Journal Article", "references": null, "title": "Successful treatment of synchronous chemoresistant pulmonary metastasis from pleomorphic rhabdomyosarcoma with stereotaxic body radiation therapy: A case report and a review of the literature.", "title_normalized": "successful treatment of synchronous chemoresistant pulmonary metastasis from pleomorphic rhabdomyosarcoma with stereotaxic body radiation therapy a case report and a review of the literature" }

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{ "abstract": "BACKGROUND\nRecurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) remains a major therapeutic challenge. In recent years, new molecular-targeted therapies, such as cabozantinib, have been approved for the treatment of advanced HCC. However, clinical experience with these new drugs in the treatment of HCC in the LT setting is very limited.\nIn 2003, a 36-year-old woman was referred to the hospital with right upper abdominal pain.\n\n\nMETHODS\nAn initial ultrasound of the liver demonstrated a large unclear lesion of the left lobe of the liver. The magnet resonance imaging findings confirmed a multifocal inoperable HCC in a non-cirrhotic liver. Seven years after receiving a living donor LT, pulmonary and intra-hepatic recurrence of the HCC was radiologically diagnosed and histologically confirmed.\n\n\nMETHODS\nFollowing an interdisciplinary therapy concept consisting of surgical, interventional-radiological (with radiofrequency ablation [RFA]) as well as systemic treatment, the patient achieved a survival of more than 10 years after tumor recurrence. As systemic first line therapy with sorafenib was accompanied by grade 3 to 4 toxicities, such as mucositis, hand-foot skin reaction, diarrhea, liver dysfunction, and hyperthyroidism, it had to be discontinued. After switching to cabozantinib from June 2018 to April 2020, partial remission of all tumor manifestations was achieved. The treatment of the remaining liver metastasis could be completed by RFA. The therapy with cabozantinib was well tolerated, only mild arterial hypertension and grade 1 to 2 mucositis were observed. Liver transplant function was stable during the therapy, no drug interaction with immunosuppressive drugs was observed.\n\n\nRESULTS\nMore than 10 years survival after recurrence of HCC after living-donor LT due to intensive multimodal therapy concepts, including surgery, RFA, and systemic therapy with cabozantinib in the second line therapy.\n\n\nCONCLUSIONS\nIn conclusion, this report highlights the tolerability and effectiveness of cabozantinib for the treatment of HCC recurrence after LT. We show that our patient with a late recurrence of HCC after LT benefitted from intensive multimodal therapy concepts, including surgery, RFA, and systemic therapy.", "affiliations": "Department of Internal Medicine I, University Hospital Bonn, Germany.;Department of Internal Medicine I, University Hospital Bonn, Germany.;Department of Internal Medicine I, University Hospital Bonn, Germany.;Department of Internal Medicine I, University Hospital Bonn, Germany.;Department of Internal Medicine I, University Hospital Bonn, Germany.;Department of Radiology, University Hospital Bonn, Germany.;Department of Radiology, University Hospital Bonn, Germany.;Department of Nuclear Medicine, University Hospital Bonn, Germany.;Department of Pathology, University Hospital Bonn, Germany.;Department of Visceral Surgery, University Hospital Bonn, Germany.;Department of Visceral Surgery, University Hospital Bonn, Germany.;Department of Visceral Surgery, University Hospital Bonn, Germany.;Department of Visceral Surgery, University Hospital Bonn, Germany.;Department of Visceral Surgery, University Hospital Bonn, Germany.;Department of Internal Medicine I, University Hospital Bonn, Germany.;Department of Internal Medicine I, University Hospital Bonn, Germany.", "authors": "Mahn|Robert|R|;Sadeghlar|Farsaneh|F|;Bartels|Alexandra|A|;Zhou|Taotao|T|;Weismüller|Tobias|T|;Kupczyk|Patrick|P|;Meyer|Carsten|C|;Gaertner|Florian C|FC|;Toma|Marieta|M|;Vilz|Tim|T|;Knipper|Petra|P|;Glowka|Tim|T|;Manekeller|Steffen|S|;Kalff|Jörg|J|;Strassburg|Christian P|CP|;Gonzalez-Carmona|Maria A|MA|0000-0003-3956-1457", "chemical_list": "D000813:Anilides; D011725:Pyridines; C558660:cabozantinib", "country": "United States", "delete": false, "doi": "10.1097/MD.0000000000027082", "fulltext": "\n==== Front\nMedicine (Baltimore)\nMedicine (Baltimore)\nMEDI\nMedicine\n0025-7974\n1536-5964\nLippincott Williams & Wilkins Hagerstown, MD\n\nMD-D-21-03928\n10.1097/MD.0000000000027082\n27082\n5700\nResearch Article\nClinical Case Report\nMultimodal and systemic therapy with cabozantinib for treatment of recurrent hepatocellular carcinoma after liver transplantation\nA case report with long term follow-up outcomes\nMahn Robert MD a\nSadeghlar Farsaneh PhD a\nBartels Alexandra MD a\nZhou Taotao MD a\nWeismüller Tobias MD a\nKupczyk Patrick MD b\nMeyer Carsten MD b\nGaertner Florian C. MD c\nToma Marieta MD d\nVilz Tim MD e\nKnipper Petra MD e\nGlowka Tim MD e\nManekeller Steffen MD e\nKalff Jörg MD e\nStrassburg Christian P. MD a\nGonzalez-Carmona Maria A. MD a ∗\nSaranathan. Maya\na Department of Internal Medicine I, University Hospital Bonn, Germany\nb Department of Radiology, University Hospital Bonn, Germany\nc Department of Nuclear Medicine, University Hospital Bonn, Germany\nd Department of Pathology, University Hospital Bonn, Germany\ne Department of Visceral Surgery, University Hospital Bonn, Germany.\n∗ Correspondence: Maria A. Gonzalez-Carmona, Department of Internal Medicine I, University of Bonn, Venusberg-Campus 1, 53105 Bonn, Germany (e-mail: maria.gonzalez-carmona@ukbonn.de).\n24 9 2021\n24 9 2021\n100 38 e2708222 6 2021\n29 7 2021\n12 8 2021\nCopyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0\n\nAbstract\n\nRationale:\n\nRecurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) remains a major therapeutic challenge. In recent years, new molecular-targeted therapies, such as cabozantinib, have been approved for the treatment of advanced HCC. However, clinical experience with these new drugs in the treatment of HCC in the LT setting is very limited.\n\nPatient concerns:\n\nIn 2003, a 36-year-old woman was referred to the hospital with right upper abdominal pain.\n\nDiagnosis:\n\nAn initial ultrasound of the liver demonstrated a large unclear lesion of the left lobe of the liver. The magnet resonance imaging findings confirmed a multifocal inoperable HCC in a non-cirrhotic liver. Seven years after receiving a living donor LT, pulmonary and intra-hepatic recurrence of the HCC was radiologically diagnosed and histologically confirmed.\n\nInterventions:\n\nFollowing an interdisciplinary therapy concept consisting of surgical, interventional-radiological (with radiofrequency ablation [RFA]) as well as systemic treatment, the patient achieved a survival of more than 10 years after tumor recurrence. As systemic first line therapy with sorafenib was accompanied by grade 3 to 4 toxicities, such as mucositis, hand-foot skin reaction, diarrhea, liver dysfunction, and hyperthyroidism, it had to be discontinued. After switching to cabozantinib from June 2018 to April 2020, partial remission of all tumor manifestations was achieved. The treatment of the remaining liver metastasis could be completed by RFA. The therapy with cabozantinib was well tolerated, only mild arterial hypertension and grade 1 to 2 mucositis were observed. Liver transplant function was stable during the therapy, no drug interaction with immunosuppressive drugs was observed.\n\nOutcomes:\n\nMore than 10 years survival after recurrence of HCC after living-donor LT due to intensive multimodal therapy concepts, including surgery, RFA, and systemic therapy with cabozantinib in the second line therapy.\n\nLessons:\n\nIn conclusion, this report highlights the tolerability and effectiveness of cabozantinib for the treatment of HCC recurrence after LT. We show that our patient with a late recurrence of HCC after LT benefitted from intensive multimodal therapy concepts, including surgery, RFA, and systemic therapy.\n\nKeywords\n\ncabozantinib\nliving-donor liver transplantation\nlong-term survival\nmultimodal therapy\nnon-cirrhotic HCC\nDeutsche Krebshilfe109255 Maria A. Gonzalez-CarmonaOPEN-ACCESSTRUE\n==== Body\npmc1 Introduction\n\nHepatocellular carcinoma (HCC) is the most common primary liver cancer worldwide.[1] Liver cirrhosis represents a major risk factor for HCC development, and HCC is the first cause of death in patients with liver cirrhosis.[2] HCC arising in a non-cirrhotic (NC-HCC) or non-fibrotic liver is a fairly rare malignancy. NC-HCC often affects younger healthy female patients and it is usually larger at diagnosis, since the patients did not participate in HCC surveillance programs. In these patients, surgical resection with curative intent is the treatment of choice.[3–5] For HCC in a cirrhotic liver within the Milan criteria (MC) (a single tumor of up to 5 cm or up to 3 tumors, each no larger than 3 cm) without macrovascular or extra-hepatic manifestations, liver transplantation (LT) represents the best treatment option with 5-year survival rates of more than 70%.[6–8] Conventional LT for HCC beyond MC for selected patients may also achieve acceptable overall survival (OS) and recurrence rates.[9,10] Due to deceased organ donation shortage, the use of living-donor liver transplantation (LDLT) is generally accepted for patients beyond MC. However, while LT for patients with unresectable NC-HCC out of MC is not well established, it seems to achieve 5-year survival rates of up to 59%.[11]\n\nHCC recurrence after LT remains a major therapeutic challenge and is of limiting prognosis.[12,13] In most cases, recurrence occurs within the first 2 years. However, cases of very late recurrence have also been reported.[14] For patients with oligometastatic intra-hepatic or extra-hepatic tumor recurrence, surgical or interventional-radiological treatments may be applied with curative intention.[12,13,15] In cases of unresectable, recurrent HCC, a systemic treatment is recommended. From 2007 to 2015, sorafenib, a multikinase inhibitor, was the only therapeutic agent showing a survival benefit in patients with advanced HCC compared to placebo.[16] In recent years, new molecular-targeted therapies, such as lenvatinib, regorafenib, cabozantinib, and ramucirumab, as well as immune checkpoint inhibitors, such as nivolumab, pembrolizumab, and atezolizumab in combination with bevacizumab, have been approved for the treatment of advanced HCC.[17–21] However, clinical experience with these new drugs in the treatment of HCC after LT is very limited, since these patients are excluded from phase III trials. Some evidence can be found for sorafenib in combination with rapamycin inhibitors for recurrent HCC after LT and for regorafenib as systemic second line therapy.[22–24]\n\nHere, we report on efficacy, feasibility, and tolerability of cabozantinib in a female patient with recurrent HCC after LDLT and who was intolerant to sorafenib. Moreover, we show the benefits from intensive multimodal therapy concepts, including surgery, radiofrequency ablation (RFA), and systemic therapy resulting in a long-term survival of more than 10 years after HCC recurrence.\n\n2 Case presentation\n\nIn 2003, a 36-year-old Caucasian woman was referred to the hospital with right upper abdominal pain. An initial ultrasound of the liver demonstrated a large unclear lesion of the left lobe of the liver. Serum level of y-GT was slightly elevated at 84 U/mL. The AFP value was negative. Medical history of the patient revealed a slight mitral valve prolapse, latent hypothyroidism, a condition after reconstructive burn surgery in 1969 and previous nicotine consumption. There was no evidence for any underlying liver disease, including viral hepatitis, non-alcoholic fatty liver, autoimmune pathologies, or genetic metabolic disorders. No intakes of alcohol, hepatotoxic drugs, or hormone substitution and no contact with hepatotoxins were documented. Magnet resonance imaging (MRI) findings were consistent with a liver adenoma. However, a highly differentiated HCC could not be ruled out. According to the decision of our interdisciplinary tumor board and after excluding extra-hepatic tumor manifestations (colonoscopy, gastroscopy, CT scan, and whole body FDG-PET/CT scan), an explorative laparotomy with the intent of a left hepatectomy was performed. Intra-operatively, an approx. 9.5 cm large tumor of the left liver lobe was resected. Histopathologic specimen confirmed a moderately differentiated HCC in a NC liver (Fig. 1A/B). However, intra-operatively performed ultrasound detected irresectable multifocal metastases in the right liver. In December 2003, as part of an individual therapy concept, the patient received an orthotopic LDLT of the right hepatic lobe from her mother. LDLT was approved by the ethics committee of the Medical Chamber of North Rhine-Westphalia, Germany. The liver explant contained up to further 7 lesions of a highly differentiated HCC. The definitive tumor stage of the explanted liver was pT3 pN0 (0/4) M0 with no microvascular involvement. Immunosuppression was initially started with tacrolimus and mycophenolate mofetil. In the following time period, the patient showed an excellent graft function. CT and MRI scans were carried out at intervals of about 3 to 6 months as follow-up. Seven years later, in February 2010, CT scan revealed lung metastases (Fig. 2A). Further tumor manifestations were ruled out with FDG-PET/CT scan and MRI of the liver. Immunosuppression was switched to sirolimus. According to the decision of our interdisciplinary tumor board, resection of the pulmonary lesions with curative intention was performed. In February 2010, May 2010, October 2013, and November 2013, further partial lung resections of new lung metastases were performed. Histologically, metastases of the previously known HCC were confirmed (Fig. 1C/D/E). In January 2014, an atypical liver resection was performed due to intra-hepatic HCC recurrence. Pulmonary segment resections followed again in July 2014, November 2014, and August 2015. Because of a new intra-hepatic HCC recurrence in January 2015, RFA of 2 liver metastases was performed. After yet another tumor recurrence in the lung with confirmation of HCC cells in the cytology by bronchoscopy in December 2015, our tumor board decided to start palliative first line systemic therapy with sorafenib. Sorafenib therapy with 800 mg per day was accompanied by grade 3 hand-foot syndrome and pronounced head pruritus. Even after dose reduction to initially 600 mg after 1 month and later 400 mg per day, sorafenib had to be discontinued in February 2016 due to intolerable grade 3 to 4 side effects, such as mucositis, hand-foot skin reaction, diarrhea, liver dysfunction with transaminase elevation, and hyperthyroidism, requiring hospitalization of the patient. Several weeks after the discontinuation of sorafenib and switching the immunosuppression to tacrolimus again, the patient recovered from the side effects. However, grade 1 hyperthyroidism and hand-foot skin reaction persisted. An initial second line therapy with regorafenib was contraindicated, since the patient did not tolerate sorafenib. In February 2017, a further progression of the HCC showing a mediastinal lymph node was documented by CT scan and confirmed by FDG-PET/CT scan (Fig. 2B). In April 2017, due to a lack of further systemic therapeutic options, it was decided to perform right lateral resection of the mediastinal lymph node metastases. The histology again confirmed HCC spreading. Further solitary pulmonary recurrences of HCC could be treated locally by CT-guided RFA in October 2017 and November 2017. In April 2018, MRI scan of the liver revealed newly appeared high-grade HCC-suspected lesions subcapsular in liver segment 8 (10 × 7 mm) and at the segment border 6/7 (7 × 6 mm). After tumor board discussion, a switch to an off label second line systemic therapy with cabozantinib was recommended. Thus, from June 2018 to April 2019, our patient received second line therapy with cabozantinib. An initial start with 40 mg was accompanied by mild (grade 1–2) oropharyngeal mucositis and mild hypertension, both of which were easy to manage. Therefore, the dose could be increased to 60 mg per day with acceptable tolerability. Occasionally, due to mild mucositis and abdominal distension, cabozantinib had to be temporarily reduced to 40 or 20 mg. After 11 months of therapy with cabozantinib, the CT scan revealed complete remission of the pulmonary lesions and low partial remission of the liver metastases as a best response to cabozantinib. After discussion of the case in our interdisciplinary tumor conference, a new round of RFA of the remaining liver metastasis could be completed in April 2019, following discontinuation of cabozantinib. Unfortunately, 2 months later, new progression of the pulmonary metastasis was observed and the therapy with cabozantinib had to be restarted in August 2019. Again, partial remission of all tumor manifestations in the lung was achieved and the therapy with cabozantinib was well tolerated with only mild arterial hypertension, grade 1 to 2 mucositis and gastrointestinal symptoms, all of which could be easily managed. In the further course of therapy, the initial dose of 40 mg/day could be increased to 60 mg/day, while the dose was adjusted to 20 to 60 mg to control the gastrointestinal side effects and mucositis. Liver transplant function and blood count cells remained stable during therapy and no drug interaction with immunosuppressive drugs was observed at any time (Fig. 3A/B/C/D).\n\nFigure 1 (A/B) H&E staining of partial liver resection with a 9.5 cm, moderately differentiated, hepatocellular carcinoma and multiple intra-hepatic metastases in 10× (A) and 20× magnification (B). Liver parenchyma without cirrhotic changes (C/D/E) H&E and Hepar1 staining from a left thoracotomy with resection of pulmonary metastases of a moderately differentiated hepatocellular carcinoma in 4× (C), 10× (D), and 10× (E) magnification.\n\nFigure 2 (A) CT scan of thorax dated February 1, 2010 (lung window, axial maximum intensity projection) shows high level suspicion of at least 7 lung metastases on both sides. (B) FDG-PET/CT scan dated April 13, 2017 shows moderately intensive FDG image of the known right hilar lymph node metastasis and CT scan of thorax/abdomen from February 1, 2017 shows progressive size right hilar lymph node metastasis. (C) CT scan of abdomen and MRI of liver from April 2018, January and April 2019 show constancy or low regression of HCC-suspicious lesions in liver segments VI and VIII. The arrows point to metastases. HCC = hepatocellular carcinoma, MRI = magnet resonance imaging.\n\nFigure 3 Diagram of the tacrolimus level (A), blood count cells (B/C), total serum bilirubin and ALT levels (D) from June 2018 to April 2020 of the patient during cabozantinib therapy.\n\n3 Discussion\n\nHere, we report on efficacy, feasibility, and tolerability of cabozantinib in a female patient intolerant to sorafenib with late recurrent HCC after LDLT due to NC-HCC. Furthermore, we report on the benefits of intensive multimodal therapies, including surgery, RFA, and systemic therapy, achieving long-term survival of more than 10 years after HCC recurrence.\n\nLittle is known about the etiology of the HCC in the presented case. The peculiarities of this case were the female sex, the young age, normal body mass index, and the absence of any underlying liver pathology. Whether environmental conditions, such as the inhalation of toxic gases after a fire accident in childhood, and chronic nicotine smoke inhalation played a role as possible triggers for the development of HCC remains unclear.\n\nThe first and unique symptom of the patient was right upper abdominal pain. As is common for NC-HCC and due to lack of symptoms, no HCC surveillance or earlier imaging were performed. Therefore, the initial ultrasound of the liver showed an already large tumor at diagnosis, indicating advanced stage.[5,25–26] Here, despite a larger tumor burden, surgical resection is the treatment of choice for HCC in NC liver, resulting in better benefit on survival than HCC in cirrhotic liver.[3,5] Patients with cirrhosis and small, unresectable HCCs within the MC (a single tumor of up to 5 cm or up to 3 tumors, each no larger than 3 cm) without vascular or extra-hepatic manifestations, who undergo orthotopic LT achieve 5-year survival rates of more than 70%.[6–8] LT for patients with unresectable NC-HCC out of MC is not well established. However, as it was the case with our patient, LT may be offered for selected patients showing acceptable survival and recurrence rates.[9–11] A European multicentric analysis reported a 5-year survival of 59% for patients independent of tumor size without macrovascular invasion and/or positive lymph nodes.[11] Because of limited organ supply, LDLT represents an alternative option to deceased donor liver transplantation. The indication for LDLT without waitlist time, as in the case of our patient, provides a curative option to selected patients with irresectable HCC, since HCC progression is limited in time.[27,28] In the case of our patient, a 7-year recurrence-free survival could be achieved.\n\nHowever, the risk of HCC recurrence after transplantation remains between 8% and 20%.[29] HCC recurrence mostly appears in the first 2 years after LT, but later relapses, as seen in our patient, have also been reported in the literature.[14] The recurrence pattern of these late recurrences often manifests as single extra-hepatic metastases. In these cases, intensive surgical treatment has shown to improve survival. In a large single-center study by Bodzin et al,[30] 106 patients who developed recurrent HCC post-LT were analyzed. Patients who underwent surgical therapy showed an improved median survival of 27.8 months versus 10.6 months for those with non-surgical therapy or 3.7 months for those following a best supportive care concept. Further studies confirmed that surgically accessible HCC recurrence after LT is associated with prolonged OS.[31,32] In addition to surgery, multimodal combined treatment with local and systemic therapies may also result in increased survival, even in patients with HCC metastasis in multiple organs, as was the case in our patient.[12,13,15] Therefore, we assume that the long survival of our patient was due to the initial aggressive surgical and interventional-radiologic treatments until the start of systemic therapy with sorafenib. Furthermore, late recurrences appear to have significant better OS compared to early recurrences within the first 2 years, as they show less aggressive tumor biology and higher response rates to local treatments.[14]\n\nWhen surgical or local therapies are not possible, systemic therapy with sorafenib is usually the recommended first line therapy.[33] Sorafenib was the first drug approved for systemic treatment of advanced HCC.[16] For the use of sorafenib in recurrent HCC after LT, a potential therapeutic benefit has also been shown in several studies, especially in combination with mammalian target of rapamycin inhibitors.[22,23,33–35] In our case, the patient was treated systemically with sorafenib. Immunosuppression was switched to a mammalian target of rapamycin inhibitors (sirolimus). However, the therapy with sorafenib was accompanied by grade 3 to 4 side effects, including mucositis, hand-foot skin reaction, diarrhea, liver dysfunction with transaminase elevation, and hyperthyroidism, requiring hospitalization of the patient and discontinuation of sorafenib. Similarly, in the study by Staufer et al,[36] severe toxicities, including acute hepatitis, diarrhea, hand-foot-skin reaction, and bone marrow suppression were reported in more than 90% of all patients receiving sorafenib with recurrent HCC after LT, indicating a high toxicity of sorafenib in this setting.\n\nRegorafenib was the initial second line systemic treatment approved in patients with HCC. In the phase III RESORCE trial, Bruix et al[19] reported a survival benefit of regorafenib versus placebo as second line therapy in patients who tolerated and progressed under sorafenib. The data on second line therapies after sorafenib failure in posttransplant patients are still poor. A multicentric, retrospective study by Lavarone et al[24] describes the feasibility of regorafenib in posttransplant patients with recurrent HCC who progressed on sorafenib (median OS of 12.9 months after regorafenib initiation and 38.4 months after initiation of sorafenib, with a 1- and 3-year OS of 68% and 23%, respectively). However, due to the poor tolerability of sorafenib, therapy switch to regorafenib was not possible in our patient. Therefore, we opted for systemic second line therapy with cabozantinib. Cabozantinib, a tyrosine kinase inhibitor targeting Vascular Endothelial Growth Factor-Rezeptor 2, AXL, and MET in patients with advanced HCC who progressed on sorafenib was evaluated in the phase III CELESTIAL trial. Compared to placebo, cabozantinib showed a significant benefit in median OS (10.2 vs. 8 months; P = .004) and PFS (5.2 vs 1.9 months; P < .0001).[20] Due to the lack of clinical experience with cabozantinib in combination with immunosuppressive agents and the potentially increased risk of side effects, we started with great caution at a reduced dose and were able to increase the dose to 60 mg per day in the further treatment course. Despite similar adverse events to sorafenib as described for cabozantinib in the CELESTIAL trial, such as hand-foot syndrome (17%), hypertension (16%), elevated aspartate aminotransferase levels (12%), diarrhea (10%), and fatigue (10%), our patient tolerated the systemic therapy with cabozantinib well.[20] Only grade 1 to 2 toxicities, such as hypertension, mucositis, or gastrointestinal complaints were observed, and no grade 3 or grade 4 toxicities occurred over the long exposition period of more than 20 months. The side effects could be easily managed with occasional dose adjustments as necessary. Furthermore, graft function and the level of tacrolimus remained stable during the entire treatment with cabozantinib and no interactions with immunosuppression were observed at any time. Finally, despite several dose adjustments, an objective response could be achieved with complete remission of the lung metastasis and a low partial remission of the liver metastasis as best response. Moreover, a new round of RFA of the remaining liver metastasis could be completed 11 months later, resulting in complete HCC remission, allowing a temporary discontinuation of the systemic therapy with cabozantinib.\n\n4 Conclusion\n\nIn conclusion, we report on a patient with inoperable HCC in a NC liver out of MC, who benefitted from LDLT. After suffering a late recurrence of HCC, our patient benefitted from intensive multimodal therapy concepts, including surgery, RFA, and systemic therapy, achieving a long-term survival of more than 10 years. Furthermore, our report highlights feasibility, tolerability, and effectiveness of cabozantinib as the second line therapy for the treatment of HCC recurrence after LT in a patient intolerant to sorafenib.\n\nAuthor contributions\n\nMAG made substantial contributions for the conception and supervision of the manuscript.\n\nRM and FS has been involved in drafting and writing the manuscript.\n\nRM, AB, TZ, and TW has been involved in revising the manuscript critically for important intellectual content.\n\nTV, PK, TG, SM, JK, and CPS made substantial contributions for acquisition of clinical data and gave final approval for the version of the manuscript to be published.\n\nCM made substantial contributions for acquisition of radiological data.\n\nMT was involved in the histopathological examinations and their evaluation.\n\nAll the authors have made significant contributions to the manuscript and have also read and approved the manuscript.\n\nConceptualization: Maria A. Gonzalez-Carmona.\n\nData curation: Robert Mahn, Farsaneh Sadeghlar, Alexandra Bartels, Taotao Zhou, Tobias Weismüller, Patrick Kupczyk, Carsten Meyer, Marieta Toma, Petra Knipper, Tim Glowka, Steffen Manekeller.\n\nFormal analysis: Robert Mahn, Farsaneh Sadeghlar, Patrick Kupczyk.\n\nMethodology: Patrick Kupczyk, Carsten Meyer.\n\nResources: Maria A. Gonzalez-Carmona.\n\nSoftware: Carsten Meyer, Florian C. Gaertner.\n\nSupervision: Maria A. Gonzalez-Carmona.\n\nValidation: Maria A. Gonzalez-Carmona.\n\nWriting – original draft: Robert Mahn, Farsaneh Sadeghlar, Patrick Kupczyk.\n\nWriting – review & editing: Alexandra Bartels, Taotao Zhou, Tobias Weismüller, Carsten Meyer, Florian C. Gaertner, Marieta Toma, Tim Vilz, Petra Knipper, Tim Glowka, Steffen Manekeller, Jörg Kalff, Christian P. Strassburg, Maria A. Gonzalez-Carmona.\n\nAbbreviations: HCC = hepatocellular carcinoma, LDLT = living-donor liver transplantation, LT = liver transplantation, MC = Milan criteria, MRI = magnet resonance imaging, NC = non-cirrhotic, OS = overall survival, RFA = radiofrequency ablation.\n\nHow to cite this article: Mahn R, Sadeghlar F, Bartels A, Zhou T, Weismüller T, Kupczyk P, Meyer C, Gaertner FC, Toma M, Vilz T, Knipper P, Glowka T, Manekeller S, Kalff J, Strassburg CP, Gonzalez-Carmona MA. Multimodal and systemic therapy with cabozantinib for treatment of recurrent hepatocellular carcinoma after liver transplantation: a case report with long term follow-up outcomes. Medicine. 2021;100:38(e27082).\n\nThis work was supported by a BONFOR grant from the University of Bonn and grant number 109255 from the German Cancer Aid Association (Deutsche Krebshilfe) awarded to MA Gonzalez-Carmona.\n\nThe patient provided written informed consent for publication of the case report, including the case details and the use of the radiological and histological images. Ethical approval for this retrospective case report was obtained by the Ethics Committee of the Medical Faculty of the University Hospital (No. 347/17).\n\nMaria A. Gonzalez-Carmona has contributed to advisory boards for Roche, Eisai, MSD, IPSEN, and AZ. None of the other authors have any potential conflicts (financial, professional, or personal) that are relevant to the manuscript. All authors approved the final version of the manuscript.\n\nAll data generated or analyzed during this study are included in this published article [and its supplementary information files].\n==== Refs\nReferences\n\n[1] European Association for the Study of the Liver. EASL Clinical Practice Guidelines: management of hepatocellular carcinoma. J Hepatol 2018;69 :182–236.29628281\n[2] Alkofer B Lepennec V Chiche L . Hepatocellular cancer in the non-cirrhotic liver. J Visc Surg 2011;148 :03–11.\n[3] Gaddikeri S McNeeley MF Wang CL . Hepatocellular carcinoma in the noncirrhotic liver. Am J Roentgenol 2014;203 :W34–47.24951228\n[4] Clavien PA Petrowsky H DeOliveira ML Graf R . Strategies for safer liver surgery and partial liver transplantation. N Engl J Med 2007;356 :1545–59.17429086\n[5] Lang H Sotiropoulos GC Dömland M . Liver resection for hepatocellular carcinoma in non-cirrhotic liver without underlying viral hepatitis. 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Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased αfetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncology 2019;20 :282–96.30665869\n[22] Gomez-Martin C Bustamante J Castroagudin JF . Efficacy and safety of sorafenib in combination with mammalian target of rapamycin inhibitors for recurrent hepatocellular carcinoma after liver transplantation. Liver Transpl 2012;18 :45–52.21932373\n[23] Sposito C Mariani L Germini A . Comparative efficacy of sorafenib versus best supportive care in recurrent hepatocellular carcinoma after liver transplantation: a case-control study. J Hepatol 2013;59 :59–66.23500153\n[24] Lavarone M Invernizzi F Czauderna C . Preliminary experience on safety of regorafenib after sorafenib failure in recurrent hepatocellular carcinoma after liver transplantation. Am J Transplant 2019;19 :3176–318.31365177\n[25] Trevisani F Frigerio M Santi V Grignaschi A Bernardi M . Hepatocellular carcinoma in non-cirrhotic liver: a reappraisal. Dig Liver Dis 2010;42 :341–7.19828388\n[26] Desai A Sandhu S Lai J-P Sandhu DS . Hepatocellular carcinoma in non-cirrhotic liver: a comprehensive review. World J Hepatol 2019;11 :01–18.\n[27] Liang W Wu L Ling X . Living donor liver transplantation versus deceased donor liver transplantation for hepatocellular carcinoma: a meta-analysis. Liver Transpl 2012;18 :1226–36.22685095\n[28] Limkemann AJP Abreu P Sapisochin G . How far can we go with hepatocellular carcinoma in living donor liver transplantation? Curr Opin Organ Transplant 2019;24 :644–50.31397731\n[29] Chagas AL Felga GEG Diniz MA . Hepatocellular carcinoma recurrence after liver transplantation in a Brazilian multicenter study: clinical profile and prognostic factors of survival. Eur J Gastroenterol Hepatol 2019;31 :1148–56.31247632\n[30] Bodzin AS Lunsford KE Markovic D Harlander-Locke MP Busuttil RW Agopian VG . Predicting mortality in patients developing recurrent hepatocellular carcinoma after liver transplantation: impact of treatment modality and recurrence characteristics. Ann Surg 2017;266 :118–25.27433914\n[31] Fernandez-Sevilla E Allard M-C Selten J . Recurrence of hepatocellular carcinoma after liver transplantation: is there a place for resection? Liver Transpl 2017;23 :440–7.28187493\n[32] Regalia E Fassati LR Valente U . Pattern and management of recurrent hepatocellular carcinoma after liver transplantation. J Hepatobiliary Pancreat Surg 1998;5 :29–34.9683751\n[33] Castelli G Burra P Giacomin A . Sorafenib use in the transplant setting. Liver Transpl 2014;20 :1021–8.24809799\n[34] Jung D-H Tak E Hwang S . Antitumor effect of sorafenib and mammalian target of rapamycin inhibitor in liver transplantation recipients with hepatocellular carcinoma recurrence. Liver Transpl 2018;24 :932–45.29710388\n[35] Invernizzi F Iavarone M Zavaglia C Mazza S Maggi U . Experience with early sorafenib treatment with mTOR inhibitors in hepatocellular carcinoma recurring after liver transplantation. Transplantation 2020;104 :568–74.31517781\n[36] Staufer K Fischer L Seegers B Vettorazzi E Nashan B Sterneck M . High toxicity of sorafenib for recurrent hepatocellular carcinoma after liver transplantation. Transpl Int 2012;25 :1158–64.22882364\n\n", "fulltext_license": "CC BY", "issn_linking": "0025-7974", "issue": "100(38)", "journal": "Medicine", "keywords": null, "medline_ta": "Medicine (Baltimore)", "mesh_terms": "D015746:Abdominal Pain; D000328:Adult; D000813:Anilides; D006528:Carcinoma, Hepatocellular; D003131:Combined Modality Therapy; D003937:Diagnosis, Differential; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008113:Liver Neoplasms; D016031:Liver Transplantation; D058990:Molecular Targeted Therapy; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local; D011183:Postoperative Complications; D011725:Pyridines; D000078703:Radiofrequency Ablation", "nlm_unique_id": "2985248R", "other_id": null, "pages": "e27082", "pmc": null, "pmid": "34559100", "pubdate": "2021-09-24", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Multimodal and systemic therapy with cabozantinib for treatment of recurrent hepatocellular carcinoma after liver transplantation: A case report with long term follow-up outcomes.", "title_normalized": "multimodal and systemic therapy with cabozantinib for treatment of recurrent hepatocellular carcinoma after liver transplantation a case report with long term follow up outcomes" }

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Multimodal and systemic therapy with cabozantinib for treatment of recurrent hepatocellular carcinoma after liver transplantation: A case report with long term follow-up outcomes. 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{ "abstract": "Previous literature has suggested that a short course of corticosteroids is similarly effective as an extended course for managing an acute exacerbation of chronic obstructive pulmonary disease (AECOPD). However, there are limited data regarding the optimal corticosteroid regimen in critically ill patients and the dosing strategies remain highly variable in this population.\nThis retrospective cohort study evaluated patients with AECOPD admitted to the intensive care unit within a 2-year period. Patients were divided into short-course (≤5 days) or extended-course (>5 days) corticosteroid taper groups. The primary end point was treatment failure, defined as the need for intubation, reintubation, or noninvasive mechanical ventilation. Secondary end points included the duration of mechanical ventilation, hospital and intensive care unit length of stay, and adverse events.\nOf the 151 patients who met the inclusion criteria, 94 received an extended taper and 57 received a short taper. Treatment failure occurred in 3 patients, who were all in the extended taper group (P = .17). In a propensity score-matched cohort, the hospital length of stay was 7 days in the short taper group compared to 11 days in the extended taper group (P < .0001). No differences in adverse events were observed.\nA short-course corticosteroid taper in critically ill patients with AECOPD is associated with reduced hospital length of stay and decreased corticosteroid exposure without increased risk of treatment failure. A prospective randomized trial is warranted.", "affiliations": "Mount Sinai Beth Israel, New York, NY, USA.;The Mount Sinai Hospital, New York, NY, USA.;The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Mount Sinai Beth Israel, New York, NY, USA.;Mount Sinai Beth Israel, New York, NY, USA.;The Mount Sinai Hospital, New York, NY, USA.", "authors": "Poon|Teresa|T|;Paris|Daryl Glick|DG|;Aitken|Samuel L|SL|;Patrawalla|Paru|P|;Bondarsky|Eric|E|;Altshuler|Jerry|J|", "chemical_list": "D000305:Adrenal Cortex Hormones", "country": "United States", "delete": false, "doi": "10.1177/0885066617741470", "fulltext": null, "fulltext_license": null, "issn_linking": "0885-0666", "issue": "35(3)", "journal": "Journal of intensive care medicine", "keywords": "COPD; ICU; corticosteroid; exacerbation", "medline_ta": "J Intensive Care Med", "mesh_terms": "D000208:Acute Disease; D000305:Adrenal Cortex Hormones; D000368:Aged; D016638:Critical Illness; D018450:Disease Progression; D004334:Drug Administration Schedule; D005260:Female; D006760:Hospitalization; D006801:Humans; D007362:Intensive Care Units; D008297:Male; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive; D012121:Respiration, Artificial; D012189:Retrospective Studies; D013997:Time Factors; D016896:Treatment Outcome; D028761:Withholding Treatment", "nlm_unique_id": "8610344", "other_id": null, "pages": "257-263", "pmc": null, "pmid": "29161935", "pubdate": "2020-03", "publication_types": "D003160:Comparative Study; D023362:Evaluation Study; D016428:Journal Article", "references": null, "title": "Extended Versus Short-Course Corticosteroid Taper Regimens in the Management of Chronic Obstructive Pulmonary Disease Exacerbations in Critically Ill Patients.", "title_normalized": "extended versus short course corticosteroid taper regimens in the management of chronic obstructive pulmonary disease exacerbations in critically ill patients" }

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EXTENDED VERSUS SHORT-COURSE CORTICOSTEROID TAPER REGIMENS IN THE MANAGEMENT OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE EXACERBATIONS IN CRITICALLY ILL PATIENTS. JOURNAL OF INTENSIVE CARE MEDICINE. 2020?35(3):257-63", "literaturereference_normalized": "extended versus short course corticosteroid taper regimens in the management of chronic obstructive pulmonary disease exacerbations in critically ill patients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200311", "receivedate": "20200311", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17526869, "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": "US-TEVA-2020-US-1204098", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": "085600", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "HIGH DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC OBSTRUCTIVE PULMONARY DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Gastrointestinal haemorrhage", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "POON T, PARIS DG, AITKEN SL, PATRAWALLA P, BONDARSKY E, ALTSHULER J. EXTENDED VERSUS SHORT-COURSE CORTICOSTEROID TAPER REGIMENS IN THE MANAGEMENT OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE EXACERBATIONS IN CRITICALLY ILL PATIENTS. J-INTENSIVE-CARE-MED 2020?35(3):257-263.", "literaturereference_normalized": "extended versus short course corticosteroid taper regimens in the management of chronic obstructive pulmonary disease exacerbations in critically ill patients", "qualification": "2", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200318", "receivedate": "20200318", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17554000, "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": "NVSC2020US066280", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": "40194", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC OBSTRUCTIVE PULMONARY DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Infection", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "POON T, PARIS DG, AITKEN SL, PATRAWALLA P, BONDARSKY E, ALTSHULER J ET AL.. EXTENDED VERSUS SHORT-COURSE CORTICOSTEROID TAPER REGIMENS IN THE MANAGEMENT OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE EXACERBATIONS IN CRITICALLY ILL PATIENTS.. JOURNAL OF INTENSIVE CARE MEDICINE. 2020?35(3):257-63", "literaturereference_normalized": "extended versus short course corticosteroid taper regimens in the management of chronic obstructive pulmonary disease exacerbations in critically ill patients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200309", "receivedate": "20200309", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17516331, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200409" } ]

{ "abstract": "A 59-year-old man developed red, swollen and warm feet accompanied by intermittent burning pain during treatment for cardiac failure and arrhythmias with several drugs including verapamil. The condition gradually worsened until there was persistent disabling burning pain and severe erythema and swelling of the feet. Aspirin and other analgesics were ineffective in relieving the discomfort. Histopathology of punch biopsies showed a mild perivascular mononuclear infiltrate and moderate perivascular oedema. Within 2 weeks of stopping verapamil the burning pain, erythema, and swelling of the feet had resolved. The clinical features and subsequent course are consistent with a diagnosis of erythermalgia secondary to verapamil.", "affiliations": "Department of Haematology, University Hospital, Erasmus University Rotterdam, The Netherlands.", "authors": "Drenth|J P|JP|;Michiels|J J|JJ|;Van Joost|T|T|;Vuzevski|V D|VD|", "chemical_list": "D014700:Verapamil", "country": "England", "delete": false, "doi": "10.1111/j.1365-2133.1992.tb00132.x", "fulltext": null, "fulltext_license": null, "issn_linking": "0007-0963", "issue": "127(3)", "journal": "The British journal of dermatology", "keywords": null, "medline_ta": "Br J Dermatol", "mesh_terms": "D004916:Erythromelalgia; D005528:Foot; D006801:Humans; D008297:Male; D008875:Middle Aged; D012867:Skin; D014700:Verapamil", "nlm_unique_id": "0004041", "other_id": null, "pages": "292-4", "pmc": null, "pmid": "1390176", "pubdate": "1992-09", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": null, "title": "Verapamil-induced secondary erythermalgia.", "title_normalized": "verapamil induced secondary erythermalgia" }

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{ "actiondrug": null, "activesubstance": { "activesubstancename": "DIGOXIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.25 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "ATRIAL FIBRILLATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DIGOXIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SPIRONOLACTONE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "25 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "ATRIAL FIBRILLATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SPIRONOLACTONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CAPTOPRIL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CARDIAC FAILURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CAPTOPRIL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VERAPAMIL HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "019614", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": "120 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "ATRIAL FIBRILLATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "120", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VERAPAMIL HYDROCHLORIDE SUSTAINED RELEASE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CAPTOPRIL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "25 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "ATRIAL FIBRILLATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CAPTOPRIL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "FUROSEMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "80 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "ATRIAL FIBRILLATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "80", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FRUSEMIDE /00032601/" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "COUMARIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CARDIAC FAILURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "COUMARIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DIGOXIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CARDIAC FAILURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DIGOXIN." }, { "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": "CARDIAC FAILURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FRUSEMIDE /00032601/" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SPIRONOLACTONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CARDIAC FAILURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SPIRONOLACTONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "COUMARIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ATRIAL FIBRILLATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "COUMARIN" } ], "patientagegroup": null, "patientonsetage": "59", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Erythromelalgia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "J P DRENTH, J J MICHIELS, T VAN JOOST, ET AL.. VERAPAMIL-INDUCED SECONDARY ERYTHERMALGIA. BRITISH JOURNAL OF DERMATOLOGY. 1992?127(3):292-294", "literaturereference_normalized": "verapamil induced secondary erythermalgia", "qualification": "1", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20190719", "receivedate": "20190719", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16598469, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20191004" } ]

{ "abstract": "BACKGROUND\nNonmotor fluctuations of psychiatric symptoms in patients suffering from Parkinson disease (PD) represent a very disabling condition, which may seriously interfere with the quality of life of patients and caregivers. In this regard, these disturbances are present with a higher frequency in advanced PD patients with associated motor complications and can appear both in \"on\" and in \"off\" period. Here we report on a case of fluctuating Cotard syndrome clearly related to \"wearing-off\" deterioration and responsive to levodopa treatment in a patient affected by advanced PD.\n\n\nMETHODS\nA 76-year-old woman presented with a 13-year history of PD. Her caregivers reported that, in the last 2 months, she has developed a sudden onset of nihilistic delusion (Cotard syndrome), mainly during the \"wearing-off\" condition and associated with end of dose dyskinesias and akathisia.As Cotard syndrome clearly improved with the administration of levodopa, the patient was successfully treated changing the levodopa schedule with the shortening of intervals between levodopa intakes in small doses.\n\n\nCONCLUSIONS\nBoth the appearance of the Cotard syndrome in this patient during the \"off\" state and the subsequent improvement of psychotic symptoms after levodopa administration strongly suggest an important correlation with the dopaminergic dysregulation.This finding suggests that dopaminergic deficit might play a key factor in the development of Cotard syndrome.", "affiliations": "Movement Disorders Center, Institute of Neurology, University of Cagliari, Cagliari, Italy.", "authors": "Solla|Paolo|P|;Cannas|Antonino|A|;Orofino|Gianni|G|;Marrosu|Francesco|F|", "chemical_list": "D000978:Antiparkinson Agents; D007980:Levodopa", "country": "United States", "delete": false, "doi": "10.1097/NRL.0000000000000010", "fulltext": null, "fulltext_license": null, "issn_linking": "1074-7931", "issue": "19(3)", "journal": "The neurologist", "keywords": null, "medline_ta": "Neurologist", "mesh_terms": "D000368:Aged; D000978:Antiparkinson Agents; D003702:Delusions; D020820:Dyskinesias; D005260:Female; D006801:Humans; D007980:Levodopa; D010300:Parkinson Disease", "nlm_unique_id": "9503763", "other_id": null, "pages": "70-2", "pmc": null, "pmid": "25692512", "pubdate": "2015-02", "publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Fluctuating Cotard syndrome in a patient with advanced Parkinson disease.", "title_normalized": "fluctuating cotard syndrome in a patient with advanced parkinson disease" }

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FLUCTUATING COTARD SYNDROME IN A PATIENT WITH ADVANCED PARKINSON DISEASE. THE NEUROLOGIST. 2015?19:70?2", "literaturereference_normalized": "fluctuating cotard syndrome in a patient with advanced parkinson disease", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20151215", "receivedate": "20151215", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11837479, "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": "OBJECTIVE\nIntroduction of cyclin-dependent inhibitors was a milestone in therapeutics for patients with estrogen receptor+/HER2- metastatic breast cancer. Despite the wide use of such agents and remarkable improvement of survival rates, drug-related adverse events are not yet fully characterized. We describe vitiligo-like lesions as a new adverse event occurring in patients with advanced breast cancer treated with cyclin-dependent inhibitors.\n\n\nMETHODS\nWe performed an international retrospective study including patients with advanced breast cancer who developed vitiligo-like lesions during treatment with cyclin-dependent kinases 4 and 6 inhibitors, in the period January 2018-December 2019. Patients > 18 years, both males and females, were recruited at six Dermatology Departments located in Italy (3), France (1) and Greece (2). We evaluated epidemiological and clinical characteristics, impact on quality of life and outcome of vitiligo-like lesions in patients treated with cyclin-dependent 4 and 6 inhibitors. The percentage of skin involved by vitiligo-like lesions was assessed using the Body Surface Area (BSA) score. Changes in patients' quality of life were investigated through the evaluation of the Dermatology Life Quality Index (DLQI) questionnaire.\n\n\nRESULTS\nSixteen women (median age: 62.5 years; range 40-79 years) treated with cyclin-dependent kinases 4 and 6 inhibitors for advanced breast cancer presented with vitiligo-like lesions during follow-up visits. Cutaneous lesions consisted of white, irregular macules and patches located mainly on sun-exposed areas in 11/16 patients or diffuse to the entire body surface in 5/16. Cutaneous lesions clearly impaired the quality of life of patients tested (DLQI ≥ 10).\n\n\nCONCLUSIONS\nWe present for the first time, to our knowledge, a case series of vitiligo-like lesions developing in patients with advanced breast cancer treated with cyclin-dependent kinases 4 and 6 inhibitors. We showed that such lesions further impair the patients' quality of life and their treatment is challenging.", "affiliations": "UOC Dermatologia, Fondazione Policlinico Universitario A. Gemelli-IRCCS, L.go Agostino Gemelli 8, 00168, Rome, Italy. pietrosollena@virgilio.it.;Dermato-Oncology Department, Cutaneous Toxicities Clinic, Andreas Sygros Hopital, National and Kapodistrian University of Athens, Athens, Greece.;Second Department of Medical Oncology, Agii Anargiri General Oncological Hospital of Kifissia, Athens, Greece.;Third Department of Medicine, Oncology Unit, Sotiria General HospitalNational and Kapodistrian University, Athens School of Medicine, Athens, Greece.;Dermato-Oncology Department, Cutaneous Toxicities Clinic, Andreas Sygros Hopital, National and Kapodistrian University of Athens, Athens, Greece.;Dermato-Oncology Department, Cutaneous Toxicities Clinic, Andreas Sygros Hopital, National and Kapodistrian University of Athens, Athens, Greece.;Section of Dermatology, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy.;Section of Dermatology, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy.;Medical Oncology, Fondazione Policlinico Universitario A. Gemelli-IRCCS, Rome, Italy.;Dermatologia,, Università Cattolica del Sacro Cuore, Rome, Italy.;Second Dermatology Department, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece.;Oncodermatology Department, Institut Universitaire du Cancer, Toulouse Oncopole, Toulouse, France.;San Camillo Forlanini Hospital, Rome, Italy.;Section of Dermatology, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy.;Oncodermatology Department, Institut Universitaire du Cancer, Toulouse Oncopole, Toulouse, France.;UOC Dermatologia, Fondazione Policlinico Universitario A. Gemelli-IRCCS, L.go Agostino Gemelli 8, 00168, Rome, Italy.", "authors": "Sollena|Pietro|P|http://orcid.org/0000-0002-1632-7791;Nikolaou|Vasiliki|V|;Soupos|Nikolaos|N|;Kotteas|Elias|E|;Voudouri|Dimitra|D|;Stratigos|Alexandros J|AJ|;Fattore|Davide|D|;Annunziata|Maria Carmela|MC|;Orlandi|Armando|A|;Di Nardo|Lucia|L|;Apalla|Zoe|Z|;Deilhes|Florian|F|;Romano|Maria Concetta|MC|;Fabbrocini|Gabriella|G|;Sibaud|Vincent|V|;Peris|Ketty|K|;|||", "chemical_list": null, "country": "Netherlands", "delete": false, "doi": "10.1007/s10549-020-05914-w", "fulltext": null, "fulltext_license": null, "issn_linking": "0167-6806", "issue": "185(1)", "journal": "Breast cancer research and treatment", "keywords": "Advanced breast cancer; CDK4/6 inhibitors; Skin adverse event; Vitiligo-like lesion", "medline_ta": "Breast Cancer Res Treat", "mesh_terms": "D000328:Adult; D000368:Aged; D001943:Breast Neoplasms; D005260:Female; D005602:France; D006801:Humans; D007558:Italy; D008297:Male; D008875:Middle Aged; D011788:Quality of Life; D012189:Retrospective Studies; D014820:Vitiligo", "nlm_unique_id": "8111104", "other_id": null, "pages": "247-253", "pmc": null, "pmid": "32914354", "pubdate": "2021-01", "publication_types": "D016428:Journal Article", "references": "21192839;4681400;31859246;23079655;32145796;24037977;28699811;28619550;28918974;10991971;25789295;29241800;30066925;25605840;26501224", "title": "Vitiligo-like lesions in patients with advanced breast cancer treated with cycline-dependent kinases 4 and 6 inhibitors.", "title_normalized": "vitiligo like lesions in patients with advanced breast cancer treated with cycline dependent kinases 4 and 6 inhibitors" }

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VITILIGO?LIKE LESIONS IN PATIENTS WITH ADVANCED BREAST CANCER TREATED WITH CYCLINE?DEPENDENT KINASES 4 AND 6 INHIBITORS. BREAST?CANCER?RES?TREAT 2021?185(1):247?253.", "literaturereference_normalized": "vitiligo like lesions in patients with advanced breast cancer treated with cycline dependent kinases 4 and 6 inhibitors", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20210812", "receivedate": "20210812", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19692724, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "IT-TEVA-2021-IT-1942118", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "LETROZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "090289", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETROZOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RIBOCICLIB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIBOCICLIB." } ], "patientagegroup": "5", "patientonsetage": "57", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Skin hypopigmentation", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "SOLLENA P, NIKOLAOU V, SOUPOS N, KOTTEAS E, VOUDOURI D, STRATIGOS AJ, ET AL. VITILIGO?LIKE LESIONS IN PATIENTS WITH ADVANCED BREAST CANCER TREATED WITH CYCLINE?DEPENDENT KINASES 4 AND 6 INHIBITORS. BREAST?CANCER?RES?TREAT 2021?185(1):247?253.", "literaturereference_normalized": "vitiligo like lesions in patients with advanced breast cancer treated with cycline dependent kinases 4 and 6 inhibitors", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20210818", "receivedate": "20210818", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19714074, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "IT-MYLANLABS-2021M1050270", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "LETROZOLE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "078190", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER STAGE IV", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETROZOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RIBOCICLIB" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER STAGE IV", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIBOCICLIB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LETROZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "078190", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2.5 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETROZOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RIBOCICLIB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "600 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIBOCICLIB." } ], "patientagegroup": null, "patientonsetage": "57", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Skin hypopigmentation", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "SOLLENA P, NIKOLAOU V, SOUPOS N, KOTTEAS E, VOUDOURI D, STRATIGOS AJ, ET AL. VITILIGO?LIKE LESIONS IN PATIENTS WITH ADVANCED BREAST CANCER TREATED WITH CYCLINE?DEPENDENT KINASES 4 AND 6 INHIBITORS. BREAST?CANCER?RES?TREAT 2021?185(1):247?253.", "literaturereference_normalized": "vitiligo like lesions in patients with advanced breast cancer treated with cycline dependent kinases 4 and 6 inhibitors", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20210812", "receivedate": "20210812", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19692737, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "IT-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-309643", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "LETROZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "91466", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2.5 MILLIGRAM, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETROZOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RIBOCICLIB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "600 MILLIGRAM, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIBOCICLIB." } ], "patientagegroup": null, "patientonsetage": "67", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Vitiligo", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Therapy partial responder", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SOLLENA P, NIKOLAOU V, SOUPOS N, KOTTEAS E, VOUDOURI E, STRATIGOS AJ, ET AL. VITILIGO?LIKE LESIONS IN PATIENTS WITH ADVANCED BREAST CANCER TREATED WITH CYCLINE?DEPENDENT KINASES 4 AND 6 INHIBITORS. BREAST CANCER RES TREAT. 2021?185:247?253", "literaturereference_normalized": "vitiligo like lesions in patients with advanced breast cancer treated with cycline dependent kinases 4 and 6 inhibitors", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20210903", "receivedate": "20210903", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19783167, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "NVSC2021IT186423", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "FULVESTRANT" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "205935", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "Breast cancer", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FULVESTRANT" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FULVESTRANT" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "205935", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Breast cancer stage IV", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FULVESTRANT" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PALBOCICLIB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "125 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "Breast cancer", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "125", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PALBOCICLIB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PALBOCICLIB" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Breast cancer stage IV", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PALBOCICLIB" } ], "patientagegroup": null, "patientonsetage": "42", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Vitiligo", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Skin hypopigmentation", "reactionmeddraversionpt": "24.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "Sollena P, Nikolaou V, Soupos N, Kotteas E, Voudouri D, Stratigos AJ et al.. Vitiligo-like lesions in patients with advanced breast cancer treated with cycline-dependent kinases 4 and 6 inhibitors. BREAST-CANCER-RES-TREAT. 2021;185(1):247-53", "literaturereference_normalized": "vitiligo like lesions in patients with advanced breast cancer treated with cycline dependent kinases 4 and 6 inhibitors", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20220125", "receivedate": "20210818", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19716577, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220424" }, { "companynumb": "IT-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-309608", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RIBOCICLIB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "600 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIBOCICLIB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LETROZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "91466", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2.5 MILLIGRAM/ 5 CYCLE", "drugenddate": null, "drugenddateformat": null, "drugindication": "HORMONE 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": "LETROZOLE." } ], "patientagegroup": null, "patientonsetage": "66", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Therapy partial responder", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vitiligo", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SOLLENA P, NIKOLAOU V, SOUPOS N, KOTTEAS E, VOUDOURI E, STRATIGOS AJ ET AL. VITILIGO?LIKE LESIONS IN PATIENTS WITH ADVANCED BREAST CANCER TREATED WITH CYCLINE?DEPENDENT KINASES 4 AND 6 INHIBITORS. BREAST CANCER RES TREAT. 2021?185:247?253", "literaturereference_normalized": "vitiligo like lesions in patients with advanced breast cancer treated with cycline dependent kinases 4 and 6 inhibitors", "qualification": null, "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20210903", "receivedate": "20210903", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19784667, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "IT-MYLANLABS-2021M1050264", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PALBOCICLIB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "125 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "125", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PALBOCICLIB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PALBOCICLIB" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER STAGE IV", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PALBOCICLIB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LETROZOLE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "078190", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER STAGE IV", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETROZOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LETROZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "078190", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2.5 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETROZOLE." } ], "patientagegroup": null, "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Skin hypopigmentation", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "SOLLENA P, NIKOLAOU V, SOUPOS N, KOTTEAS E, VOUDOURI D, STRATIGOS AJ, ET AL. VITILIGO?LIKE LESIONS IN PATIENTS WITH ADVANCED BREAST CANCER TREATED WITH CYCLINE?DEPENDENT KINASES 4 AND 6 INHIBITORS. BREAST?CANCER?RES?TREAT 2021?185(1):247?253.", "literaturereference_normalized": "vitiligo like lesions in patients with advanced breast cancer treated with cycline dependent kinases 4 and 6 inhibitors", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20210813", "receivedate": "20210813", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19697247, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "IT-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-309660", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "LETROZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "91466", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2.5 MILLIGRAM, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETROZOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RIBOCICLIB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "600 MILLIGRAM, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIBOCICLIB." } ], "patientagegroup": null, "patientonsetage": "57", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Therapy partial responder", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vitiligo", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "SOLLENA P, NIKOLAOU V, SOUPOS N, KOTTEAS E, VOUDOURI E, STRATIGOS AJ ET AL. VITILIGO?LIKE LESIONS IN PATIENTS WITH ADVANCED BREAST CANCER TREATED WITH CYCLINE?DEPENDENT KINASES 4 AND 6 INHIBITORS. BREAST CANCER RES TREAT. 2021?185:247?253", "literaturereference_normalized": "vitiligo like lesions in patients with advanced breast cancer treated with cycline dependent kinases 4 and 6 inhibitors", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20210902", "receivedate": "20210902", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19780697, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "IT-TEVA-2021-IT-1942121", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RIBOCICLIB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIBOCICLIB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LETROZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "090289", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETROZOLE." } ], "patientagegroup": "5", "patientonsetage": "48", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Skin hypopigmentation", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "SOLLENA P, NIKOLAOU V, SOUPOS N, KOTTEAS E, VOUDOURI D, STRATIGOS AJ, ET AL. VITILIGO?LIKE LESIONS IN PATIENTS WITH ADVANCED BREAST CANCER TREATED WITH CYCLINE?DEPENDENT KINASES 4 AND 6 INHIBITORS. BREAST?CANCER?RES?TREAT 2021?185(1):247?253.", "literaturereference_normalized": "vitiligo like lesions in patients with advanced breast cancer treated with cycline dependent kinases 4 and 6 inhibitors", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20210819", "receivedate": "20210819", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19719917, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "IT-TEVA-2021-IT-1942122", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RIBOCICLIB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIBOCICLIB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LETROZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "090289", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETROZOLE." } ], "patientagegroup": "5", "patientonsetage": "54", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Skin hypopigmentation", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "SOLLENA P, NIKOLAOU V, SOUPOS N, KOTTEAS E, VOUDOURI D, STRATIGOS AJ, ET AL. VITILIGO?LIKE LESIONS IN PATIENTS WITH ADVANCED BREAST CANCER TREATED WITH CYCLINE?DEPENDENT KINASES 4 AND 6 INHIBITORS. BREAST?CANCER?RES?TREAT 2021?185(1):247?253.", "literaturereference_normalized": "vitiligo like lesions in patients with advanced breast cancer treated with cycline dependent kinases 4 and 6 inhibitors", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20210819", "receivedate": "20210819", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19719898, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "IT-TEVA-2021-IT-1942133", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "LETROZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "090289", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETROZOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RIBOCICLIB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIBOCICLIB." } ], "patientagegroup": "6", "patientonsetage": "67", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Skin hypopigmentation", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "SOLLENA P, NIKOLAOU V, SOUPOS N, KOTTEAS E, VOUDOURI D, STRATIGOS AJ, ET AL. VITILIGO?LIKE LESIONS IN PATIENTS WITH ADVANCED BREAST CANCER TREATED WITH CYCLINE?DEPENDENT KINASES 4 AND 6 INHIBITORS. BREAST?CANCER?RES?TREAT 2021?185(1):247?253.", "literaturereference_normalized": "vitiligo like lesions in patients with advanced breast cancer treated with cycline dependent kinases 4 and 6 inhibitors", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20210818", "receivedate": "20210818", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19714526, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "IT-TEVA-2021-IT-1942116", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "FULVESTRANT" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "210063", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FULVESTRANT." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PALBOCICLIB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "125", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PALBOCICLIB" } ], "patientagegroup": "5", "patientonsetage": "42", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Skin hypopigmentation", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "SOLLENA P, NIKOLAOU V, SOUPOS N, KOTTEAS E, VOUDOURI D, STRATIGOS AJ, ET AL. VITILIGO?LIKE LESIONS IN PATIENTS WITH ADVANCED BREAST CANCER TREATED WITH CYCLINE?DEPENDENT KINASES 4 AND 6 INHIBITORS. BREAST?CANCER?RES?TREAT 2021?185(1):247?253.", "literaturereference_normalized": "vitiligo like lesions in patients with advanced breast cancer treated with cycline dependent kinases 4 and 6 inhibitors", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20210818", "receivedate": "20210818", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19714076, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "IT-MYLANLABS-2021M1050265", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "LETROZOLE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "078190", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER STAGE IV", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETROZOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LETROZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "078190", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2.5 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETROZOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RIBOCICLIB" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER STAGE IV", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIBOCICLIB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RIBOCICLIB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "600 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIBOCICLIB." } ], "patientagegroup": null, "patientonsetage": "66", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Skin hypopigmentation", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "SOLLENA P, NIKOLAOU V, SOUPOS N, KOTTEAS E, VOUDOURI D, STRATIGOS AJ, ET AL. VITILIGO?LIKE LESIONS IN PATIENTS WITH ADVANCED BREAST CANCER TREATED WITH CYCLINE?DEPENDENT KINASES 4 AND 6 INHIBITORS. BREAST?CANCER?RES?TREAT 2021?185(1):247?253.", "literaturereference_normalized": "vitiligo like lesions in patients with advanced breast cancer treated with cycline dependent kinases 4 and 6 inhibitors", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20210812", "receivedate": "20210812", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19692736, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "IT-TEVA-2021-IT-1942128", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "LETROZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "090289", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETROZOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RIBOCICLIB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIBOCICLIB." } ], "patientagegroup": "6", "patientonsetage": "71", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Skin hypopigmentation", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SOLLENA P, NIKOLAOU V, SOUPOS N, KOTTEAS E, VOUDOURI D, STRATIGOS AJ, ET AL. VITILIGO?LIKE LESIONS IN PATIENTS WITH ADVANCED BREAST CANCER TREATED WITH CYCLINE?DEPENDENT KINASES 4 AND 6 INHIBITORS. BREAST?CANCER?RES?TREAT 2021?185(1):247?253.", "literaturereference_normalized": "vitiligo like lesions in patients with advanced breast cancer treated with cycline dependent kinases 4 and 6 inhibitors", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20210819", "receivedate": "20210819", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19719896, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "IT-MYLANLABS-2021M1050268", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "LETROZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "078190", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2.5 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETROZOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LETROZOLE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "078190", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER STAGE IV", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETROZOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RIBOCICLIB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "600 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIBOCICLIB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RIBOCICLIB" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER STAGE IV", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIBOCICLIB." } ], "patientagegroup": null, "patientonsetage": "54", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Skin hypopigmentation", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "SOLLENA P, NIKOLAOU V, SOUPOS N, KOTTEAS E, VOUDOURI D, STRATIGOS AJ, ET AL. VITILIGO?LIKE LESIONS IN PATIENTS WITH ADVANCED BREAST CANCER TREATED WITH CYCLINE?DEPENDENT KINASES 4 AND 6 INHIBITORS. BREAST?CANCER?RES?TREAT 2021?185(1):247?253.", "literaturereference_normalized": "vitiligo like lesions in patients with advanced breast cancer treated with cycline dependent kinases 4 and 6 inhibitors", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20210813", "receivedate": "20210813", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19697196, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "IT-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-309646", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "LETROZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "91466", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2.5 MG , UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER STAGE IV", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETROZOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RIBOCICLIB" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "600 MG , UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER STAGE IV", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIBOCICLIB." } ], "patientagegroup": null, "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Vitiligo", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Therapy partial responder", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SOLLENA P, NIKOLAOU V, SOUPOS N, KOTTEAS E, VOUDOURI E, STRATIGOS AJ ET AL. VITILIGO?LIKE LESIONS IN PATIENTS WITH ADVANCED BREAST CANCER TREATED WITH CYCLINE?DEPENDENT KINASES 4 AND 6 INHIBITORS. BREAST CANCER RES TREAT. 2021?185:247?253", "literaturereference_normalized": "vitiligo like lesions in patients with advanced breast cancer treated with cycline dependent kinases 4 and 6 inhibitors", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20210903", "receivedate": "20210903", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19782856, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "IT-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-309648", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RIBOCICLIB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "600 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIBOCICLIB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LETROZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "91466", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2.5 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "HORMONE 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": "LETROZOLE." } ], "patientagegroup": null, "patientonsetage": "53", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Therapy partial responder", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vitiligo", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "SOLLENA P, NIKOLAOU V, SOUPOS N, KOTTEAS E, VOUDOURI D, STRATIGOS AJ ET AL. VITILIGO?LIKE LESIONS IN PATIENTS WITH ADVANCED BREAST CANCER TREATED WITH CYCLINE?DEPENDENT KINASES 4 AND 6 INHIBITORS. 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Vitiligo-like lesions in patients with advanced breast cancer treated with cycline-dependent kinases 4 and 6 inhibitors. 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VITILIGO?LIKE LESIONS IN PATIENTS WITH ADVANCED BREAST CANCER TREATED WITH CYCLINE?DEPENDENT KINASES 4 AND 6 INHIBITORS. BREAST?CANCER?RES?TREAT 2021?185(1):247?253.", "literaturereference_normalized": "vitiligo like lesions in patients with advanced breast cancer treated with cycline dependent kinases 4 and 6 inhibitors", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20210818", "receivedate": "20210818", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19714306, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "IT-MYLANLABS-2021M1050254", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RIBOCICLIB" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER STAGE IV", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIBOCICLIB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LETROZOLE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "078190", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER STAGE IV", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETROZOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RIBOCICLIB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "600 MILLIGRAM, CYCLE", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIBOCICLIB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LETROZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "078190", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2.5 MILLIGRAM, CYCLE", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETROZOLE." } ], "patientagegroup": null, "patientonsetage": "66", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Skin hypopigmentation", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "SOLLENA P, NIKOLAOU V, SOUPOS N, KOTTEAS E, VOUDOURI D, STRATIGOS AJ, ET AL. VITILIGO?LIKE LESIONS IN PATIENTS WITH ADVANCED BREAST CANCER TREATED WITH CYCLINE?DEPENDENT KINASES 4 AND 6 INHIBITORS. BREAST?CANCER?RES?TREAT 2021?185(1):247?253.", "literaturereference_normalized": "vitiligo like lesions in patients with advanced breast cancer treated with cycline dependent kinases 4 and 6 inhibitors", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20210812", "receivedate": "20210812", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19692726, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "IT-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-309661", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RIBOCICLIB" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "600 MG , UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER STAGE IV", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIBOCICLIB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LETROZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "91466", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2.5 MG , UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER STAGE IV", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETROZOLE." } ], "patientagegroup": null, "patientonsetage": "40", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Therapy partial responder", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vitiligo", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "SOLLENA P, NIKOLAOU V, SOUPOS N, KOTTEAS E, VOUDOURI E, STRATIGOS AJ ET AL. VITILIGO?LIKE LESIONS IN PATIENTS WITH ADVANCED BREAST CANCER TREATED WITH CYCLINE?DEPENDENT KINASES 4 AND 6 INHIBITORS. BREAST CANCER RES TREAT. 2021?185:247?253", "literaturereference_normalized": "vitiligo like lesions in patients with advanced breast cancer treated with cycline dependent kinases 4 and 6 inhibitors", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20210903", "receivedate": "20210903", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19783799, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "IT-MYLANLABS-2021M1050262", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "LETROZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "078190", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2.5 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETROZOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RIBOCICLIB" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER STAGE IV", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIBOCICLIB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LETROZOLE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "078190", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER STAGE IV", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETROZOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RIBOCICLIB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "600 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIBOCICLIB." } ], "patientagegroup": null, "patientonsetage": "48", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Skin hypopigmentation", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "SOLLENA P, NIKOLAOU V, SOUPOS N, KOTTEAS E, VOUDOURI D, STRATIGOS AJ, ET AL. VITILIGO?LIKE LESIONS IN PATIENTS WITH ADVANCED BREAST CANCER TREATED WITH CYCLINE?DEPENDENT KINASES 4 AND 6 INHIBITORS. BREAST?CANCER?RES?TREAT 2021?185(1):247?253.", "literaturereference_normalized": "vitiligo like lesions in patients with advanced breast cancer treated with cycline dependent kinases 4 and 6 inhibitors", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20210813", "receivedate": "20210813", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19697229, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": null, "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "LETROZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "090934", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2.5 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "Breast cancer", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETROZOLE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RIBOCICLIB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "600 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "Breast cancer stage IV", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIBOCICLIB" } ], "patientagegroup": "5", "patientonsetage": "48", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Skin hypopigmentation", "reactionmeddraversionpt": "24.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "Sollena P, Nikolaou V, Soupos N, Kotteas E, Voudouri D, Stratigos AJ, et al. Vitiligo-like lesions in patients with advanced breast cancer treated with cycline-dependent kinases 4 and 6 inhibitors. Breast-Cancer-Res-Treat 2021;185(1):247-253.", "literaturereference_normalized": "vitiligo like lesions in patients with advanced breast cancer treated with cycline dependent kinases 4 and 6 inhibitors", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20220218", "receivedate": "20220218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 20490679, "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": "IT-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-309663", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PALBOCICLIB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "125 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "125", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PALBOCICLIB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LETROZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "91466", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2.5 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "HORMONE 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": "LETROZOLE." } ], "patientagegroup": null, "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Therapy partial responder", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vitiligo", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "SOLLENA P, NIKOLAOU V, SOUPOS N, KOTTEAS E, VOUDOURI E, STRATIGOS AJ ET AL. VITILIGO?LIKE LESIONS IN PATIENTS WITH ADVANCED BREAST CANCER TREATED WITH CYCLINE?DEPENDENT KINASES 4 AND 6 INHIBITORS. BREAST CANCER RES TREAT. 2021?185:247?253", "literaturereference_normalized": "vitiligo like lesions in patients with advanced breast cancer treated with cycline dependent kinases 4 and 6 inhibitors", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20210903", "receivedate": "20210903", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19783169, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "IT-TEVA-2021-IT-1942124", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RIBOCICLIB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIBOCICLIB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LETROZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "090289", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETROZOLE." } ], "patientagegroup": "6", "patientonsetage": "79", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Skin hypopigmentation", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "SOLLENA P, NIKOLAOU V, SOUPOS N, KOTTEAS E, VOUDOURI D, STRATIGOS AJ, ET AL. VITILIGO?LIKE LESIONS IN PATIENTS WITH ADVANCED BREAST CANCER TREATED WITH CYCLINE?DEPENDENT KINASES 4 AND 6 INHIBITORS. BREAST?CANCER?RES?TREAT 2021?185(1):247?253.", "literaturereference_normalized": "vitiligo like lesions in patients with advanced breast cancer treated with cycline dependent kinases 4 and 6 inhibitors", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20210819", "receivedate": "20210819", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19719922, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "IT-MYLANLABS-2021M1050257", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RIBOCICLIB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "600 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIBOCICLIB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LETROZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "078190", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2.5 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETROZOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RIBOCICLIB" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER STAGE IV", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIBOCICLIB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LETROZOLE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "078190", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER STAGE IV", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETROZOLE." } ], "patientagegroup": null, "patientonsetage": "53", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Skin hypopigmentation", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "SOLLENA P, NIKOLAOU V, SOUPOS N, KOTTEAS E, VOUDOURI D, STRATIGOS AJ, ET AL. VITILIGO?LIKE LESIONS IN PATIENTS WITH ADVANCED BREAST CANCER TREATED WITH CYCLINE?DEPENDENT KINASES 4 AND 6 INHIBITORS. BREAST?CANCER?RES?TREAT 2021?185(1):247?253.", "literaturereference_normalized": "vitiligo like lesions in patients with advanced breast cancer treated with cycline dependent kinases 4 and 6 inhibitors", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20210812", "receivedate": "20210812", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19692712, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "IT-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-309651", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "LETROZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "91466", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2.5 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "HORMONE 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": "LETROZOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RIBOCICLIB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "600 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER STAGE IV", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIBOCICLIB." } ], "patientagegroup": null, "patientonsetage": "79", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Therapy partial responder", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vitiligo", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "SOLLENA P, NIKOLAOU V, SOUPOS N, KOTTEAS E, VOUDOURI D, STRATIGOS AJ ET AL. VITILIGO?LIKE LESIONS IN PATIENTS WITH ADVANCED BREAST CANCER TREATED WITH CYCLINE?DEPENDENT KINASES 4 AND 6 INHIBITORS. BREAST CANCER RES TREAT. 2021?185:247?253", "literaturereference_normalized": "vitiligo like lesions in patients with advanced breast cancer treated with cycline dependent kinases 4 and 6 inhibitors", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20210903", "receivedate": "20210903", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19784622, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "IT-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-309647", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "LETROZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "91466", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2.5 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER STAGE IV", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETROZOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RIBOCICLIB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "600 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIBOCICLIB." } ], "patientagegroup": null, "patientonsetage": "73", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Therapy partial responder", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vitiligo", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "SOLLENA P, NIKOLAOU V, SOUPOS N, KOTTEAS E, VOUDOURI E, STRATIGOS AJ ET AL. VITILIGO?LIKE LESIONS IN PATIENTS WITH ADVANCED BREAST CANCER TREATED WITH CYCLINE?DEPENDENT KINASES 4 AND 6 INHIBITORS. BREAST CANCER RES TREAT. 2021?185:247?253", "literaturereference_normalized": "vitiligo like lesions in patients with advanced breast cancer treated with cycline dependent kinases 4 and 6 inhibitors", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20210903", "receivedate": "20210903", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19783802, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "IT-TEVA-2021-IT-1942117", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RIBOCICLIB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIBOCICLIB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LETROZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "090289", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETROZOLE." } ], "patientagegroup": "5", "patientonsetage": "40", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Skin hypopigmentation", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "SOLLENA P, NIKOLAOU V, SOUPOS N, KOTTEAS E, VOUDOURI D, STRATIGOS AJ, ET AL. VITILIGO?LIKE LESIONS IN PATIENTS WITH ADVANCED BREAST CANCER TREATED WITH CYCLINE?DEPENDENT KINASES 4 AND 6 INHIBITORS. BREAST?CANCER?RES?TREAT 2021?185(1):247?253.", "literaturereference_normalized": "vitiligo like lesions in patients with advanced breast cancer treated with cycline dependent kinases 4 and 6 inhibitors", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20210818", "receivedate": "20210818", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19714072, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "IT-MYLANLABS-2021M1050269", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RIBOCICLIB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "600 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIBOCICLIB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LETROZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "078190", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2.5 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETROZOLE." } ], "patientagegroup": null, "patientonsetage": "73", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Skin hypopigmentation", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "SOLLENA P, NIKOLAOU V, SOUPOS N, KOTTEAS E, VOUDOURI D, STRATIGOS AJ, ET AL. VITILIGO?LIKE LESIONS IN PATIENTS WITH ADVANCED BREAST CANCER TREATED WITH CYCLINE?DEPENDENT KINASES 4 AND 6 INHIBITORS. BREAST?CANCER?RES?TREAT 2021?185(1):247?253.", "literaturereference_normalized": "vitiligo like lesions in patients with advanced breast cancer treated with cycline dependent kinases 4 and 6 inhibitors", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20210811", "receivedate": "20210811", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19685952, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "IT-MYLANLABS-2021M1050267", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "LETROZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "078190", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2.5 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETROZOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RIBOCICLIB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "600 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIBOCICLIB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RIBOCICLIB" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER STAGE IV", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIBOCICLIB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LETROZOLE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "078190", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER STAGE IV", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETROZOLE." } ], "patientagegroup": null, "patientonsetage": "40", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Skin hypopigmentation", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "SOLLENA P, NIKOLAOU V, SOUPOS N, KOTTEAS E, VOUDOURI D, STRATIGOS AJ, ET AL. VITILIGO?LIKE LESIONS IN PATIENTS WITH ADVANCED BREAST CANCER TREATED WITH CYCLINE?DEPENDENT KINASES 4 AND 6 INHIBITORS. BREAST?CANCER?RES?TREAT 2021?185(1):247?253.", "literaturereference_normalized": "vitiligo like lesions in patients with advanced breast cancer treated with cycline dependent kinases 4 and 6 inhibitors", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20210812", "receivedate": "20210812", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19692732, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "IT-TEVA-2021-IT-1942130", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "LETROZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "090289", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETROZOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RIBOCICLIB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIBOCICLIB." } ], "patientagegroup": "5", "patientonsetage": "53", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Skin hypopigmentation", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "SOLLENA P, NIKOLAOU V, SOUPOS N, KOTTEAS E, VOUDOURI D, STRATIGOS AJ, ET AL. VITILIGO?LIKE LESIONS IN PATIENTS WITH ADVANCED BREAST CANCER TREATED WITH CYCLINE?DEPENDENT KINASES 4 AND 6 INHIBITORS. BREAST?CANCER?RES?TREAT 2021?185(1):247?253.", "literaturereference_normalized": "vitiligo like lesions in patients with advanced breast cancer treated with cycline dependent kinases 4 and 6 inhibitors", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20210818", "receivedate": "20210818", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19714240, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "IT-MYLANLABS-2021M1050255", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "LETROZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "078190", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2.5 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETROZOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RIBOCICLIB" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER STAGE IV", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIBOCICLIB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LETROZOLE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "078190", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER STAGE IV", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETROZOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RIBOCICLIB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "600 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIBOCICLIB." } ], "patientagegroup": null, "patientonsetage": "71", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Skin hypopigmentation", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SOLLENA P, NIKOLAOU V, SOUPOS N, KOTTEAS E, VOUDOURI D, STRATIGOS AJ, ET AL. VITILIGO?LIKE LESIONS IN PATIENTS WITH ADVANCED BREAST CANCER TREATED WITH CYCLINE?DEPENDENT KINASES 4 AND 6 INHIBITORS. BREAST?CANCER?RES?TREAT 2021?185(1):247?253.", "literaturereference_normalized": "vitiligo like lesions in patients with advanced breast cancer treated with cycline dependent kinases 4 and 6 inhibitors", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20210811", "receivedate": "20210811", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19685950, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "IT-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-309657", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "LETROZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "91466", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2.5 MILLIGRAM, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER STAGE IV", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETROZOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RIBOCICLIB" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "600 MILLIGRAM, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER STAGE IV", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIBOCICLIB." } ], "patientagegroup": null, "patientonsetage": "73", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Vitiligo", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Therapy partial responder", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SOLLENA P, NIKOLAOU V, SOUPOS N, KOTTEAS E, VOUDOURI E, STRATIGOS AJ, ET AL. VITILIGO?LIKE LESIONS IN PATIENTS WITH ADVANCED BREAST CANCER TREATED WITH CYCLINE?DEPENDENT KINASES 4 AND 6 INHIBITORS. BREAST CANCER RES TREAT. 2021?185:247?253", "literaturereference_normalized": "vitiligo like lesions in patients with advanced breast cancer treated with cycline dependent kinases 4 and 6 inhibitors", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20210903", "receivedate": "20210903", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19784380, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "IT-MYLANLABS-2021M1050266", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RIBOCICLIB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "600 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIBOCICLIB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LETROZOLE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "078190", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER STAGE IV", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETROZOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RIBOCICLIB" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER STAGE IV", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIBOCICLIB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LETROZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "078190", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2.5 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETROZOLE." } ], "patientagegroup": null, "patientonsetage": "59", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Skin hypopigmentation", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "SOLLENA P, NIKOLAOU V, SOUPOS N, KOTTEAS E, VOUDOURI D, STRATIGOS AJ, ET AL. VITILIGO?LIKE LESIONS IN PATIENTS WITH ADVANCED BREAST CANCER TREATED WITH CYCLINE?DEPENDENT KINASES 4 AND 6 INHIBITORS. BREAST?CANCER?RES?TREAT 2021?185(1):247?253.", "literaturereference_normalized": "vitiligo like lesions in patients with advanced breast cancer treated with cycline dependent kinases 4 and 6 inhibitors", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20210813", "receivedate": "20210813", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19697245, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "IT-TEVA-2021-IT-1942115", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "LETROZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "090289", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETROZOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PALBOCICLIB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "125", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PALBOCICLIB" } ], "patientagegroup": "5", "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Skin hypopigmentation", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "SOLLENA P, NIKOLAOU V, SOUPOS N, KOTTEAS E, VOUDOURI D, STRATIGOS AJ, ET AL. VITILIGO?LIKE LESIONS IN PATIENTS WITH ADVANCED BREAST CANCER TREATED WITH CYCLINE?DEPENDENT KINASES 4 AND 6 INHIBITORS. BREAST?CANCER?RES?TREAT 2021?185(1):247?253.", "literaturereference_normalized": "vitiligo like lesions in patients with advanced breast cancer treated with cycline dependent kinases 4 and 6 inhibitors", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20210818", "receivedate": "20210818", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19714075, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "IT-TEVA-2021-IT-1942135", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "LETROZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "090289", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETROZOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RIBOCICLIB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIBOCICLIB." } ], "patientagegroup": "6", "patientonsetage": "66", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Skin hypopigmentation", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "SOLLENA P, NIKOLAOU V, SOUPOS N, KOTTEAS E, VOUDOURI D, STRATIGOS AJ, ET AL. VITILIGO?LIKE LESIONS IN PATIENTS WITH ADVANCED BREAST CANCER TREATED WITH CYCLINE?DEPENDENT KINASES 4 AND 6 INHIBITORS. BREAST?CANCER?RES?TREAT 2021?185(1):247?253.", "literaturereference_normalized": "vitiligo like lesions in patients with advanced breast cancer treated with cycline dependent kinases 4 and 6 inhibitors", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20210818", "receivedate": "20210818", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19714575, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "IT-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-309659", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RIBOCICLIB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "600 MILLIGRAM, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIBOCICLIB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LETROZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "91466", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2.5 MILLIGRAM, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETROZOLE." } ], "patientagegroup": null, "patientonsetage": "59", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Therapy partial responder", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vitiligo", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "SOLLENA P, NIKOLAOU V, SOUPOS N, KOTTEAS E, VOUDOURI E, STRATIGOS AJ ET AL. VITILIGO?LIKE LESIONS IN PATIENTS WITH ADVANCED BREAST CANCER TREATED WITH CYCLINE?DEPENDENT KINASES 4 AND 6 INHIBITORS. BREAST CANCER RES TREAT. 2021?185:247?253", "literaturereference_normalized": "vitiligo like lesions in patients with advanced breast cancer treated with cycline dependent kinases 4 and 6 inhibitors", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20210903", "receivedate": "20210903", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19782855, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "IT-TEVA-2021-IT-1942119", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RIBOCICLIB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIBOCICLIB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LETROZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "090289", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETROZOLE." } ], "patientagegroup": "5", "patientonsetage": "59", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Skin hypopigmentation", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "SOLLENA P, NIKOLAOU V, SOUPOS N, KOTTEAS E, VOUDOURI D, STRATIGOS AJ, ET AL. VITILIGO?LIKE LESIONS IN PATIENTS WITH ADVANCED BREAST CANCER TREATED WITH CYCLINE?DEPENDENT KINASES 4 AND 6 INHIBITORS. BREAST?CANCER?RES?TREAT 2021?185(1):247?253.", "literaturereference_normalized": "vitiligo like lesions in patients with advanced breast cancer treated with cycline dependent kinases 4 and 6 inhibitors", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20210818", "receivedate": "20210818", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19714071, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "IT-TEVA-2021-IT-1942123", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RIBOCICLIB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIBOCICLIB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LETROZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "090289", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETROZOLE." } ], "patientagegroup": "6", "patientonsetage": "66", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Skin hypopigmentation", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "SOLLENA P, NIKOLAOU V, SOUPOS N, KOTTEAS E, VOUDOURI D, STRATIGOS AJ, ET AL. VITILIGO?LIKE LESIONS IN PATIENTS WITH ADVANCED BREAST CANCER TREATED WITH CYCLINE?DEPENDENT KINASES 4 AND 6 INHIBITORS. 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VITILIGO?LIKE LESIONS IN PATIENTS WITH ADVANCED BREAST CANCER TREATED WITH CYCLINE?DEPENDENT KINASES 4 AND 6 INHIBITORS. BREAST?CANCER?RES?TREAT 2021?185(1):247?253.", "literaturereference_normalized": "vitiligo like lesions in patients with advanced breast cancer treated with cycline dependent kinases 4 and 6 inhibitors", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20210818", "receivedate": "20210818", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19714073, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "IT-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-309653", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RIBOCICLIB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, 600MG", "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": "RIBOCICLIB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LETROZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "91466", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, 2.5MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "HORMONE THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETROZOLE." } ], "patientagegroup": null, "patientonsetage": "66", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Therapy partial responder", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vitiligo", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "SOLLENA P, NIKOLAOU V, SOUPOS N, KOTTEAS E, VOUDOURI E, STRATIGOS AJ, ET AL. VITILIGO?LIKE LESIONS IN PATIENTS WITH ADVANCED BREAST CANCER TREATED WITH CYCLINE?DEPENDENT KINASES 4 AND 6 INHIBITORS. BREAST CANCER RES TREAT. 2021?185:247?253", "literaturereference_normalized": "vitiligo like lesions in patients with advanced breast cancer treated with cycline dependent kinases 4 and 6 inhibitors", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20210903", "receivedate": "20210903", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19784623, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" } ]

{ "abstract": "The use of gonadotropin-releasing hormone analogs has been reported in the treatment of gelastic seizures and precocious puberty associated with hypothalamic hamartomas, but not in other seizure types without hypothalamic hamartoma. We describe a 7.5 year-old girl whose seizures subsided after gonadotropin-releasing hormone analog implant, administered for precocious puberty.", "affiliations": "Positron Emission Tomography (PET) Center, Children's Hospital of Michigan, Detroit Medical Center, Detroit, MI.;Positron Emission Tomography (PET) Center, Children's Hospital of Michigan, Detroit Medical Center, Detroit, MI; Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI; Department of Neurology, Wayne State University School of Medicine, Detroit, MI; Department of Radiology, Wayne State University School of Medicine, Detroit, MI.;Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI; Department of Endocrinology, Wayne State University School of Medicine, Detroit, MI.;Positron Emission Tomography (PET) Center, Children's Hospital of Michigan, Detroit Medical Center, Detroit, MI; Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI; Department of Neurology, Wayne State University School of Medicine, Detroit, MI. Electronic address: hchugani@pet.wayne.edu.", "authors": "Govil-Dalela|Tuhina|T|;Kumar|Ajay|A|;Moltz|Kathleen C|KC|;Chugani|Harry T|HT|", "chemical_list": "D000927:Anticonvulsants; D007987:Gonadotropin-Releasing Hormone; C029256:histrelin", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0022-3476", "issue": "174()", "journal": "The Journal of pediatrics", "keywords": "GnRH; estradiol; seizures", "medline_ta": "J Pediatr", "mesh_terms": "D000927:Anticonvulsants; D002648:Child; D005260:Female; D007987:Gonadotropin-Releasing Hormone; D006801:Humans; D008279:Magnetic Resonance Imaging; D049268:Positron-Emission Tomography; D011629:Puberty, Precocious; D012640:Seizures", "nlm_unique_id": "0375410", "other_id": null, "pages": "264-6", "pmc": null, "pmid": "27156180", "pubdate": "2016-07", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Use of Gonadotropin-Releasing Hormone for Intractable Seizures in a Girl with Precocious Puberty without Hypothalamic Hamartoma.", "title_normalized": "use of gonadotropin releasing hormone for intractable seizures in a girl with precocious puberty without hypothalamic hamartoma" }

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"reactionmeddraversionpt": "20.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Multiple-drug resistance", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Focal dyscognitive seizures", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "GOVIL-DALELA T, KUMAR A, MOLTZ KC, CHUGANI HT. USE OF GONADOTROPIN-RELEASING HORMONE FOR INTRACTABLE SEIZURES IN A GIRL WITH PRECOCIOUS PUBERTY WITHOUT HYPOTHALAMIC HAMARTOMA. THE JOURNAL OF PEDIATRICS. 2016;174:264-6", "literaturereference_normalized": "use of gonadotropin releasing hormone for intractable seizures in a girl with precocious puberty without hypothalamic hamartoma", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170728", "receivedate": "20170728", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13803812, "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" } ]

{ "abstract": "We report the case of a 74-year-old woman who developed pulmonary edema and shock shortly after ingestion of one tablet of hydrochlorothiazide/amiloride. The clinical findings and course of the disease were characteristic of hydrochlorothiazide-induced pulmonary edema. 14 similar case are reported in the literature. Attention is drawn to this rare but dangerous side effect of a frequently used diuretic.", "affiliations": "Medizinische Abteilung, Kantonsspital Schaffhausen.", "authors": "Caduff|F|F|;Gloor|H J|HJ|", "chemical_list": "D004338:Drug Combinations; D006852:Hydrochlorothiazide; D000584:Amiloride", "country": "Switzerland", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0036-7672", "issue": "118(4)", "journal": "Schweizerische medizinische Wochenschrift", "keywords": null, "medline_ta": "Schweiz Med Wochenschr", "mesh_terms": "D000368:Aged; D000584:Amiloride; D004338:Drug Combinations; D005260:Female; D006801:Humans; D006852:Hydrochlorothiazide; D011654:Pulmonary Edema; D011859:Radiography; D012769:Shock", "nlm_unique_id": "0404401", "other_id": null, "pages": "139-42", "pmc": null, "pmid": "3344418", "pubdate": "1988-01-31", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Hydrochlorothiazide-induced lung edema with shock.", "title_normalized": "hydrochlorothiazide induced lung edema with shock" }

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{ "abstract": "Metformin as the first drug of choice for glucose lowering in gestational diabetes (GDM) is still controversial, despite recent publications reporting similar outcomes in comparison to insulin, both for offspring and mothers. The use of metformin during pregnancy is increasing and several recent guidelines recommend metformin use in GDM pregnancies. Background, current metformin use and unresolved concerns are discussed in the context of the article from Gante and coworkers.", "affiliations": "Department of Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital, Oslo, Norway.", "authors": "Qvigstad|Elisabeth|E|", "chemical_list": "D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D008687:Metformin", "country": "England", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0804-4643", "issue": "178(3)", "journal": "European journal of endocrinology", "keywords": null, "medline_ta": "Eur J Endocrinol", "mesh_terms": "D001786:Blood Glucose; D016640:Diabetes, Gestational; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents; D007328:Insulin; D008687:Metformin; D017410:Practice Guidelines as Topic; D011247:Pregnancy", "nlm_unique_id": "9423848", "other_id": null, "pages": "C1-C5", "pmc": null, "pmid": "29339526", "pubdate": "2018-03", "publication_types": "D016428:Journal Article", "references": null, "title": "The diversity of gestational diabetes: a therapeutic challenge.", "title_normalized": "the diversity of gestational diabetes a therapeutic challenge" }

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{ "abstract": "BACKGROUND\nJejunal lymphatic malformations are congenital lesions that are seldom diagnosed in adults and rarely seen on imaging.\n\n\nMETHODS\nA 61-year-old Caucasian woman was initially diagnosed and treated for mucinous ovarian carcinoma. After an exploratory laparotomy with left salpingo-oophorectomy, a computed tomography scan of the abdomen and pelvis demonstrated suspicious fluid-containing lesions involving a segment of jejunum and adjacent mesentery. Resection of the lesion during subsequent debulking surgery revealed that the lesion seen on imaging was a jejunal lymphatic malformation and not a cancerous implant.\n\n\nCONCLUSIONS\nAbdominal lymphatic malformations are difficult to diagnose solely on imaging but should remain on the differential in adult cancer patients with persistent cystic abdominal lesions despite chemotherapy and must be differentiated from metastatic implants.", "affiliations": "Department of Radiological Sciences, University of California Irvine, 101 The City Drive South, Route 140, Orange, CA, 92868, USA.;Department of Radiological Sciences, University of California Irvine, 101 The City Drive South, Route 140, Orange, CA, 92868, USA. rhoushya@hs.uci.edu.;Department of Radiological Sciences, University of California Irvine, 101 The City Drive South, Route 140, Orange, CA, 92868, USA.;Department of Radiological Sciences, University of California Irvine, 101 The City Drive South, Route 140, Orange, CA, 92868, USA.;Department of Radiological Sciences, University of California Irvine, 101 The City Drive South, Route 140, Orange, CA, 92868, USA.;Department of Pathology & Laboratory Medicine, University of California Irvine School of Medicine, Irvine, CA, 92697, USA.;Department of Obstetrics and Gynecology, University of California Irvine, 333 City Boulevard West, Suite 1400, Orange, CA, 92868, USA.", "authors": "Rupasinghe|Mark|M|;Houshyar|Roozbeh|R|;Chahine|Chantal|C|;Bui|Thanh-Lan|TL|;Glavis-Bloom|Justin|J|;Cheng|Caleb|C|;Tseng|Jill|J|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1186/s13256-021-02872-9", "fulltext": "\n==== Front\nJ Med Case Rep\nJ Med Case Rep\nJournal of Medical Case Reports\n1752-1947\nBioMed Central London\n\n2872\n10.1186/s13256-021-02872-9\nCase Report\nA 61-year-old woman with jejunal lymphatic malformation visualized on computed tomography: a case report\nRupasinghe Mark mrupasin@hs.uci.edu\n\n1\nHoushyar Roozbeh rhoushya@hs.uci.edu\n\n1\nChahine Chantal chahinechantal@gmail.com\n\n1\nBui Thanh-Lan thanhltb@hs.uci.edu\n\n1\nGlavis-Bloom Justin jglavisb@hs.uci.edu\n\n1\nCheng Caleb calebc8@hs.uci.edu\n\n2\nTseng Jill jillt2@hs.uci.edu\n\n3\n1 grid.266093.8 0000 0001 0668 7243 Department of Radiological Sciences, University of California Irvine, 101 The City Drive South, Route 140, Orange, CA 92868 USA\n2 grid.266093.8 0000 0001 0668 7243 Department of Pathology & Laboratory Medicine, University of California Irvine School of Medicine, Irvine, CA 92697 USA\n3 grid.266093.8 0000 0001 0668 7243 Department of Obstetrics and Gynecology, University of California Irvine, 333 City Boulevard West, Suite 1400, Orange, CA 92868 USA\n27 5 2021\n27 5 2021\n2021\n15 3022 3 2021\n19 4 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open 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.\nBackground\n\nJejunal lymphatic malformations are congenital lesions that are seldom diagnosed in adults and rarely seen on imaging.\n\nCase presentation\n\nA 61-year-old Caucasian woman was initially diagnosed and treated for mucinous ovarian carcinoma. After an exploratory laparotomy with left salpingo-oophorectomy, a computed tomography scan of the abdomen and pelvis demonstrated suspicious fluid-containing lesions involving a segment of jejunum and adjacent mesentery. Resection of the lesion during subsequent debulking surgery revealed that the lesion seen on imaging was a jejunal lymphatic malformation and not a cancerous implant.\n\nConclusions\n\nAbdominal lymphatic malformations are difficult to diagnose solely on imaging but should remain on the differential in adult cancer patients with persistent cystic abdominal lesions despite chemotherapy and must be differentiated from metastatic implants.\n\nKeywords\n\nLymphatic malformation\nCytoreduction surgical procedures\nDiagnostic imaging\nissue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\n\nLymphatic malformations, previously known as “lymphangiomas,” are developmental anomalies of lymphatic ducts that are more commonly found in the head, neck, or axilla. Abdominal lymphatic malformations are exceptionally rare and account for less than 1% of all lymphatic malformations [1]. They can present with symptoms ranging from mild abdominal pain to an acute abdomen. Although lymphatic malformations directly associated with the bowel are rarely, if ever, imaged, computed tomography (CT) occasionally reveals cystic structures on the mesentery that compress adjacent bowel [2]. A definitive diagnosis is typically achieved after surgical excision and histologic examination demonstrate dilated lymphatic channels notable for continuous, flat endothelia [3]. In this case report, we present a 61-year-old woman whose exceptionally rare jejunal lymphatic malformation was seen on CT but was initially believed to be a peritoneal implant from her ovarian carcinoma.\n\nCase presentation\n\nA 61-year-old Caucasian woman presented with 5-year history of abdominal pain and distension, fatigue, and 1-year history of abnormal uterine bleeding. Initial workup revealed a carcinoembryonic antigen value of 8.1 ng/mL (normal < 3.9 ng/mL), cancer antigen-125 value of 134 U/mL (normal < 38.1 ng/mL), and a large left adnexal mass on ultrasound. Preoperative CT of the patient’s abdomen and pelvis without oral contrast initially revealed hypodense, ovoid lesions in the left lower quadrant mesentery adjacent to a short segment of small bowel (Fig. 1).Fig. 1. This portion of an abdominopelvic CT taken prior to the preexploratory laparotomy demonstrates hypodense spherical and ovoid locules (arrows) within the mesentery and adjacent to the small bowel (arrowhead)\n\nThe patient underwent an exploratory laparotomy which confirmed a diagnosis of mucinous ovarian carcinoma. One-month postoperative surveillance CT of the abdomen and pelvis with oral contrast demonstrated marked decrease in ascites and a 7–8-cm segment of small bowel in the left lower quadrant with low-density mural wall and bowel fold thickening. Additionally, there were hypodense ovoid lesions in the adjacent mesentery, which are the same lesions seen on the preoperative CT (Fig. 2). These findings were thought to represent persistent presence of peritoneal and serosal tumor implants.Fig. 2. Abdominopelvic CT demonstrating an 8-cm segment of small bowel with low-density mural wall thickening (arrowheads) and multiple grape-like ovoid hypodense mesenteric fluid-containing structures (arrow)\n\nThe patient subsequently began chemotherapy with folinic acid, fluorouracil, and oxaliplatin (FOLFOX) and completed two treatment cycles. Trastuzumab was then added, and the patient underwent an additional three cycles of FOLFOX–trastuzumab. A repeat abdominopelvic CT 4 months after the exploratory laparotomy showed resolution of ascites, but redemonstrated unchanged findings in the short segment of small bowel and adjacent mesentery in the left lower quadrant. These findings were again thought to represent persistent peritoneal and serosal tumor implants despite chemotherapy.\n\nShortly after the repeat CT, the patient underwent extensive tumor debulking. Intraoperatively, an 8-cm segment of jejunum with rubbery-like texture and adjacent mesentery was excised (Fig. 3). Histologic examination revealed a lymphatic malformation with variously sized lymphatic channels lined by a single, continuous layer of endothelia (Fig. 4). No residual intraperitoneal tumor was identified. The patient was subsequently discharged with a plan to complete FOLFOX–trastuzumab chemotherapy for her metastatic ovarian carcinoma.Fig. 3. Lymphatic malformation. The gross photograph demonstrates a portion of jejunum with an 8-cm tan–white, irregular, nodular, mucosal lesion\n\nFig. 4. Lymphatic malformation at high power (H&E). The image demonstrates dilated lymphatic channels of varying sizes, lined by a single layer of endothelial cells. Disorganized smooth muscle is focally present\n\nDiscussion\n\nLess than 1% of lymphatic malformations occur in the small bowel [4]. While no consensus exists for their development, they likely form when isolated lymphatic channels fail to connect appropriately to more prominent main channels, but evidence suggests that they can also be acquired from traumatic, inflammatory, or iatrogenic processes [5]. In adults, case reports indicate a variable presentation ranging from asymptomatic incidental findings [6] to acute [7] or chronic [8] abdominal pain, gastrointestinal bleeding [9], intussusception [4], and volvulus [10].\n\nWhen imaged on CT, lymphatic malformations are typically described as cystic mesenteric structures filled with hypodense fluid that compress immediately adjacent bowel [8]. Contrast enhancement may reveal the presence of septae [2], but the cystic portion of the malformation is either filled with nonenhancing fluid, or rarely, with hemorrhage or calcifications [12].\n\nOur patient’s lymphatic malformation had several features that mimicked peritoneal and serosal mucinous tumor implants. Tumor implants typically show thicker walls and septa, “scalloping” of visceral surfaces due to compressive forces from mucin produced by the peritoneal implants, and heterogeneous internal densities [13]. The ovoid mesenteric fluid-containing structures in our patient were part of the lymphatic malformation; however, in the setting of mucinous ovarian tumor, they mimicked peritoneal carcinomatosis with trapped malignant ascites. Additionally, lymphatic fluid within the jejunal wall likely caused the hypodense intramural thickening that mimicked serosal tumor implants.\n\nGiven the rarity of lymphatic malformations of the bowel and mesentery, there are few radiology studies devoted to diagnosis and characterization; however, contrast-enhanced magnetic resonance imaging may be a potentially useful test in distinguishing lymphatic malformations from mucinous tumor implants [14]. Lymphatic malformations typically have high signal intensity on T2-weighted imaging and lower internal T1 signal [2]. Mucinous tumors, on the other hand, typically have internally heterogeneous T1 and T2 signal intensities, although tumors containing a high concentration of mucin could display higher T1 and lower T2 signal intensities [15].\n\nGastrointestinal lymphatic malformations are typically treated with surgical removal considering their potential for mass effects, although sclerotherapy [16] and lymphovenous anastomosis [17] have been successfully reported. Histologic examination of the removed malformations typically show dilated lymphatic channels with flat, continuous endothelia [3]. They can be classified as macrocystic, microcystic, or mixed [19] depending on their microscopic size, although this classification is difficult to interpret radiologically.\n\nConclusion\n\nLymphatic malformations of the small bowel are exceptionally rare anomalous developments of the lymphatic system. In the setting of mucinous tumors, lymphatic malformations with their variable presentation and nonspecific imaging appearance can present a diagnostic challenge as they mimic tumor deposits. Increased awareness of this entity may help improve patient care.\n\nAbbreviations\n\nCT Computed tomography\n\nFOLFOX Folinic acid, fluorouracil, oxaliplatin\n\nAcknowledgements\n\nNot applicable.\n\nAuthors' contributions\n\nJT was the attending physician who performed the procedure and managed patient care. MR, TLB, and Ch.C collected patient data. RH and JGB analyzed patient imaging. Ca.C analyzed patient pathology. All authors were active in manuscript drafting, revision, and final approval. All authors read and approved the final manuscript.\n\nFunding\n\nNot applicable.\n\nAvailability of data and materials\n\nNot applicable.\n\nDeclarations\n\nEthics approval and consent to participate\n\nInformed consent was obtained from the patient for publication of anonymized case details.\n\nConsent for publication\n\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Roisman I Manny J Fields S Shiloni E Intra-abdominal lymphangioma Br J Surg 1989 76 5 485 489 10.1002/bjs.1800760519 2660949\n2. Levy AD Cantisani V Miettinen M Abdominal lymphangiomas: imaging features with pathologic correlation Am J Roentgenol 2004 182 6 1485 1491 10.2214/ajr.182.6.1821485 15149994\n3. Rieker RJ Quentmeier A Weiss C Kretzschmar U Amann K Mechtersheimer G Bläker H Otto HF Cystic lymphangioma of the small-bowel mesentery Pathol Oncol Res 2000 6 2 146 148 10.1007/BF03032366 10936792\n4. Samuelson H Giannotti G Guralnick A Jejunal lymphangioma causing intussusception in an adult: an unusual case with review of the literature Ann Med Surg 2018 1 34 39 42 10.1016/j.amsu.2018.08.020\n5. Kennedy TL Cystic hygroma-lymphangioma: a rare and still unclear entity Laryngoscope 1989 99 S1 1 10.1288/00005537-198910001-00001\n6. Lawless ME Lloyd KA Swanson PE Upton MP Yeh MM Lymphangiomatous lesions of the gastrointestinal tract: a clinicopathologic study and comparison between adults and children Am J Clin Pathol 2015 144 4 563 569 10.1309/AJCPO8TW6EMAJSRP 26386077\n7. Jayasundara JA Perera E de Silva MV Pathirana AA Lymphangioma of the jejunal mesentery and jejunal polyps presenting as an acute abdomen in a teenager Ann R Coll Surg Engl 2017 99 3 108 9 10.1308/rcsann.2017.0012\n8. Aprea G Guida F Canfora A Ferronetti A Giugliano A Ciciriello MB Savanelli A Amato B Mesenteric cystic lymphangioma in adult: a case series and review of the literature BMC Surg 2013 13 1 1 5 10.1186/1471-2482-13-1 23356494\n9. Tan B Zhang SY Wang YN Li Y Shi XH Qian JM Jejunal cavernous lymphangioma manifested as gastrointestinal bleeding with hypogammaglobulinemia in adult: a case report and literature review World J Clin Cases. 2020 8 1 140 10.12998/wjcc.v8.i1.140 31970180\n10. Suthiwartnarueput W Kiatipunsodsai S Kwankua A Chaumrattanakul U Lymphangioma of the small bowel mesentery: a case report and review of the literature World J Gastroenterol: WJG 2012 18 43 6328 10.3748/wjg.v18.i43.6328 23180956\n11. Allen JG Riall TS Cameron JL Askin FB Hruban RH Campbell KA Abdominal lymphangiomas in adults J Gastrointest Surg 2006 10 5 746 751 10.1016/j.gassur.2005.10.015 16713549\n12. Wohlgemuth WA Brill R Dendl LM Stangl F Stoevesandt D Schreyer AG Abdominal lymphatic malformations Radiologe 2018 58 1 29 33 10.1007/s00117-017-0337-5 29796772\n13. Levy AD Shaw JC Sobin LH Secondary tumors and tumorlike lesions of the peritoneal cavity: imaging features with pathologic correlation Radiographics 2009 29 2 347 373 10.1148/rg.292085189 19325052\n14. Romeo V Maurea S Mainenti PP Camera L Aprea G Cozzolino I Salvatore M Correlative imaging of cystic lymphangiomas: ultrasound, CT and MRI comparison Acta Radiologica Open. 2015 4 5 2047981614564911 10.1177/2047981614564911 26019889\n15. Lee NK Kim S Kim HS Jeon TY Kim GH Kim DU Park DY Kim TU Kang DH Spectrum of mucin-producing neoplastic conditions of the abdomen and pelvis: cross-sectional imaging evaluation World J Gastroenterol 2011 17 43 4757 10.3748/wjg.v17.i43.4757 22147976\n16. Madsen HJ Annam A Harned R Nakano TA Larroque LO Kulungowski AM Symptom resolution and volumetric reduction of abdominal lymphatic malformations with sclerotherapy J Surg Res 2019 1 233 256 261 10.1016/j.jss.2018.07.031\n17. Ishiura R, Mitsui K, Danno K, Banda CH, Inoue M, Narushima M. Successful treatment of large abdominal lymphatic malformations and chylous ascites with intra-abdominal lymphovenous anastomosis. J Vasc Surg. 2020.\n18. Limaiem F Khalfallah T Marsaoui L Bouraoui S Lahmar A Mzabi S Jejunal lymphangioma: an unusual cause of intussusception in an adult patient Pathologica. 2015 107 1 19 21 26591627\n19. ISSVA Classification of Vascular Anomalies: 2018 International Society for the Study of Vascular Anomalies. http://issva.org/classification. Accessed 01 Dec 2020.\n\n", "fulltext_license": "CC BY", "issn_linking": "1752-1947", "issue": "15(1)", "journal": "Journal of medical case reports", "keywords": "Cytoreduction surgical procedures; Diagnostic imaging; Lymphatic malformation", "medline_ta": "J Med Case Rep", "mesh_terms": "D002288:Adenocarcinoma, Mucinous; D000328:Adult; D005260:Female; D006801:Humans; D007583:Jejunum; D007813:Laparotomy; D008643:Mesentery; D008875:Middle Aged; D014057:Tomography, X-Ray Computed", "nlm_unique_id": "101293382", "other_id": null, "pages": "302", "pmc": null, "pmid": "34039402", "pubdate": "2021-05-27", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "30210794;22147976;2660949;29796772;30502256;32505686;26591627;26386077;31970180;10936792;15149994;23180956;16713549;2677565;28252346;26019889;19325052", "title": "A 61-year-old woman with jejunal lymphatic malformation visualized on computed tomography: a case report.", "title_normalized": "a 61 year old woman with jejunal lymphatic malformation visualized on computed tomography a case report" }

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{ "abstract": "OBJECTIVE\nPrimary intracranial malignant peripheral nerve sheath tumors (MPNSTs) not associated with cranial nerves are rare and aggressive neoplasms. The rarity of presentation has precluded rigorous analysis of diagnosis, risk factors, treatment, and survival. We analyzed every reported case through exhaustive literature review. In addition, we present our own experience managed with resection, radiotherapy, and first use of targeted therapy in a tumor of this type for a BRAF mutation identified during next-generation sequencing.\n\n\nMETHODS\nTwo databases, PubMed and Embase, and crossed references were queried for intracranial MPNSTs not associated with a cranial nerve. Extracted variables included demographics, risk factors, tumor characteristics, interventions, and outcomes. Univariate and multivariate analysis was performed to identify factors with survival benefit.\n\n\nRESULTS\nA total of 56 patients (including the present case) were included from 743 literature results. There was a male/female ratio of 1.5:1 and mean diagnosis age of 29.7 ± 21.8 years. Seventy-one percent of cases were sporadic and 23% neurofibromatosis type 1 related. Median survival was 29 ± 22.1 months with 1-year survival of 60%. Factors associated on univariate analysis with reduced survival were subtotal resection (P = 0.05), older age (P = 0.023), triton histology (P < 0.001), and early recurrence (≤6 months) (P = 0.018). On multivariate analysis, gross total resection reduced mortality risk (P = 0.011), whereas triton histology (P = 0.017) and infratentorial tumor location (P = 0.037) increased mortality.\n\n\nCONCLUSIONS\nWe present a systematic review of intracranial MPNSTs not associated with a cranial nerve. These tumors have poor prognosis and benefit from aggressive resection, multimodal treatment, and close follow-up. Next-generation sequencing can show molecular alterations for potential targeted therapy.", "affiliations": "Department of Neurosurgery, Beth Israel Deaconess Medical Center, Lowry Medical Office Building, Boston, Massachusetts, USA; Department of Neurosurgery, Boston Medical Center, Boston, Massachusetts, USA. Electronic address: cmackel@bidmc.harvard.edu.;Department of Pathology and Laboratory Medicine, Boston Medical Center, Boston, Massachusetts, USA.;Department of Pathology and Laboratory Medicine, Boston Medical Center, Boston, Massachusetts, USA.;Department of Pathology and Laboratory Medicine, Boston Medical Center, Boston, Massachusetts, USA.;Department of Neurosurgery, Boston Medical Center, Boston, Massachusetts, USA.", "authors": "Mackel|Charles E|CE|;Medeiros|Isabela|I|;Moore|Brian E|BE|;Zhao|Qing|Q|;Jha|Ribhu|R|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1016/j.wneu.2021.09.072", "fulltext": null, "fulltext_license": null, "issn_linking": "1878-8750", "issue": "156()", "journal": "World neurosurgery", "keywords": "Intracerebral; Intracranial; MINST; MPNST; Malignant peripheral nerve sheath tumor", "medline_ta": "World Neurosurg", "mesh_terms": null, "nlm_unique_id": "101528275", "other_id": null, "pages": "76-91", "pmc": null, "pmid": "34563719", "pubdate": "2021-12", "publication_types": "D016428:Journal Article; D016454:Review", "references": null, "title": "Intracranial Malignant Peripheral Nerve Sheath Tumors Not Associated with a Cranial Nerve: Systematic Review and Illustrative Case.", "title_normalized": "intracranial malignant peripheral nerve sheath tumors not associated with a cranial nerve systematic review and illustrative case" }

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{ "abstract": "What is known and objectives: Multiple adverse drug reactions (ADRs) are expected, and thus should be prevented in the elderly comorbid patient on polypharmacy. Rosuvastatin is commonly prescribed for the treatment and prevention of atherosclerotic diseases, and in rare cases, is associated with rhabdomyolysis. Maprotiline is a tetracyclic antidepressant, infrequently used in the United States, but seemingly more broadly in European countries. Acute colonic pseudo-obstruction (Ogilvie's syndrome) caused by maprotiline has thus far, to our knowledge, not yet been described in the literature.\n\n\nMETHODS\nWe present a unique case of synchronous rhabdomyolysis and Ogilvie's syndrome in an 80-year-old lung cancer survivor following a recent ischemic stroke for which she was prescribed clopidogrel and rosuvastatin for secondary prevention, and maprotiline for post-stroke, new-onset insomnia and anxiety. The ADRs resolved on removal of the offending agents and initiation of conservative treatment. Retrospective pharmacogenetic testing of the patient's drug-metabolizing enzymes and transporters was performed to guide further management and prevent future potential drug interactions and ADRs. What is novel and conclusions: This is an interesting, albeit unfortunate, complex case that depicts the risk of rare adverse effects to medications and their potential relationship to pharmacogenetics. The impact of anticholinergic side effects of antidepressants on gastrointestinal motility, risk of myopathies with statins, increased susceptibility to ADRs caused by drug-drug interactions, and the utility of pharmacogenomic testing are discussed. The question whether commercially available pharmacogenomic tools are relevant for everyday use to direct patient care and reduce harmful drug-drug interactions is addressed and warrants further research.
.", "affiliations": null, "authors": "Sreter|Katherina B|KB|;Barisic|Blazenka|B|;Popovic-Grle|Sanja|S|", "chemical_list": "D018687:Antidepressive Agents, Second-Generation; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D027381:Liver-Specific Organic Anion Transporter 1; C503999:SLCO1B1 protein, human; D008376:Maprotiline; D000068718:Rosuvastatin Calcium; D003577:Cytochrome P-450 Enzyme System", "country": "Germany", "delete": false, "doi": "10.5414/CP202784", "fulltext": null, "fulltext_license": null, "issn_linking": "0946-1965", "issue": "55(5)", "journal": "International journal of clinical pharmacology and therapeutics", "keywords": null, "medline_ta": "Int J Clin Pharmacol Ther", "mesh_terms": "D000369:Aged, 80 and over; D018687:Antidepressive Agents, Second-Generation; D003112:Colonic Pseudo-Obstruction; D003577:Cytochrome P-450 Enzyme System; D004347:Drug Interactions; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D027381:Liver-Specific Organic Anion Transporter 1; D008376:Maprotiline; D010597:Pharmacogenetics; D000071185:Pharmacogenomic Testing; D000071184:Pharmacogenomic Variants; D010641:Phenotype; D019338:Polypharmacy; D012206:Rhabdomyolysis; D012307:Risk Factors; D000068718:Rosuvastatin Calcium", "nlm_unique_id": "9423309", "other_id": null, "pages": "442-448", "pmc": null, "pmid": "28257284", "pubdate": "2017-05", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Pharmacogenomics and tailored polypharmacy: an 80-year-old lady with rosuvastatin-associated rhabdomyolysis and maprotiline-related Ogilvie's syndrome
.", "title_normalized": "pharmacogenomics and tailored polypharmacy an 80 year old lady with rosuvastatin associated rhabdomyolysis and maprotiline related ogilvie s syndrome" }

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PHARMACOGENOMICS AND TAILORED POLYPHARMACY: AN 80-YEAR-OLD LADY WITH ROSUVASTATIN-ASSOCIATED RHABDOMYOLYSIS AND MAPROTILINE-RELATED OGILVIE^S SYNDROME. INT J CLIN PHARMACOL THER (DOI: 10.5414/CP202784). 2017;55(5):442-448", "literaturereference_normalized": "pharmacogenomics and tailored polypharmacy an 80 year old lady with rosuvastatin associated rhabdomyolysis and maprotiline related ogilvie s syndrome", "qualification": "3", "reportercountry": "HR" }, "primarysourcecountry": "HR", "receiptdate": "20170613", "receivedate": "20170613", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13647458, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170830" }, { "companynumb": "HR-ACCORD-049450", "fulfillexpeditecriteria": "1", "occurcountry": "HR", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { 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PHARMACOGENOMICS AND TAILORED POLYPHARMACY: AN 80-YEAR-OLD LADY WITH ROSUVASTATIN-ASSOCIATED RHABDOMYOLYSIS AND MAPROTILINE-RELATED OGILVIE^S SYNDROME?. INT J CLIN PHARMACOL THER. 2017 MAR 3.", "literaturereference_normalized": "pharmacogenomics and tailored polypharmacy an 80 year old lady with rosuvastatin associated rhabdomyolysis and maprotiline related ogilvie s syndrome", "qualification": "1", "reportercountry": "HR" }, "primarysourcecountry": "HR", "receiptdate": "20170320", "receivedate": "20170320", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13349430, "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": "HR-TEVA-759417ISR", "fulfillexpeditecriteria": "1", "occurcountry": "HR", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": 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PHARMACOGENOMICS AND TAILORED POLYPHARMACY: AN 80-YEAR-OLD LADY WITH ROSUVASTATIN-ASSOCIATED RHABDOMYOLYSIS AND MAPROTILINE-RELATED OGILVIE^S SYNDROME. 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"drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MAPROTILINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PANTOPRAZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "40 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": "40", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PANTOPRAZOLE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FORMOTEROL" }, "drugadditional": "3", "drugadministrationroute": "055", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INHALER", "drugdosagetext": "1 PUFF, BID", "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": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FORMOTEROL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUDESONIDE" }, "drugadditional": "3", "drugadministrationroute": "055", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INHALER", "drugdosagetext": "1 PUFF, BID", "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": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUDESONIDE." } ], "patientagegroup": null, "patientonsetage": "80", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Constipation", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Abdominal distension", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Intestinal dilatation", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Gastrointestinal sounds abnormal", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rhabdomyolysis", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Intestinal pseudo-obstruction", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "SRETER KB, BARISIC B, POPOVIC-GRLE S. PHARMACOGENOMICS AND TAILORED POLYPHARMACY: AN 80-YEAR-OLD LADY WITH ROSUVASTATIN-ASSOCIATED RHABDOMYOLYSIS AND MAPROTILINE-RELATED OGILVIE^S SYNDROME. INTERNATIONAL JOURNAL OF CLINICAL PHARMACOLOGY AND THERAPEUTICS. 2017;55(5):442-8", "literaturereference_normalized": "pharmacogenomics and tailored polypharmacy an 80 year old lady with rosuvastatin associated rhabdomyolysis and maprotiline related ogilvie s syndrome", "qualification": "3", "reportercountry": "HR" }, "primarysourcecountry": "HR", "receiptdate": "20170823", "receivedate": "20170823", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13898341, "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": "HR-MYLANLABS-2017M1053394", "fulfillexpeditecriteria": "1", "occurcountry": "HR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "PANTOPRAZOLE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "40 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": "PANTOPRAZOLE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "MAPROTILINE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "75 MG (TOTAL DAILY DOSE)", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANXIETY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MAPROTILINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "MAPROTILINE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "75 MG (TOTAL DAILY DOSE)", "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": "MAPROTILINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CODEINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "15 MG (3 TABLETS)", "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": "CODEINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "BUDESONIDE\\FORMOTEROL" }, "drugadditional": null, "drugadministrationroute": "055", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 PUFF TWICE A DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "2", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "320", "drugstructuredosageunit": "004", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUDESONIDE W/FORMOTEROL" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 MG IN THE EVENINGS", "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": "CLONAZEPAM." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CLOPIDOGREL BISULFATE" }, "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": "CLOPIDOGREL" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ROSUVASTATIN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "079161", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "40MG, THEN UNSPECIFIED DOSE IN EVENING", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ROSUVASTATIN." } ], "patientagegroup": null, "patientonsetage": "80", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Rhabdomyolysis", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Intestinal pseudo-obstruction", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "SRETER KB, BARISIC B, POPOVIC-GRLE S. PHARMACOGENOMICS AND TAILORED POLYPHARMACY: AN 80-YEAR-OLD LADY WITH ROSUVASTATIN-ASSOCIATED RHABDOMYOLYSIS AND MAPROTILINE-RELATED OGILVIE^S SYNDROME. INT-J-CLIN-PHARMACOL-THER 2017;55(5):442-448.", "literaturereference_normalized": "pharmacogenomics and tailored polypharmacy an 80 year old lady with rosuvastatin associated rhabdomyolysis and maprotiline related ogilvie s syndrome", "qualification": "3", "reportercountry": "HR" }, "primarysourcecountry": "HR", "receiptdate": "20170830", "receivedate": "20170830", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13921343, "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" } ]

{ "abstract": "Oxaliplatin-based chemotherapy is widely used for advanced colorectal cancer treatment, but it occasionally induces liver injury that is characterized histologically by sinusoidal dilatation, hepatic plate atrophy and/or venular obstruction. Most of the patients do not reveal apparent radiological abnormalities, however. Here, we report the case of a 47-year-old man with a radiologically detectable mass-forming oxaliplatin-induced sinusoidal injury that mimicked multiple liver tumors. These mass lesions were found on computed tomography images after the administration of six cycles of folinic acid, fluorouracil and oxaliplatin therapy as adjuvant chemotherapy for Stage III rectal cancer. The patient had to undergo liver resection because imaging studies could not exclude metastases. The histological examination revealed that a resected mass lesion was composed of severe sinusoidal dilatation. Milder dilatation was also seen in the surrounding parenchyma. We diagnosed the patient as having an oxaliplatin-induced sinusoidal injury with severe deviation. As oxaliplatin is a standard agent in colorectal cancer therapy today, all clinicians and pathologists should be aware of such non-neoplastic lesions as one of the rare differential diagnoses of metastatic liver tumor, to prevent overtreatment.", "affiliations": "*Department of Pathology, Japanese Red Cross Society Himeji Hospital, 1-12-1 Shimoteno, Himeji 670-8540, Japan. kaoriuchino@yahoo.co.jp.", "authors": "Uchino|Kaori|K|;Fujisawa|Masayoshi|M|;Watanabe|Takanori|T|;Endo|Yoshikatsu|Y|;Nobuhisa|Tetsuji|T|;Matsumoto|Yusuke|Y|;Kai|Kyohei|K|;Sato|Shiso|S|;Notohara|Kenji|K|;Matsukawa|Akihiro|A|", "chemical_list": "D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D002955:Leucovorin; D005472:Fluorouracil", "country": "England", "delete": false, "doi": "10.1093/jjco/hyt113", "fulltext": null, "fulltext_license": null, "issn_linking": "0368-2811", "issue": "43(10)", "journal": "Japanese journal of clinical oncology", "keywords": "colorectal liver metastases; oxaliplatin; sinusoidal obstruction syndrome", "medline_ta": "Jpn J Clin Oncol", "mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D017024:Chemotherapy, Adjuvant; D015179:Colorectal Neoplasms; D003937:Diagnosis, Differential; D005472:Fluorouracil; D006498:Hepatectomy; D006801:Humans; D002955:Leucovorin; D008099:Liver; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D014057:Tomography, X-Ray Computed", "nlm_unique_id": "0313225", "other_id": null, "pages": "1034-8", "pmc": null, "pmid": "23958518", "pubdate": "2013-10", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Oxaliplatin-induced liver injury mimicking metastatic tumor on images: a case report.", "title_normalized": "oxaliplatin induced liver injury mimicking metastatic tumor on images a case report" }

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{ "abstract": "Accidental ingestion or consumption of supra-therapeutic doses of methadone can result in neurological sequelae in humans. We aimed to determine the neurological deficits of methadone-poisoned patients admitted to a referral poisoning hospital using brain magnetic resonance (MR) and diffusion weighted (DW) imaging.\n\n\n\nIn this retrospective study, brain MRIs of the patients admitted to our referral center due to methadone intoxication were reviewed. Methadone intoxication was confirmed based on history, congruent clinical presentation, and confirmatory urine analysis. Each patient had an MRI with Echo planar T1, T2, FLAIR, and DWI and apparent deficient coefficient (ADC) sequences without contrast media. Abnormalities were recorded and categorized based on their anatomic location and sequence.\n\n\n\nTen patients with abnormal MRI findings were identified. Eight had acute- and two had delayed-onset encephalopathy. Imaging findings included bilateral confluent or patchy T2 and FLAIR high signal intensity in cerebral white matter, cerebellar involvement, and bilateral occipito-parietal cortex diffusion restriction in DWI. Internal capsule involvement was identified in two patients while abnormality in globus pallidus and head of caudate nuclei were reported in another. Bilateral cerebral symmetrical confluent white matter signal abnormality with sparing of subcortical U-fibers on T2 and FLAIR sequences were observed in both patients with delayed-onset encephalopathy.\n\n\n\nAcute- and delayed-onset encephalopathies are two rare adverse events detected in methadone-intoxicated patients. Brain MRI findings can be helpful in detection of methadone-induced encephalopathy.", "affiliations": "Department of Radiology, Loghman-Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.;Department of Radiology, Loghman-Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.;Drug Health Services, Sydney Local Health District, Sydney, NSW, Australia.;Social Determinants of Health Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. hassanian@sbmu.ac.ir.;Social Determinants of Health Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.;Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.", "authors": "Haghighi-Morad|Maryam|M|;Naseri|Zahra|Z|;Jamshidi|Nazila|N|;Hassanian-Moghaddam|Hossein|H|0000-0003-4370-0544;Zamani|Nasim|N|;Ahmad-Molaei|Leila|L|", "chemical_list": "D008691:Methadone", "country": "England", "delete": false, "doi": "10.1186/s12880-020-0410-9", "fulltext": "\n==== Front\nBMC Med ImagingBMC Med ImagingBMC Medical Imaging1471-2342BioMed Central London 41010.1186/s12880-020-0410-9Research ArticleMethadone-induced encephalopathy: a case series and literature review Haghighi-Morad Maryam 1Naseri Zahra 1Jamshidi Nazila 2http://orcid.org/0000-0003-4370-0544Hassanian-Moghaddam Hossein hassanian@sbmu.ac.ir 34Zamani Nasim 34Ahmad-Molaei Leila 51 grid.411600.2Department of Radiology, Loghman-Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran 2 0000 0001 2105 7653grid.410692.8Drug Health Services, Sydney Local Health District, Sydney, NSW Australia 3 grid.411600.2Social Determinants of Health Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran 4 grid.411600.2Department of Clinical Toxicology, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran 5 grid.411600.2Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran 17 1 2020 17 1 2020 2020 20 627 9 2019 3 1 2020 © The Author(s). 2020Open 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\nAccidental ingestion or consumption of supra-therapeutic doses of methadone can result in neurological sequelae in humans. We aimed to determine the neurological deficits of methadone-poisoned patients admitted to a referral poisoning hospital using brain magnetic resonance (MR) and diffusion weighted (DW) imaging.\n\nMethods\nIn this retrospective study, brain MRIs of the patients admitted to our referral center due to methadone intoxication were reviewed. Methadone intoxication was confirmed based on history, congruent clinical presentation, and confirmatory urine analysis. Each patient had an MRI with Echo planar T1, T2, FLAIR, and DWI and apparent deficient coefficient (ADC) sequences without contrast media. Abnormalities were recorded and categorized based on their anatomic location and sequence.\n\nResults\nTen patients with abnormal MRI findings were identified. Eight had acute- and two had delayed-onset encephalopathy. Imaging findings included bilateral confluent or patchy T2 and FLAIR high signal intensity in cerebral white matter, cerebellar involvement, and bilateral occipito-parietal cortex diffusion restriction in DWI. Internal capsule involvement was identified in two patients while abnormality in globus pallidus and head of caudate nuclei were reported in another. Bilateral cerebral symmetrical confluent white matter signal abnormality with sparing of subcortical U-fibers on T2 and FLAIR sequences were observed in both patients with delayed-onset encephalopathy.\n\nConclusions\nAcute- and delayed-onset encephalopathies are two rare adverse events detected in methadone-intoxicated patients. Brain MRI findings can be helpful in detection of methadone-induced encephalopathy.\n\nKeywords\nMethadoneAcute encephalopathyDelayed leukoencephalopathyMagnetic resonance imaginghttp://dx.doi.org/10.13039/501100005851Shahid Beheshti University of Medical Sciences14911Hassanian-Moghaddam Hossein issue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nMethadone is a synthetic opioid that is increasingly used as an analgesic and in maintenance therapy of opioid-addicted patients [1, 2]. Accidental ingestion of methadone or consumption of its supra-therapeutic doses have been shown to cause multi-organ damage in both humans and animals [1, 3–5].\n\nThere have been several previous case reports describing acute-onset encephalopathy (AOE) and delayed-onset leukoencephalopathy (DOL) as adverse complications of methadone intoxication [4–6]. AOE presents with MRI abnormalities within the first admission of the patient. DOL, however, manifests with abnormalities detected on MRI in patients who have initially responded to treatment (complete resolution of symptoms), but are then re-admitted after a period of lucidity (usually days to weeks post the primary event) with neurological or psychiatric deterioration [7–10].\n\nAOE is one of the severe neurologic complications of methadone intoxication, that has previously been associated with carbon monoxide and heroin toxicities [7, 8]. To date, eight case reports have been published reporting AOE associated with methadone toxicity, ages ranging from 22-month-old to 65 years old [1, 4, 5, 11–16]. These cases have reported a range of neurologic complications, including restrictive diffusion throughout the cerebral gray matter, bilateral diffuse cerebellar edema or infarction, hippocampal and basal ganglia (globus pallidus), fluid-attenuated inversion recovery (FLAIR) intensities, absence of central intracranial blood flow, supra and infratentorial gray matter thickening, and non-enhancing T2 hyperintensities and restriction diffusion in the white matter of both hemispheres with sparing of subcortical U fibers [4, 5, 11–16].\n\nDOL was first described in a 24-year-old patient who developed apathy and disorientation after the initial improvement from a mixed methadone-benzodiazepine poisoning [16]. Other case studies have reported a range of DOL symptoms, including disorientation, paranoid and bizarre behavior, and severe progressive cognitive decline with bilateral cerebral white matter hyperintensities. MRI changes in these case reports have included diffuse abnormal T2 and FLAIR signals in the corona radiate, centrum semiovale and subcortical white matter throughout all lobes, and signal abnormalities in temporomesial, substantia nigra, and basal ganglia [6, 8, 9, 12, 13, 17–21]. The aim of our study was to identify and describe the pattern of neurological deficits and associated brain magnetic resonance imaging (MRI) changes in methadone-poisoned patients.\n\nMethods\nIn this retrospective file audit, the clinical records of all patients admitted to our referral poisoning hospital with the diagnosis of methadone intoxication between May 2016 and March 2018 were reviewed. A total of 2930 cases were identified, of whom only 10 fulfilled the inclusion criteria.\n\nDefinitions\nMethadone intoxication was defined based on history, clinical presentations of respiratory depression (opioid toxidrome) or loss of consciousness (LOC) responsive to administration of naloxone, as well as detection of methadone in urine analysis. The patients were classified into two subtypes: acute- and delayed-onset encephalopathy (AOE and DOL, respectively) based on clinical history. Patients with persistent neurological deficits in their first admission were categorized to have AOE based on their MRI changes. Those who had been discharged after either complete or partial recovery from acute intoxication, but then deteriorated with neurological signs or symptoms within several days or weeks necessitating readmission were considered to have DOL [7–9]. The most prevalent delayed symptoms included psychotic delirium, fluctuating state of consciousness, depression, apathy, and bizarre behaviors [9–13]. Complete knowledge of time courses and clinical presentation was a prerequisite in categorization of the patients. Imaging was performed due to persistent neurological deficits several days after admission or if there was re-occurrence of neurotoxicity after a lucid interval of at least 1 week.\n\nInclusion criteria\nAOE: Patients who had been admitted due to methadone intoxication and had undergone imaging due to persistent neurological deficits were enrolled in AOE group.\n\nDOL: Neurological deficits were defined as a deterioration of neurologic function leading to readmission within one to 3 weeks after discharge without any new toxic exposure. Patients fulfilling this criteria were enrolled into the DOL group.\n\nExclusion criteria\nIf methadone diagnosis was not confirmed after the review of the history, presentation, and urine analysis. Patients who had co-ingestions confirmed by urine analysis were also excluded (e.g. Alcohol). Any cases with possible intoxication, with a coingestants known to cause MRI complications (carbon monoxide [CO], methanol, cyanide, etc.) were excluded.\n\nImaging\nScans were performed by a 1.5-T multi-planar MRI device. Echo planar T1 (TR: 591 ms, TE:15 ms, Spatial Resolution: 6.2 mm slice thickness, FoV: 230 mm*230 mm), T2 (TR: 4048 ms, TE:90 ms, Spatial Resolution: FLAIR, diffusion weighted imaging (DWI) and apparent deficient coefficient (ADC) sequences without contrast media were performed. The scan time was 15 min. All images were reviewed by a single radiologist experienced in MRI. Detected abnormalities were recorded and categorized based on their anatomic location and sequence. The areas with both restriction in DWI and low signal in abnormal diffusion restriction (ADC) were considered abnormal.\n\nResults\nEight patients had a brain MRI performed during their first admission due to persistent neurological deficit despite active treatment (AOE group; Tables 1 and 2). This group included four children (aged 23 months to 16 years) who had accidentally ingested methadone. The other two had developed new neurological deficits days after the initial recovery from intoxication (DOL group; Table 3). All ten patients had abnormal findings on MRI.\nTable 1 Clinical characteristics of patients with AOE\n\nPatient number\tAge/ Sex\tInitial presentation\tUrine toxicology\tTime to imaging\t\n1\t13 yr, F\tCyanosis\tMethadone\tDay 5\t\n2\t16 yr, F\tApnea\tMethadone\tDay 7\t\n3\t23mo, M\tCyanosis\tMethadone, benzodiazepine\tDay 5\t\n4\t30 yr, M\tIntoxication then witnessed apnea\tMethadone\tDay 2\t\n5\t31 yr, M\tConfusion then witnessed apnea\tMethadone, opiate\tDay 12\t\n6\t32 yr, F\tLOC\tMethadone\tDay 3\t\n7\t33 yr, M\tLOC\tMethadone, opiate\tDay 2\t\n8\t5 yr, M\tLOC\tMethadone\tDay 2\t\n\nTable 2 Brain MRI findings in patients with AOE\n\nNumber\tAge/ Sex\tBilateral cerebral white matter T2 and FLAIR hyperintensity\tBilateral cerebellar white and gray matter T2 and FLAIR hyperintensity\tBilateral parieto-occipital T2 and FLAIR hyperintensity (PRES features)\tInternal capsule involvement\tOther structures\tInfarction\tHemorrhage\t\n1\t13 yr, F\tYes\tYes\tYes\t–\t–\tNo\tNo\t\n2\t16 yr, F\tYes\t–\t–\t–\t–\tNo\tNo\t\n3\t23mo, M\tYes\t–\t–\t–\t–\tNo\tNo\t\n4\t30 yr, M\t–\tYes\tYes\n\nWith restriction in DWI and low signal in ADC sequences\n\n\t–\t–\tNo\tNo\t\n5\t31 yr, M\tYes\t–\t–\tYes\tSplenium of corpus callosum\tNo\tNo\t\n6\t32 yr, F\t–\t–\tYes\n\nWith restriction in DWI and low signal in ADC sequences\n\n\t–\t–\tNo\tNo\t\n7\t33 yr, M\tYes\t–\t–\tYes with restriction in DWI and ADC sequences\t–\tNo\tNo\t\n8\t5 yr, M\t–\tYes\tYes\n\nWith restriction in DWI and low signal in ADC sequences\n\n\t–\tGlobus pallidus and caudate nuclei\tNo\tNo\t\n\nTable 3 Clinical characteristics and brain MRI findings of patients with DOL\n\nNumber\tAge/ Sex\tToxic agent\tClinical presentation in relapse phase\tTime to relapse after initial intoxication\tInitial imaging\tDelayed phase brain MRI findings\tDWI and ADC\t\n9\t47 yr, M\tMethadone\tDisorientation, seizure like activity\t9 days\tNo\tConfluent bilateral symmetrical cerebral white matter T2 and FLAIR hyperintensity with sparing of sub cortical U-fibers\tNo restriction\t\n10\t49 yr, M\tMethadone\tConfusion\t18 days\tNo\tConfluent bilateral symmetrical cerebral white matter T2 and FLAIR hyperintensity with sparing of sub cortical U-fibers\tNo restriction\t\n\n\nAOE group\nSeven patients in this group were male and median age was 23 years [range; 23 months to 33 years). Based on urine analysis, three cases had positive urine for other drugs. One had received benzodiazepine as a part of medical management. Other two were multi-opioid abusers, but had only overdosed on methadone. Imaging findings in this group included bilateral confluent or patchy T2 and FLAIR high signal intensity areas in cerebral white matter in six (Fig. 1), cerebellar involvement in four (Fig. 2), and bilateral occipitoparietal cortex signal abnormality (low on T1 and high on T2) associated with diffusion restriction (confirmed with low signal intensity in ADC) in three cases (Fig. 3) and without restriction in one case. Internal capsule involvement was detected in two patients with hyper-signal corpus callosum in one. Abnormalities in the globus pallidus and the head of caudate nuclei were reported in only one patient. The MRIs were performed at 2- and 12-day intervals after initial presentation with methadone intoxication (defined as the primary toxic event).\nFig. 1 Axial (a) T2 and (b) FLAIR sequences of a 31-year-old man (patient number 5) , 12 days after presenting to emergency department with AOE symptoms, symmetric areas of hyperintensity in both centrum semiovale are seen. Axial (c) and (d) FLAIR sequences of the same patient at the mid ventricular level show hyperintensity in the splenium of corpus callosum\n\n\nFig. 2 Axial (a) T2 and (b) FLAIR sequences from posterior fossa at the level of fourth ventricle in a 30 year old male ( patient number 4) two days after primary symptoms of AOE, high signal areas are seen in posterior part of cerebellum with gray and white mater involvement\n\n\nFig. 3 Axial (a) T2 and (b) FLAIR sequences of a 5- year-old boy (patient number 8) , two days after initial presentation of AOE , bilateral symmetric hyperintense areas are seen in basal ganglia (globus pallidus and head of caudate) in keeping with cortical and subcortical hyperintense areas in occipital lobes which has restricted in DWI (c) with low ADC signal (d)\n\n\n\nDOL group\nThe two patients in this group were 47 and 49 years old and had a 9- and 18-day lucid interval, respectively, between the initial presentation and clinical relapse (Table 3). Confluent bilateral symmetrical cerebral white matter signal abnormality with sparing of subcortical U-fibers on T2 and FLAIR sequences were observed in both of these patients (Fig. 4).\nFig. 4 Axial (a) T2 and (b) FLAIR sequences in a 47-year-old male with DOE (patient number 9) above the ventricular level show confluent bilateral symmetrical cerebral white mater hyperintensity with sparing of subcortical U-fibers. Axial (c) DWI and (d) ADC sequences also show T2 shine through phenomenon without any evidence of diffusion restriction\n\n\n\nDiscussion\nMethadone-induced encephalopathy is a rare event. To date, this phenomenon remains poorly characterized [4, 5, 21]. The brain MRI changes reported in the literature are summarized in Table 4 and include: cerebellum abnormalities [1, 4, 10–14], bilateral cerebral white matter abnormalities [4, 5, 11, 12, 14], signal changes in hippocampus [10], globus pallidus [13], and in a single case report in the head of caudate nuclei [4]. In addition, there is a single case report of a 2-year-old infant found to have cerebral white matter, cerebellar, and globus pallidus hypodensities based on computed tomography (CT) scan [22].\nTable 4 Summary of published case reports of AOE\n\nAuthor(s)\tAge/sex\tClinical presentation\tClinical findings in discharge\tLab Data\tTime to imaging\tMRI findings\t\nAnselmo M. Et al (2005) [10]\t3yo, M\tLOC, irregular breathing, low BP\tMild Ataxia\tUrine toxicology: positive for methadone after 36 h\tDay 6\tHigh T2 in cerebellar hemispheres and hippocampus\t\nMills F. Et al (2008) [11]\t3yo, F\tLOC, hard breathing, hypothermia\tSpastic dysplasia and dystonia\tUrine toxicology: positive for methadone\tDay 2\tFLAIR: damage to gray matter and white matter of cerebellum with marked swelling\t\nRiascos R (2008) [12]\t22mo,-\tLOC\tBrain death\tUrine toxicology: positive for methadone, acetaminophen and salicylate\tIn admission day\tDiffuse bilateral cerebellar infarction, absence of central intra cranial blood flow, supra and infra tentorial gray matter thickening\t\nCorré J. Et al (2013) [13]\t29yo, M\tLOC, hypothermia, bradypnea\tGood recovery, except persistent renal failure and kinetic cerebellar syndrome\tBlood analysis was positive for alcohol, cannabis, methadone (146 ng/ml), and benzodiazepines\tAt first day of admission.\tFLAIR and DWI: high in both cerebellar and basal ganglia (globus pallidus)\t\nMetkees M. Et al (2015) [14]\t15yo, F\tLOC, hypothermia, hypercapnia, HTN\tDeath\tDetailed history revealed methadone ingestion of unknown quantity\tNot mentioned\tT2 and DWI: high in white matter of both hemisphere (sparing sub cortical U-fibers and deep gray matter, cortical or cerebellar)\t\nCerase A. Et al (2011) [4]\t49yo, M\tLOC\tComplete recovery after 3 mo.\tSerum toxicology: positive for methadone\tNot mentioned\tT2 and FLAIR: high in white matter of right cerebellum and deep gray and white matter of both cerebral hemispheres.\t\nR.A. Salgado et al. (2009) [5]\t65yo, F\tApathy, a catatonic state with extreme rigidity, reflexes in the upper limbs, and a bilaterally positive Babinski sign\tIn the following month, the patient slowly recovered.\tSerum and urine toxicology shows large amount of methadone\tDay 27\tFLAIR and T2: symmetric signal intensity abnormality in the deep white matter of both cerebral hemisphere with sparing of sub cortical U-fibers without corresponding diffusion restriction\t\nRando J. (2016) [1]\t14yo, M\tHypothermia, HTN, respiratory depression\tAphasia, truncal ataxia\tSerum toxicology: positive for methadone\tIn admission day\tFLAIR: cereberallitis\t\n\n\nIn our AOE patients, the most frequent MRI finding was bilateral confluent or patchy cerebral white matter hyperintensity (n = 5). Cerebellar abnormalities were detected in only three cases despite this was the most common observed abnormality in previous studies [1, 10, 13]. A consistent (n = 4) and new finding in these patients was bilateral parieto-occipital cortex T2 and FLAIR hyperintensity. This radiological finding has also been reported in patients with posterior reversible encephalopathy syndrome (PRES [23];). PRES has been reported as a consequence of or in conjunction with a variety of critical illness states including severe hypertension, hemolytic-uremic syndrome, thrombocytopenic thrombotic purpura, and in association with drug toxicities such as cisplatin, cyclophosphamide, interferon [23–25], and opiates such as morphine [26, 27]. In keeping with the findings in PRES, three of our patients had bilateral parieto-occipital cortex restriction in DWI which was confirmed by ADC sequence. Additionally, restriction was observed in one patient with internal capsule involvement (case 7). Restriction in bilateral cerebral white matter has previously been reported secondary to methadone toxicity [4, 11]. One study suggested that “deep watershed infarct” resulted in the restriction imaging observed [11]. Given our observations and previous published reports, it can be postulated that the changes in AOE due to methadone could result in PRES.\n\nWe also had two patients who had internal capsule involvement. This finding is in accordance with previously published reports as a characteristic of heroin toxicity [28]. In our both patients, morphine and methadone were detected in urine analysis. Therefore, heroin use cannot be ruled out. Additional confirmatory testing for supplementary heroin metabolites would have been useful in these two individuals. However this was not available in our center. One of them (Case 5) demonstrated lesions in splenium of corpus callosum, a finding never reported before in either heroin or methadone intoxication. This finding may be a transient lesion of splenium and has been associated with various clinical conditions such as seizures, metabolic disturbances, infections, CNS malignancy, and drugs and toxins (antidepressants, antiepileptics, antipsychotics, chemotherapy agents, and pesticides) [15, 28–38]. We also had a single patient (case 8) who showed involvement of the globus pallidus and head of caudate nuclei. This finding has been observed in association with methadone toxicity [4, 13]. Previously, brain imaging changes associated with methadone intoxication were suggested to be as a consequence of hypoxic events secondary to overdose [12]. However, hypoxia-associated cerebral adverse effects on imaging seem to be only a result of prolonged hypoxia [39, 40]. Majority of our patients did not have a persistent documented hypoxic insult. Brain neuroimaging was performed on admission, and before the worsening of patient’s condition. Secondly, brain and cerebellar damage demonstrated at both diagnosis and follow-up showed a clear-cut prominent involvement of the subcortical white matter. In adulthood, hypoxic-ischemic insults usually result in watershed zone infarcts when mild to moderate, and affect the gray matter in the basal ganglia, thalami, cerebral cortex, cerebellum, and hippocampi when severe. Furthermore, severe insult generally includes a stage of diffuse cerebral edema with loss of differentiation between gray and white matter, a finding that was not noted in the patients reported. Furthermore, acute and early subacute phases of hypoxia-induced encephalopathy primarily affect the basal ganglia, thalamus, and cortex [41]. We reported bilateral cerebral white matter and cerebellum abnormalities as the most common brain MRI finding.\n\nTo date, only 8 case reports evaluating 11 patients have been published reporting delayed-onset methadone-induced leukoencephalopathy [6, 10, 16–20], summarized in Table 5. The most frequent imaging findings in case reports of patients with DOL is bilateral cerebral white matter T2 and FLAIR hyperintensity [6, 8, 9, 16, 18, 20] followed by corpus callosum [9, 16] and globus pallidus [8] involvement. This is in keeping with our observation of bilateral cerebral white matter hyperintensity. However, the findings in DOL group are not generalizable, as there were only two cases in this group, who also lacked imaging in their acute phase for comparison with the DOL phase imaging. Furthermore, during examination of DWI and ADC, no restriction was found in either case. Four patients have been described with restriction in DWI scans, although a correlation with ADC was not reported in them [9, 17, 18, 20]. It is possible that the restrictions observed in these patients is related to T2 shine through, as this phenomenon has also been observed in our patients.\nTable 5 Summary of published works on DOL\n\nAuthor(s) year\tAge/ Sex\tToxic agent\tTime to relapse after initial intoxication\tClinical presentation in relapse phase\tFirst imaging findings\tDelayed phase MRI findings\tDWI and ADC sequences findings\tPrognosis\t\nLjungar B. et al. 2014 [17]\t34 yr, M\tMethadone\t33 days\tPhysical, psychological and cognitive deterioration\tCerebral white matter T2 hyperintensity\tCystic changes in bilateral cerebral white matter\tHyperintensity in DWI without ADC confirmation\tRecovery\t\nMittal M. et al. 2010 [6]\t38 yr, M\tMethadone, benzodiazepine\t3 weeks\tPhysical, psychological and behavioral manifestations\tNo imaging\tCerebral white matter T2 hyperintensity\tNo restriction\tPartial recovery\t\nArciniegas 2004 [16]\t24 yr, M\tMethadone, diazepam\tNot mentioned\tApathy, disorientation\tNo imaging\tCerebral white matter and corpus callosum T2 hyperintensity\tNot mentioned\tPartial recovery\t\nTorralba A- Moron 2016 [8]\t42 yr, M\tMethadone, alcohol, benzodiazepine\t13 days\tMyoclonus, fluctuated consciousness,\tNormal CT scan\tCerebral white matter and globous pallidus T2 hyperintensity\tNot mentioned\tLack of attention and dysexecutive and amnestic abnormalities persisted\t\n43 yr, M\tMethadone\tNot mentioned\tlow level of consciousness and a bradypnoea\tNot mentioned\tCerebral white matter and globous pallidus T2 hyperintensity\tNot mentioned\tdeath\t\nZanin A. 2010 [19]\t30mo, F\tMethadone\t19 days\tAgitation, slurred speech, abnormal movement\tNormal\tTempromesial, Substantia Nigra and basal ganglia\tNo restriction\tRecovery after 2 month\t\nAndrew Meyer M. 2013 [20]\t43 yr, F\tMethadone, diazepam\t3 weeks\tForgetful& confused, social withdrawal, lack of hygiene\tNo imaging\tCerebral white matter T2 hyperintensity\tHyperintensity in DWI without ADC confirmation\tRecovery\t\nCarroll I. 2012 [9]\t43 yr, F\tAlprazolam, methadone\t33 days\tApathy, inappropriate behavior\tNo imaging\tCerebral white matter and corpus callosum T2 hyperintensity\tCorpus Collosum hyperintensity in DWI without ADC confirmation\tFull recovery after 6 month\t\nShprecher D. 2008 [18]\t39 yr, F\tMethadone, cocaine\t4 weeks\tdisorientation\tNo imaging\tCerebral white matter T2 hyperintensity\tHyperintensity in DWI without ADC confirmation\tPartial recovery\t\n58 yr, F\tmethadone\t21 days\tParanoid and inappropriate behavioral\tNo imaging\tCerebral white matter T2 hyperintensity\tNot mentioned\tPartial recovery\t\n56 yr, F\tMethadone, fentanyl, benzodiazepine\t15 days\tCognitive deterioration\tNot mentioned\tCerebral white matter T2 hyperintensity\tHyperintensity in DWI without ADC confirmation\tPartial recovery\t\n\n\nAlmost all published case reports to date are in adult patients, except for a single case of 30-month-old infant. There are no previous publications on DOL due to other reasons (strangulation, CO poisoning, benzodiazepine overdose, etc.) in adults younger than 30 years [7]. Since both of our patients were also adults, it is possible that DOL is a phenomenon more common among adult patients. DOL has been previously suggested to be due to hypoxia [6, 16]. However, given that neither of our patients had history of prolonged unconsciousness or respiratory depression, hypoxia as an etiology can be excluded. The lucid intervals of one to 5 weeks have been reported in earlier case reports [7], which was reinforced with our cases.\n\nConclusion\nMethadone intoxication can result in a spectrum of encephalopathies ranging from AOE to DOL which can be diagnosed using MRI findings. Future studies on larger sample sizes are required to elucidate this association with its possible imaging findings. Our study is the first to demonstrate that MRI changes due to methadone intoxication can parallel those observed in PRES in both adults and children. Given that both heroin and morphine have been previously reported to present with changes suggestive of PRES, it is reasonable to extrapolate this to be an opioid class effect. In DOL, bilateral T2 and FLAIR white matter hyperintensity was the common finding. Therefore, in patients with a recent history of methadone intoxication who represent with relapsing neurological symptoms, DOL needs to be considered.\n\nAbbreviations\nADCApparent deficient coefficient\n\nAOEAcute-onset encephalopathy\n\nCNSCentral nervous system\n\nCOCarbon monoxide\n\nCTComputed tomography\n\nDOLDelayed-onset leukoencephalopathy\n\nDWIDiffusion weighted imaging\n\nFLAIRFluid-attenuated inversion recovery\n\nLOCLoss of consciousness\n\nMRIMagnetic resonance imaging\n\nPRESPosterior reversible encephalopathy syndrome\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nThis manuscript is based on the thesis of Dr. Naseri.\n\nAuthors’ contributions\nHHM is the guarantor of integrity of the entire study. NZ, MHM and HHM gave the study concepts and designed the study. NJ, MHM, and ZN did the literature research. HHM performed the data analysis. HHM performed the statistical analysis. ZN prepared the manuscript draft and NJ did edit the final manuscript. All co-authors approved final submitted manuscript. All authors read and approved the final manuscript.\n\nFunding\nShahid Beheshti University of Medical Sciences fund this study with no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.\n\nAvailability of data and materials\nAll data generated or analysed during this study are included in this published article.\n\nEthics approval and consent to participate\nThis study was approved by the local ethics committee at Shahid Beheshti University of Medical Sciences (no 14911, IR.SBMU.REC.1397.011). Informed written consent was taken from all participants.\n\nConsent for publication\nNot applicable.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. 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Metkees M Meesa IR Srinivasan A Methadone-induced acute toxic leukoencephalopathy Pediatr Neurol 2015 52 2 256 257 10.1016/j.pediatrneurol.2014.10.021 25433910 \n15. Cho J-S Ha S-W Han Y-S Park S-E Hong K-M Han J-H Mild Encephalopathy with Reversible Lesion in the Splenium of the Corpus Callosum and Bilateral Frontal White Matter J Clin Neurol 2007 3 1 53 10.3988/jcn.2007.3.1.53 19513344 \n16. Arciniegas DB Frey KL Anderson CA Brousseau KM Harris SN Amantadine for neurobehavioural deficits following delayed post-hypoxic encephalopathy Brain Inj 2004 18 12 1309 1318 10.1080/02699050410001720130 15666573 \n17. Bileviciute-Ljungar I Häglund V Carlsson J Von Heijne A Clinical and radiological findings in methadone-induced delayed leukoencephalopathy J Rehabil Med. 2014 46 8 828 830 10.2340/16501977-1820 24909124 \n18. Shprecher DR, Flanigan KM, Smith AG, Smith SM, Schenkenberg T, Ph D, et al. Clinical and Diagnostic Features of Delayed Hypoxic. Low Extrem. 2008;20(4):473–7.\n19. Zanin A Masiero S Severino MS Calderone M Da Dalt L Laverda AM A delayed methadone encephalopathy: Clinical and neuroradiological findings J Child Neurol. 2010 25 6 748 751 10.1177/0883073809343318 19808992 \n20. Meyer MA Delayed post-hypoxic leukoencephalopathy: case report with a review of disease pathophysiology Neurol Int. 2013 5 3 13 10.4081/ni.2013.e13 \n21. Li W Li Q Wang Y Zhu J Ye J Yan X Methadone-induced Damage to White Matter Integrity in Methadone Maintenance Patients: A Longitudinal Self-control DTI Study Sci Rep 2016 6 January 1 8 10.1038/srep19662 28442746 \n22. Hassanian-moghaddam H Zamani N An Overview on Methadone-Intoxicated Patients 2016 525 531 \n23. Hobson EV Craven I Catrin BS Posterior reversible encephalopathy syndrome: A truly treatable neurologic illness Perit Dial Int. 2012 32 6 590 594 10.3747/pdi.2012.00152 23212858 \n24. Al-Sherif AH Posterior Reversible Encephalopathy Syndrome (PRES): Restricted Diffusion does not Necessarily Mean Irreversibility Polish J Radiol. 2015 80 210 216 10.12659/PJR.893460 \n25. Rijkers K An unusual case of posterior reversible encephalopathy syndrome in a patient being weaned from intrathecal morphine Int Med Case Rep J 2016 9 117 120 27274314 \n26. Eran A Barak M Combined General and Spinal Anesthesia with Intrathecal Morphine 2009 609 612 \n27. Lapat KD Yousaf M Joshi TR Heroin-induced toxic leukoencephalopathy Appl Radiol. 2016 45 3 36 37 \n28. Keogh CF Andrews GT Forkheim KE Graeb DA Neuroimaging Features of Heroin Inhalation Toxicity: “Chasing the Dragon” Image (Rochester, NY) 2003 180 3 847 850 \n29. Edwards TJ Sherr EH Barkovich AJ Richards LJ Clinical, Genetic and Imaging Findings Identify New Causes for Corpus Callosum Development Syndromes Brain 2014 137 6 1579 1613 10.1093/brain/awt358 24477430 \n30. Naik K Mali R Kunam S Saroja A ‘Wine Glass’ sign in recurrent postpartum hypernatremic osmotic cerebral demyelination Ann Indian Acad Neurol 2013 16 1 106 10.4103/0972-2327.107719 23661977 \n31. Tada H Takanashi J Barkovich AJ Oba H Maeda M Tsukahara H Clinically mild encephalitis/encephalopathy with a reversible splenial lesion Neurology 2004 63 10 1854 1858 10.1212/01.WNL.0000144274.12174.CB 15557501 \n32. Garg R Malhotra H Sharma P Vidhate M Boomerang sign: Clinical significance of transient lesion in splenium of corpus callosum Ann Indian Acad Neurol 2012 15 2 151 10.4103/0972-2327.95005 22566735 \n33. Vyas S Khandelwal N Singh P Gogoi D Transient splenial lesion: Further experience with two cases Indian J Radiol Imaging 2010 20 4 254 10.4103/0971-3026.73531 21423898 \n34. Maeda M Shiroyama T Tsukahara H Shimono T Aoki S Takeda K Transient splenial lesion of the corpus callosum associated with antiepileptic drugs: evaluation by diffusion-weighted MR imaging Eur Radiol 2003 13 8 1902 1906 10.1007/s00330-002-1679-5 12942292 \n35. Starkey J Kobayashi N Numaguchi Y Moritani T Cytotoxic Lesions of the Corpus Callosum That Show Restricted Diffusion: Mechanisms, Causes, and Manifestations RadioGraphics 2017 37 2 562 576 10.1148/rg.2017160085 28165876 \n36. Hornik A, Rodriguez Porcel FJ, Agha C, Flaster M, Morales Vidal S, Schneck MJ, et al. Central and Extrapontine Myelinolysis Affecting the Brain and Spinal Cord. An Unusual Presentation of Pancreatic Encephalopathy. Front Neurol. 2012;3. Available from:. 10.3389/fneur.2012.00135/abstract.\n37. Loh Y Restricted Diffusion of the Splenium in Acute Wernicke’s Encephalopathy J Neuroimaging 2005 15 4 373 375 10.1177/1051228405279037 16254404 \n38. Kimura K, Fuchigami T, Ishii W, Imai Y, Tanabe S, et al. Mumps-virus-associated clinically mild encephalopathy with a reversible splenial lesion. Int J Clin Pediatr. 2012;1(4-5):124–8.\n39. Weiss N Galanaud D Carpentier A Naccache L Puybasset L Clinical review: Prognostic value of magnetic resonance imaging in acute brain injury and coma Crit Care 2007 11 5 1 12 10.1186/cc6107 \n40. Heinz UE Rollnik JD Outcome and prognosis of hypoxic brain damage patients undergoing neurological early rehabilitation Neurology BMC Res Notes 2015 8 1 1 11 10.1186/s13104-015-1175-z 25645429 \n41. Haaga JR Boll DT CT and MRI of the whole body 1994 6 577 578\n\n", "fulltext_license": "CC BY", "issn_linking": "1471-2342", "issue": "20(1)", "journal": "BMC medical imaging", "keywords": "Acute encephalopathy; Delayed leukoencephalopathy; Magnetic resonance imaging; Methadone", "medline_ta": "BMC Med Imaging", "mesh_terms": "D000293:Adolescent; D000328:Adult; D001927:Brain Diseases; D002648:Child; D002675:Child, Preschool; D038524:Diffusion Magnetic Resonance Imaging; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D008691:Methadone; D011857:Radiographic Image Interpretation, Computer-Assisted; D012189:Retrospective Studies; D066127:White Matter; D055815:Young Adult", "nlm_unique_id": "100968553", "other_id": null, "pages": "6", "pmc": null, "pmid": "31952488", "pubdate": "2020-01-17", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review", "references": "26794650;15378662;26081628;12591709;23661977;24909124;20977538;24147210;22566735;19892815;23060853;17980050;16970857;24477430;12942292;21423898;17541658;19808992;22341930;26357591;26164407;25960819;19151296;17952429;23212858;27274314;21209817;16254404;15557501;28165876;25433910;23762729;19196933;15666573;19513344;25197273", "title": "Methadone-induced encephalopathy: a case series and literature review.", "title_normalized": "methadone induced encephalopathy a case series and literature review" }

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AL. METHADONE-INDUCED ENCEPHALOPATHY: A CASE SERIES AND LITERATURE REVIEW. HAGHIGHI-MORAD ET AL. BMC MEDICAL IMAGING. 2020?20:6:UNK", "literaturereference_normalized": "methadone induced encephalopathy a case series and literature review", "qualification": "3", "reportercountry": "IR" }, "primarysourcecountry": "US", "receiptdate": "20200211", "receivedate": "20200211", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17400357, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "IR-ELITE LABORATORIES INC.-2020ELT00007", "fulfillexpeditecriteria": "1", "occurcountry": "IR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHADONE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "210484", "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": "METHADONE" } ], "patientagegroup": null, "patientonsetage": "32", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Encephalopathy", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HAGHIGHI-MORAD M, NASERI Z, JAMSHIDI N, HASSANIAN-MOGHADDAM H, ZAMANI N, AHMAD-MOLAEI L. METHADONE-INDUCED ENCEPHALOPATHY: A CASE SERIES AND LITERATURE REVIEW. BMC MED IMAGING. 2020?20(1):6", "literaturereference_normalized": "methadone induced encephalopathy a case series and literature review", "qualification": "3", "reportercountry": "IR" }, "primarysourcecountry": "IR", "receiptdate": "20200207", "receivedate": "20200207", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17389227, "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": "IR-VISTAPHARM, INC.-VER202002-000296", "fulfillexpeditecriteria": "1", "occurcountry": "IR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHADONE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "040088", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "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": "METHADONE" } ], "patientagegroup": null, "patientonsetage": "33", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Encephalopathy", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HASSANIAN-MOGHADDAM H, HAGHIGHI-MORAD M, NASERI Z, JAMSHIDI N, ZAMANI N, AHMAD-MOLAEI L. METHADONE-INDUCED ENCEPHALOPATHY: A CASE SERIES AND LITERATURE REVIEW. BMC MED IMAGING. 2020?20(6):1-9.", "literaturereference_normalized": "methadone induced encephalopathy a case series and literature review", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "IR", "receiptdate": "20200215", "receivedate": "20200215", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17422757, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "SE-ALKEM LABORATORIES LIMITED-SE-ALKEM-2020-00230", "fulfillexpeditecriteria": "1", "occurcountry": "SE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHADONE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "090635", "drugbatchnumb": "UNKNOWN", "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": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHADONE HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": "34", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Leukoencephalopathy", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HAGHIGHI-MORAD M, NASERI Z, JAMSHIDI N, HASSANIAN-MOGHADDAM H, ET. AL. METHADONE-INDUCED ENCEPHALOPATHY: A CASE SERIES AND LITERATURE REVIEW. HAGHIGHI-MORAD ET AL. BMC MEDICAL IMAGING. 2019?20:6:UNK", "literaturereference_normalized": "methadone induced encephalopathy a case series and literature review", "qualification": "3", "reportercountry": "IR" }, "primarysourcecountry": "SE", "receiptdate": "20200211", "receivedate": "20200211", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17400627, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2020-00234", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DIAZEPAM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "SUICIDE ATTEMPT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DIAZEPAM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHADONE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "090635", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "SUICIDE ATTEMPT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHADONE HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": "43", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Leukoencephalopathy", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Leukocytosis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pneumonia aspiration", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "HAGHIGHI-MORAD M, NASERI Z, JAMSHIDI N, HASSANIAN-MOGHADDAM H ET AL.. METHADONE-INDUCED ENCEPHALOPATHY: A CASE SERIES AND LITERATURE REVIEW. BMC MEDICAL IMAGING. 2020?20(1):UNK", "literaturereference_normalized": "methadone induced encephalopathy a case series and literature review", "qualification": "3", "reportercountry": "IR" }, "primarysourcecountry": "US", "receiptdate": "20200211", "receivedate": "20200211", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17400358, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "IR-ELITE LABORATORIES INC.-2020ELT00003", "fulfillexpeditecriteria": "1", "occurcountry": "IR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHADONE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "210484", "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": "METHADONE" } ], "patientagegroup": null, "patientonsetage": "16", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Encephalopathy", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HAGHIGHI-MORAD M, NASERI Z, JAMSHIDI N, HASSANIAN-MOGHADDAM H, ZAMANI N, AHMAD-MOLAEI L.. METHADONE-INDUCED ENCEPHALOPATHY: A CASE SERIES AND LITERATURE REVIEW.. BMC MED IMAGING.. 2020?20(1):6", "literaturereference_normalized": "methadone induced encephalopathy a case series and literature review", "qualification": "3", "reportercountry": "IR" }, "primarysourcecountry": "IR", "receiptdate": "20200207", "receivedate": "20200207", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17389228, "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": "IR-EPIC PHARMA LLC-2020EPC00044", "fulfillexpeditecriteria": "1", "occurcountry": "IR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHADONE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "090065", "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": "METHADONE" } ], "patientagegroup": null, "patientonsetage": "16", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Encephalopathy", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HAGHIGHI-MORAD M, NASERI Z, JAMSHIDI N, HASSANIAN-MOGHADDAM H, ZAMANI N, AHMAD-MOLAEI L.. METHADONE-INDUCED ENCEPHALOPATHY: A CASE SERIES AND LITERATURE REVIEW. BMC MED IMAGING. 2020?20(1):6", "literaturereference_normalized": "methadone induced encephalopathy a case series and literature review", "qualification": "3", "reportercountry": "IR" }, "primarysourcecountry": "IR", "receiptdate": "20200210", "receivedate": "20200210", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17397858, "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": "IR-VISTAPHARM, INC.-VER202002-000297", "fulfillexpeditecriteria": "1", "occurcountry": "IR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHADONE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "040088", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "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": "METHADONE" } ], "patientagegroup": null, "patientonsetage": "5", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Encephalopathy", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HAGHIGHI-MORAD M, NASERI Z, JAMSHIDI N, HASSANIAN-MOGHADDAM H, ZAMANI N, AHMAD-MOLAEI L. METHADONE-INDUCED ENCEPHALOPATHY: A CASE SERIES AND LITERATURE REVIEW. BMC MED IMAGING. 2020 JAN 17?20(6):1-9.", "literaturereference_normalized": "methadone induced encephalopathy a case series and literature review", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "IR", "receiptdate": "20200215", "receivedate": "20200215", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17422758, "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": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2020-00231", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "COCAINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "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": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "COCAINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHADONE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "090635", "drugbatchnumb": "UNKNOWN", "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": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHADONE HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": "39", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pneumonia aspiration", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Leukoencephalopathy", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HAGHIGHI-MORAD M, NASERI Z, JAMSHIDI N, HASSANIAN-MOGHADDAM H, ET. AL. METHADONE-INDUCED ENCEPHALOPATHY: A CASE SERIES AND LITERATURE REVIEW. HAGHIGHI-MORAD ET AL. BMC MEDICAL IMAGING. 2020?20:6:UNK", "literaturereference_normalized": "methadone induced encephalopathy a case series and literature review", "qualification": "3", "reportercountry": "IR" }, "primarysourcecountry": "US", "receiptdate": "20200211", "receivedate": "20200211", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17400356, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "IR-VISTAPHARM, INC.-VER202002-000295", "fulfillexpeditecriteria": "1", "occurcountry": "IR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHADONE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "040088", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "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": "METHADONE" } ], "patientagegroup": null, "patientonsetage": "32", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Encephalopathy", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HASSANIAN-MOGHADDAM H, HAGHIGHI-MORAD M, NASERI Z, JAMSHIDI N, ZAMANI N, AHMAD-MOLAEI L. METHADONE-INDUCED ENCEPHALOPATHY: A CASE SERIES AND LITERATURE REVIEW. BMC MED IMAGING. 2020?20(6):1-9.", "literaturereference_normalized": "methadone induced encephalopathy a case series and literature review", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "IR", "receiptdate": "20200215", "receivedate": "20200215", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17422756, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "IR-EPIC PHARMA LLC-2020EPC00048", "fulfillexpeditecriteria": "1", "occurcountry": "IR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHADONE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "090065", "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": "METHADONE" } ], "patientagegroup": null, "patientonsetage": "32", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Encephalopathy", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HAGHIGHI-MORAD M, NASERI Z, JAMSHIDI N, HASSANIAN-MOGHADDAM H, ZAMANI N, AHMAD-MOLAEI L. METHADONE-INDUCED ENCEPHALOPATHY: A CASE SERIES AND LITERATURE REVIEW. BMC MED IMAGING. 2020?20(1):6", "literaturereference_normalized": "methadone induced encephalopathy a case series and literature review", "qualification": "3", "reportercountry": "IR" }, "primarysourcecountry": "IR", "receiptdate": "20200210", "receivedate": "20200210", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17397856, "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": "IR-VISTAPHARM, INC.-VER202002-000298", "fulfillexpeditecriteria": "1", "occurcountry": "IR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHADONE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "040088", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "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": "METHADONE" } ], "patientagegroup": null, "patientonsetage": "47", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Leukoencephalopathy", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HASSANIAN-MOGHADDAM H, NASERI Z, JAMSHIDI N, HAGHIGHI-MORAD M, ZAMANI N, AHMAD-MOLAEI L. METHADONE-INDUCED ENCEPHALOPATHY: A CASE SERIES AND LITERATURE REVIEW. BMC MED IMAGING. 2020?20(6):1-9.", "literaturereference_normalized": "methadone induced encephalopathy a case series and literature review", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "IR", "receiptdate": "20200215", "receivedate": "20200215", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17422759, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "IR-ELITE LABORATORIES INC.-2020ELT00004", "fulfillexpeditecriteria": "1", "occurcountry": "IR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHADONE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "210484", "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": "METHADONE" } ], "patientagegroup": null, "patientonsetage": "23", "patientonsetageunit": "802", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Encephalopathy", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HAGHIGHI-MORAD M, NASERI Z, JAMSHIDI N, HASSANIAN-MOGHADDAM H, ZAMANI N, AHMAD-MOLAEI L.. METHADONE-INDUCED ENCEPHALOPATHY: A CASE SERIES AND LITERATURE REVIEW.. BMC MED IMAGING.. 2020?20(1):6", "literaturereference_normalized": "methadone induced encephalopathy a case series and literature review", "qualification": "3", "reportercountry": "IR" }, "primarysourcecountry": "IR", "receiptdate": "20200207", "receivedate": "20200207", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17389229, "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": "IR-EPIC PHARMA LLC-2020EPC00050", "fulfillexpeditecriteria": "1", "occurcountry": "IR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHADONE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "090065", "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": "METHADONE" } ], "patientagegroup": null, "patientonsetage": "5", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Encephalopathy", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HAGHIGHI-MORAD M, NASERI Z, JAMSHIDI N, HASSANIAN-MOGHADDAM H, ZAMANI N, AHMAD-MOLAEI L.. METHADONE-INDUCED ENCEPHALOPATHY: A CASE SERIES AND LITERATURE REVIEW. BMC MED IMAGING. 2020?20(1):6", "literaturereference_normalized": "methadone induced encephalopathy a case series and literature review", "qualification": "3", "reportercountry": "IR" }, "primarysourcecountry": "IR", "receiptdate": "20200210", "receivedate": "20200210", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17397859, "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": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2020-00233", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHADONE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "090635", "drugbatchnumb": "UNKNOWN", "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": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHADONE HYDROCHLORIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FENTANYL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "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": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FENTANYL." } ], "patientagegroup": null, "patientonsetage": "56", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Intentional overdose", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rhabdomyolysis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Leukoencephalopathy", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HAGHIGHI-MORAD M, NASERI Z, JAMSHIDI N, HASSANIAN-MOGHADDAM H, ET.AL. METHADONE-INDUCED ENCEPHALOPATHY: A CASE SERIES AND LITERATURE REVIEW. BMC MEDICAL IMAGING. 2020?20:6", "literaturereference_normalized": "methadone induced encephalopathy a case series and literature review", "qualification": "3", "reportercountry": "IR" }, "primarysourcecountry": "US", "receiptdate": "20200211", "receivedate": "20200211", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17400359, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "IR-EPIC PHARMA LLC-2020EPC00046", "fulfillexpeditecriteria": "1", "occurcountry": "IR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHADONE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "090065", "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": "METHADONE" } ], "patientagegroup": null, "patientonsetage": "30", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Encephalopathy", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HAGHIGHI-MORAD M, NASERI Z, JAMSHIDI N, HASSANIAN-MOGHADDAM H, ZAMANI N, AHMAD-MOLAEI L. METHADONE-INDUCED ENCEPHALOPATHY: A CASE SERIES AND LITERATURE REVIEW. BMC MED IMAGING. 2020?20(1):6", "literaturereference_normalized": "methadone induced encephalopathy a case series and literature review", "qualification": "3", "reportercountry": "IR" }, "primarysourcecountry": "IR", "receiptdate": "20200210", "receivedate": "20200210", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17397862, "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": "IR-ELITE LABORATORIES INC.-2020ELT00011", "fulfillexpeditecriteria": "1", "occurcountry": "IR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHADONE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "210484", "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": "METHADONE" } ], "patientagegroup": null, "patientonsetage": "49", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Leukoencephalopathy", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HAGHIGHI-MORAD M, NASERI Z, JAMSHIDI N, HASSANIAN-MOGHADDAM H, ZAMANI N, AHMAD-MOLAEI L. METHADONE-INDUCED ENCEPHALOPATHY: A CASE SERIES AND LITERATURE REVIEW. BMC MED IMAGING. 2020?20(1):6", "literaturereference_normalized": "methadone induced encephalopathy a case series and literature review", "qualification": "3", "reportercountry": "IR" }, "primarysourcecountry": "IR", "receiptdate": "20200207", "receivedate": "20200207", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17389222, "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": "IR-VISTAPHARM, INC.-VER202002-000291", "fulfillexpeditecriteria": "1", "occurcountry": "IR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHADONE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "040088", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "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": "METHADONE" } ], "patientagegroup": null, "patientonsetage": "16", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Encephalopathy", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HASSANIAN-MOGHADDAM H, HAGHIGHI-MORAD M, NASERI Z, JAMSHIDI N, ZAMANI N, AHMAD-MOLAEI L. METHADONE-INDUCED ENCEPHALOPATHY: A CASE SERIES AND LITERATURE REVIEW. BMC MED IMAGING. 2020?20(6):1-9.", "literaturereference_normalized": "methadone induced encephalopathy a case series and literature review", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "IR", "receiptdate": "20200215", "receivedate": "20200215", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17422752, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "IR-VISTAPHARM, INC.-VER202002-000299", "fulfillexpeditecriteria": "1", "occurcountry": "IR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHADONE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "040088", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "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": "METHADONE" } ], "patientagegroup": null, "patientonsetage": "49", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Leukoencephalopathy", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HASSANIAN-MOGHADDAM H, HAGHIGHI-MORAD M, NASERI Z, JAMSHIDI N, ZAMANI N, AHMAD-MOLAEI L. METHADONE-INDUCED ENCEPHALOPATHY: A CASE SERIES AND LITERATURE REVIEW. BMC MED IMAGING. 2020?20(9):1-9.", "literaturereference_normalized": "methadone induced encephalopathy a case series and literature review", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "IR", "receiptdate": "20200215", "receivedate": "20200215", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17422760, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "IR-EPIC PHARMA LLC-2020EPC00051", "fulfillexpeditecriteria": "1", "occurcountry": "IR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHADONE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "090065", "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": "METHADONE" } ], "patientagegroup": null, "patientonsetage": "47", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Leukoencephalopathy", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HAGHIGHI-MORAD M, NASERI Z, JAMSHIDI N, HASSANIAN-MOGHADDAM H, ZAMANI N, AHMAD-MOLAEI L. METHADONE-INDUCED ENCEPHALOPATHY: A CASE SERIES AND LITERATURE REVIEW. BMC MED IMAGING. 2020?20(1):6", "literaturereference_normalized": "methadone induced encephalopathy a case series and literature review", "qualification": "3", "reportercountry": "IR" }, "primarysourcecountry": "IR", "receiptdate": "20200210", "receivedate": "20200210", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17397860, "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": "IR-ELITE LABORATORIES INC.-2020ELT00008", "fulfillexpeditecriteria": "1", "occurcountry": "IR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHADONE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "210484", "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": "METHADONE" } ], "patientagegroup": null, "patientonsetage": "33", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Encephalopathy", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HAGHIGHI-MORAD M, NASERI Z, JAMSHIDI N, HASSANIAN-MOGHADDAM H, ZAMANI N, AHMAD-MOLAEI L. METHADONE-INDUCED ENCEPHALOPATHY: A CASE SERIES AND LITERATURE REVIEW. BMC MED IMAGING. 2020?20(1):6", "literaturereference_normalized": "methadone induced encephalopathy a case series and literature review", "qualification": "3", "reportercountry": "IR" }, "primarysourcecountry": "IR", "receiptdate": "20200207", "receivedate": "20200207", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17389230, "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": "IR-VISTAPHARM, INC.-VER202002-000294", "fulfillexpeditecriteria": "1", "occurcountry": "IR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHADONE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "040088", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "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": "METHADONE" } ], "patientagegroup": null, "patientonsetage": "31", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Encephalopathy", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HASSANIAN-MOGHADDAM H, NASERI Z, JAMSHIDI N, HAGHIGHI-MORAD M, ZAMANI N, AHMAD-MOLAEI L. METHADONE-INDUCED ENCEPHALOPATHY: A CASE SERIES AND LITERATURE REVIEW. BMC MED IMAGING. 2020 JAN 17?20(6):1-9.", "literaturereference_normalized": "methadone induced encephalopathy a case series and literature review", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "IR", "receiptdate": "20200215", "receivedate": "20200215", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17422755, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "IR-ELITE LABORATORIES INC.-2020ELT00006", "fulfillexpeditecriteria": "1", "occurcountry": "IR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHADONE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "210484", "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": "METHADONE" } ], "patientagegroup": null, "patientonsetage": "31", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Encephalopathy", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HAGHIGHI-MORAD M, NASERI Z, JAMSHIDI N, HASSANIAN-MOGHADDAM H, ZAMANI N, AHMAD-MOLAEI L.. METHADONE-INDUCED ENCEPHALOPATHY: A CASE SERIES AND LITERATURE REVIEW. BMC MED IMAGING.. 2020?20(1):6", "literaturereference_normalized": "methadone induced encephalopathy a case series and literature review", "qualification": "3", "reportercountry": "IR" }, "primarysourcecountry": "IR", "receiptdate": "20200207", "receivedate": "20200207", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17389225, "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": "IR-EPIC PHARMA LLC-2020EPC00045", "fulfillexpeditecriteria": "1", "occurcountry": "IR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHADONE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "090065", "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": "METHADONE" } ], "patientagegroup": null, "patientonsetage": "23", "patientonsetageunit": "802", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Encephalopathy", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HAGHIGHI-MORAD M, NASERI Z, JAMSHIDI N, HASSANIAN-MOGHADDAM H, ZAMANI N, AHMAD-MOLAEI L.. METHADONE-INDUCED ENCEPHALOPATHY: A CASE SERIES AND LITERATURE REVIEW. BMC MED IMAGING. 2020?20(1):6", "literaturereference_normalized": "methadone induced encephalopathy a case series and literature review", "qualification": "3", "reportercountry": "IR" }, "primarysourcecountry": "IR", "receiptdate": "20200210", "receivedate": "20200210", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17397855, "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": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2020-00229", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DIAZEPAM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "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": "DIAZEPAM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHADONE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "090635", "drugbatchnumb": "UNKNOWN", "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": "METHADONE HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": "24", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypoxic-ischaemic encephalopathy", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Accidental overdose", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HAGHIGHI-MORAD M, NASERI Z, JAMSHIDI N, HASSANIAN-MOGHADDAM H ET AL.. METHADONE-INDUCED ENCEPHALOPATHY: A CASE SERIES AND LITERATURE REVIEW. BMC MEDICAL IMAGING. 2020?20:6", "literaturereference_normalized": "methadone induced encephalopathy a case series and literature review", "qualification": "3", "reportercountry": "IR" }, "primarysourcecountry": "US", "receiptdate": "20200211", "receivedate": "20200211", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17400355, "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": "IR-ELITE LABORATORIES INC.-2020ELT00009", "fulfillexpeditecriteria": "1", "occurcountry": "IR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHADONE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "210484", "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": "METHADONE" } ], "patientagegroup": null, "patientonsetage": "5", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Encephalopathy", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HAGHIGHI-MORAD M, NASERI Z, JAMSHIDI N, HASSANIAN-MOGHADDAM H, ZAMANI N, AHMAD-MOLAEI L.. METHADONE-INDUCED ENCEPHALOPATHY: A CASE SERIES AND LITERATURE REVIEW. BMC MED IMAGING. 2020?20(1):6", "literaturereference_normalized": "methadone induced encephalopathy a case series and literature review", "qualification": "3", "reportercountry": "IR" }, "primarysourcecountry": "IR", "receiptdate": "20200207", "receivedate": "20200207", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17389231, "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": "IR-EPIC PHARMA LLC-2020EPC00043", "fulfillexpeditecriteria": "1", "occurcountry": "IR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHADONE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "090065", "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": "METHADONE" } ], "patientagegroup": null, "patientonsetage": "13", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Encephalopathy", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HAGHIGHI-MORAD M, NASERI Z, JAMSHIDI N, HASSANIAN-MOGHADDAM H, ZAMANI N, AHMAD-MOLAEI L. METHADONE-INDUCED ENCEPHALOPATHY: A CASE SERIES AND LITERATURE REVIEW. BMC MED IMAGING. 2020?20(1):6", "literaturereference_normalized": "methadone induced encephalopathy a case series and literature review", "qualification": "3", "reportercountry": "IR" }, "primarysourcecountry": "IR", "receiptdate": "20200210", "receivedate": "20200210", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17397861, "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": "IR-VISTAPHARM, INC.-VER202002-000290", "fulfillexpeditecriteria": "1", "occurcountry": "IR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHADONE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "040088", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "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": "METHADONE" } ], "patientagegroup": null, "patientonsetage": "13", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Encephalopathy", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HASSANIAN-MOGHADDAM H, NASERI Z, JAMSHIDI N, MARYAM H, ZAMANI N, AHMAD-MOLAEI L. METHADONE-INDUCED ENCEPHALOPATHY: A CASE SERIES AND LITERATURE REVIEW. 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METHADONE-INDUCED ENCEPHALOPATHY: A CASE SERIES AND LITERATURE REVIEW. 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METHADONE-INDUCED ENCEPHALOPATHY: A CASE SERIES AND LITERATURE REVIEW. BMC MED IMAGING. 2020?20(6):1-9. DOI:HTTPS://DOI.ORG/10.1186/S12880-020-0410-9", "literaturereference_normalized": "methadone induced encephalopathy a case series and literature review", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "IR", "receiptdate": "20200215", "receivedate": "20200215", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17422753, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "IR-EPIC PHARMA LLC-2020EPC00049", "fulfillexpeditecriteria": "1", "occurcountry": "IR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHADONE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "090065", "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": "METHADONE" } ], "patientagegroup": null, "patientonsetage": "33", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Encephalopathy", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HAGHIGHI-MORAD M, NASERI Z, JAMSHIDI N, HASSANIAN-MOGHADDAM H, ZAMANI N, AHMAD-MOLAEI L.. METHADONE-INDUCED ENCEPHALOPATHY: A CASE SERIES AND LITERATURE REVIEW. 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{ "abstract": "BACKGROUND\nWhereas laboratory data and clinical experience suggest that metabolic acidosis deleteriously affects certain cardiovascular functions and may contribute to hemodynamic compromise, treatment of acidemia itself with alkalinization therapy, predominantly in the form of bolus dosing of intravenous sodium bicarbonate, has not been shown to improve hemodynamics or patient-oriented outcomes in clinical trials. Detailed examination of the biochemical effects of standard sodium bicarbonate administration reveals a possible explanation: ionized serum hypocalcemia, serum hypercarbia, and a paradoxical decrease in intracellular pH occur when bicarbonate is given alone and rapidly, without adjustment in minute ventilation or calcium supplementation. \"Adapted alkalinization\" treatment countering these side effects through hyperventilation, calcium supplementation, and slower sodium bicarbonate infusion has been studied in animals, but not yet described in humans.\n\n\nMETHODS\nWe report a case of successful treatment of severe hemodynamic instability and vasopressor hyporesponsiveness in the setting of profound metabolic acidosis with such an adapted alkalinization approach, plus short-term continuous renal replacement therapy, in a critically ill patient, all performed in the emergency department. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Emergency physicians encounter patients with severe metabolic acidosis, shock, and hemodynamic instability despite vasopressor agents. Adapted alkalinization therapy with sodium bicarbonate, hyperventilation, and calcium administration may promote hemodynamic stability in such patients and allow for successful treatment of the underlying disease process.", "affiliations": "Department of Emergency Medicine, Einstein Healthcare Network, Einstein Medical Center Philadelphia, Philadelphia, Pennsylvania.;Department of Emergency Medicine, Einstein Healthcare Network, Einstein Medical Center Philadelphia, Philadelphia, Pennsylvania.", "authors": "Drumheller|Byron C|BC|;Sabolick|Erin E|EE|", "chemical_list": "D014662:Vasoconstrictor Agents; D017693:Sodium Bicarbonate", "country": "United States", "delete": false, "doi": "10.1016/j.jemermed.2020.09.022", "fulltext": null, "fulltext_license": null, "issn_linking": "0736-4679", "issue": "60(1)", "journal": "The Journal of emergency medicine", "keywords": "acidosis; catecholamines; renal replacement therapy; shock; sodium bicarbonate", "medline_ta": "J Emerg Med", "mesh_terms": "D000138:Acidosis; D000818:Animals; D000079664:Continuous Renal Replacement Therapy; D004636:Emergency Service, Hospital; D006439:Hemodynamics; D006801:Humans; D006863:Hydrogen-Ion Concentration; D017693:Sodium Bicarbonate; D014662:Vasoconstrictor Agents", "nlm_unique_id": "8412174", "other_id": null, "pages": "67-72", "pmc": null, "pmid": "33875156", "pubdate": "2021-01", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Hemodynamic Instability and Abnormal Vasopressor Responsiveness in the Setting of Severe Metabolic Acidosis Treated With Adapted Alkalinization and Continuous Renal Replacement Therapy in the Emergency Department.", "title_normalized": "hemodynamic instability and abnormal vasopressor responsiveness in the setting of severe metabolic acidosis treated with adapted alkalinization and continuous renal replacement therapy in the emergency department" }

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{ "abstract": "The dipeptidyl peptidase-4 inhibitor (DPP-4i) alogliptin is an oral, antidiabetic treatment that is approved in many countries to treat patients with type 2 diabetes mellitus (T2DM), including the USA, Europe, and Japan. Alogliptin is efficacious both as monotherapy and as add-on/combination therapy with other commonly prescribed T2DM treatments, such as metformin and pioglitazone. Overall, alogliptin is well-tolerated in patients with T2DM, including older patients, those with renal and/or hepatic impairment, and those at high risk of cardiovascular events. There is a low risk of hypoglycemia, weight gain, acute pancreatitis, and gastrointestinal adverse events with alogliptin treatment, as demonstrated in long-term trials (lasting up to 4.5 years) and in a real-world setting. Additionally, alogliptin has a generally favorable or similar safety profile in comparison to other antidiabetic agents (metformin, thiazolidinediones, sulfonylureas, glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter 2 inhibitors, α-glucosidase inhibitors, and insulin). However, further evaluation would be required to determine the mechanism and effect of alogliptin on heart failure, bullous pemphigoid, and inflammatory bowel disease. Of note, due to the ethnic diversity in the epidemiology of T2DM, alogliptin has been shown to be more efficacious in Asian patients than in non-Asian patients with T2DM, but with a similar tolerability profile. These data indicate that DPP-4is, including alogliptin, are important treatment options, especially for Asian patients with T2DM, for whom they have potential as a first-line therapy. This benefit-risk assessment aims to place alogliptin within the current armamentarium of T2DM and aid physicians when choosing optimal diabetes treatment for their patients.", "affiliations": "Department of Medicine, Kawasaki Medical School, 577 Matsushima, Okayama, 701-0192, Japan. kka@med.kawasaki-m.ac.jp.;Japan Medical Office, Takeda Pharmaceutical Company Limited, 1-1, Doshomachi 4-chome, Chuo-ku, Osaka, 540-8645, Japan.;Global Patient Safety Evaluation Japan, Pharmacovigilance Department, Takeda Pharmaceutical Company Limited, 1-1, Doshomachi 4-chome, Chuo-ku, Osaka, 540-8645, Japan.;Global Patient Safety Evaluation Japan, Pharmacovigilance Department, Takeda Pharmaceutical Company Limited, 1-1, Doshomachi 4-chome, Chuo-ku, Osaka, 540-8645, Japan.", "authors": "Kaku|Kohei|K|http://orcid.org/0000-0003-1574-0565;Kisanuki|Koichi|K|;Shibata|Mari|M|;Oohira|Takashi|T|", "chemical_list": "D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D004177:Dipyrone", "country": "New Zealand", "delete": false, "doi": "10.1007/s40264-019-00857-8", "fulltext": "\n==== Front\nDrug SafDrug SafDrug Safety0114-59161179-1942Springer International Publishing Cham 85710.1007/s40264-019-00857-8Review ArticleBenefit-Risk Assessment of Alogliptin for the Treatment of Type 2 Diabetes Mellitus http://orcid.org/0000-0003-1574-0565Kaku Kohei +81-462-1111kka@med.kawasaki-m.ac.jp 1Kisanuki Koichi 2Shibata Mari 3Oohira Takashi 31 grid.415086.e0000 0001 1014 2000Department of Medicine, Kawasaki Medical School, 577 Matsushima, Okayama, 701-0192 Japan 2 grid.419841.10000 0001 0673 6017Japan Medical Office, Takeda Pharmaceutical Company Limited, 1-1, Doshomachi 4-chome, Chuo-ku, Osaka, 540-8645 Japan 3 grid.419841.10000 0001 0673 6017Global Patient Safety Evaluation Japan, Pharmacovigilance Department, Takeda Pharmaceutical Company Limited, 1-1, Doshomachi 4-chome, Chuo-ku, Osaka, 540-8645 Japan 25 10 2019 25 10 2019 2019 42 11 1311 1327 © The Author(s) 2019Open Access This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial 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 dipeptidyl peptidase-4 inhibitor (DPP-4i) alogliptin is an oral, antidiabetic treatment that is approved in many countries to treat patients with type 2 diabetes mellitus (T2DM), including the USA, Europe, and Japan. Alogliptin is efficacious both as monotherapy and as add-on/combination therapy with other commonly prescribed T2DM treatments, such as metformin and pioglitazone. Overall, alogliptin is well-tolerated in patients with T2DM, including older patients, those with renal and/or hepatic impairment, and those at high risk of cardiovascular events. There is a low risk of hypoglycemia, weight gain, acute pancreatitis, and gastrointestinal adverse events with alogliptin treatment, as demonstrated in long-term trials (lasting up to 4.5 years) and in a real-world setting. Additionally, alogliptin has a generally favorable or similar safety profile in comparison to other antidiabetic agents (metformin, thiazolidinediones, sulfonylureas, glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter 2 inhibitors, α-glucosidase inhibitors, and insulin). However, further evaluation would be required to determine the mechanism and effect of alogliptin on heart failure, bullous pemphigoid, and inflammatory bowel disease. Of note, due to the ethnic diversity in the epidemiology of T2DM, alogliptin has been shown to be more efficacious in Asian patients than in non-Asian patients with T2DM, but with a similar tolerability profile. These data indicate that DPP-4is, including alogliptin, are important treatment options, especially for Asian patients with T2DM, for whom they have potential as a first-line therapy. This benefit-risk assessment aims to place alogliptin within the current armamentarium of T2DM and aid physicians when choosing optimal diabetes treatment for their patients.\n\nElectronic supplementary material\nThe online version of this article (10.1007/s40264-019-00857-8) contains supplementary material, which is available to authorized users.\n\nhttp://dx.doi.org/10.13039/100008373Takeda Pharmaceutical Companyissue-copyright-statement© Springer Nature Switzerland AG 2019\n==== Body\nKey Points\n\nAlogliptin is an efficacious, oral, dipeptidyl peptidase-4 inhibitor (DPP-4i) for the treatment of type 2 diabetes mellitus (T2DM), which may be used alone or as add-on/combination therapy.\t\nAlogliptin is generally safe, with a low risk of hypoglycemia, weight gain, acute pancreatitis, and gastrointestinal adverse events; however, caution is required when treating patients with renal and/or hepatic impairment.\t\nAlogliptin and other DPP-4is are prominent treatment options, especially in Asia, as they have demonstrated higher efficacy in Asian compared with non-Asian T2DM patients, without compromising safety.\t\n\n\n\nIntroduction\nAlogliptin is an oral, dipeptidyl peptidase-4 inhibitor (DPP-4i), which has been extensively studied in phase II/III studies in patients with type 2 diabetes mellitus (T2DM) [1–19]. In clinical [1–22] and real-world settings [23–25], alogliptin has been generally well-tolerated and has demonstrated a reduction in hemoglobin A1c (HbA1c) when administered alone or as add-on/combination therapy with other antidiabetic agents [1–22, 24, 25].\n\nAlogliptin was first approved to treat T2DM in 2010 in Japan, and subsequently in the USA and EU in 2013 [26–28]. The recommended dose of alogliptin as monotherapy is 25 mg in the USA and Japan; it is not approved as monotherapy but as a 25-mg add-on therapy in the EU [26–28]. Fixed-dose combinations (FDCs) of alogliptin + metformin and alogliptin + pioglitazone are also approved in Japan, the USA, and the EU [29–34]. The alogliptin + metformin FDC treatment is available as twice-daily (BID) 12.5 mg alogliptin with 500- or 1000-mg metformin tablets (USA), as BID 12.5 mg alogliptin with 850- or 1000-mg metformin tablets (EU), and as once-daily 25 mg alogliptin with 500 mg metformin (Japan) [29, 30, 32]. Alogliptin + pioglitazone FDC therapy is available as 12.5 or 25 mg alogliptin with 15-, 30-, or 45-mg pioglitazone doses [31, 33, 34].\n\nAlogliptin is primarily excreted unchanged via renal clearance [35]. As such, reports suggest that exposure to alogliptin increases with decreasing glomerular filtration rate (GFR) [36, 37]. Thus, to maintain similar systemic exposure, dose adjustments for alogliptin are not required for patients with mild renal impairment (creatinine clearance [CrCl] ≥ 60 to < 90 mL/min [US definition] or ≥ 50 to ≤ 80 mL/min [EU definition]). However, in patients with moderate renal impairment (CrCl ≥ 30 to < 60 mL/min [US] or ≥ 30 to ≤ 50 mL/min [EU]) [27, 28], the recommended daily dose is 12.5 mg, and in patients with severe chronic kidney disease (CKD) (CrCl ≥ 15 to < 30 mL/min) [27] or end-stage renal disease (ESRD) (CrCl < 15 mL/min), it is 6.25 mg. In patients with CKD receiving hemodialysis (HD-CKD), a 3-h dialysis session removed roughly 7% of alogliptin; hence, alogliptin can be administered regardless of the timing of the session [27].\n\nAlthough metformin monotherapy is the preferred first-line treatment for patients with T2DM in the USA and Europe (based on its efficacy, favorable tolerability profile, low cost, and weight neutrality) [38–40], alternative options are required for patients with metformin contraindications, intolerance, or those who cannot achieve glycemic control with metformin alone (Table 1) [38, 39, 41]. In fact, in Asia, metformin is not always the recommended first-line treatment, because of the different pathophysiology of (i.e., β-cell dysfunction with less adiposity and greater insulin sensitivity), and genetic susceptibility for, T2DM in Asian patients compared with Western patients [42–44]. In Japan, despite higher drug acquisition costs compared with metformin, DPP-4is are an option for first-line use [45] (a setting in which they are already the most widely prescribed antidiabetic drug class [46]), unlike in the USA and Europe, where they are recommended as add-on medications [38, 39, 47]. In this regard, DPP-4is have demonstrated greater glucose-lowering efficacy in Asian versus non-Asian patients with T2DM [48]. Notably, the Japanese Diabetes Society recommends antidiabetic agents on a patient-centric basis [45]. There are eight DPP-4is approved worldwide for T2DM: alogliptin, sitagliptin, vildagliptin, linagliptin, teneligliptin, anagliptin, saxagliptin, and gemigliptin [49]. The long-acting agents omarigliptin and trelagliptin are only approved in Japan, while evogliptin and gemigliptin are approved in some countries, not including the USA and EU [49]. The FDC of alogliptin + metformin has been available in Japan since 2016 [33].Table 1 Summary of recommended antidiabetic agents for the treatment of type 2 diabetes mellitus [38, 39, 41]\n\nTreatment (route of administration)\tPrimary physiological action(s)\tHypoglycemia risk\tWeight gain\tMost frequent side effects\tCost\t\nMetformin (oral)\t↓ Hepatic glucose production\tLow\tNeutral/Loss\tGastrointestinal\tLow\t\nTZD (oral)\t↑ Insulin sensitivity\tLow\tGain\tWeight gain\tLow\t\nSU (oral)\t↑ Insulin secretion\tModerate\tGain\tHypoglycemia\tLow\t\nDPP-4i (oral)\t↑ Glucose-dependent insulin secretion\n\n↓ Glucose-dependent glucagon secretion\n\n\tLow\tNeutral\tRare\tHigh\t\nGLP-1 receptor agonist (injection)\t↑ Glucose-dependent insulin secretion\n\n↓ Glucose-dependent glucagon secretion\n\n\tLow\tLoss\tGastrointestinal\tHigh\t\nSGLT2i (oral)\tBlocks glucose reabsorption by kidneys, increasing glucosuria\tLow\tLoss\tGenitourinary infections\tHigh\t\nα-GI (oral)\tSlows intestinal carbohydrate digestion/absorption\tLow\tNeutral\tModest HbA1c efficacy, gastrointestinal\tModerate\t\nInsulin (injection)\t↑ Glucose disposal\n\n↓ Hepatic glucose production\n\n\tHigh\tGain\tHypoglycemia, weight gain\tVariablea\t\nα-GI α-glucosidase inhibitor, DPP-4i dipeptidyl peptidase-4 inhibitor, GLP-1 glucagon-like peptide-1, HbA1c hemoglobin A1c, SGLT2i sodium-glucose cotransporter 2 inhibitor, SU sulfonylurea, TZD thiazolidinedione, ↑ increased, ↓ decreased\n\naCost is dependent on type/brand (analogs > human insulins) and dosage\n\n\n\nThis review will focus on alogliptin. We aim to evaluate the benefits and risks associated with alogliptin and to put alogliptin treatment into perspective within the armamentarium of current therapies for patients with T2DM. Key studies for alogliptin were identified by searching PubMed using the terms ‘alogliptin’ and ‘diabetes’ (search date: 21 March 2019). The publications identified in the search were reviewed manually for their relevance for inclusion in this article.\n\nBenefit Evaluation\nT2DM is a chronic progressive metabolic disorder associated with, but not limited to, micro- and macrovascular complications and hepatic and renal impairment [50, 51]. The following section evaluates the benefit of alogliptin monotherapy and add-on/combination therapy based on clinical and real-world studies and studies assessing the health economic impact of treating diabetes.\n\nEpidemiology and Natural History of T2DM\nIn 2016, an estimated 1.6 million deaths were attributable to diabetes [52]. The development of T2DM is associated with non-modifiable and/or modifiable risk factors [53, 54]. Key non-modifiable risk factors include genetic factors, metabolic disturbances, ethnicity, and older age, while modifiable factors include obesity, a sedentary lifestyle, an unhealthy diet, and smoking [53, 54]. Despite modifiable risk factors, the global prevalence of T2DM is expected to rise to 629 million by 2045 compared with an estimated 425 million in 2017. In Asia, T2DM is an increasing epidemic. Studies have demonstrated ethnic differences in the epidemiology and natural history of T2DM [42, 55]. For example, although Asians with diabetes generally have a lower body mass index (BMI) [55], they have higher insulin sensitivity and lower insulin response compared with non-Asians [42]. Analyses also suggest that decreased insulin secretion is a common cause of T2DM [42, 55] in Asians and, moreover, diabetes occurs at a much lower mean BMI than in non-Asians [55]. Consequently, the choice of and response to treatment will differ between ethnicities; for example, insulin secretagogues, such as sulfonylureas (SUs), are more commonly prescribed in Asians than non-Asians [55].\n\nPurpose and Outcome of Treatment\nThe aim of treatment is to help patients achieve glycemic control, a quality of life (QoL) similar to those without diabetes, and to minimize the risk of long-term complications [56]. Another objective of T2DM treatment is to reduce burden on the economy [56]. Optimal management of T2DM is complex [56]. Poorly controlled diabetes can lead to complications and negatively impact patient outcomes and QoL [50, 51]. Guidelines recommend diet and lifestyle changes, followed by administration of one or more oral antidiabetic agents or injectable treatment [57] if glycemic control is inadequate [56]. Several factors related to antidiabetes medication should be considered when making treatment decisions, including glycemic control (HbA1c levels), pleiotropic effects (e.g., blood pressure), patient preferences, existing comorbidities, adverse-effect profile, risk of hypoglycemia, and necessity for weight loss [38, 58].\n\nMechanism of Action, Pharmacokinetic, and Pharmacodynamic Profile\nAlogliptin, a highly potent and selective, noncovalent inhibitor of DPP-4, was developed using Structure-based Drug Design System technology [59]. Notably, alogliptin is > 10,000-fold more selective for DPP-4 than DPP-2, -8, and -9 [59, 60]; this is particularly important as DPP-8 and -9 have been associated with the activation of pro-inflammatory caspase-1, which is, in turn, involved in pyroptosis [61]. By inhibiting DPP-4 activity, alogliptin slows the inactivation of incretin hormones, glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP); GLP-1 and GIP increase insulin secretion and inhibit glucagon secretion when glucose levels are high [26, 27]. Thus, alogliptin improves glycemic control via a glucose-dependent mechanism [26, 27].\n\nAlogliptin is rapidly absorbed and evenly distributed in the tissues [27, 35]. DPP-4i efficacy requires steady-state trough DPP-4 activity inhibition of approximately 80% [62], and alogliptin has been shown to suppress this by up to 99% after 14 days of once-daily administration at therapeutic doses [35]. The absolute bioavailability of alogliptin is high (100%) [27], is not significantly affected by food [63], and has not been associated with any clinically significant interactions with common antidiabetic drugs, such as metformin [63], pioglitazone [64] (a thiazolidinedione [TZD]), and glyburide (an SU) [64]. Alogliptin does not undergo extensive metabolism, and cytochrome P450 (CYP)-related metabolism is negligible; thus, no dose adjustments are required with concomitant use of CYP substrates or inhibitors [27]. Further, no clinically relevant interactions have been observed between alogliptin and p-glycoprotein inhibitors or substrates [26, 27]. For a comparison of the clinical pharmacology (pharmacokinetic and pharmacodynamic properties) of alogliptin with other DPP-4is, please refer to a recent review by Chen et al. (2015) [65].\n\nEvidence of Benefit\nClinical Trials\nAlogliptin has demonstrated improvements in glycemic control, as indicated by changes in HbA1c in treatment-naïve and previously treated patients in global and Asian phase II/III placebo-controlled and active-controlled studies, as (1) monotherapy [1, 12]; (2) dual therapy (add-on/combination) with metformin, SUs, TZDs, α-glucosidase inhibitors (α-GIs), and insulin [2–5, 13–19, 66–70]; and (3) triple (add-on) therapy to insulin with or without metformin, and add-on to metformin with a TZD (Online Resource, Table S1, see the electronic supplementary material [ESM]) [6–10, 15]. Below, we evaluate the effect of alogliptin on glycemic control (change in HbA1c) compared with placebo, focusing on data from phase III studies that have a primary efficacy endpoint of change in HbA1c from baseline to at least week 12, with most evaluating at week 26.\n\nAlogliptin monotherapy (12.5 mg and 25 mg) resulted in significant glycemic control compared with placebo at week 26 in treatment-naïve patients with [1] uncontrolled T2DM on diet and exercise therapy alone (Online Resource, Table S1; both alogliptin doses p < 0.001). In the same study, 44% of patients achieved HbA1c levels ≤ 7.0% (guideline recommended target) [38, 39, 45] and a significant reduction in fasting plasma glucose at 26 weeks in the alogliptin group compared with placebo (both alogliptin doses; p < 0.001). Five other phase III, placebo-controlled, 26-week studies in patients with T2DM examined the effect of alogliptin dual therapy (with metformin or an SU) [13, 14] or triple therapy (with pioglitazone ± metformin or an SU, or with insulin ± metformin) [6, 7, 9] on glycemic control. In all five studies, 12.5-mg and 25-mg alogliptin doses as add-on treatment demonstrated significant reductions in HbA1c compared with placebo (Online Resource, Table S1; p < 0.001).\n\nThe results of a meta-analysis of phase II/III and III studies revealed significantly greater reductions in HbA1c in Asian patients compared with non-Asian patients who received alogliptin (p = 0.02), with similar safety (p = 0.71) [71]. These data are further supported by studies investigating alogliptin monotherapy [12], dual therapy (to metformin, pioglitazone, α-GI, or insulin) [3–5, 16, 19], and triple therapy (to pioglitazone ± metformin) in Asia [10], all of which reported a significant reduction in HbA1c levels with alogliptin versus placebo (Online Resource, Table S1; p < 0.001).\n\nReal-World Evidence\nThe efficacy of alogliptin has also been demonstrated in a real-world setting, primarily in Japan, via retrospective and observational studies. Results from the ATTAK-J study conducted in Japanese patients with T2DM revealed a 0.54% ± 1.22% reduction in HbA1c following 1 year of treatment with alogliptin [25]. In the same study, a significantly higher proportion of patients achieved HbA1c levels < 7.0% after 3 months of alogliptin treatment compared with baseline (p < 0.001) [25]. Further analysis revealed that increased adherence to diet therapy led to a further reduction in HbA1c at 12 months, despite the removal of SU treatment [25]. In support of these data, a significant reduction in HbA1c (vs. baseline; p = 0.0005) was found in a subgroup of patients from a long-term, 3.5-year retrospective study of Japanese patients with T2DM receiving alogliptin and SU who either did not change their antidiabetic drugs or did not reduce the dose or strength of their SU, thus demonstrating the effective long-term durability of alogliptin [24].\n\nPrescription patterns of T2DM treatments are changing as more patients are prescribed newer second-line oral treatments, such as DPP-4is, sodium-glucose cotransporter 2 inhibitors (SGLT2is), and α-GIs [47, 72–76]. A large-scale (n = 20,000), 3-year, prospective, observational, real-world study (Japan-Based clinical ReseArch Network for Diabetes Registry [J-BRAND Registry]), designed to examine the safety and efficacy of alogliptin compared with non-DPP-4i oral hypoglycemic agents in Japanese patients with T2DM, is ongoing [23]. The J-BRAND Registry study will help determine the long-term appropriate use of alogliptin when used alone or in combination with other antidiabetic agents.\n\nTolerability\nData from long-term studies that have evaluated the safety/tolerability of alogliptin will now be discussed. Treatment-emergent adverse events (TEAEs) and adverse events of special interest (AESIs) will be examined in detail in Sect. 3.\n\nOverall, alogliptin is well-tolerated, as demonstrated in long-term studies (≥ 52 weeks), both in a clinical trial and in real-world settings [17, 77]. When compared with glipizide (an SU) or standard of care (SoC) [17, 77], there were no differences observed in the incidence of adverse events (AEs) between alogliptin- and comparator-treated patients [17, 77]; most AEs were mild in severity [17, 77]. A 1-year retrospective analysis (ATTAK-J) also revealed low rates of AEs [25] in patients with T2DM receiving alogliptin (2.5%; n = 314).\n\nThese findings are further supported by a meta-analysis examining the efficacy and safety of alogliptin as monotherapy or combination therapy [78, 79]. Here, the number of patients who discontinued due to AEs was not significantly different in patients treated with alogliptin versus placebo or other antidiabetic control treatments (odds ratio [OR] 0.83; 95% confidence interval [CI] 0.61–1.58 for alogliptin 12.5 mg; OR 0.98; 95% CI 0.44–1.58 for alogliptin 25 mg) [78]. Additionally, a systematic review and meta-analysis examining DPP-4i safety reported that treatment was generally well-tolerated [80]. The study highlighted the need for future studies evaluating the effects of DPP-4is on heart failure (HF) and acute pancreatitis [80], as discussed in Sect. 3.\n\nConvenience and Preference\nIn chronic conditions, such as T2DM, adherence to treatment is often poor, with an average of approximately 50% in developed countries [81]. Decreased adherence leads to poor clinical outcomes and QoL, and negatively impacts healthcare costs [57]. To improve treatment adherence, guidelines recommend considering patient preferences when determining optimal T2DM management [38, 45].\n\nOne initiative to improve adherence is to understand patient preferences for an antidiabetic treatment [38, 39, 45]. In a recent US survey conducted in patients with diabetes (type 1 or 2), the most influential attributes to patient preference were treatment regimen (e.g., mode and frequency of administration), risk of diarrhea, weight change, risk of hypoglycemia, and treatment efficacy [82]. In the same survey, patients demonstrated a preference for DPP-4is over GLP-1 receptor agonists, SGLT2is, SUs, and TZDs due to their favorable regimen and risk profile [82]. For example, similar to DPP-4is, GLP-1 receptor agonists also target the incretin system [38, 39, 83]; however, GLP-1 receptor agonists are injectable, while DPP-4is have oral formulations [83]. In a US- and European-based survey, patients significantly preferred, and were significantly more likely to prefer, a DPP-4i oral formulation to a GLP-1 injectable formulation (both p < 0.001) [83]. Additionally, the frequency of administration is an important regimen-related factor that has been linked to both adherence and patient QoL [84]. For instance, a once-daily regimen of DPP-4i significantly improved Diabetes Therapy-Related Quality of Life 17 questionnaire scores from baseline to week 12 when compared with the thrice-daily regimen of an α-GI, voglibose (p = 0.034) [84]. Furthermore, FDC regimens, similar to alogliptin/metformin and alogliptin/pioglitazone formulations, have been shown to improve adherence compared with two-pill regimens [85]. FDCs could therefore benefit the patient, result in cost-savings to the healthcare system, and save manufacturing and distribution costs [85].\n\nHealth Economic Impact\nT2DM is associated with significant healthcare costs, placing a considerable burden on the economy [86]. According to the International Diabetes Federation, the global healthcare costs of diabetes treatment and related complications in 2017 were estimated to be US$850 billion in patients aged 18–99 years; this expenditure is expected to reach US$958 billion by 2045 [86]. Interventions to prevent or control diabetes, as recommended by guidelines such as those of the American Diabetes Association (e.g., intensive glycemic control and lifestyle changes) [38], have proven to be cost-effective [87].\n\nAn analysis of 29 randomized controlled trials (RCTs) by Pedrazzoli et al. suggested that alogliptin as a monotherapy and add-on/combination therapy was more cost-effective than other DPP-4is, such as sitagliptin, saxagliptin, and linagliptin [88]. The total savings with alogliptin in Europe, particularly in combination with metformin, were up to €158 per patient-year [PY] based on a higher proportion of patients achieving a target HbA1c of < 7%, reduced need for alogliptin treatment escalation, better lipid profile, proven cardiovascular (CV) safety, lower hypoglycemia incidence, and increased adherence to treatment [88]. Notably, alogliptin is available as FDCs; thus, pill burden and pharmacy dispensing fees may allow for adherence improvement and further cost savings, respectively [89]. Studies have reported that alogliptin in combination with metformin is an alternative, cost-effective treatment compared with SUs in patients with T2DM [90, 91]. In a UK study, long-term alogliptin + metformin combination treatment achieved greater estimated lifetime quality-adjusted life-year (QALY) gains compared with SU + metformin; the associated incremental cost-effectiveness ratios (ICERs) were £10,959/QALY (12.5 mg alogliptin) and £7217/QALY (25 mg alogliptin) [90]. Results from a US study showed that DPP-4i + metformin therapy had an ICER of US$19,420 per life-year gained compared with SU + metformin [91]; incremental costs and life-years gained were US$11,849 and 0.61 years, respectively [91]. Similarly, in a pharmacoeconomic analysis of DPP-4is (sitagliptin, vildagliptin, and alogliptin) in Japan, 25 mg alogliptin was the second most cost-effective treatment (ICER of ¥102,062 per patient) after 100 mg vildagliptin [92]. Further studies comparing the cost-effectiveness of alogliptin in combination with other treatments available for T2DM are required, as are health economic analyses of alogliptin versus other antidiabetic therapies (e.g., metformin) in first-line use (especially in Asian patients).\n\nAlternative Therapies\nBelow we compare (head-to-head, direct comparisons) alogliptin with other antidiabetic treatments recommended for patients with T2DM.\n\nPhase III international studies and studies in Asian patients have compared the efficacy (change in HbA1c) of alogliptin as dual and triple therapy (in combination with metformin, pioglitazone, an SU, or metformin + pioglitazone) with component monotherapies or an active comparator (Online Resource, Table S1, see the ESM) [5, 9, 15, 17, 18]. In each study, alogliptin in combination was significantly more efficacious in decreasing HbA1c levels versus placebo or component monotherapy (p values from < 0.05 to < 0.0001; Online Resource, Table S1) [5, 9, 15, 17, 18]. However, when used as monotherapies, alogliptin and metformin yielded similar results to each other after 26 weeks of treatment [5, 18].\n\nAlogliptin as add-on therapy with metformin has demonstrated sustained efficacy in a phase III, international, multicenter, 2-year study in patients with inadequate glycemic control who received metformin in combination with either alogliptin or an SU (Online Resource, Table S1) [17]. Patients receiving alogliptin (12.5 mg and 25 mg) demonstrated significantly superior HbA1c control and were more likely to achieve an HbA1c target of ≤ 7.0% compared with the SU, glipizide (both p < 0.001; Online Resource, Table S1) [17]. In the same study, a significantly higher proportion of patients receiving alogliptin 12.5 mg or 25 mg achieved HbA1c ≤ 7.0% without hypoglycemia or weight gain compared with glipizide (glipizide 10.7% vs. alogliptin 12.5 mg 24.2% and alogliptin 25 mg 26.9%; p < 0.001 for both comparisons) [17]. These data support alogliptin as a long-term efficacious and viable treatment option for patients with T2DM.\n\nRisk Evaluation\nSafety evaluations and primarily adverse reaction profiles are some of the major considerations physicians face when making treatment decisions for patients with T2DM [58]. The following section will focus on TEAEs and AESIs based on standardized Medical Dictionary for Regulatory Activities (MedDRA) queries for alogliptin monotherapy and as add-on/combination therapy compared directly with placebo or active comparators.\n\nAlogliptin was generally well-tolerated in clinical studies of up to 4.5 years in duration [2, 17, 93, 94]; mean exposure to alogliptin was 40 weeks in patients treated for > 1 year [27]. The overall TEAE incidence rates were similar between alogliptin and placebo or the active comparator (286.1 vs. 283.3 events per 100 PYs, respectively; Fig. 1 [93]) in the 2016 pooled safety analysis of 20 double-blind RCTs by Munsaka et al., which included 16,933 patients with T2DM (alogliptin [monotherapy and combination or add-on therapy] n = 10,403; comparator [placebo or active-control] n = 6530; Fig. 1 [93]). In another pooled analysis of controlled phase II/III studies, the most commonly reported TEAEs occurring in > 3% of patients receiving alogliptin 25 mg, which were numerically more frequent versus placebo, were nasopharyngitis, upper respiratory tract infection, headache, diarrhea, and urinary tract infection; nasopharyngitis was the only TEAE that occurred more frequently in patients receiving alogliptin 25 mg versus an active comparator (Table 2) [36]. TEAEs were primarily described as mild or moderate in severity in both pooled analyses [36, 93], with few severe TEAEs [36]. There were no severe TEAEs that occurred in > 1.0% of patients in any group in the pooled analysis of controlled phase II/III studies [36]. The proportion of patients experiencing at least one serious adverse event (SAE) was also low and similar between treatment groups (from 3.2% in the placebo to 5.2% in the active comparator group) [36]. Cardiac disorders were the most commonly reported SAE, which were comparable between patients treated with alogliptin 25 mg (1.0%) and active comparators (1.2%), yet greater than in patients treated with placebo (0.4%) [36]. Most deaths were considered unrelated to the study drug; however, in one open-label alogliptin extension study, ten deaths (0.003%) were considered to have a possible relationship to the study drug [36, 94]. In a pooled analysis of 23 phase II–IV RCTs, the proportion of patients who discontinued because of a TEAE was lower in the alogliptin groups (6.1%) than the placebo group (7.1%), but similar to the active comparator group (6.1%) [95]. Data from a meta-analysis comparing Asian and non-Asian studies demonstrated no difference in the number of any AEs (11 studies; p = 0.71) or SAEs (15 studies; p = 0.08), as well as the number of hypoglycemic events (12 studies; p = 0.58) and weight gain (eight studies; p = 0.47) [71].Fig. 1 Adverse events of special interest in a pooled analysis of 20 double-blind randomized controlled clinical studies [93]. CI confidence interval, PT preferred term, SMQ standardized Medical Dictionary for Regulatory Activities (MedDRA) queries, TMQ sponsor defined custom MedDRA query.\n\nReprinted with permission from the Springer Nature Customer Service Centre GmbH: Springer Nature, Diabetologia [93], © Springer-Verlag Berlin Heidelberg 2016 (2016). Please note that this figure is NOT republished under the CC BY-NC license\n\nTable 2 Most common adverse events in a pooled analysis of randomized controlled phase II and III studies with alogliptin [95]\n\nAdverse event\tPlacebo (n = 4349)\tActive comparator (n = 2496)\tAlogliptin 12.5 mg (n = 2944)\tAlogliptin 25 mg (n = 8068)\tAlogliptin total (n = 11,299)a\t\nAny TEAE, n (%)\t3001 (69.0)\t1716 (68.8)\t1944 (66.0)\t5486 (68.0)\t7586 (67.1)\t\n Nasopharyngitis\t217 (5.0)\t125 (5.0)\t216 (7.3)\t461 (5.7)\t691 (6.1)\t\n Hypertension\t233 (5.4)\t122 (4.9)\t108 (3.7)\t375 (4.6)\t484 (4.3)\t\n URTI\t143 (3.3)\t124 (5.0)\t140 (4.8)\t318 (3.9)\t461 (4.1)\t\n Headache\t112 (2.6)\t124 (5.0)\t121 (4.1)\t295 (3.7)\t426 (3.8)\t\n Diarrhea\t144 (3.3)\t141 (5.6)\t110 (3.7)\t302 (3.7)\t415 (3.7)\t\n UTI\t138 (3.2)\t109 (4.4)\t116 (3.9)\t277 (3.4)\t402 (3.6)\t\n Back pain\t109 (2.5)\t102 (4.1)\t107 (3.6)\t246 (3.0)\t359 (3.2)\t\n Arthralgia\t84 (1.9)\t85 (3.4)\t85 (2.9)\t199 (2.5)\t287 (2.5)\t\n Influenza\t74 (1.7)\t99 (4.0)\t74 (2.5)\t186 (2.3)\t261 (2.3)\t\n Dizziness\t93 (2.1)\t78 (3.1)\t74 (2.5)\t179 (2.2)\t259 (2.3)\t\n Renal impairment\t177 (4.1)\t6 (0.2)\t7 (0.2)\t220 (2.7)\t227 (2.0)\t\n Angina pectoris\t197 (4.5)\t10 (0.4)\t10 (0.3)\t214 (2.7)\t225 (2.0)\t\n Dyslipidemia\t63 (1.4)\t96 (3.8)\t42 (1.4)\t158 (2.0)\t200 (1.8)\t\n Hyperglycemia\t136 (3.1)\t43 (1.7)\t11 (0.4)\t145 (1.8)\t156 (1.4)\t\n Angina unstable\t140 (3.2)\t7 (0.3)\t3 (0.1)\t121 (1.5)\t124 (1.1)\t\n Hypoglycemia\t164 (3.8)\t100 (4.0)\t22 (0.7)\t192 (2.4)\t215 (1.9)\t\nTable shows TEAEs occurring in ≥ 3% of patients in any group. Table is ordered in descending frequency of TEAEs in the alogliptin total group\n\nTEAE treatment-emergent adverse event, URTI upper respiratory tract infection, UTI urinary tract infection\n\naAlso includes patients who received 6.25-, 50-, and 100-mg alogliptin doses\n\n\n\nBased primarily on the pooled safety analysis by Munsaka et al., this section will focus on the following AEs and AESIs: hypoglycemia, weight gain, CV events, acute pancreatitis, skin-related AEs, gastrointestinal events, renal failure, and hepatotoxicity [93]. There is limited evidence to suggest safety differences between the drugs in the gliptin class [96]. Therefore, where data are available, we have compared (head-to-head, direct comparisons) the safety of alogliptin with placebo and alternative antidiabetic treatments for T2DM (Table 1). Although not considered here, there is some evidence for an increase in non-serious infections, especially low-grade upper respiratory tract infections, in patients treated with DPP-4is (including alogliptin) compared with users of other antidiabetic drugs during post-marketing evaluation [97].\n\nHypoglycemia\nHypoglycemia is a common and important complication of diabetes therapy, and is associated with diminished QoL, aggravated clinical outcomes, and, in severe cases, seizures, coma, and death [98]. It can also result in treatment discontinuations and increased healthcare costs [99]. Special populations, including older patients (aged ≥ 65 years), have a higher risk of developing hypoglycemia [11, 100]. Older patients, including those who are healthy, are at increased risk of developing hypoglycemia [100], and may require more careful HbA1c and body weight targets than their younger counterparts, as suggested by guidelines [38].\n\nGenerally, in patients with T2DM, hypoglycemic events were infrequent or comparable to placebo and mild in severity in phase II/III studies of alogliptin monotherapy and add-on/combination therapy with metformin, SUs, metformin + SU, insulin, metformin + insulin, pioglitazone, pioglitazone + metformin, pioglitazone + metformin + SU, and an α-GI [1, 3, 7, 8, 12–14, 16, 17, 21, 67, 69, 70, 101]. Furthermore, incidences of any hypoglycemic event occurred in ≤ 8.3% of at-risk, older patients receiving alogliptin (12.5 and 25 mg as monotherapy or add-on/combination therapy) versus ≤ 10.5% in patients treated with placebo in a pooled analysis of phase II/III studies [11]. In the same analysis of older patients, the highest incidences of hypoglycemic severity occurred in the placebo group (10.5%) [11].\n\nAs depicted in Table 1, SU therapy has a higher risk of hypoglycemia compared with DPP-4is. While DPP-4is as an add-on therapy to SU treatment have been shown to increase the risk of hypoglycemia [102], this was contradicted in an international phase III study reported by Pratley et al., which demonstrated that 12.5 and 25 mg alogliptin as add-on therapy to SU treatment did not increase the incidence of hypoglycemia [14]. Additionally, the frequency of hypoglycemic events was substantially lower in alogliptin + metformin-treated patients (2.5% and 1.4% for alogliptin 12.5-mg and 25-mg groups, respectively) versus SU + metformin-treated patients (23.2%) in a 2-year study (Del Prato et al., 2014; Online Resource, Table S1, see the ESM), with the majority of the first hypoglycemia events occurring within the first 20 weeks of SU treatment [17]. In the same study, severe hypoglycemia was reported in five patients receiving an SU compared with one patient in the alogliptin 12.5-mg group and none in the 25-mg group [17]. Notably, in older patients, alogliptin 25-mg monotherapy had a substantially lower risk of hypoglycemia compared with SU monotherapy (Rosenstock et al., 2013; Online Resource, Table S1) [101].\n\nMetformin and alogliptin are considered unlikely to cause serious hypoglycemia (Table 1) [39, 103]. This is supported by an international phase III study [18] and a Japanese phase II/III study [70] (Pratley et al., 2014, and Seino et al., 2012b; Online Resource, Table S1), where patients receiving alogliptin and metformin monotherapies had a similar incidence of hypoglycemia. Yet, in another Asian study (Ji et al., 2017; Online Resource, Table S1), more patients in the metformin group (500 mg BID) experienced a hypoglycemic event (6.2%) compared with the alogliptin group (12.5 mg BID; 1.2%) [5]; further studies may be required to compare the risks of hypoglycemia in the Asian population.\n\nCompared with SoC, alogliptin significantly lowered HbA1c levels without increasing hypoglycemia (0.3% vs. SoC 0.1%; p = 0.004) after 104 weeks of treatment in the Study of Preventive Effects of Alogliptin on Diabetic Atherosclerosis (SPEAD-A), a 104-week multicenter, open-label, blinded endpoint, parallel study comparing alogliptin with SoC in Japanese patients with T2DM [77].\n\nIn summary, although alogliptin monotherapy is unlikely to cause serious hypoglycemia, treating physicians should remain vigilant if DPP-4is, such as alogliptin, are used as add-on treatments to SUs and insulin therapies, which have a moderate-to-high risk of hypoglycemia (Table 1) [102].\n\nWeight Gain\nApproximately 58–90% of patients with T2DM are overweight or obese [104]; hence, lifestyle changes to prevent weight gain are important for glycemic control and CV health [38, 56]. Phase II/III studies have demonstrated that alogliptin monotherapy and add-on/combination therapy decreased HbA1c levels with minimal changes in weight gain versus placebo [2, 7, 12, 14, 17, 21, 70]. However, it should be noted that DPP-4is may have lower efficacy in obese patients because DPP-4 induces insulin resistance in adipocytes that are found in the circulation of overweight and obese patients [105]. These findings are also supported by a retrospective study that demonstrated that the efficacy of DPP-4i monotherapy was significantly decreased in diets high in saturated fatty acids (multiple regression analysis; p < 0.01) [106], highlighting the importance of diet therapy and avoiding weight gain [38, 39, 45, 106].\n\nWeight gain is a major side effect with TZDs, SUs, and insulin therapies [38, 107], as summarized in Table 1. So far, there have only been three comparison studies between TZDs or SUs and alogliptin treatment. Data from an international phase III study (DeFronzo et al., 2012; Online Resource, Table S1, see the ESM) showed decrease in body weight was modest but significantly lower in patients receiving alogliptin (− 0.02 and − 0.7 kg for alogliptin 12.5 and 25 mg, respectively) versus the pooled pioglitazone group (+1.5 kg pooled 15, 30, and 45 mg pioglitazone) [9]. Similarly, in a 2-year study (Del Prato et al. 2014; Online Resource, Table S1), weight gain was significantly greater in patients treated with SU + metformin compared with alogliptin (12.5 or 25 mg) + metformin (both doses p < 0.001) [17]. Of note, treatment with 25 mg alogliptin in older patients resulted in a modest but significant decrease in body weight compared with SU therapy after 1 year of treatment (− 0.62 vs. 0.60 kg; p < 0.001) [101].\n\nFor alternative therapies, such as metformin, the risk of weight gain is neutral/less compared with neutral for DPP-4is (Table 1). This is supported by a phase III study (Pratley et al., 2014; Online Resource, Table S1), where metformin monotherapy led to the greatest weight reduction (− 0.80 and − 1.25 kg with metformin 500 and 1000 mg BID, respectively), while alogliptin monotherapy was weight neutral (− 0.01 kg with alogliptin 12.5 mg BID) [18]. Compared with SoC, the mean change in BMI was significantly lower in alogliptin-treated patients (0.3 ± 1.9 kg/m2 vs. 20.3 ± 1.7 kg/m2 in the SoC group; p = 0.003) [77].\n\nHence, as TZDs, SUs, and insulin are associated with weight gain [39], it is recommended that treating physicians remain vigilant with respect to weight gain, particularly in patients receiving add-on therapy to alogliptin or combination therapy.\n\nCV Events\nT2DM is strongly associated with micro- and macrovascular complications, with almost 50% of patients developing HF [50, 108]. In 2008, the US Food and Drug Administration (FDA) issued specific guidance for assessing the CV safety, pre- and post-approval, of new antidiabetic agents [2]. Subsequently, in 2018, the American Diabetes Association released an update of the “Standards of Medical Care in Diabetes” document, including, for the first time, new recommendations for patients with T2DM and heart disease around choosing medications proven to improve heart health [109]. These recommendations have been carried over to the 2019 update [110], emphasizing the importance of CV health in diabetes management. Currently, these guidelines recommend SGLT2is and GLP-1 receptor agonists [110]; meta-analyses investigating the CV safety of DPP-4is have demonstrated a neutral effect of these agents on major CV endpoints and all-cause death [111].\n\nThe pivotal Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE) study evaluated the effect of alogliptin in addition to SoC for diabetes (excluding DPP-4is and GLP-1 receptor agonists) on CV-related outcomes in 5380 T2DM patients who had recently experienced acute coronary syndrome. Rates of major adverse CV event (MACE) incidences (CV death, non-fatal myocardial infarction [MI], or non-fatal stroke) were similar between the alogliptin and placebo groups (11.3% and 11.8% of patients, respectively; hazard ratio [HR] 0.96; upper boundary of one-sided repeated CI 1.16; p < 0.001 for non-inferiority) [2]. Secondary and post hoc analyses from the EXAMINE study [2, 108, 112–114] further supported these findings, demonstrating no significant differences between alogliptin- and placebo-treated patients in the five-component composite CV endpoint (CV death, stroke, MI, unstable angina, and coronary revascularization; p = 0.72) [113], CV hospitalizations (p = 0.70) [113], and mortality (HR 0.88; 95% CI 0.71–1.09) [115]. In another subgroup, rates of CV death (p = 0.01) and all-cause mortality (p = 0.033) were significantly lower in the alogliptin group versus placebo [114] in patients receiving either metformin or an SU as SoC. It should be noted, however, that the composite outcome in a subgroup of high-risk patients with previous history of HF displayed trends of reduced CV death and increased hospital admission for HF in the post hoc analysis by Zannad et al., suggesting that survivor bias cannot be ruled out [108].\n\nPreviously, there had been concern with respect to the increased risk of CV complications with concomitant use of DPP-4is and angiotensin-converting enzyme (ACE) inhibitors, a commonly prescribed class of drug for HF. High doses of ACE inhibitors prevent degradation of substance P, and as it is a DPP-4 substrate, it was hypothesized that the combination of both inhibitors could lead to stimulation of substance P, activation of the sympathetic nervous system, and a subsequent increase in the risk of CV complications [22]. An ACE inhibitor was used by 62% of patients in the EXAMINE trial, and a stratified analysis from the EXAMINE study revealed no differences between the alogliptin and placebo groups with respect to composite rates for CV death and HF in patients also receiving ACE inhibitors (p = 0.57) [22].\n\nThere is ongoing debate whether DPP-4is increase the risk of HF and the underlying mechanisms [116, 117]. A meta-analysis of the effect of DPP-4is on HF risk using controlled trials and observational studies found either a similar risk of HF between DPP-4is and control medications in controlled studies, or a possible increased risk in observational studies [118]; however, the evidence was of low or very low quality, leading the authors to conclude that the effect was uncertain. Post-marketing reports of HF in patients receiving linagliptin, saxagliptin, sitagliptin, and vildagliptin submitted via the FDA AE reporting system (FAERS) suggest that the CV safety of this class requires further monitoring [119, 120], while a Korean population-based cohort study found no increased risk of HF with DPP-4is versus SUs [121]. In contrast, another population-based study from Korea demonstrated a significantly increased risk of hospitalization for HF with DPP-4is versus SUs [122]. Further studies designed to examine the CV effect of alogliptin are ongoing, including the TRACT study, which aims to clarify possible anti-atherogenic effects by means of fractional flow reserve in Japanese patients with T2DM [123]. Nevertheless, warnings about HF risk have been added to the labels of several DPP-4is, including saxagliptin [124], alogliptin [26], and vildagliptin [125]. In contrast, other therapies, particularly GLP-1 receptor agonists (e.g., semaglutide and liraglutide) and SGLT2is (e.g., canagliflozin and empagliflozin), appear to have protective effects against CV disease [126].\n\nThere have been limited comparisons between alternative therapies and alogliptin for CV events, with a few studies each examining SoCs, metformin, SUs, or TZDs with alogliptin [9, 17, 18, 77, 101]. Similar to the pooled analysis described above [93], overall incidences of CV AEs were similar in Japanese patients with T2DM treated with alogliptin or SoC in the SPEAD-A study [77]. Moreover, alogliptin, but not SoC treatment, attenuated the progression of carotid intima-media thickness by week 104 relative to baseline [77]. In a comparison with metformin, the incidences of MACE were low in the alogliptin monotherapy group (one and two events in the alogliptin 25-mg once-daily and alogliptin 12.5-mg BID groups, respectively) in a phase III study (no MACE were reported for the metformin monotherapy group [18]; Pratley et al. 2014, Online Resource, Table S1, see the ESM). There was a trend towards lower confirmed MACE incidences (CV death, non-fatal MI, or non-fatal stroke) in the alogliptin + metformin group (0.7% and 0.9% for alogliptin 12.5 mg and 25 mg, respectively) compared to in the SU + metformin group (1.3%) in a 2-year phase III study [17]. In a separate phase III study (DeFronzo et al., 2012; Online Resource, Table S1), two cases of congestive HF were reported in pioglitazone-treated patients (one possibly related to therapy), while no cases were reported with alogliptin monotherapy and alogliptin add-on to pioglitazone [9]. Consensus statements recommend caution when administering TZDs to patients with New York Heart Association (NYHA) class I–II HF and to avoid use in NYHA class III–IV.\n\nBile Duct, Gallbladder, and Pancreatic Safety\nIn 2013, based on case reports and the results of one observational study, the FDA added warnings about acute pancreatitis to DPP-4i labeling [127, 128]. Since 2013, post-marketing reports have suggested an association between DPP-4is, including alogliptin, and acute pancreatitis [27, 129]. However, results from the EXAMINE study reported comparable incidences of acute pancreatitis between alogliptin- and placebo-treated patients with diabetes and high CV risk (alogliptin n = 12/2701 [0.4%]; placebo n = 8/2679 [0.3%]); more importantly, no cases were fatal [2]. Furthermore, no cases of pancreatitis were reported in a Japanese study comparing alogliptin + metformin-treated and placebo-treated patients [70].\n\nThere have been a few studies comparing the incidence of acute pancreatitis in alogliptin-treated and active comparator-treated patients; these include a pooled study and SU analyses. The incidence of acute pancreatitis in alogliptin-treated patients was low and similar to comparators (placebo and active) in a pooled analysis of 20 RCTs (0.22 vs. comparators 0.15 incidences per 100 PYs; Fig. 1 [93]). In alogliptin versus SU studies, one year-long study demonstrated no incidences of pancreatitis in both monotherapy groups [101]. Additionally, in a 2-year, phase III study (Del Prato et al., 2014; Online Resource, Table S1, see the ESM), pancreatitis occurred in one patient (0.1%) in the alogliptin 25-mg + metformin group and three (0.3%) in the SU + metformin group [17]. Nonetheless, treating physicians are advised to remain vigilant of the association between DPP-4is and acute pancreatitis when making treatment decisions.\n\nSome observational studies and post-marketing reports have described an increase in the risk of pancreatic cancer and cholangiocarcinoma in patients exposed to DPP-4is [130]. However, other studies have failed to demonstrate an association between DPP-4i use and pancreatic cancer [131–133], and one Korean registry study even reported a reduction in the risk of malignancy for DPP-4is compared with metformin (HR 0.57; 95% CI 0.51–0.64) [134]. While further studies are required to determine if there is a genuine class or even drug-specific effect, doctors must be alert to the potential risk of late-onset pancreatic malignancy in T2DM patients receiving DPP-4i treatment. Use of DPP-4is does not appear to increase the risk of bile duct or gallbladder diseases (cholelithiasis, cholecystitis, and cholangitis) compared with the use of at least two oral antidiabetic drugs from other classes [135].\n\nSkin-Related Adverse Events\nSkin-related AEs, including allergic reactions, have been monitored as a result of concerns from preclinical evaluation in monkeys and reports of hypersensitivity reactions with other DPP-4is [36]. In a pooled analysis, alogliptin was associated with a low incidence of hypersensitivity reactions, with 0.2% of patients developing an anaphylactic reaction compared with 0% for placebo [36]. Data from post-marketing experiences with alogliptin show that skin and subcutaneous disorders were the most common events reported by system organ class (124 non-serious and 18 serious) [36].\n\nRecent studies suggest that DPP-4 inhibition is associated with bullous pemphigoid [136–141]. Although the HLA-DQB1*03:01 gene is not commonly associated with general bullous pemphigoid or T2DM, a study conducted in Japanese patients revealed a potential association between DPP-4i treatment and onset of non-inflammatory bullous pemphigoid [137]. Several observational studies, including reports of adverse drug reactions in pharmacovigilance databases, have demonstrated differential effects of individual DPP-4is on the risk of bullous pemphigoid, implying a drug-specific effect [136–141]. The risk of bullous pemphigoid appears to be highest among patients exposed to vildagliptin, whereas patients exposed to alogliptin appear to have a relatively low risk of developing the complication. Further research is required to understand the mechanisms underlying these observations.\n\nInflammatory Bowel Disease\nGastrointestinal side effects are an AESI and one of the main factors influencing patient preference [82]. Alogliptin treatment has demonstrated comparable rates of diarrhea to pioglitazone after 26 weeks of treatment, as reported in the DeFronzo et al., 2012 study (alogliptin 12.5 or 25 mg + pioglitazone [15, 30, and 45 mg] and pooled pioglitazone monotherapy groups [2.3%, 5.1%, and 3.6%, respectively]) [9]. Additionally, patients treated with alogliptin (12.5 and 25 mg) and an SU as add-on to metformin had similar incidences of diarrhea (6.9%, 6.8% and 7.2%, respectively) [17].\n\nTo date, there has only been one observational study examining the association between DPP-4is and inflammatory bowel disease (IBD) activity [142]. Abrahami et al. reported that the HR for IBD in patients receiving DPP-4i therapy versus other antidiabetic treatments was 1.75 (95% CI 1.22–2.49), which gradually increased, peaking 3–4 years after starting DPP-4i treatment (HR 2.90; 95% CI 1.31–6.41); yet, the HR decreased after the 4-year peak [142]. The increased incidence rate for IBD in patients receiving DPP-4i treatment may be a consequence of the involvement of DPP-4 in several immune responses [143]. Further studies are required to examine the association between IBD and DPP-4is, especially as the long-term use of DPP-4is increases, and treating physicians should remain aware of this potential association when making treatment decisions.\n\nRenal Failure\nDiabetes is one of the leading causes of CKD, which affects 40% of patients [144]. A pooled analysis has suggested that diabetes, hypertension, or a combination of the two were the cause of over 80% of ESRD cases [145].\n\nAt the time of writing, there were few studies of alogliptin treatment in patients with CKD; however, in the studies available, alogliptin has been generally well-tolerated and efficacious [27, 36, 146–148]. For example, no increases in occurrence of AEs including hypoglycemia were reported at week 48 in a study examining alogliptin treatment (monotherapy and add-on therapy [mitiglinide and/or α-GI]) in Japanese HD-CKD patients (n = 30); a significant reduction in interdialytic body weight gain (p = 0.04) was observed in the alogliptin as add-on treatment arm. Moreover, HbA1c and glycated albumin levels were significantly reduced versus baseline levels (p < 0.0001) [146]. These observations are further supported by the results of a 2-year study examining alogliptin treatment in Japanese HD-CKD patients, in which treatment was well-tolerated and HbA1c levels had significantly decreased after 2 years (p < 0.05) [147]. In the real-world setting, alogliptin treatment maintained renal function after 6 months of treatment in Japanese non-dialysis CKD patients [148]. Of note, in the 25-mg alogliptin group, pruritus was the only AESI with ≥ 1% incidence in patients with mild or moderate renal impairment versus patients with normal renal function at baseline [36]. Further studies are warranted to examine the effect of alogliptin on renal function in a real-world setting.\n\nDose adjustments for many of the recommended antidiabetic agents [27, 149] are mandated in renally impaired patients with T2DM. In the published literature, there are limited comparisons examining the effect of alogliptin versus other antidiabetic agents on renal function in patients with T2DM and no CKD. For example, there was no statistically significant difference in estimated GFR from baseline to week 104 between alogliptin (− 1 ± 10 mL/min/1.73 m2) and SoC (0 ± 10 mL/min/1.73 m2; p = 0.27) in the SPEAD-A study [77]. Additionally, cumulative incidences of ESRD were comparable between alogliptin + metformin and SU + metformin groups in a 2-year observational study (4.78% and 4.66% for alogliptin [12.5 and 25 mg, respectively] + metformin and 4.86% for SU + metformin [90], respectively).\n\nHepatotoxicity\nThe liver plays a key role in the pathogenesis of diabetes, with the care of diabetes both affected by, or causing effects on, the liver [150]. Hepatic abnormalities, such as cirrhosis, are estimated to account for 4.4–12.5% of deaths in patients with diabetes [151].\n\nResults from pharmacokinetic studies have demonstrated that alogliptin exposure was not affected in patients with mild or moderate hepatic impairment [27, 37] (Child–Pugh grade A and B), and therefore dose adjustments are not required in this setting. However, the pharmacokinetic profile of alogliptin has not yet been examined in patients with severe hepatic impairment (Child–Pugh grade C) and therefore alogliptin is not currently recommended for this patient population [27]. Findings from a single-arm, 12-month, multicenter study evaluating alogliptin (25 mg) efficacy in patients with T2DM and non-alcoholic fatty acid disease suggested that alogliptin may prevent progression of non-alcoholic fatty liver disease with early T2DM [152].\n\nIn the EXAMINE study, there was a numerical increase in the number of patients with increased liver enzymes with alogliptin versus placebo (although there were no statistical differences in serum aminotransferase values > 3 × the upper limit of normal at any time) [2], and there were subsequent post-marketing reports of alogliptin-associated hepatotoxicity [153] that prompted some debate; a subsequent analysis of the FAERS showed no hepatotoxicity signal for alogliptin and significant associations for sitagliptin, saxagliptin, and vildagliptin [154]. Currently, there is insufficient evidence to confirm whether alogliptin was the cause of the fatal and non-fatal hepatic failure documented in post-marketing reports; nevertheless, alogliptin should be administered with caution in patients with abnormal liver tests [27] and should be discontinued in patients with suspected hepatotoxicity [27].\n\nRisk Evaluation for All DPP4is in Real-World Studies\nObservational studies have shown that DPP-4is are associated with fewer gastrointestinal side effects than metformin, GLP-1 receptor agonists, and acarbose, and less hypoglycemia than SUs and insulin (reviewed by Scheen, 2018 [117]). Weight gain is also less with DPP-4is than with SUs, glitazones, and insulin [117]. Any potential increased risk of acute pancreatitis has not been confirmed in observational studies [117]. While the data from observational studies regarding HF is somewhat conflicting, there does not appear to be an increased risk of HF or hospitalization for HF with DPP-4is compared with other glucose-lowering agents in this setting [117]. With regard to CV outcomes, observational studies show reductions with DPP-4is versus other glucose-lowering agents in MACE, MI, stroke, and CV- and all-cause mortality.\n\nIn the ATTAK-J study, 12 months of alogliptin had no significant effect on body weight, blood pressure, or liver function [25]. Both total and low-density lipoprotein (LDL)-cholesterol were significantly reduced from baseline at 12 months (− 6.84 and − 7.22 mg/dL, respectively; p = 0.023 and p = 0.001). There was a significant increase in serum creatinine and a significant decrease in estimated GFR. The incidence of hypoglycemia was 0.6%. A reduction in LDL-cholesterol was also seen in the long-term observational study of Japanese patients with T2DM receiving alogliptin (106.5 ± 25.0 to 96.3 ± 20.9 mg/dL; p = 0.0406) [24].\n\nExpert Opinion\nWith more classes of antidiabetic agents available than ever before, physicians have to consider multiple factors, such as glycemic control, patient preferences, safety profile, risk of hypoglycemia, and necessity for weight loss [38, 58], when determining patient-centric, optimal management of T2DM [38, 39, 45, 58]. Alogliptin is an effective therapy that acts synergistically with agents including metformin and pioglitazone to provide superior efficacy compared with component monotherapies, as well as SU + metformin combination therapy [5, 9, 15, 17, 18, 66, 77].\n\nFrom a safety perspective, alogliptin is generally well-tolerated, with a low risk of hypoglycemia, weight gain, acute pancreatitis, and hepatotoxicity [1–3, 7, 8, 11–14, 17, 18, 21, 27, 37, 67, 69, 70, 93, 101]. Dose adjustments are required in patients with moderate renal impairment to ESRD, and caution is required in patients with renal and/or hepatic impairment [27, 36, 146–148]. Although the EXAMINE study and post hoc analyses demonstrated that alogliptin is well-tolerated in patients with a high HF risk [2, 108, 112–115], there are not currently enough data available to determine the cause and effect of alogliptin on the risk of HF [117]. Similarly, while there are new potential concerns for DPP-4i treatments, such as bullous pemphigoid and IBD [137, 142], further evaluation is required.\n\nAlogliptin generally exhibits a favorable safety profile, with an incidence of 286.1 TEAEs per 100 PYs [93], compared with active comparators (283.3 TEAEs per 100 PYs). For alogliptin, the risk of hypoglycemia is decreased versus SoCs and SUs [17, 77, 101] or comparable versus metformin [18, 39, 70, 155]; risks for acute pancreatitis are low and comparable to SUs [17]; gastrointestinal AE risks are comparable to SUs and TZDs [9, 17]; CV risks are less than with SoCs and metformin [18, 77], and possibly with SUs and TZDs [9, 17], although alogliptin cannot be considered to have the same cardioprotective effects as GLP-1 receptor agonists and SGLT2is [126]. Furthermore, weight gain risks are less with alogliptin versus TZDs, SUs, and SoCs [9, 17, 77], but increased versus metformin [18]; as the efficacy of DPP-4i monotherapy is decreased in diets high in saturated fatty acids, avoidance of weight gain through diet therapy is an important consideration.\n\nThe main limitation of the current benefit-risk assessment is the lack of statistical analyses, including data reported in post-marketing databases, such as the FAERS. However, we anticipate that this assessment is a useful aid to physicians when choosing an optimal therapy for T2DM management for their patient.\n\nConclusions\nAlogliptin treatment is one of the suitable medications for patients with T2DM who require glycemic control, with a low risk of hypoglycemia, weight gain, and gastrointestinal AEs, and for those who prefer a once-daily oral regimen, with caution required in those who have underlying CV risks. Notably, alogliptin has demonstrated greater efficacy in Asian patients than in non-Asian patients with T2DM, while maintaining a similar tolerability profile. This suggests that DPP-4is, including alogliptin, represent important treatment options, especially for Asian patients with T2DM, for whom they have potential as a first-line therapy.\n\nElectronic supplementary material\nBelow is the link to the electronic supplementary material.\nSupplementary material 1 (PDF 127 kb)\n\n \n\nAcknowledgements\nWriting support was provided by Mai Kurihara of FireKite, an Ashfield company, part of UDG Healthcare plc, during the development of this manuscript, which was funded by Takeda Pharmaceutical Co. Ltd. (Tokyo, Japan).\n\nCompliance with Ethical Standards\nFunding\nThis review was funded by Takeda Pharmaceutical Co. Ltd.\n\nConflict of interest\nKohei Kaku has received grants/pending grants from Boehringer Ingelheim Japan, Mitsubishi Tanabe-Pharma, and Taisho Toyama Pharmaceutical; consulting fees/honorarium from Sanwa Kagaku Kenkyusho; payment for lectures including services on speakers bureaus from Astellas Pharma, AstraZeneca, Boehringer Ingelheim Japan, Elli Lilly Japan, MSD, Novo Nordisk Pharma, Ono-Yakuhin, Sanwa Kagaku Kenkyusho, Taisho Toyama Pharmaceutical, and Takeda Pharmaceutical Company Limited. Koichi Kisanuki, Mari Shibata, and Takashi Oohira are employees of Takeda Pharmaceutical Company Limited.\n==== Refs\nReferences\n1. DeFronzo RA Fleck PR Wilson CA Mekki Q Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin in patients with type 2 diabetes and inadequate glycemic control: a randomized, double-blind, placebo-controlled study Diabetes Care 2008 31 12 2315 2317 18809631 \n2. 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Ayers D Kanters S Goldgrub R Hughes M Kato R Kragh N Network meta-analysis of liraglutide versus dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes in Japanese patients Curr Med Res Opin 2017 33 9 1653 1661 28635331\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "0114-5916", "issue": "42(11)", "journal": "Drug safety", "keywords": null, "medline_ta": "Drug Saf", "mesh_terms": "D003924:Diabetes Mellitus, Type 2; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004177:Dipyrone; D006801:Humans; D007004:Hypoglycemic Agents; D018570:Risk Assessment", "nlm_unique_id": "9002928", "other_id": null, "pages": "1311-1327", "pmc": null, "pmid": "31654243", "pubdate": "2019-11", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review", "references": "29391064;23990497;27820798;23289982;19622714;28635331;30090931;19793357;28058763;29203362;30559235;28811859;27171508;26497885;24400655;19125992;26893835;19487634;26628419;28465788;23531118;25132212;29219149;25721222;27843332;24380242;23992602;24664619;29946194;24561488;24492687;18809631;21733058;30857540;25765696;23625197;23452780;27186364;29279487;23296071;15616252;25411627;26173919;30624566;23704681;24764569;27787778;29468916;29573125;27142267;10392666;27191539;27745828;22237690;27809608;29667232;17327353;29582574;21806314;22583697;29581078;25190226;28167928;24421302;27480840;27236239;20682680;26865535;24623020;26277887;28770321;29655237;27031194;26888382;17441705;25538310;27067162;23774306;20040339;29335646;22106975;22561447;28275958;20724648;25227623;27891757;23344728;30826768;28075066;24843617;31099200;26439384;26888822;21206515;11321935;25331711;27843494;26767082;19650752;16490580;29643323;29264712;24073725;19758359;21270195;19125778;18405788;24130353;27200603;25336392;27779433;27179720;30718926;22314122;27549920;24465132;21682833;26417410;18288541;29172255;20668156;18538760;11434798;23551121;29563098;22419732;30002201;27478902;27289121;28899989", "title": "Benefit-Risk Assessment of Alogliptin for the Treatment of Type 2 Diabetes Mellitus.", "title_normalized": "benefit risk assessment of alogliptin for the treatment of type 2 diabetes mellitus" }

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BENEFIT-RISK ASSESSMENT OF ALOGLIPTIN FOR THE TREATMENT OF TYPE 2 DIABETES MELLITUS. 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BENEFIT-RISK ASSESSMENT OF ALOGLIPTIN FOR THE TREATMENT OF TYPE 2 DIABETES MELLITUS. 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BENEFIT-RISK ASSESSMENT OF ALOGLIPTIN FOR THE TREATMENT OF TYPE 2 DIABETES MELLITUS. 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BENEFIT-RISK ASSESSMENT OF ALOGLIPTIN FOR THE TREATMENT OF TYPE 2 DIABETES MELLITUS. DRUG SAFETY. 2019?UNK:1-7", "literaturereference_normalized": "benefit risk assessment of alogliptin for the treatment of type 2 diabetes mellitus", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "IT", "receiptdate": "20191206", "receivedate": "20191206", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17120296, "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" }, { "companynumb": "IT-ALKEM LABORATORIES LIMITED-IT-ALKEM-2019-09561", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MORE THAN OR EQUAL TO 1500MG OR MAXIMUM TOLERATED DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KAKU K, KISANUKI K, SHIBATA M AND OOHIRA T.. BENEFIT-RISK ASSESSMENT OF ALOGLIPTIN FOR THE TREATMENT OF TYPE 2 DIABETES MELLITUS. DRUG SAFETY. 2019?UNK:1-7", "literaturereference_normalized": "benefit risk assessment of alogliptin for the treatment of type 2 diabetes mellitus", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "IT", "receiptdate": "20191206", "receivedate": "20191206", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17120286, "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" }, { "companynumb": "IT-ALKEM LABORATORIES LIMITED-IT-ALKEM-2019-09573", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "ALOGLIPTIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "25 MILLIGRAM, OD", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALOGLIPTIN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MORE THAN OR EQUAL TO 1500MG OR MAXIMUM TOLERATED DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KAKU K, KISANUKI K, SHIBATA M AND OOHIRA T.. BENEFIT-RISK ASSESSMENT OF ALOGLIPTIN FOR THE TREATMENT OF TYPE 2 DIABETES MELLITUS. DRUG SAFETY. 2019?UNK:1-7", "literaturereference_normalized": "benefit risk assessment of alogliptin for the treatment of type 2 diabetes mellitus", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "IT", "receiptdate": "20191206", "receivedate": "20191206", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17120306, "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" }, { "companynumb": "IT-ALKEM LABORATORIES LIMITED-IT-ALKEM-2019-09552", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MORE THAN OR EQUAL TO 1500MG OR MAXIMUM TOLERATED DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KAKU K, KISANUKI K, SHIBATA M AND OOHIRA T.. BENEFIT-RISK ASSESSMENT OF ALOGLIPTIN FOR THE TREATMENT OF TYPE 2 DIABETES MELLITUS. DRUG SAFETY. 2019?UNK:1-7", "literaturereference_normalized": "benefit risk assessment of alogliptin for the treatment of type 2 diabetes mellitus", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "IT", "receiptdate": "20191206", "receivedate": "20191206", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17120299, "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" }, { "companynumb": "IT-ALKEM LABORATORIES LIMITED-IT-ALKEM-2019-09565", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MORE THAN OR EQUAL TO 1500MG OR MAXIMUM TOLERATED DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KAKU K, KISANUKI K, SHIBATA M AND OOHIRA T.. BENEFIT-RISK ASSESSMENT OF ALOGLIPTIN FOR THE TREATMENT OF TYPE 2 DIABETES MELLITUS. DRUG SAFETY. 2019?UNK:1-7", "literaturereference_normalized": "benefit risk assessment of alogliptin for the treatment of type 2 diabetes mellitus", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "IT", "receiptdate": "20191206", "receivedate": "20191206", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17120289, "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" }, { "companynumb": "IT-ALKEM LABORATORIES LIMITED-IT-ALKEM-2019-09567", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MORE THAN OR EQUAL TO 1500MG OR MAXIMUM TOLERATED DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KAKU K, KISANUKI K, SHIBATA M AND OOHIRA T.. BENEFIT-RISK ASSESSMENT OF ALOGLIPTIN FOR THE TREATMENT OF TYPE 2 DIABETES MELLITUS. DRUG SAFETY. 2019?UNK:1-7", "literaturereference_normalized": "benefit risk assessment of alogliptin for the treatment of type 2 diabetes mellitus", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "IT", "receiptdate": "20191206", "receivedate": "20191206", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17120282, "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" }, { "companynumb": "IT-ALKEM LABORATORIES LIMITED-IT-ALKEM-2019-09556", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MORE THAN OR EQUAL TO 1500MG OR MAXIMUM TOLERATED DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KAKU K, KISANUKI K, SHIBATA M AND OOHIRA T.. BENEFIT-RISK ASSESSMENT OF ALOGLIPTIN FOR THE TREATMENT OF TYPE 2 DIABETES MELLITUS. DRUG SAFETY. 2019?UNK:1-7", "literaturereference_normalized": "benefit risk assessment of alogliptin for the treatment of type 2 diabetes mellitus", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "IT", "receiptdate": "20191206", "receivedate": "20191206", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17120302, "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" }, { "companynumb": "IT-ALKEM LABORATORIES LIMITED-IT-ALKEM-2019-09559", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MORE THAN OR EQUAL TO 1500MG OR MAXIMUM TOLERATED DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KAKU K, KISANUKI K, SHIBATA M AND OOHIRA T.. BENEFIT-RISK ASSESSMENT OF ALOGLIPTIN FOR THE TREATMENT OF TYPE 2 DIABETES MELLITUS. DRUG SAFETY. 2019?UNK:1-7", "literaturereference_normalized": "benefit risk assessment of alogliptin for the treatment of type 2 diabetes mellitus", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "IT", "receiptdate": "20191206", "receivedate": "20191206", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17120280, "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" }, { "companynumb": "IT-ALKEM LABORATORIES LIMITED-IT-ALKEM-2019-09548", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MORE THAN OR EQUAL TO 1500MG OR MAXIMUM TOLERATED DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KAKU K, KISANUKI K, SHIBATA M AND OOHIRA T.. BENEFIT-RISK ASSESSMENT OF ALOGLIPTIN FOR THE TREATMENT OF TYPE 2 DIABETES MELLITUS. DRUG SAFETY. 2019?UNK:1-7", "literaturereference_normalized": "benefit risk assessment of alogliptin for the treatment of type 2 diabetes mellitus", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "IT", "receiptdate": "20191206", "receivedate": "20191206", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17120270, "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" }, { "companynumb": "IT-ALKEM LABORATORIES LIMITED-IT-ALKEM-2019-09554", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MORE THAN OR EQUAL TO 1500MG OR MAXIMUM TOLERATED DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KAKU K, KISANUKI K, SHIBATA M AND OOHIRA T.. BENEFIT-RISK ASSESSMENT OF ALOGLIPTIN FOR THE TREATMENT OF TYPE 2 DIABETES MELLITUS. DRUG SAFETY. 2019?UNK:1-7", "literaturereference_normalized": "benefit risk assessment of alogliptin for the treatment of type 2 diabetes mellitus", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "IT", "receiptdate": "20191206", "receivedate": "20191206", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17120300, "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" }, { "companynumb": "IT-ALKEM LABORATORIES LIMITED-IT-ALKEM-2019-09550", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MORE THAN OR EQUAL TO 1500MG OR MAXIMUM TOLERATED DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KAKU K, KISANUKI K, SHIBATA M AND OOHIRA T.. BENEFIT-RISK ASSESSMENT OF ALOGLIPTIN FOR THE TREATMENT OF TYPE 2 DIABETES MELLITUS. 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BENEFIT-RISK ASSESSMENT OF ALOGLIPTIN FOR THE TREATMENT OF TYPE 2 DIABETES MELLITUS. 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BENEFIT-RISK ASSESSMENT OF ALOGLIPTIN FOR THE TREATMENT OF TYPE 2 DIABETES MELLITUS. 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BENEFIT-RISK ASSESSMENT OF ALOGLIPTIN FOR THE TREATMENT OF TYPE 2 DIABETES MELLITUS. 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BENEFIT-RISK ASSESSMENT OF ALOGLIPTIN FOR THE TREATMENT OF TYPE 2 DIABETES MELLITUS. 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BENEFIT-RISK ASSESSMENT OF ALOGLIPTIN FOR THE TREATMENT OF TYPE 2 DIABETES MELLITUS. 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BENEFIT-RISK ASSESSMENT OF ALOGLIPTIN FOR THE TREATMENT OF TYPE 2 DIABETES MELLITUS. 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BENEFIT-RISK ASSESSMENT OF ALOGLIPTIN FOR THE TREATMENT OF TYPE 2 DIABETES MELLITUS. 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BENEFIT-RISK ASSESSMENT OF ALOGLIPTIN FOR THE TREATMENT OF TYPE 2 DIABETES MELLITUS. DRUG SAFETY. 2019?UNK:1-7", "literaturereference_normalized": "benefit risk assessment of alogliptin for the treatment of type 2 diabetes mellitus", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "IT", "receiptdate": "20191206", "receivedate": "20191206", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17120303, "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": "Fanconi anemia is a rare autosomal recessive disorder, clinically and genetically heterogeneous, characterized by typical clinical features, such as short stature, microcephaly, skeletal abnormalities, abnormal skin pigmentations, developmental delay and congenital heart, kidney anomalies etc. Pancytopenia leading to bone marrow failure occurs in the first decade. Patients with Fanconi anemia have a high risk of hematologic malignancies and solid tumors. The diagnosis of Fanconi anemia is based on cytogenetic testing for increased rates of spontaneous chromosomal breakage and increased sensitivity to diepoxybutane or mitomycin C. Fanconi anemia is a heterogeneous disorder, at least 15 complementation groups are described, and 15 genes in which mutations are responsible for all of the 15 Fanconi anemia complementation groups have been identified. Unlike other Fanconi anemia complementation groups, for complementation group D1 (FANCD1), the bone marrow failure is not a typical feature, but early-onset leukemia and specific solid tumors, most often medulloblastoma and Wilms tumor, are typical for this complementation group.", "affiliations": null, "authors": "Puchmajerová|A|A|;Švojgr|K|K|;Novotná|D|D|;Macháčková|E|E|;Sumerauer|D|D|;Smíšek|P|P|;Kodet|R|R|;Kynčl|M|M|;Křepelová|A|A|;Foretová|L|L|", "chemical_list": null, "country": "Czech Republic", "delete": false, "doi": "10.14735/amko2016s89", "fulltext": null, "fulltext_license": null, "issn_linking": "0862-495X", "issue": "29 Suppl 1()", "journal": "Klinicka onkologie : casopis Ceske a Slovenske onkologicke spolecnosti", "keywords": null, "medline_ta": "Klin Onkol", "mesh_terms": "D000483:Alleles; D005199:Fanconi Anemia; D024522:Genes, BRCA2; D006801:Humans; D009154:Mutation", "nlm_unique_id": "9425213", "other_id": null, "pages": "S89-92", "pmc": null, "pmid": "26691948", "pubdate": "2016", "publication_types": "D004740:English Abstract; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Fanconi Anemia, Complementation Group D1 Caused by Biallelic Mutations of BRCA2 Gene--Case Report.", "title_normalized": "fanconi anemia complementation group d1 caused by biallelic mutations of brca2 gene case report" }

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{ "abstract": "BACKGROUND\nHereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease that results in telangiectasia of the sinonasal tract, gastro-intestinal tract as well as possible arteriovenous malformations of the lung, liver and brain. One of the most common disease manifestations of HHT is epistaxis. Severe recurrent epistaxis necessitating iron therapy and blood transfusion is often managed with septodermoplasty. Its initial description was as an open surgical technique requiring nasal packing.\n\n\nMETHODS\nWe describe a modified approach to septodermoplasty done completely endoscopically and without nasal packing for a patient with severe epistaxis due to HHT.\n\n\nCONCLUSIONS\nThe described technique modifications for the presented case allowed for same day discharge following surgery, complete take of the skin graft and resultant epistaxis control that ended thepatient's transfusion dependency. The merits of these modifications should be further evaluated in a clinical trial.", "affiliations": "Department of Otolaryngology-Head and Neck Surgery, University of Ottawa, The Ottawa Hospital, 737 Parkdale Ave., Room 459, Ottawa, ON, K1Y 1J8, Canada. mbastianelli@toh.on.ca.;Department of Otolaryngology-Head and Neck Surgery, University of Ottawa, The Ottawa Hospital, 737 Parkdale Ave., Room 459, Ottawa, ON, K1Y 1J8, Canada. kiltysj@gmail.com.", "authors": "Bastianelli|Mark|M|;Kilty|Shaun J|SJ|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1186/s40463-015-0112-4", "fulltext": "\n==== Front\nJ Otolaryngol Head Neck SurgJ Otolaryngol Head Neck SurgJournal of Otolaryngology - Head & Neck Surgery1916-02081916-0216BioMed Central London 11210.1186/s40463-015-0112-4Case ReportTechnique modifications for septodermoplasty: an illustrative case Bastianelli Mark 613-798-5555 x18514mbastianelli@toh.on.ca Kilty Shaun J. 613-798-5555 x18514kiltysj@gmail.com Department of Otolaryngology-Head and Neck Surgery, University of Ottawa, The Ottawa Hospital, 737 Parkdale Ave., Room 459, Ottawa, ON K1Y 1J8 Canada Ottawa Hospital Research Institute (OHRI), Ottawa, ON Canada 30 12 2015 30 12 2015 2015 44 592 6 2015 22 12 2015 © Bastianelli and Kilty. 2015\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\nHereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease that results in telangiectasia of the sinonasal tract, gastro-intestinal tract as well as possible arteriovenous malformations of the lung, liver and brain. One of the most common disease manifestations of HHT is epistaxis. Severe recurrent epistaxis necessitating iron therapy and blood transfusion is often managed with septodermoplasty. Its initial description was as an open surgical technique requiring nasal packing.\n\nCase presentation\nWe describe a modified approach to septodermoplasty done completely endoscopically and without nasal packing for a patient with severe epistaxis due to HHT.\n\nConclusion\nThe described technique modifications for the presented case allowed for same day discharge following surgery, complete take of the skin graft and resultant epistaxis control that ended thepatient's transfusion dependency. The merits of these modifications should be further evaluated in a clinical trial.\n\nKeywords\nSeptodermoplastyHereditary hemorrhagic telangiectasiaEpistaxisissue-copyright-statement© The Author(s) 2015\n==== Body\nBackground\nHereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease, which results in blood vessel malformation most commonly within mucous membranes and the skin. In the late 19th century Osler, Weber and Rendu described a series of patients with a constellation of symptoms including frequent epistaxis, recurrent gastrointestinal bleeding, iron deficiency anemia and multiple telangiectasia on the vermillion border of the lips and fingertips [1–3]. These patients were subsequently recognized as a definite medical entity known as Osler Weber Rendu syndrome, now otherwise known as HHT.\n\nThe common mucosal vascular malformation that occurs in HHT, telangiectasia, often bleed spontaneously or with minimal trauma. Although the initial clinical disease presentation can vary, the most common symptom of patients with HHT is recurrent epistaxis. Epistaxis is typically the earliest sign of the disease while mucocutaneous and gastrointestinal telangiectasia develop progressively with age [4]. The average age of onset for epistaxis is 12 years of age, with nearly 100 % of patients affected by epistaxis by age 40 [5–7].\n\nTreatment for HHT-related epistaxis is focused on the reduction of the frequency and severity of bleeding. Multiple modalities have reportedly been used including oral tranexamic acid [8], and topical estrogen-containing ointment [9]. A relatively new modality of therapy has been Bevacizumab, a monocolonal antibody inhibitor of vascular endothelial growth factor (VEGF) [10]. Previous studies have demonstrated that intransal administration of Bevacizumab can significantly diminish the frequency and severity of epistaxis in this patient population [11–13]. Although strict medical management can reduce symptom severity, many patients are refractory to pure medical measures and require oral iron supplementation and/or regular blood transfusions. For patients who have failed medical therapy surgical options, including laser coagulation or septodermoplasty, are often employed. Laser ablation however usually requires multiple sessions and is less effective for lesions greater than 2 mm in diameter [14]. Currently, the gold standard for severe recurrent epistaxis for patients with HHT is septodermoplasty. This technique was initially described in 1962 by Saunders et al [15] and it involves the removal of affected nasal epithelium and its replacement with a split-thickness skin graft (STSG). A variation of this technique for severe epistaxis management, known as Young’s procedure [16] involves a septodermoplasty with complete nasal closure.\n\nThe objective of this report is to use an illustrative case to describe technique alterations for septodermoplasty that may improve patient care by providing an alternative for improved surgeon visualization, for rapid hemostasis and for secure STSG placement without nasal packing.\n\nCase presentation\nA 64 year old female known for HHT is referred to our clinic for recurrent epistaxis for nearly 50 years. She has had recurrent symptoms since the age of 16 when her condition was diagnosed. All three of her siblings also were diagnosed with HHT and her mother passed away from an intracranial hemorrhage. Eight years prior to presentation she had undergone a left-sided septodermoplasty via a lateral rhinotomy approach. This operation had significantly reduced the frequency of her symptoms and for several years her epistaxis was under control with the use of low dose thalidomide. However, she was referred to our clinic due to increased epistaxis severity and frequency over the prior 12 months necessitating more frequent transfusions.\n\nAt the time of consultation the patient was concerned about daily severe left sided epistaxis despite several months use of topical bevacizumab and oral tranexamic acid. She required intravenous iron and blood transfusions every two months. Her baseline hemoglobin at the time of our consultation was 75 g/L (normal = 120 – 160 g/L). Her HHT epistaxis severity score [17] was severe (normalized score 9.49). On examination, she had multiple telangiectasia on her fingers, face, lips and palate. Her endoscopic examination revealed bilateral telangiectasia along the nasal septum. There was extensive crusting along the entire left nasal cavity with which any manipulation resulted in immediate profuse epistaxis. Given the severity of the patient’s epistaxis despite medical therapy, she was offered endoscopic left-sided septodermoplasty. The surgical goals were to improve her quality of life by reducing the number and severity of epistaxis episodes while diminishing the need for blood transfusions. The patient was content with the treatment plan and agreed to undergo surgical intervention.\n\nOperative procedure\nThe endoscopic procedure was performed under general anesthesia with endotracheal intubation. The nasal cavity was prepared by inserting pledgets soaked in topical adrenaline (1:1000) placed in both nostrils for decongestion. Using a zero degree endoscope the residual STSG and mucosa of the left septum was dissected in a supraperichondrial plane that resulted in the expected significant diffuse hemorrhage. Immediate hemostasis was attained using a topical gelatin-thrombin matrix, Floseal (FloSeal Hemostatic Matrix; Baxter Healthcare Corporation, Deerfield, IL, USA) (Fig. 1). The mucosal defect (Fig. 2) measured approximately 3 cm in anterior-posterior dimension.Fig. 1 Left septodermoplasty demonstrating application of Floseal for hemostasis\n\nFig. 2 Left septodermoplasty demonstrating the septal mucosal defect\n\n\n\nA 4 x 2 cm split thickness skin graft was harvested from the right thigh, pie-crusted with a 15 blade and then placed endoscopically along the length of the septal defect. As seen in Fig. 3, the graft was placed with an overlap of the mucosa of the nasal floor and the residual superior septal mucosa. Finally, 2 mL of fibrin sealant (TISSEEL fibrin sealant, Baxter Healthcare Corporation, Deerfield, IL, USA) was then applied first to the edges then central portion of the STSG (Fig. 4). Packing was not used post-operatively and the patient was discharged home on the same day of surgery.Fig. 3 Left septodermoplasty demonstrating endoscopic STSG placement\n\nFig. 4 Endoscopic application of TISSEEL sealant over the STSG\n\n\n\nPost-operative course\nClinical follow-up two weeks after surgery (Fig. 5) showed that the entire graft had taken and the left-sided epistaxis had dramatically diminished. The patient was very content with the results of the procedure. At 6 months follow-up, her baseline hemoglobin had improved to 102 g/L and she was requiring transfusions every 4 months with her hematologist’s intent to stop the transfusions if her hemoglobin remained greater than 100 g/L. Her epistaxis severity score at 6 month follow up was mild (normalized score 3.05).Fig. 5 Endoscopic image at two weeks follow-up post left sided septodermoplasty\n\n\n\nDiscussion\nThe frequency and duration of epistaxis is a major determinant of quality of life in patients with HHT [18–21]. Septodermoplasty has been shown to adequately decrease symptom severity in 80-100 % of patients up to 6 months post-operatively [22–24]. Many variations of a septodermoplasty have previously been described. Saunders originally described using a lateral rhinotomy approach, which continues to be the most common approach to septodermoplasty. Other variations have included closure of nasal valve (Young’s procedure) [16] as well as buccal mucosal grafts instead of a STSG [25].\n\nAlthough different approaches have previously been reported we submit that the technique described herein provides several advantages. Firstly, under endoscopic guidance optimal visualization for the entire surgical field is achieved. Ultimately, this allows for increased precision when excising the mucosa as well as ensuring accurate placement of the STSG. Second hemostasis is readily and rapidly achieved with the use of a topical gelatin-thrombin matrix following excision of the nasal septal mucosa. A dry surgical field is imperative when placing the STSG as this diminishes the likelihood of graft hematoma and subsequent failure of the graft [26–28]. Finally, by using a fibrin tissue glue, nasal packing is not required to secure the graft, arrest bleeding, nor to prevent post-operative hematoma. Further, nasal packing can often be a significant source of pain and morbidity in the immediate post-operative period [29, 30]. The colonisation of nasal packing by Staphylococcus aureus could also result in STSG loss due to its subsequent infection and disrupted healing [29–32].\n\nConclusion\nEndoscopic septodermoplasty is a minimally invasive method of performing this classically open surgical procedure. Minimizing blood loss in this chronically anemic patient population is imperative, the use of a topical gelatin-thrombin matrix allows for rapid hemostasis for a sizeable surgical wound. This also provides a dry surgical bed to receive the skin graft and the use of fibrin tissue glue is a packing-free method of securing the skin graft that decreases postoperative patient discomfort as well as decreasing the chances of skin graft loss due to infection from nasal packing bacterial colonisation. We suggest that future studies should compare long-term efficacy of this technique and its cost-benefit with open septodermoplasty.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this Case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nBoth MB and SK conceived, designed, drafted and approved the final manuscript.\n\nAcknowledgement\nNone to declare.\n\nFunding source\nNo funding was ascertained by any of the authors in performing this project.\n==== Refs\nReferences\n1. Weber F Multiple hereditary developmental angiomata (telangiectases) of the skin and mucous membranes associated with recurring hemorrhages Lancet 1907 2 4377 160 2 \n2. Hj R Épistaxis répétées chez un sujet porteur de petits angiomes cutanés et muqueux Gazette des Hopitaux Civils et Militaires 1896 135 1322 23 \n3. Osler W On a family form of recurring epistaxis, associated with multiple telangiectases of the skin and mucous membranes Bull Johns Hopkins Hosp. 1901 12 333 7 \n4. Plauchu H de Chadarevian JP Bideau A Robert JM Age-related clinical profile of hereditary hemorrhagic telangiectasia in an epidemiologically recruited population Am J Med Genet 1989 32 3 291 7 10.1002/ajmg.1320320302 2729347 \n5. Bourdeau A Dumont DJ Letarte M A murine model of hereditary hemorrhagic telangiectasia J Clin Invest 1999 104 10 1343 51 10.1172/JCI8088 10562296 \n6. Berg J Porteous M Reinhardt D Gallione C Holloway S Umasunthar T Hereditary haemorrhagic telangiectasia: a questionnaire based study to delineate the different phenotypes caused by endoglin and ALK1 mutations J Med Genet 2003 40 8 585 90 10.1136/jmg.40.8.585 12920067 \n7. Sharathkumar AA Shapiro A Hereditary haemorrhagic telangiectasia Haemophilia 2008 14 6 1269 80 10.1111/j.1365-2516.2008.01774.x 19141168 \n8. Fernandez LA Garrido-Martin EM Sanz-Rodriguez F Ramirez JR Morales-Angulo C Zarrabeitia R Therapeutic action of tranexamic acid in hereditary haemorrhagic telangiectasia (HHT): regulation of ALK-1/endoglin pathway in endothelial cells Thromb Haemost 2007 97 2 254 62 17264955 \n9. Bergler W Sadick H Gotte K Riedel F Hormann K Topical estrogens combined with argon plasma coagulation in the management of epistaxis in hereditary hemorrhagic telangiectasia Ann Otol Rhinol Laryngol 2002 111 3 Pt 1 222 8 10.1177/000348940211100306 11913682 \n10. Dupuis-Girod S Ginon I Saurin JC Marion D Guillot E Decullier E Bevacizumab in patients with hereditary hemorrhagic telangiectasia and severe hepatic vascular malformations and high cardiac output Jama 2012 307 9 948 55 10.1001/jama.2012.250 22396517 \n11. Riss D Burian M Wolf A Kranebitter V Kaider A Arnoldner C Intranasal submucosal bevacizumab for epistaxis in hereditary hemorrhagic telangiectasia: a double-blind, randomized, placebo-controlled trial Head Neck 2015 37 6 783 7 10.1002/hed.23655 24595923 \n12. Karnezis TT Davidson TM Efficacy of intranasal Bevacizumab (Avastin) treatment in patients with hereditary hemorrhagic telangiectasia-associated epistaxis Laryngoscope 2011 121 3 636 8 10.1002/lary.21415 21344445 \n13. Simonds J Miller F Mandel J Davidson TM The effect of bevacizumab (Avastin) treatment on epistaxis in hereditary hemorrhagic telangiectasia Laryngoscope 2009 119 5 988 92 10.1002/lary.20159 19194865 \n14. Harvey RJ Kanagalingam J Lund VJ The impact of septodermoplasty and potassium-titanyl-phosphate (KTP) laser therapy in the treatment of hereditary hemorrhagic telangiectasia-related epistaxis Am J Rhinol 2008 22 2 182 7 10.2500/ajr.2008.22.3145 18416977 \n15. Saunders W Hereditary hemorrhagic telangiectasia, its familial pattern, clinical characteristics, and surgical treatment Arch Otolaryngol Head Neck Surg. 1962 76 245 60 10.1001/archotol.1962.00740050253010 \n16. Young A Closure of the nostrils in atrophic rhinitis J Laryngol Otol 1967 81 5 515 24 10.1017/S0022215100067426 6024992 \n17. Hoag JB Terry P Mitchell S Reh D Merlo CA An epistaxis severity score for hereditary hemorrhagic telangiectasia Laryngoscope 2010 120 4 838 43 10.1002/lary.20818 20087969 \n18. Merlo CA Yin LX Hoag JB Mitchell SE Reh DD The effects of epistaxis on health-related quality of life in patients with hereditary hemorrhagic telangiectasia Int Forum Allergy Rhinol 2014 4 11 921 5 10.1002/alr.21374 25145809 \n19. Pasculli G Resta F Guastamacchia E Di Gennaro L Suppressa P Sabba C Health-related quality of life in a rare disease: hereditary hemorrhagic telangiectasia (HHT) or Rendu-Osler-Weber disease Qual Life Res 2004 13 10 1715 23 10.1007/s11136-004-7865-y 15651542 \n20. Geisthoff UW Heckmann K D'Amelio R Grunewald S Knobber D Falkai P Health-related quality of life in hereditary hemorrhagic telangiectasia Otolaryngol Head Neck Surg 2007 136 5 726 33 10.1016/j.otohns.2006.12.019 17478205 \n21. Pfister M Zalaman IM Blumenstock G Mauz PS Baumann I Impact of genotype and mutation type on health-related quality of life in patients with hereditary hemorrhagic telangiectasia Acta Otolaryngol 2009 129 8 862 6 10.1080/00016480802468138 18855162 \n22. Ichimura K Tanaka H Yamamoto Y Nakamura K Nasal dermoplasty for Japanese hereditary hemorrhagic telangiectasia Auris Nasus Larynx 2006 33 4 423 8 10.1016/j.anl.2006.03.001 16707240 \n23. Fiorella ML Ross D Henderson KJ White RI Jr Outcome of septal dermoplasty in patients with hereditary hemorrhagic telangiectasia Laryngoscope 2005 115 2 301 5 10.1097/01.mlg.0000154754.39797.43 15689755 \n24. Ross DA Nguyen DB Inferior turbinectomy in conjunction with septodermoplasty for patients with hereditary hemorrhagic telangiectasia Laryngoscope 2004 114 4 779 81 10.1097/00005537-200404000-00037 15064642 \n25. Siegel MB Keane WM Atkins JF Jr Rosen MR Control of epistaxis in patients with hereditary hemorrhagic telangiectasia Otolaryngol Head Neck Surg 1991 105 5 675 9 1754250 \n26. Reddy S El-Haddawi F Fancourt M Farrant G Gilkison W Henderson N The incidence and risk factors for lower limb skin graft failure Dermatol Res Pract. 2014 2014 582080 25132847 \n27. Robson MC Krizek TJ Predicting skin graft survival J Trauma 1973 13 3 213 7 10.1097/00005373-197303000-00005 4571903 \n28. Kim S Chung SW Cha IH Full thickness skin grafts from the groin: donor site morbidity and graft survival rate from 50 cases J Korean Assoc Oral Maxillofac Surg 2013 39 1 21 6 10.5125/jkaoms.2013.39.1.21 24471013 \n29. Ardehali MM Bastaninejad S Use of nasal packs and intranasal septal splints following septoplasty Int J Oral Maxillofac Surg 2009 38 10 1022 4 10.1016/j.ijom.2009.05.012 19577902 \n30. Veluswamy A Handa S Shivaswamy S Nasal septal clips: an alternative to nasal packing after septal surgery? Indian J Otolaryngol Head Neck Surg 2012 64 4 346 50 10.1007/s12070-011-0388-2 24294576 \n31. Liedberg NC Reiss E Artz CP The effect of bacteria on the take of split-thickness skin grafts in rabbits Ann Surg 1955 142 1 92 6 10.1097/00000658-195507000-00011 14388615 \n32. Hogsberg T Bjarnsholt T Thomsen JS Kirketerp-Moller K Success rate of split-thickness skin grafting of chronic venous leg ulcers depends on the presence of Pseudomonas aeruginosa: a retrospective study PLoS One 2011 6 5 e20492 10.1371/journal.pone.0020492 21655269\n\n", "fulltext_license": "CC BY", "issn_linking": "1916-0208", "issue": "44()", "journal": "Journal of otolaryngology - head & neck surgery = Le Journal d'oto-rhino-laryngologie et de chirurgie cervico-faciale", "keywords": null, "medline_ta": "J Otolaryngol Head Neck Surg", "mesh_terms": "D000768:Anesthesia, General; D016063:Blood Loss, Surgical; D004724:Endoscopy; D004844:Epistaxis; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008875:Middle Aged; D019060:Minimally Invasive Surgical Procedures; D009297:Nasal Mucosa; D009300:Nasal Septum; D018570:Risk Assessment; D012720:Severity of Illness Index; D016038:Skin Transplantation; D013683:Telangiectasia, Hereditary Hemorrhagic; D016896:Treatment Outcome", "nlm_unique_id": "101479544", "other_id": null, "pages": "59", "pmc": null, "pmid": "26714786", "pubdate": "2015-12-30", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "24294576;19577902;18416977;15651542;16707240;15689755;14388615;21655269;12920067;25132847;22396517;4571903;18855162;1754250;24471013;25145809;19141168;15064642;19194865;6024992;10562296;20087969;2729347;21344445;14497539;11913682;17264955;17478205;24595923", "title": "Technique modifications for septodermoplasty: an illustrative case.", "title_normalized": "technique modifications for septodermoplasty an illustrative case" }

[ { "companynumb": "CA-CELGENEUS-CAN-2016104604", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "WHOLE BLOOD" }, "drugadditional": null, "drugadministrationroute": "041", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION FOR INFUSION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HEREDITARY HAEMORRHAGIC TELANGIECTASIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BLOOD" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "THALIDOMIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "020785", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "OFF LABEL USE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "THALOMID" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "WHOLE BLOOD" }, "drugadditional": null, "drugadministrationroute": "041", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION FOR INFUSION", "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": "BLOOD" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "IRON" }, "drugadditional": null, "drugadministrationroute": "041", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION FOR INFUSION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HEREDITARY HAEMORRHAGIC TELANGIECTASIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IRON" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "THALIDOMIDE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "020785", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULES", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "EPISTAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "THALOMID" } ], "patientagegroup": null, "patientonsetage": "64", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Epistaxis", "reactionmeddraversionpt": "19.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "BASTIANELLI M. TECHNIQUE MODIFICATIONS FOR SEPTODERMOPLASTY: AN ILLUSTRATIVE CASE.. JOURNAL OF OTOLARYNOLOGY- HEAD AND NECK SURGERY. 2015 DEC 30;59:.", "literaturereference_normalized": "technique modifications for septodermoplasty an illustrative case", "qualification": "3", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20161031", "receivedate": "20161031", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12897600, "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": "Combined spinal-epidural (CSE) analgesia is a frequently used method of labor analgesia. Although it is considered safe and effective, CSE can be complicated by local anesthetic systemic toxicity (LAST), a potentially life-threatening condition. We present a case of LAST that developed in a primigravida 50 minutes after uneventful placement of a CSE. Her symptoms resolved within 10 minutes of administering intralipid emulsion. She subsequently underwent cesarean delivery under spinal anesthesia for failure to progress without sequelae in the mother or infant. LAST in pregnancy can occur at traditionally subthreshold dosing; anesthesiologists must be vigilant to ensure prompt and effective treatment.", "affiliations": "From the *Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; †Department of Anesthesiology, Jackson Memorial Hospital, Miami, Florida; ‡Department of Anesthesiology, Mayo Clinic, Rochester, Minnesota; and §Department of Anesthesiology, University of Miami, Miami, Florida.", "authors": "Dun-Chi Lin|Jonathan|J|;Sivanesan|Eellan|E|;Horlocker|Terese T|TT|;Missair|Andres|A|", "chemical_list": "D000779:Anesthetics, Local; D000931:Antidotes; D005217:Fat Emulsions, Intravenous; D008012:Lidocaine", "country": "United States", "delete": false, "doi": "10.1213/XAA.0000000000000477", "fulltext": null, "fulltext_license": null, "issn_linking": "2325-7237", "issue": "8(9)", "journal": "A & A case reports", "keywords": null, "medline_ta": "A A Case Rep", "mesh_terms": "D000328:Adult; D015360:Analgesia, Epidural; D016362:Analgesia, Obstetrical; D000779:Anesthetics, Local; D000931:Antidotes; D002585:Cesarean Section; D005217:Fat Emulsions, Intravenous; D005260:Female; D006801:Humans; D060186:Infusions, Spinal; D008012:Lidocaine; D011041:Poisoning; D011247:Pregnancy; D016896:Treatment Outcome", "nlm_unique_id": "101637720", "other_id": null, "pages": "235-237", "pmc": null, "pmid": "28099175", "pubdate": "2017-05-01", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "12430104;17721262;21494132;22189574;22749556;23267002;23454825;25207682;26469367;27404223;7198411;9175963", "title": "Two for One: A Case Report of Intravenous Lipid Emulsion to Treat Local Anesthetic Systemic Toxicity in Term Pregnancy.", "title_normalized": "two for one a case report of intravenous lipid emulsion to treat local anesthetic systemic toxicity in term pregnancy" }

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"patientagegroup": null, "patientonsetage": "29", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "87.3", "reaction": [ { "reactionmeddrapt": "Renal failure", "reactionmeddraversionpt": "20.1", "reactionoutcome": null }, { "reactionmeddrapt": "Hypertension", "reactionmeddraversionpt": "20.1", "reactionoutcome": null }, { "reactionmeddrapt": "Palpitations", "reactionmeddraversionpt": "20.1", "reactionoutcome": null }, { "reactionmeddrapt": "Hypoalbuminaemia", "reactionmeddraversionpt": "20.1", "reactionoutcome": null }, { "reactionmeddrapt": "Incorrect route of drug administration", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anaesthetic complication", "reactionmeddraversionpt": "20.1", "reactionoutcome": null }, { "reactionmeddrapt": "Dysgeusia", "reactionmeddraversionpt": "20.1", "reactionoutcome": null }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { 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{ "abstract": "Limited information exists on the clinical behavior of the Ewing sarcoma family of tumors (ESFT) of the kidney. We reviewed the records of 30 patients (aged 8-69 years) with ESFT of the kidney seen at our institution between 1990 and 2013. We analyzed the event-free survival (EFS) and overall survival (OS) for associations with patient demographics, disease group, tumor size, tumor thrombus, and treatment. Six patients (20%) had tumors confined to the kidney (Group I), seven (23.3%) had local tumor extension beyond the kidney (Group II), and 17 (56.7%) had distant metastasis at diagnosis (Group III). Twenty-five (83.3%) patients underwent radical (19 upfront, five delayed) or partial (one upfront) nephrectomy, 25 (83.3%) chemotherapy and four (13.3%) radiotherapy. The 4-year EFS and OS were 43% (95% CI, 26-61%) and 63% (95% CI, 46-81%), respectively. EFS and OS were significantly associated with disease group and chemotherapy (p < 0.039). The presence of tumor thrombus in renal vein and/or inferior vena cava was associated with worse EFS (p = 0.053). Patients with disease confined to the kidney treated with nephrectomy and adjuvant chemotherapy have favorable outcomes. Local tumor extension beyond the kidney, tumor thrombus, and distant metastasis are unfavorable factors that warrant intensification or novel approaches of therapy.", "affiliations": "Department of Pediatrics, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.;Department of Investigational Cancer Therapeutics, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.;Department of Biostatistics, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.;Department of Pediatrics, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.;Department of Pediatrics, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.;Department of Pediatrics, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.;Department of Genitourinary Medical Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.;Department of Sarcoma Medical Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.;Department of Sarcoma Medical Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.;Department of Sarcoma Medical Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.;Department of Pediatrics, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.", "authors": "Tarek|Nidale|N|;Said|Rabih|R|;Andersen|Clark R|CR|;Suki|Tina S|TS|;Foglesong|Jessica|J|0000-0002-1283-717X;Herzog|Cynthia E|CE|;Tannir|Nizar M|NM|;Patel|Shreyaskumar|S|;Ratan|Ravin|R|;Ludwig|Joseph A|JA|;Daw|Najat C|NC|0000-0002-6941-8005", "chemical_list": null, "country": "Switzerland", "delete": false, "doi": "10.3390/cancers12102927", "fulltext": "\n==== Front\nCancers (Basel)\nCancers (Basel)\ncancers\nCancers\n2072-6694 MDPI \n\n33050651\n10.3390/cancers12102927\ncancers-12-02927\nArticle\nPrimary Ewing Sarcoma/Primitive Neuroectodermal Tumor of the Kidney: The MD Anderson Cancer Center Experience\nTarek Nidale 12* Said Rabih 3 Andersen Clark R. 4 Suki Tina S. 1 https://orcid.org/0000-0002-1283-717XFoglesong Jessica 15 Herzog Cynthia E. 1 Tannir Nizar M. 6 Patel Shreyaskumar 7 Ratan Ravin 7 Ludwig Joseph A. 7 https://orcid.org/0000-0002-6941-8005Daw Najat C. 1* 1 Department of Pediatrics, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; TSSuki@mdanderson.org (T.S.S.); jfoglesong@luriechildrens.org (J.F.); cherzog@mdanderson.org (C.E.H.)\n2 Department of Pediatrics and Adolescent Medicine, American University of Beirut Medical Center, Beirut 1107, Lebanon\n3 Department of Investigational Cancer Therapeutics, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; rhsaid@stgeorgehospital.org\n4 Department of Biostatistics, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; CRAndersen@mdanderson.org\n5 Division of Hematology, Oncology, Neuro-Oncology & Stem Cell Transplant, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL 60611, USA\n6 Department of Genitourinary Medical Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; ntannir@mdanderson.org\n7 Department of Sarcoma Medical Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; spatel@mdanderson.org (S.P.); RRatan@mdanderson.org (R.R.); jaludwig@mdanderson.org (J.A.L.)\n* Correspondence: nidale.tarek@aub.edu.lb (N.T.); ndaw@mdanderson.org (N.C.D.); Tel.: +1-713-792-6620 (N.C.D.)\n11 10 2020 \n10 2020 \n12 10 292727 8 2020 05 10 2020 © 2020 by the authors.2020Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).Simple Summary\nThe Ewing sarcoma family of tumors (ESFT)s rarely originate in the kidneys and their treatment is significantly different from the other common kidney tumors. The standard treatment for ESFT of other sites includes multi-agent chemotherapy and local control with surgery and or radiation therapy. Limited information exists on the clinical behavior and management of ESFTs of the kidney. This study aims to describe our experience with these rare tumors over a period of 23 years at MD Anderson Cancer Center to identify potential prognostic factors and help develop management guidelines. We found that the 4-year overall survival for patients without metastasis was 85% compared to 47% for patients with metastasis. Patients with tumors confined to the kidney treated with nephrectomy and adjuvant chemotherapy have favorable outcomes. Local tumor extension beyond the kidney, tumor thrombus, and distant metastasis are unfavorable factors that warrant intensification or novel approaches of therapy.\n\nAbstract\nLimited information exists on the clinical behavior of the Ewing sarcoma family of tumors (ESFT) of the kidney. We reviewed the records of 30 patients (aged 8–69 years) with ESFT of the kidney seen at our institution between 1990 and 2013. We analyzed the event-free survival (EFS) and overall survival (OS) for associations with patient demographics, disease group, tumor size, tumor thrombus, and treatment. Six patients (20%) had tumors confined to the kidney (Group I), seven (23.3%) had local tumor extension beyond the kidney (Group II), and 17 (56.7%) had distant metastasis at diagnosis (Group III). Twenty-five (83.3%) patients underwent radical (19 upfront, five delayed) or partial (one upfront) nephrectomy, 25 (83.3%) chemotherapy and four (13.3%) radiotherapy. The 4-year EFS and OS were 43% (95% CI, 26–61%) and 63% (95% CI, 46–81%), respectively. EFS and OS were significantly associated with disease group and chemotherapy (p < 0.039). The presence of tumor thrombus in renal vein and/or inferior vena cava was associated with worse EFS (p = 0.053). Patients with disease confined to the kidney treated with nephrectomy and adjuvant chemotherapy have favorable outcomes. Local tumor extension beyond the kidney, tumor thrombus, and distant metastasis are unfavorable factors that warrant intensification or novel approaches of therapy. \n\nEwing sarcomakidneyrenaltumor thrombustreatmentchemotherapysurvivaloutcome\n==== Body\n1. Introduction\nThe Ewing sarcoma family of tumors (ESFT) represents a group of small round cell neoplasms including osseous and extra-osseous Ewing sarcoma (EWS), soft tissue primitive neuro-ectodermal tumors (PNET), and malignant small-cell tumor of the thoracopulmonary region (Askin’s tumor) [1]. These highly aggressive sarcomas are poorly differentiated and commonly arise from the axial and appendicular skeleton of teenagers and young adults, but they also develop from soft tissue [2]. Extra-osseous EWS develops primarily in the trunk and extremities; rare sites including the retroperitoneum, head and neck, orbit, parameningeal, and genitourinary including bladder and prostate, have been described [3].\n\nESFT of the kidney is a very rare entity representing less than 5% of renal tumors [4]. It was first reported in 1975 [5] and has a non-specific clinical presentation and non-diagnostic radiological findings. Because of its rarity, these tumors are easily mistaken for other more common tumors involving the kidney. Tissue diagnosis is usually confirmed by demonstrating positive CD99 expression by immune-histochemistry and the presence of a reciprocal translocation between the EWS gene on chromosome 22 and members of the ETS family, most commonly FLI1 or ERG. The most common chromosomal translocation results in an oncogenic EWS-FLI1 fusion protein involved in tumorigenesis. The N-terminal EWSR1 gene belongs to the FET family of RNA binding proteins, which includes FUS, EWS, and TAF15. Presence of the fusion protein has been shown to recruit the BAF chromatin-remodeling complex (also known as SWI/SNF) to DNA binding sites, which dysregulates hundreds of genes and ultimately drives tumorigenesis [6,7].\n\nPrimary renal ESFTs have been characterized by a high potential for rapid metastasis leading to death [8,9]. In addition, there is no consensus on the optimal management of these tumors due to the paucity of available data. The current therapeutic approach has been extrapolated from the experience of treating ESFT of other sites with multimodal therapy, including multi-agent chemotherapy with surgery and, or radiation therapy [9,10,11]. Most published case series have described the clinical and, or histopathological features of these tumors [8,11,12,13,14], but few studies have described the treatment and patient outcomes [9,15,16,17]. Previous reports indicated that most patients with ESFT of the kidney present with advanced disease and have a guarded prognosis [18,19].\n\nThe purpose of the current study is to describe the clinical characteristics, treatment, and outcomes of patients with ESFT of the kidney who were seen at our institution to identify potential prognostic factors and help develop management guidelines for these rare tumors. \n\n2. Results\n2.1. Patient Characteristics\nOf 910 patients with ESFT seen at our institution over a period of 23 years, 31 (3.4%) had primary ESFT arising within the kidney. One patient was excluded from the analyses due to initial misdiagnosis and treatment as a renal cell carcinoma. The clinical characteristics of the 30 patients included in this study are summarized in Table 1. The most common presenting symptoms were flank or abdominal pain (70%) and hematuria (36.7%). Eight (26.7%) patients presented with systemic symptoms such as fever or weight loss. Imaging studies at presentation identified a large renal mass in all patients. In the 29 patients for whom data was available, tumor extension to the renal vein was present in two patients, to the inferior vena cava (IVC) in six, and to the IVC and right atrium in one. The diagnosis was made by primary tumor resection in 19 (63.3%) patients and by biopsy in 11 (36.7%) patients. EWS gene rearrangement was found in 17 of 19 tested tumors (89.5%) by polymerase chain reaction or fluorescent in situ hybridization analysis.\n\nSix patients (20%) had tumor confined to the kidney (Group I), seven patients (23.3%) had local tumor extension beyond the kidney (Group II), and 17 patients (56.7%) had metastatic disease at diagnosis (Group III). The most common sites of metastasis were the lungs (n = 8, 47%) and bones (n = 6, 35.3%). Metastasis to the liver (n = 2), bone marrow (n = 2) and leptomeninges (n = 1) was also seen. The age distribution was similar among the three groups. The median largest tumor dimension was 11 cm (range, 4–19 cm). \n\n2.2. Treatment\n2.2.1. Surgery\nAll but one of the 13 (92.3%) patients in group I and group II underwent upfront nephrectomy (n = 11) or partial nephrectomy (n = 1); one patient in group II with tumor extension into the right atrium underwent a tumor biopsy followed by neoadjuvant chemotherapy and radical nephrectomy (patient #11). Of the 17 patients with metastatic disease at diagnosis, 10 (58.8%) patients had a tumor biopsy initially, and seven (41.2%) had upfront nephrectomy. Of the ten patients who had a biopsy initially, one patient had upfront nephrectomy followed by chemotherapy, and nine received neoadjuvant chemotherapy with delayed nephrectomy in four. Four patients did not undergo surgery because of disease progression while receiving chemotherapy (n = 3) and achieving complete remission with chemotherapy alone (n = 1), and data was not available in one patient (n = 1).\n\n2.2.2. Chemotherapy\nVarious chemotherapeutic agents and regimens were used and are summarized in Table 2. Of the 29 patients on whom data is available, four patients did not receive chemotherapy or received only one chemotherapy cycle due to patient refusal (n = 2), delay in establishing the diagnosis (n = 1), or unknown reason (n = 1). The most commonly used chemotherapeutic agents were vincristine, cyclophosphamide, doxorubicin, ifosfamide, etoposide, cisplatin, irinotecan, and temozolomide. The most common initial chemotherapy used was vincristine, doxorubicin, and cyclophosphamide (VDC) either alone (n = 7, 23.3%) or in combination with ifosfamide and etoposide (IE) (n = 7, 23.3%). The second most common combination used was vincristine, doxorubicin, and ifosfamide (VDI).\n\nOf the six group I patients, four patients received adjuvant chemotherapy: VDC alone (n = 1), VDC alternating with IE (n = 1), VDC with VDI (n = 1), or ifosfamide and doxorubicin (ID) alternating with cisplatin and etoposide (PE) (n = 1). The remaining two patients were non-compliant and received only one cycle of chemotherapy (patient #2, 6).\n\nOf the seven group II patients, five patients received adjuvant chemotherapy, and one patient with tumor extending through the IVC to the right atrium underwent an initial biopsy followed by neoadjuvant chemotherapy and delayed nephrectomy. These patients received the following combinations: VDC (n = 2), VDC alternating with IE (n = 2), VDI (n = 1) or other (n = 1). Two patients also received maintenance chemotherapy with irinotecan and temozolomide. The seventh patient with a tumor thrombus in the renal vein (patient #13) did not receive any chemotherapy as part of his primary treatment.\n\nOf the 17 group III patients, 15 patients received chemotherapy, including VDC (n = 4), VDC alternating with IE (n = 4) or with PE (n = 1), VDI alone (n = 1) or combined with PE (n = 2), and other combinations (n = 3). One patient received only one cycle of chemotherapy (patient #27) and data was not available in another patient (patient #24).\n\n2.2.3. Radiation Therapy\nRadiotherapy was used in a small number of patients: none in group I, one patient in group II (patient #11) received 45Gy to the tumor bed, and three patients in group III received radiation to the tumor bed (n = 2; patients #15, 16) and metastatic bone lesions (n = 3; patients #14, 15, and 16). \n\n2.3. Patient Outcomes\nOf the 30 patients, 13 (43%) died, and 18 (60%) experienced relapse, progression, or death. Median event-free survival (EFS) and overall survival (OS) were 1.5 years and 5.5 years, respectively, with median follow-ups of 0.9 years and 1.9 years, over a range of 0.3 years to 15.4 years (Figure 1). The 4-year rates of EFS and OS for the 30 patients were 43% (95% CI, 26–61%) and 63% (95% CI, 46–81%), respectively. The 4-year rates of EFS and OS for patients without metastasis at diagnosis were 54% (95% CI, 27–81%) and 85% (95% CI, 65–100%), respectively, compared to those with metastasis 35% (95% CI, 13–58%) and 47% (95% CI, 23–71%), respectively.\n\nOf the six patients with disease confined to the kidney (group I), four patients survived without evidence of disease. The remaining two patients, both of whom were not compliant with adjuvant chemotherapy, developed local recurrence: one had a short follow up of 11 months, and the other eventually died of metastatic disease. \n\nOf the seven patients with local tumor extension beyond the kidney (group II), four patients survived. None of these four patients had tumor extension to the renal vein or IVC, and all four underwent primary radical nephrectomy followed by adjuvant chemotherapy. Two of these four patients survived without evidence of disease, and the other two patients were alive with disease, one of whom had a late relapse at local and distant sites, and the second had a local relapse followed by pulmonary relapse. The remaining three patients died of disease; all three patients had a tumor thrombus at diagnosis. One of these three patients underwent primary radical nephrectomy and caval thrombectomy followed by adjuvant chemotherapy, then developed local relapse followed by pulmonary relapse. The second patient underwent upfront nephrectomy without adjuvant chemotherapy, then developed lung metastasis. The third patient underwent an initial biopsy followed by neoadjuvant chemotherapy, secondary radical nephrectomy and thrombectomy followed by radiation therapy 45Gy, then developed lung metastasis.\n\nOf the 17 patients with metastatic disease (group III), all but one patient (94.1%) had tumor recurrence or progression on therapy. Three patients in this group (patients #19, 23, and 24) who started chemotherapy a median of 8 weeks (range, 7–9 weeks) after initial nephrectomy developed lung nodules after upfront tumor resection and before initiation of chemotherapy. Two of these three patients had a tumor thrombus extending through the IVC, and one had a pulmonary embolus after surgery without evidence of distant venous thrombus.\n\n2.4. Prognostic Factors\nAll four patients with tumors confined to the kidney (Group I) who underwent radical nephrectomy followed by adjuvant chemotherapy were alive and disease-free. Three of 5 patients with local tumor extension beyond the kidney without distant metastasis (Group II) who underwent initial nephrectomy followed by adjuvant chemotherapy developed local and distant relapse and one patient (with a tumor thrombus extending to the right atrium) who received neoadjuvant chemotherapy, delayed nephrectomy and radiation to the tumor bed suffered a distant relapse. The presence of renal vein or IVC thrombus may contribute to the development of early lung metastasis. Three of five patients with a tumor thrombus in the renal vein or IVC and no metastasis at diagnosis developed metastasis to the lung within 2.5 months after nephrectomy and before initiating chemotherapy. Metastatic disease at diagnosis was associated with an adverse outcome; all but one patient with metastasis died of disease.\n\nWe analyzed EFS and OS for associations with patient demographics, tumor size, disease group, presence of metastasis, tumor thrombus, and treatment. There were no significant associations between EFS or OS with age, sex, race, or ethnicity. There was a trend for worse EFS for patients with larger tumors (p = 0.07), but not with OS (p = 0.13). Importantly, we found significant associations between EFS (p = 0.039) and OS (p = 0.025) with disease group (Figure 2). As expected, the presence of metastasis was associated with worse EFS (p = 0.058) and OS (p = 0.029). Also, the presence of thrombus in the renal vein and, or the IVC was associated with worse EFS (p = 0.053), but the association with OS did not reach statistical significance (p = 0.15) (Figure 3). Furthermore, EFS (p < 0.0001) and OS (p = 0.036) were significantly associated with the use of chemotherapy (Figure 4), but not with whether the patient had surgery or not (p > 0.16). Timing of nephrectomy (upfront vs. delayed) was significantly associated with OS; 6 of 20 patients (30%) who underwent upfront nephrectomy died, whereas 4 of 5 patients (80%) who underwent delayed surgery died (p = 0.041). The association with EFS did not reach statistical significance (p = 0.20). \n\n3. Discussion\nIn this study, we reviewed our experience with 30 patients with ESFT of the kidney who were seen at our institution over a period of 23 years. We found that 20% of the patients had tumors confined to the kidney, 23.3% had tumors extending locally beyond the kidney (capsular invasion, perinephric tissue invasion, lymphovascular invasion, presence of renal vein and, or IVC thrombus, or extension within the abdomen excluding the liver), and 56.7% had metastasis at diagnosis. The 4-year rates of EFS and OS for patients without metastasis at diagnosis were 54% (95% CI, 27–81%) and 85% (95% CI, 65–100%), respectively, compared to those with metastasis 35% (95% CI, 13–58%) and 47% (95% CI, 23–71%), respectively. Patient outcomes were significantly associated with disease group, presence of metastasis, presence of tumor thrombus, and the use of chemotherapy.\n\nOf all patients with ESFT seen at our institution, 3.4% had their tumors originating from the kidney. This rate is higher than the 1.5% rate reported by Zollner et al. [17], which could reflect the referral pattern to our institution and, or a prior underestimation of the true incidence of these tumors. In fact, reported cases of primary renal ESFT have been more frequent in recent years, mainly due to improved molecular studies, which allowed a more accurate diagnosis of renal tumors. The diagnosis of primary renal ESFT can be challenging. In addition to the morphological and immunohistochemical features, the diagnosis requires confirmation by identifying the pathognomonic genetic alteration. The 2020 WHO classification of soft tissue and bone tumours defines Ewing sarcoma as a small round cell sarcoma showing gene fusions involving one member of the FET family of genes (usually EWSR1) and a member of the ETS family of transcription factors [20]. In our series, we observed a preponderance for male sex (66.7%) and young adults (median age at diagnosis 30.5 years) as previously described [10,14,21]. The age group is somewhat different from the age distribution of EWS in general, which is diagnosed at a younger age usually less than 20 years old [2,22]. Similar to previous reports [10,11,12,15,17,21,23], the presenting symptoms of primary renal ESFT are non-specific as other renal tumor malignancies and various benign conditions may have a similar presentation [24]. The median largest dimension of the tumor at diagnosis was 11 cm, with a trend for worse EFS for patients with larger tumors. Tumor size has been associated with an unfavorable outcome in ESFT [25,26]. \n\nOur data showed that 56.7% of patients presented with metastatic disease at diagnosis, mainly to the lungs, liver, and bones. Additionally, three patients developed metastasis to the lung soon after diagnosis and before initiation of systemic therapy. These results are in concordance with previous reports describing metastasis in 40−65% of newly-diagnosed patients with primary renal EWS/PNET [11,16,17,23]. The rate of metastatic disease at diagnosis is significantly higher than that reported for patients with EWS of all sites [2,25,26]. This high incidence of metastatic disease reflects the aggressive nature of this tumor or a delay in diagnosis since the retroperitoneum is an ample space that allows growth of the tumor before manifestation of symptoms. \n\nThe diagnosis of primary renal ESFT is challenging due to delayed symptoms, non-specific clinical presentation, and non-distinctive radiological features [11,12,21,23]. In fact, Lee et al. showed that the most common and representative imaging elements were the presence of a large necrotic and hemorrhagic mass with extensive venous thrombosis, similar to advanced renal cell carcinoma [27]. Other investigators suggested that some features may indicate a PNET rather than a renal cell carcinoma [27,28,29,30,31] including (1) the presence of bulky disease, (2) an endophytic infiltrative growth pattern, (3) the presence of multiple irregular septum-like structures, (4) the difference in the pattern of necrosis and hemorrhage within the mass that tends to be multifocal and diffuse in PNET and central in renal cell carcinoma, (5) the very weak enhancement of the tumor compared to the normal renal cortex and (6) a higher rate of renal vein thrombosis and distant metastasis. Further radiological studies are warranted to elucidate potential radiological characteristic features.\n\nOur study showed that patients with disease confined to the kidney who underwent a complete resection followed by adjuvant chemotherapy had a favorable outcome, contrary to patients who did not complete recommended adjuvant treatment. We also observed that patients with local extension beyond the kidney responded initially to surgery and adjuvant chemotherapy, but had a significant rate of relapse (mainly local failure followed by distant metastasis) and that the presence of renal vein or IVC thrombus could contribute to the development of early pulmonary metastasis. Additionally, this study showed that despite several patients with metastatic disease having had an initial response to systemic chemotherapy, all but one of the 17 patients died of disease. Likewise, reported cases in the literature showed a high risk for recurrence/metastasis in patients with localized disease treated with nephrectomy alone [16,32,33] and poor outcomes in patients with metastatic disease [9,23]. Similar to ESFTs of all sites, the outcome of our patients with metastatic tumors of the kidney was dismal despite multimodal therapy, highlighting the need for novel treatment approaches for this very high-risk group.\n\nOur findings suggest that surgery with adjuvant chemotherapy for patients with tumor confined to the kidney is potentially curative. Our results also affirm the importance of early initiation of chemotherapy before the development of metastasis and suggest a potential role for radiation therapy in local control. The standard of care for patients with ESFTs of all sites consists of neoadjuvant chemotherapy followed by local control (surgery and, or radiation therapy) and further chemotherapy. Our patients with primary ESFTs of the kidney who underwent upfront nephrectomy did not appear to have had an adverse survival outcome. In fact, 12 of our 13 patients with non-metastatic disease had upfront surgery and had a favorable outcome when adjuvant chemotherapy was used. Our finding of a worse survival for patients who underwent delayed nephrectomy likely reflects the advanced disease stage in these patients rather than a delay in local control. For Ewing sarcoma of all sites, radiotherapy is currently recommended for unresectable tumors or unexpected positive margins [34] and may play a role in the local control of primary renal tumors with local extension beyond the kidney [10]. Our patient with group II disease who received radiotherapy to the tumor bed did not have a local relapse but a distant relapse. Among patients with primary renal Ewing sarcoma treated according to the EURO.EWING.99 protocol, patients with locally advanced disease had local disease control and improved outcome when they received radiotherapy to the tumor bed [17]. A larger study of patients of primary EFTS of the kidney with similar disease extent treated in a homogenous fashion is needed to determine the optimal timing (upfront vs. delayed) of surgery and the role of radiation therapy in local control.\n\nThree of our five patients with non-metastatic tumors and a tumor thrombus in the renal vein or IVC developed metastasis to the lung within 2.5 months after nephrectomy, suggesting a potential benefit from using neoadjuvant chemotherapy or initiation of systemic therapy soon after tumor resection [35]. The current standard approach to the most common primary renal tumors, renal cell carcinoma (RCC) in adults and Wilms tumor in children, in North America is upfront surgery whenever feasible. A renal mass biopsy may be obtained in selected patients such as those with unresectable or metastatic tumors as it allows early initiation of neoadjuvant chemotherapy and potentially improve tumor resectability. On the other hand, a renal biopsy is highly recommended in cases where the diagnosis of RCC or Wilms tumor is doubtful based on imaging findings. If the diagnosis of primary EFTS of the kidney is established by biopsy, administration of neoadjuvant chemotherapy may prevent the development of metastatic disease and offers the advantage of administering ifosfamide, a potentially nephrotoxic drug, prior to surgical consolidation. Although the risks previously associated with biopsy of renal tumors, including tumor dissemination along the track and concerns for inaccuracy in diagnosis, have become rare [28,29,30], performing a renal tumor biopsy at diagnosis is usually avoided. In all 11 patients from our cohort who underwent a percutaneous biopsy, no complications were reported, and the specimen obtained was adequate for an accurate immunohistological diagnosis and EWS gene rearrangement testing (7 of 9 tested positive). Successful percutaneous biopsies have been reported in the literature to diagnose primary renal ESFT [16,35,36,37] and should be considered in selected patients. \n\nOur study was limited by its retrospective nature, the small number of patients, the unavailability of complete data for some patients, the heterogeneity of the treatments received over the prolonged study duration, and the short duration of follow up for certain patients. In addition, molecular testing by either fluorescent in situ hybridization (FISH) or polymerase chain reaction (PCR) was not commonly performed in the 1990’s to confirm the diagnosis of ESFT [38] and hence not required for inclusion in this study, but it is currently routinely performed for proper characterization of ESFTs. The small number of patients in our study may not have permitted the detection of significant differences among variables and limited our ability to make definitive conclusions. A larger study of patients with molecularly confirmed ESFTs who are treated homogenously is needed to make firm conclusions about impact of therapy and survival outcomes. The rarity of primary renal EWS makes a prospective study not feasible. \n\n4. Materials and Methods\nWe searched the tumor registry database at MD Anderson Cancer Center to identify all patients with histologically proven primary renal ESFT who were diagnosed between January 1990 and December 2013. The diagnosis of EWS/PNET was based on histology, and the morphological appearance of the tumor combined with immunohistochemistry. Data on molecular testing of the tumor was collected when available, but confirmation by molecular testing was not required for study inclusion. Information regarding the clinical characteristics, treatment, and outcome of patients was collected by reviewing the medical records. All available reports on pathology findings and imaging studies were reviewed. Tumor size was obtained from measurements of pathological specimens from pathology reports for patients who underwent upfront nephrectomy or from reports of initial imaging studies for patients who did not. This retrospective review was approved by the Institutional Review Board at MD Anderson Cancer Center (PA13-0760).\n\n4.1. Patient Classification\nPatients were classified into three categories according to disease extension at diagnosis: (a) Group I was defined as a tumor confined to the kidney that was completely resected with negative resection margins, (b) Group II was defined as a tumor that extended locally beyond the kidney without distant metastasis with one of the following: (1) capsular invasion, (2) perinephric tissue invasion, (3) lymphovascular invasion, (4) presence of renal vein and, or IVC thrombus, or (5) tumor extension within the abdomen excluding the liver, (c) Group III was defined as the presence of distant metastatic disease.\n\n4.2. Statistical Methods \nThe EFS and OS were calculated from the time of diagnosis. For EFS, an event was defined as relapse/progression, second malignant neoplasm, or death from any cause, whichever occurred first. Local failure was defined as relapse in the operative bed, abdomen outside the operative bed, or pelvis; tumor spread to the liver was considered distant metastasis. OS and EFS were estimated using Kaplan-Meier plots [39], together with corresponding estimates of the median survival, and the median and range of follow-up time. The 4-year EFS and OS were estimated as percentages with 95% Wald confidence intervals.\n\nAssociations between EFS or OS and discrete variables including age, sex, race, ethnicity, tumor size, disease group, presence of metastasis, tumor thrombus, surgery, and chemotherapy were summarized by Kaplan-Meier models and assessed by the log-rank test. In the analysis of outcome survival in relation to chemotherapy use, patients who received only one cycle of chemotherapy were considered as not having received chemotherapy. In cases where the discrete variable had more than two levels, pairwise comparisons by the log-rank test were performed, and Hommel-adjusted p-values were reported to compensate for multiple comparisons. The Cox proportional hazard model was used to assess associations between EFS or OS and continuous variables (age and tumor size); a penalized spline was used to ensure proportionality of hazards in the models with relation to tumor size. A 5% level of statistical significance was assumed in all analyses. All statistical analyses were performed using R statistical software (version 3.6.3, R Core Team 2020).\n\n5. Conclusions\nPrimary renal ESFT is a rare presentation of extraosseous EWS that may affect young adults and should be included in the differential diagnosis of primary renal tumors. Local tumor extension beyond the kidney, tumor thrombus and distant metastasis are unfavorable prognostic factors. The mortality rate is high for patients with locally advanced and metastatic disease despite multimodal therapy approaches. In patients with localized disease, complete surgical resection and adjuvant chemotherapy could provide long-term disease-free survival. Local tumor extension beyond the kidney is associated with a high risk of local and, or distant relapse, suggesting the need for further intensification of therapy. Confirmation of our findings in a larger cohort of patients with established molecular diagnosis treated in a homogenous fashion is needed.\n\nAcknowledgments\nThe authors would like to thank Kim Sung for her assistance in data collection.\n\nAuthor Contributions\nConceptualization, N.T. and N.C.D.; Data curation, N.T. and T.S.S.; Formal analysis, C.R.A.; Methodology, N.T. and N.C.D.; Supervision, N.C.D.; Writing—original draft, N.T., R.S. and N.C.D.; Writing—review & editing, N.T., J.F., C.E.H., N.M.T., S.P., R.R., J.A.L. and N.C.D. All authors have read and agreed to the published version of the manuscript.\n\nFunding\nThis research received no external funding.\n\nConflicts of Interest\nThe authors declare no conflict of interest.\n\nFigure 1 Overall survival and event-free survival distributions for 30 patients with ESFTs of the kidney. Shaded regions are 95% confidence intervals with darker shading where these overlap.\n\nFigure 2 Overall survival and event-free survival distributions according to the disease group.\n\nFigure 3 Overall survival and event-free survival distributions according to the presence of thrombus in the renal vein and, or IVC.\n\nFigure 4 Overall survival and event-free survival distributions according to the use of chemotherapy.\n\ncancers-12-02927-t001_Table 1Table 1 Clinical Characteristics of 30 Patients with Primary ESFT of the Kidney.\n\nCharacteristic\tNo. (%)\t\nAge at diagnosis, years\t\n\t\nMedian\t30.5\t\nRange\t(8−69)\t\nSex\t\n\t\nMale\t20 (66.7)\t\nFemale\t10 (33.3)\t\nRace\t\n\t\nWhite\t29 (96.7)\t\nAsian\t1 (3.3)\t\nEthnicity\t\n\t\nNon-Hispanic\t19 (65.5)\t\nHispanic\t9 (31)\t\nOther\t1 (3.4)\t\nGroup\t\n\t\nI\t6 (20)\t\nII\t7 (23.3)\t\nIII\t17 (56.7)\t\nTumor size, cm\t\n\t\nMedian\t11\t\nRange\t(4−19)\t\nThrombus in renal vein or inferior vena cava *\t\n\t\nYes\t9 (31)\t\nNo\t20 (69)\t\nTreatment ^\t\n\t\nUpfront radical nephrectomy\t19 (65.5)\t\nDelayed radical nephrectomy\t5 (17.2)\t\nUpfront partial nephrectomy\t1 (3.4)\t\nChemotherapy\t25 (86.2)\t\nRadiation therapy\t4 (13.3)\t\n* Data not available for one patient; ^ Data not available about surgery for one patient and chemotherapy in another patient.\n\ncancers-12-02927-t002_Table 2Table 2 Clinical characteristics, treatment and outcomes of 30 patients with primary ESFT of the kidney.\n\nPatient\tAge (Years)\tEthnicity/Sex\tEWS Rearrangement \n(PCR and/or FISH)\tTumor Extent\tNephrectomy\tPrimary Treatment \nChemotherapy, \nRadiation Therapy\tSite of First Relapse, Time from Diagnosis\tPatient Outcome\t\nGroup I patients: Tumor confined to the kidney\t\n1\t14\tH/M\t+\tNone\tUpfront\tVDC, IE × 14 cycles, \nNo RT\t\n\tAlive, NED, 32 mo\t\n2\t21\tW/M\t+\tNone\tUpfront\tVDC × 1 cycle \nNon compliance, No RT\tLocal, 6 mo \nlung, 12 mo\tDead, 21 mo\t\n3\t24\tW/F\tD/U\tNone\tUpfront\tVDC × 4 cycles \nVDI × 2 cycles, No RT\t\n\tAlive, NED, 185 mo\t\n4\t27\tW/F\t+\tNone\tUpfront\tVDC, No RT\t\n\tAlive, NED, 97 mo\t\n5\t31\tAs/F\tD/U\tNone on surgical specimen \n(Questionable RV and IVC thrombus on imaging)\tUpfront \n(Preoperative embolization)\tID, PE × 15 weeks \nNo RT\t\n\tAlive, NED, 132 mo\t\n6\t41\tH/M\t+\tNone\tUpfront \n(partial nephrectomy)\tVDCA × 1 cycle \nNon compliance, No RT\tLocal recurrence, 9 mo\tAWD, 11 mo\t\nGroup II patients: Tumor extending beyond the kidney\t\n7\t18\tW/M\t+\tD/U\tUpfront\tVDC, IE × 1 yr, \nNo RT\tRetroperitoneal, lungs, bone, 9 yrs\tAWD, 134 mo\t\n8\t23\tW/M\t+\tPerinephric fat, \nLV invasion \nadrenal gland, tail of pancreas\tUpfront\tVDI × 1 cycle, \nVAC × 3 cycles \nVD × 2 cycles \nIrT × 8 cycles, No RT\t\n\tAlive, NED, 25 mo\t\n9\t32\tW/M\tD/U\tPerinephric fat, \nLV invasion\tUpfront\tVDC × 6 cycles \nNo RT\tLocal, 33 mo \nlungs, 38 mo\tAWD, 37 mo\t\n10\t34\tH/F\t+\tPerinephric fat\tUpfront\tVDI × 6 cycles, \nIrT × 8 cycles, No RT\t\n\tAlive, NED, 25 mo\t\n11\t12\tW/M\t- \n(FISH and PCR)\tPerinephric fat, LNs, RV and IVC thrombus \n(RA thrombus on imaging)\tDelayed \n(following 15 weeks)\tVDC, IE × 45 weeks \nRT, tumor bed, 45Gy\tLungs, 17 mo\tDead, 65 mo\t\n12\t45\tW/M\tD/U\tPerinephric fat, LNs, RV and IVC thrombus\tUpfront\tVDC × 4 cycles \nNo RT\tLocal, 28 mo \nlungs, 5 yrs\tDead, 89 mo\t\n13\t69\tW/F\tD/U\tRV thrombus\tUpfront\tNone\tLungs, 4 mo\tDead, 22 mo\t\nGroup III patients: Metastatic disease\t\n14\t8\tW/M\t+\tBone and BM\tUpfront\tVDC, IE \nRT, bone metastasis\tD/U\tLost to follow up, \nAWD, 3 mo\t\n15\t9\tH/F\t+\tLNs, Bone\tDelayed\tVDIE × 6 cycles \nVI × 2 cycles \nRT, tumor bed, 45Co-60 & bone metastasis, 55.8Co-60\tD/U\tAWD, 10 mo\t\n16\t18\tAr/F\t+\tLocal invasion, LNs, bone and BM\tDelayed \n(following6 cycles)\tVDC, IE × 14 cycles \nRT, tumor bed, 50.4Gy & bone metastasis\tBone and BM, 20 mo\tDead, 46 mo\t\n17\t19\tH/M\t+\tLungs\tNo\tVDI × 6 cycles \nPE × 3 cycles \nVIrT × 2 cycles, No RT\tLocal progression, 5 mo\tDead, 21 mo\t\n18\t22\tH/M\t+\tLocal invasion, LNs, bone\tDelayed \n(following 4 cycles)\tVDC × 2 cycle, \nPE × 3 cycles, No RT\tDistant progression, bones, 4 mo\tDead, 10 mo\t\n19\t23\tW/M\tD/U\tPerinephric fat \n(post-operative pulmonary embolism, followed by lung metastases)\tUpfront\tVDI × 6 cycles \nNo RT\tLungs, 11 mo\tDead, 22 mo\t\n20\t25\tH/M\tD/U\tRV and IVC thrombus, lungs\tUpfront\tVDC × 4 cycles \nNo RT\tDistant progression, lungs, 7 mo\tDead, 16 mo\t\n21\t30\tW/M\tD/U\tRV thrombus, lungs\tUpfront\tVDC, No RT\tD/U\tAWD, 8 mo\t\n22\t32\tW/F\t- \n(PCR)\tLNs, RV and IVC thrombus, lungs\tDelayed \n(following 4 cycles)\tPE × 2 cycles \nPE/Taxol × 3 cycles \nNo RT\tDisease progression, D/U, 7 mo\tDead, 16 mo\t\n23\t32\tH/M\t+\tPerinephric fat, RV and IVC thrombus \n(Lung nodules identified prior to chemo, absent at initial imaging)\tUpfront \n(preoperative embolization)\tVDC × 8 cycles, \nVIrT × 6 cycles \nNo RT\tLungs, 24 mo\tAWD, 25 mo\t\n24\t33\tW/F\t+\tRV and IVC thrombus \n(post-operative pulmonary embolism, followed by lung metastases)\tUpfront\tD/U\tD/U\tAWD, 4 mo\t\n25\t34\tH/M\t+\tLNs, RV and IVC thrombus, retroperitoneum, liver\tUpfront\tID × 3 cycles \nNo RT\tLocal progression, 5 mo\tDead, 8 mo\t\n26\t35\tW/M\tD/U\tPerinephric fat, LV invasion, lungs\tUpfront\tVDC, IE × 6 cycles \nAuto-stem cell transplant \nNo RT\tLungs, 17 mo\tAWD, 38 mo\t\n27\t39\tW/F\t+\tLNs, bone\tNo\tIrT × 1 cycle, RT (D/U)\tDisease progression, D/U\tDead, 3 mo\t\n28\t41\tW/M\tD/U\tLocal invasion, LNs, bone and leptomeningeal spread\tD/U\tVDC × 5 cycles, \nIE × 2 cycles, No RT\tD/U\tAWD, 5 mo\t\n29\t43\tW/M\t+\tLNs, retroperitoneum\tNo\tVDC × 4 cycles, \nNo RT\tLocal and distant progression, bones, 4 mo\tDead, 6 mo\t\n30\t50\tW/M\tD/U\tLNs (above and below diaphragm), liver\tNo\tPE, ID, × 6 cycles \nVDI × 3 cycles \nOral E × 15 mo, No RT\t\n\tAlive, NED, 113 mo\t\nAbbreviations: A-Actinomycin D, As-Asian, Ar-Arabic, AWD-Alive with disease, BM-Bone marrow, C-Cyclophosphamide, D-Doxorubicin, D/U-Data unavailable, E-Etoposide, F-Female, H-Hispanic, I-Ifosfamide, Ir-Irinotecan, IVC-Inferior vena cava, M-Male, mo-month, LN-Lymph node, LV-Lymphovascular, NED-No evidence of disease, P-Cisplatin, RA-Right atrium, RT-Radiation therapy, RV-Renal vein, T-Temozolomide, V-Vincristine, W-White/Non-Hispanic, yrs-years.\n==== Refs\nReferences\n1. 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Assoc. 1958 53 457 481 10.1080/01621459.1958.10501452\n\n", "fulltext_license": "CC BY", "issn_linking": "2072-6694", "issue": "12(10)", "journal": "Cancers", "keywords": "Ewing sarcoma; chemotherapy; kidney; outcome; renal; survival; treatment; tumor thrombus", "medline_ta": "Cancers (Basel)", "mesh_terms": null, "nlm_unique_id": "101526829", "other_id": null, "pages": null, "pmc": null, "pmid": "33050651", "pubdate": "2020-10-11", "publication_types": "D016428:Journal Article", "references": "21548122;22083212;16904430;10688096;18308106;25251206;11176062;23800653;30362816;11201694;9053479;7029300;21692057;30962207;18925450;21747604;10963639;11859203;28844694;19940655;23374800;22503609;1129029;17569105;17134738;8040301;23730330;23761687;25222071;22295994;20186557;28429277;16554591;19478963;22534242;21965263;18525097", "title": "Primary Ewing Sarcoma/Primitive Neuroectodermal Tumor of the Kidney: The MD Anderson Cancer Center Experience.", "title_normalized": "primary ewing sarcoma primitive neuroectodermal tumor of the kidney the md anderson cancer center experience" }

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CANCERS. 2020?12 (10):1?15", "literaturereference_normalized": "primary ewing sarcoma primitive neuroectodermal tumor of the kidney the md anderson cancer center experience", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210118", "receivedate": "20210118", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18753630, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210419" }, { "companynumb": "US-009507513-2012USA011311", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "DOXORUBICIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "EWING^S SARCOMA", "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": "6", "activesubstance": { "activesubstancename": "TEMOZOLOMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021029", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": "8 CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "EWING^S SARCOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TEMODAR" }, { "actiondrug": null, "activesubstance": null, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 CYCLE", "drugenddate": null, "drugenddateformat": null, "drugindication": "EWING^S SARCOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXORUBICIN (+) IFOSFAMIDE (+) VINCRISTINE SULFATE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "VINCRISTINE SULFATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "EWING^S SARCOMA", "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": null, "activesubstance": null, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3 CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "EWING^S SARCOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE (+) DACTINOMYCIN (+) VINCRISTINE SULFATE" } ], "patientagegroup": null, "patientonsetage": "23", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TAREK N, SAID R, ANDERSEN CR, SUKI TS, FOGLESONG J, HERZOG CE, ET AL.. PRIMARY EWING SARCOMA/PRIMITIVE NEUROECTODERMAL TUMOR OF THE KIDNEY: THE MD ANDERSON CANCER CENTER EXPERIENCE. CANCERS. 2020?12 (10):1?15", "literaturereference_normalized": "primary ewing sarcoma primitive neuroectodermal tumor of the kidney the md anderson cancer center experience", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210118", "receivedate": "20210118", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18753631, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210419" }, { "companynumb": "US-009507513-2101USA008567", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "TEMOZOLOMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021029", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": "1 CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "EWING^S SARCOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TEMODAR" } ], "patientagegroup": null, "patientonsetage": "39", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TAREK N, SAID R, ANDERSEN CR, SUKI TS, FOGLESONG J, HERZOG CE, ET AL.. PRIMARY EWING SARCOMA/PRIMITIVE NEUROECTODERMAL TUMOR OF THE KIDNEY: THE MD ANDERSON CANCER CENTER EXPERIENCE. CANCERS. 2020?12 (10):1?15", "literaturereference_normalized": "primary ewing sarcoma primitive neuroectodermal tumor of the kidney the md anderson cancer center experience", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210118", "receivedate": "20210118", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18753633, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210419" } ]

{ "abstract": "Therapy related acute promyelocytic leukemia (ta-APL) is a rare complication of chemotherapy for other malignant tumors. We report two such cases, one of whom was exposed only to carboplatin two years before developing ta-APL and the other one was treated with cisplatin, etoposide and bleomycin five years prior to developing ta-APL.", "affiliations": "Haematology Department, Doncaster Royal Infirmary, Thorne Road, Doncaster, DN2 5LT, UK.", "authors": "Martin|Jacqueline|J|;Majumdar|Gautam|G|", "chemical_list": "D000970:Antineoplastic Agents; D017671:Platinum Compounds; D016190:Carboplatin; D002945:Cisplatin", "country": "England", "delete": false, "doi": "10.1038/sj.thj.6200198", "fulltext": null, "fulltext_license": null, "issn_linking": "1466-4860", "issue": "3(6)", "journal": "The hematology journal : the official journal of the European Haematology Association", "keywords": null, "medline_ta": "Hematol J", "mesh_terms": "D000328:Adult; D000970:Antineoplastic Agents; D016190:Carboplatin; D002945:Cisplatin; D005260:Female; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute; D008297:Male; D008875:Middle Aged; D016609:Neoplasms, Second Primary; D017671:Platinum Compounds", "nlm_unique_id": "100965523", "other_id": null, "pages": "321-3", "pmc": null, "pmid": "12522457", "pubdate": "2002", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Platinum compounds and therapy related acute promyelocytic leukemia.", "title_normalized": "platinum compounds and therapy related acute promyelocytic leukemia" }

[ { "companynumb": "GB-PFIZER INC-2017300015", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CARBOPLATIN" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": "076517", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1020 MG, CYCLIC (EVERY FOUR WEEKS FOR SIX SUCH COURSES)", "drugenddate": null, "drugenddateformat": null, "drugindication": "ENDOMETRIAL ADENOCARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1020", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBOPLATIN." } ], "patientagegroup": null, "patientonsetage": "46", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute promyelocytic leukaemia", "reactionmeddraversionpt": "20.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Second primary malignancy", "reactionmeddraversionpt": "20.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "MARTIN, J.. PLATINUM COMPOUNDS AND THERAPY RELATED ACUTE PROMYELOCYTIC LEUKEMIA. THE HEMATOLOGY JOURNAL. 2002;3:321-323", "literaturereference_normalized": "platinum compounds and therapy related acute promyelocytic leukemia", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20170718", "receivedate": "20170713", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13749594, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171127" } ]

{ "abstract": "The (±)-threo-4-fluoromethylphenidate (4F-MPH) is a fluorinated analog of the prescription central nervous system stimulant medication, methylphenidate. This novel psychoactive substance was first detected in drug paraphernalia at the Miami-Dade County Medical Examiner Department Toxicology Laboratory in 2016 but was not detected in a biological specimen until 2018. Limited literature is available on 4F-MPH, with predominate literature being published out of Europe, and no known toxicities reported in the USA. Post-mortem specimens were screened using both gas chromatography mass spectrometry and liquid chromatography ion trap mass spectrometry (LC-Ion Trap-MSn). In addition, a validated method for the quantification of 4F-MPH was developed using liquid chromatography-tandem mass spectrometry (LC-MS-MS), with a linear range of 0.01-0.500 mg/L and acceptable validation criteria including precision, bias, carry-over, linearity and endogenous/exogenous interferences. In addition to the detection of 4F-MPH, 3-methoxy-PCP, amphetamine, methamphetamine, 6-monoacetylmorphine, morphine, codeine and tetrahydrocannabinol were also identified in the decedent. A single source of blood was collected (femoral vein) and quantified in all blood tubes used for collection, with concentrations varying from 0.012 to 0.05 mg/L. Additional specimens available for screening included gastric contents and urine. An additional peak having the same targeted ions and transitions as 4F-MPH was identified in both the LC-Ion Trap-MSn screening procedure and the LC-MS-MS quantitative procedure. This peak suggests the presence of a structural isomer, possibly (±)-erythro-4-fluoromethylphenidate, which cannot be confirmed due to there being no available certified reference material. This case report presents the first time that 4F-MPH was detected in a decedent, as well as the first time 4F-MPH has been listed in the official cause of death of a decedent in Florida.", "affiliations": "Miami-Dade Medical Examiner Department, Toxicology Laboratory, 1851 NW 10th Ave., Miami, USA.;Miami-Dade Medical Examiner Department, Toxicology Laboratory, 1851 NW 10th Ave., Miami, USA.;Miami-Dade Medical Examiner Department, Toxicology Laboratory, 1851 NW 10th Ave., Miami, USA.;District 20 Medical Examiner Department, 3838 Domestic Ave., Naples, USA.;Miami-Dade Medical Examiner Department, Toxicology Laboratory, 1851 NW 10th Ave., Miami, USA.", "authors": "Shoff|Elisa N|EN|;Kahl|Joseph H|JH|;Hime|George W|GW|;Coburn|Marta|M|;Boland|Diane M|DM|", "chemical_list": "C000656358:4-fluoromethylphenidate; D000697:Central Nervous System Stimulants; D008774:Methylphenidate", "country": "England", "delete": false, "doi": "10.1093/jat/bkz061", "fulltext": null, "fulltext_license": null, "issn_linking": "0146-4760", "issue": "43(8)", "journal": "Journal of analytical toxicology", "keywords": "4-fluoromethylphenidate; LC–MS-MS; NPS; post-mortem toxicology", "medline_ta": "J Anal Toxicol", "mesh_terms": "D000328:Adult; D000697:Central Nervous System Stimulants; D002851:Chromatography, High Pressure Liquid; D017809:Fatal Outcome; D053593:Forensic Toxicology; D006801:Humans; D008297:Male; D008774:Methylphenidate; D015203:Reproducibility of Results; D013048:Specimen Handling; D019966:Substance-Related Disorders; D053719:Tandem Mass Spectrometry", "nlm_unique_id": "7705085", "other_id": null, "pages": "666-672", "pmc": null, "pmid": "31424072", "pubdate": "2019-09-10", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "4-Fluoromethylphenidate: Fatal Intoxication Involving a Previously Unreported Novel Psychoactive Substance in the USA.", "title_normalized": "4 fluoromethylphenidate fatal intoxication involving a previously unreported novel psychoactive substance in the usa" }

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"activesubstancename": "AMPHETAMINE" }, "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": "AMPHETAMINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DRONABINOL" }, "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": "9-TETRAHYDROCANNABINOL" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MORPHINE SULFATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "074862", "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": "MORPHINE SULFATE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHAMPHETAMINE" }, "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": "METHAMPHETAMINE" } ], "patientagegroup": null, "patientonsetage": "25", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pulmonary oedema", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Drug dependence", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Bladder dilatation", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Psychotic symptom", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Brain oedema", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "DOI: 10.1093/JAT/BKZ061 SHOFF EN, KAHL JH, HIME GW, COBURN M, BOLAND DM.. 4-FLUOROMETHYLPHENIDATE: FATAL INTOXICATION INVOLVING A PREVIOUSLY UNREPORTED NOVEL PSYCHOACTIVE SUBSTANCE IN THE USA. JOURNAL OF ANALYTICAL TOXICOLOGY. 2019?1-7", "literaturereference_normalized": "4 fluoromethylphenidate fatal intoxication involving a previously unreported novel psychoactive substance in the usa", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190920", "receivedate": "20190920", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16835002, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20191005" }, { "companynumb": "US-HIKMA PHARMACEUTICALS USA INC.-US-H14001-19-04994", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": 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"drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "THREO- 4-FLUOROMETHYLPHENIDATE" } ], "patientagegroup": null, "patientonsetage": "25", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hallucination, visual", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Unresponsive to stimuli", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Paranoia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Hallucination, auditory", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Urinary retention", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Intentional overdose", "reactionmeddraversionpt": "22.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Pulmonary oedema", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Brain oedema", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SHOFF E, KAHL J, HIME G, COBURN M, BOLAND D. 4-FLUOROMETHYLPHENIDATE: FATAL INTOXICATION INVOLVING A PREVIOUSLY UNREPORTED NOVEL PSYCHOACTIVE SUBSTANCE IN THE USA. JOURNAL OF ANALYTICAL TOXICOLOGY, DOI: 10.1093/JAT/BKZ061. 2019?1-7.", "literaturereference_normalized": "4 fluoromethylphenidate fatal intoxication involving a previously unreported novel psychoactive substance in the usa", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190926", "receivedate": "20190926", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16855143, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20191005" } ]

{ "abstract": "BACKGROUND\nHyperuricemia caused by pegylated-interferon-α2a and ribavirin therapy has been rarely reported. We report a case of severe hyperuricemia and urate nephropathy in a liver transplant recipient with recurrent hepatitis C, which required discontinuation of therapy, rasburicase, and hemo-dialysis.\n\n\nMETHODS\nA 64-year-old female liver transplant recipient was begun on treatment of fibrosis cholestatic hepatitis with pegylated-interferon-α2a and ribavirin therapy. She received a one-time dose of pegylated-interferon-α2a 135 mcg subcutaneously, and ribavirin was initiated. Within 24 hours of treatment initiation, she developed an acute kidney injury with serum creatinine increased from a baseline 132.6 μmol/L (1.5 mg/dL) to 459.7 μmol/L (5.2 mg/dL) within 72 hours. Ultrasound and computed tomography of the kidneys were normal with no stones and urinalysis showed no crystals. Her ribavirin dosage was adjusted based on her changing renal function. Within 72 hours after treatment initiation, her serum uric acid level was 1392 μmol/L (23.4 mg/dL), for which she received rasburicase 3 mg intravenously. Ribavirin was discontinued at this time. The next day, her serum uric acid level and remained elevated at 1166 μmol/L (19.6 mg/dL) and she received a second dose of rasburicase 7.5 mg and hemodialysis. Her serum uric acid level decreased to 131 μmol/L (2.2 mg/dL) and remained within normal limits; however, she continued to require intermittent hemodialysis until she died from complications of sepsis 38 days after admission. After discontinuation, she was not rechallenged with pegylated-interferon-α2a /and ribavirin.\n\n\nCONCLUSIONS\nA liver transplant recipient with recurrent hepatitis C developed severe hyperuricemia and urate nephropathy shortly after receiving pegylated-interferon-α2a and ribavirin therapy. The patient's hyperuricemia was managed with rasbu-ricase and hemodialysis. This rare but potentially serious adverse reaction can limit the use of these agents in patients with recurrence of life threatening hepatitis C after liver transplant.", "affiliations": "From the Department of Pharmacy, Einstein Medical Center Philadelphia, PA, USA.", "authors": "Knorr|John P|JP|;Chewaproug|Daranee|D|;Neeli|Surekha|S|;Torres|Elio|E|;Zaki|Radi|R|", "chemical_list": "D006074:Gout Suppressants; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; C469709:rasburicase; D012254:Ribavirin; D014503:Urate Oxidase", "country": "Turkey", "delete": false, "doi": "10.6002/ect.2014.0081", "fulltext": null, "fulltext_license": null, "issn_linking": "1304-0855", "issue": "13(6)", "journal": "Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation", "keywords": null, "medline_ta": "Exp Clin Transplant", "mesh_terms": "D005260:Female; D006074:Gout Suppressants; D006801:Humans; D033461:Hyperuricemia; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D016031:Liver Transplantation; D008875:Middle Aged; D011183:Postoperative Complications; D011994:Recombinant Proteins; D012254:Ribavirin; D014503:Urate Oxidase", "nlm_unique_id": "101207333", "other_id": null, "pages": "596-9", "pmc": null, "pmid": "25806515", "pubdate": "2015-12", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Severe Interferon/Ribavirin-Induced Hyperuricemia and Urate Nephropathy Requiring Rasburicase and Hemodialysis in a Liver Transplant Recipient.", "title_normalized": "severe interferon ribavirin induced hyperuricemia and urate nephropathy requiring rasburicase and hemodialysis in a liver transplant recipient" }

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"SULFAMETHOXAZOLE/TRIMETHOPRIM" } ], "patientagegroup": null, "patientonsetage": "64", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Sepsis", "reactionmeddraversionpt": "19.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Hyperuricaemia", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Leukopenia", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Urosepsis", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neutrophil count decreased", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": ", CHEWAPROUG D, NEELI S, TORRES E AND ZAKI R. SEVERE INTERFERON/RIBAVIRIN-INDUCED HYPERURICEMIA AND URATE NEPHROPATHY REQUIRING RASBURICASE AND HEMODIALYSIS IN A LIVER TRANSPLANT RECIPIENT. EXPERIMENTAL AND CLINICAL TRANSPLANTATION 2015?13 (6):596-599.", "literaturereference_normalized": "severe interferon ribavirin induced hyperuricemia and urate nephropathy requiring rasburicase and hemodialysis in a liver transplant recipient", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160129", "receivedate": "20151229", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11877494, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160526" }, { "companynumb": "PHHY2015US165933", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { 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null, "drugtreatmentdurationunit": null, "medicinalproduct": "SULFAMETHOXAZOLE-TRIMETHOPRIM (SMZ)" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TELAPREVIR" }, "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": "TELAPREVIR" } ], "patientagegroup": null, "patientonsetage": "64", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Urosepsis", "reactionmeddraversionpt": "18.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Urate nephropathy", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hyperuricaemia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KNORR JP, CHEWAPROUG D, NEELI S, TORRES E, ZAKI R.. SEVERE INTERFERON/RIBAVIRIN-INDUCED HYPERURICEMIA AND URATE NEPHROPATHY REQUIRING RASBURICASE AND HEMODIALYSIS IN A LIVER TRANSPLANT RECIPIENT. EXP-CLIN-TRANSPLANT. 2015?13(6):596-9", "literaturereference_normalized": "severe interferon ribavirin induced hyperuricemia and urate nephropathy requiring rasburicase and hemodialysis in a liver transplant recipient", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20151228", "receivedate": "20151228", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11872007, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160305" }, { "companynumb": "US-STRIDES ARCOLAB LIMITED-2015SP002599", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": 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"drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "135 MCG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATITIS C", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PEGASYS" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MAGNESIUM OXIDE" }, "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": "MAGNESIUM OXIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hyperuricaemia", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Urate nephropathy", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hyperkalaemia", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KNORR JP, CHEWAPROUG D, NEELI S, TORRES E, ZAKI R. SEVERE INTERFERON/RIBAVIRIN-INDUCED HYPERURICEMIA AND URATE NEPHROPATHY REQUIRING RASBURICASE AND HEMODIALYSIS IN A LIVER TRANSPLANT RECIPIENT. 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"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": "RIBAVIRIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM" }, "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": 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"drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALGANCICLOVIR" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "RIBAVIRIN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "018859", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATITIS CHOLESTATIC", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "200", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIBAVIRIN." }, { "actiondrug": "5", "activesubstance": { 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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": "MAGNESIUM OXIDE." }, { "actiondrug": "1", "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": "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": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "AMLODIPINE BESYLATE" }, "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": "AMLODIPINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PREDNISONE" }, "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": "PREDNISONE." } ], "patientagegroup": null, "patientonsetage": "64", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hyperuricaemia", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Urate nephropathy", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KNORR J, CHEWAPROUG D, NEELI S, TORRES E, ZAKI R. SEVERE INTERFERON/RIBAVIRIN-INDUCED HYPERURICEMIA AND URATE NEPHROPATHY REQUIRING RASBURICASE AND HEMODIALYSIS IN A LIVER TRANSPLANT RECIPIENT. EXPERIMENTAL AND CLINICAL TRANSPLANTATION. 2015?13 (6):596-599.", "literaturereference_normalized": "severe interferon ribavirin induced hyperuricemia and urate nephropathy requiring rasburicase and hemodialysis in a liver transplant recipient", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160105", "receivedate": "20160105", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11890226, "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": "US-AUROBINDO-AUR-APL-2016-01185", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { 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Severe interferon/ribavirin-induced hyperuricemia and urate nephropathy requiring rasburicase and hemodialysis in a liver transplant recipient.. 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null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METOPROLOL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ESOMEPRAZOLE" }, "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, 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"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": "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": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": 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"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": "VALGANCICLOVIR" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "RIBAVIRIN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "200", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIBAVIRIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PEGINTERFERON ALFA-2A" }, "drugadditional": null, "drugadministrationroute": "058", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATITIS CHOLESTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "135", "drugstructuredosageunit": "004", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PEGASYS" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PREDNISONE" }, "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": "PREDNISONE." } ], "patientagegroup": null, "patientonsetage": "64", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hyperuricaemia", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hepatitis cholestatic", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hyperkalaemia", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Leukopenia", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Urosepsis", "reactionmeddraversionpt": "19.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Urate nephropathy", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Enterococcal infection", "reactionmeddraversionpt": "19.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Clostridium difficile colitis", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KNORR J, CHEWAPROUG D, NEELI S, TORRES E, ZAKI R. SEVERE INTERFERON/RIBAVIRIN-INDUCED HYPERURICEMIA AND URATE NEPHROPATHY REQUIRING RASBURICASE AND HEMODIALYSIS IN A LIVER TRANSPLANT RECIPIENT. EXP CLIN TRANSPLANT. 2015?13(6):596-9.", "literaturereference_normalized": "severe interferon ribavirin induced hyperuricemia and urate nephropathy requiring rasburicase and hemodialysis in a liver transplant recipient", "qualification": "1", "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "US", "receiptdate": "20160111", "receivedate": "20160111", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11905892, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160526" }, { "companynumb": "US-WATSON-2015-28985", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { 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"drugstructuredosageunit": "004", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PEGASYS" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "090402", "drugbatchnumb": "UNCONFIRMED", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNK", "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": "TACROLIMUS (WATSON LABORATORIES)" } ], "patientagegroup": null, "patientonsetage": "64", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hyperuricaemia", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Urate nephropathy", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KNORR JP, CHEWAPROUG D, NEELI S, TORRES E, ZAKI R. SEVERE INTERFERON/RIBAVIRIN-INDUCED HYPERURICEMIA AND URATE NEPHROPATHY REQUIRING RASBURICASE AND HEMODIALYSIS IN A LIVER TRANSPLANT RECIPIENT. EXP CLIN TRANSPLANT. 2015?13(6):596-9", "literaturereference_normalized": "severe interferon ribavirin induced hyperuricemia and urate nephropathy requiring rasburicase and hemodialysis in a liver transplant recipient", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160211", "receivedate": "20160112", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11910695, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160526" } ]

{ "abstract": "The combination of myopathy and neuropathy with fibrosis and contractures has apparently not yet been reported from the use of meperidine. We describe a patient addicted to meperidine in whom bilateral hand numbness and weakness developed and electrodiagnostic studies revealed moderate slowing of motor nerve conduction velocities. Neurolysis of the median and ulnar nerves resulted in markedly improved symptoms.", "affiliations": null, "authors": "Yamanaka|M|M|;Parsa|F D|FD|", "chemical_list": "D008614:Meperidine", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0032-1052", "issue": "75(4)", "journal": "Plastic and reconstructive surgery", "keywords": null, "medline_ta": "Plast Reconstr Surg", "mesh_terms": "D000328:Adult; D005260:Female; D006801:Humans; D007273:Injections, Intramuscular; D008475:Median Nerve; D008614:Meperidine; D009135:Muscular Diseases; D009408:Nerve Compression Syndromes; D014459:Ulnar Nerve", "nlm_unique_id": "1306050", "other_id": null, "pages": "582-3", "pmc": null, "pmid": "3983261", "pubdate": "1985-04", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Compression neuropathy from muscle fibrosis induced by repeated meperidine injections.", "title_normalized": "compression neuropathy from muscle fibrosis induced by repeated meperidine injections" }

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{ "abstract": "Rheumatoid vasculitis is a rare extra-articular complication of rheumatoid arthritis. The most common manifestation is cutaneous; however, it can manifest in various organ systems and is associated with a high degree of morbidity and mortality. Diagnosis is challenging, and there are no validated diagnostic or classification criteria. Most cases should be confirmed with tissue biopsy when possible given the severity of disease and the extent of immunosuppression required to treat this condition. We report the case of a 54-year-old white woman with long-standing, uncontrolled, and seropositive rheumatoid arthritis with a history of elevated anticardiolipin IgG and IgM antibodies who presented with acute stenosis of her left femoral artery which ultimately required a left above-the-knee amputation. Histopathology revealed findings consistent with vasculitis and thrombosis, and subsequent imaging revealed multifocal arterial and venous thromboses. She was diagnosed with rheumatoid vasculitis and antiphospholipid antibody syndrome, and was treated with high-dose glucocorticoids, cyclophosphamide, and warfarin. Rheumatoid vasculitis is a rare but devastating complication of rheumatoid arthritis, and vigilance for this condition must be maintained, especially in patients with long-standing, seropositive disease.", "affiliations": "Division of Rheumatology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.;Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.;Division of Rheumatology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.", "authors": "Ghadiali|Jay|J|https://orcid.org/0000-0002-2454-1552;Talwar|Aditya|A|;Ligon|Colin|C|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1177/2050313X211015895", "fulltext": "\n==== Front\nSAGE Open Med Case Rep\nSAGE Open Med Case Rep\nSCO\nspsco\nSAGE Open Medical Case Reports\n2050-313X\nSAGE Publications Sage UK: London, England\n\n10.1177/2050313X211015895\n10.1177_2050313X211015895\nCase Report\nAn arm and a leg: A case of rheumatoid vasculitis and antiphospholipid antibody syndrome\nhttps://orcid.org/0000-0002-2454-1552\nGhadiali Jay 1\nTalwar Aditya 2\nLigon Colin 1\n1 Division of Rheumatology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA\n2 Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA\nJay Ghadiali, Division of Rheumatology, Department of Medicine, University of Pennsylvania, White Building, 5th Floor, 3400 Spruce Street, Philadelphia, PA 19104, USA. Email: jay.ghadiali@pennmedicine.upenn.edu\n20 5 2021\n2021\n9 2050313X21101589520 12 2020\n19 4 2021\n© The Author(s) 2021\n2021\nSAGE Publications\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (https://us.sagepub.com/en-us/nam/open-access-at-sage).\nRheumatoid vasculitis is a rare extra-articular complication of rheumatoid arthritis. The most common manifestation is cutaneous; however, it can manifest in various organ systems and is associated with a high degree of morbidity and mortality. Diagnosis is challenging, and there are no validated diagnostic or classification criteria. Most cases should be confirmed with tissue biopsy when possible given the severity of disease and the extent of immunosuppression required to treat this condition. We report the case of a 54-year-old white woman with long-standing, uncontrolled, and seropositive rheumatoid arthritis with a history of elevated anticardiolipin IgG and IgM antibodies who presented with acute stenosis of her left femoral artery which ultimately required a left above-the-knee amputation. Histopathology revealed findings consistent with vasculitis and thrombosis, and subsequent imaging revealed multifocal arterial and venous thromboses. She was diagnosed with rheumatoid vasculitis and antiphospholipid antibody syndrome, and was treated with high-dose glucocorticoids, cyclophosphamide, and warfarin. Rheumatoid vasculitis is a rare but devastating complication of rheumatoid arthritis, and vigilance for this condition must be maintained, especially in patients with long-standing, seropositive disease.\n\nRheumatoid vasculitis\nrheumatoid arthritis\nantiphospholipid syndrome\ncyclophosphamide\ncover-dateJanuary-December 2021\ntypesetterts1\n==== Body\nIntroduction\n\nRheumatoid arthritis (RA) is a chronic, systemic rheumatic disease that affects 0.5%–1% of people in Europe and North America.1 The hallmark of RA is synovial inflammation.2 However, RA can affect numerous systems outside of the joints. These extra-articular manifestations (ExRA) include cutaneous, pulmonary, ocular, cardiac, neurologic, hematologic, and vascular complications. One cohort-based study reported an ExRA incidence rate of 3.67 per 100 patient years.3 Rheumatoid vasculitis (RV) is one of the most severe types of ExRA, with an estimated mortality of 50%–60% at 5 years.4\n\nThe antiphospholipid antibody syndrome (APS) is a systemic autoimmune condition characterized by thrombotic and obstetric complications in patients with persistent antiphospholipid antibodies (aPL).5 These antibodies are found with greater prevalence in certain systemic rheumatic conditions, particularly systemic lupus erythematosus. RA patients have a higher prevalence of these autoantibodies compared to the general population, and they are associated with thromboembolic complications.6\n\nWe report the case of a patient with treatment-refractory RA leading to RV and concurrent APS which resulted in limb ischemia with vasculitic and multiple thrombotic events in arterial and venous vessels.\n\nCase presentation\n\nThe patient is a 54-year-old white female with a medical history of seropositive RA, positive anticardiolipin IgG and IgM antibodies, and a remote pulmonary embolism treated with apixaban who presented with a 5-day history of left foot swelling, pain, paresthesia, and skin discoloration. A computed tomography (CT) angiogram showed focal stenosis of the left femoral artery. She underwent stenting and a bypass which was complicated by graft occlusion, and she required a subsequent left above-the-knee amputation (AKA). Three days after her left AKA, thrombi in her aortic arch (Figure 1(a)), right brachial artery (Figure 1(b)), right ulnar artery, left subclavian artery, and superior vena cava were discovered despite therapeutic anticoagulation with intravenous heparin.\n\nFigure 1. Representative images from the CT angiography of the chest and the right upper extremity: (a) nonocclusive arterial thrombus within the midportion of the aortic arch and (b) partially occlusive thrombus within the right brachial artery.\n\nHer RA had been poorly controlled since her diagnosis, which was more than 20 years prior. Prior to her admission, she had been taking methotrexate 20 mg subcutaneous per week, tocilizumab 162 mg subcutaneous per week, and prednisone 15 mg PO daily. She had previously experienced ExRA of episcleritis and rheumatoid nodulosis. Upon discussion with her outpatient rheumatologist, she was noted to have elevated titers of anticardiolipin IgG and IgM antibodies but was never given the diagnosis of APS. She was on indefinite anticoagulation with apixaban 5 mg twice daily for her remote pulmonary embolism history.\n\nExamination revealed synovitis of bilateral proximal interphalangeal, metacarpophalangeal, and wrist joints. She was noted to have scattered nodulosis of her fingers and her elbows, acrocyanosis of the digits of her right hand, and scattered nailfold hemorrhages. Laboratory evaluation revealed a white blood count of 18,800/μL, hemoglobin of 8.9 g/dL, platelets of 656,000/μL, and a normal comprehensive metabolic panel. Additional testing revealed a c-reactive protein of 24.30 mg/dL (normal < 0.60 mg/dL), C4 level of 13 mg/dL (normal 16–47 mg/dL), C3 level of 134 mg/dL (normal 88–201 mg/dL), antineutrophilic cytoplasmic antibody testing with perinuclear staining (negative MPO and PR3 titers), anticardiolipin IgG and IgM with values both greater than the 99th percentile (done in our in-house laboratory), rheumatoid factor of >1060 IU/mL (normal < 12.4 IU/mL), and an anti-CCP antibody level of 243 units (normal < 19 units).\n\nThe pathology of the left knee revealed vasculitis of the deep muscular arteries and veins, as well as widespread inflammatory and non-inflammatory thrombi (Figure 2). With this information, the patient’s widespread thrombosis and threatened limbs were attributed to RV along with a hypercoagulable state conferred by APS. She was treated with methylprednisolone 1 g IV daily for 3 days and was started on prednisone 60 mg PO daily with a slow taper. In addition, she was treated with cyclophosphamide IV utilizing the dosing regimen from CYCLOPS trial.7 Her anticoagulation was changed to warfarin. She established care in our clinic, and repeat anticardiolipin antibody levels were rechecked 4 months later. Her anticardiolipin IgG normalized, but her anticardiolipin IgM titer remained greater than the 99th percentile.\n\nFigure 2. Pathology from left AKA. A small venule that is completely occluded by a non-inflammatory thrombus (white arrow). A vessel with complete destruction of the wall and lumen by acute inflammation, with a red arrow placed on what remains of the vessel wall. An associated small nerve is also seen (black arrowhead).\n\nDiscussion\n\nRV typically occurs in patients with long-standing, seropositive RA.4 There is a slight male predominance. It mostly affects small- to medium-sized vessels, but all vessel sizes can be involved.8 There are no validated classification or diagnostic criteria; however, classification criteria proposed by Scott and Bacon remain one of the most cited.9 RV can present extremely heterogeneously. The most common manifestation is cutaneous, but has been reported to affect the peripheral nervous system, eyes, heart, lungs, kidneys, and the gastrointestinal system.8 Multiple studies have shown that while the overall incidence of RV is decreasing, the overall mortality related to RV, once diagnosed, has not changed significantly over the past several decades.4 This emphasizes the importance of disease control and a high level of suspicion in high-risk patients for early intervention.\n\nThere are no randomized controlled trials (RCTs) to help guide treatment strategies in RV. Much of the treatment paradigm is based on the treatment for primary systemic vasculitides, particularly the ANCA-associated vasculitides. Treatment of severe disease typically involves high-dose glucocorticoids alongside a concurrent disease-modifying antirheumatic drug such as cyclophosphamide or rituximab. There are reports of agents such as azathioprine, methotrexate, mycophenolate mofetil, TNF inhibitors, abatacept, and tocilizumab being used for this indication as well.8,10 Given the high morbidity and mortality of RV even with these treatments, prevention through tight RA control and early recognition of RV remain the cornerstones of management.\n\nThe usage of direct oral anticoagulants (DOACs), which has increased for thromboembolic disease in the general population, remains controversial in patients with APS. The guidance from important groups in the field, such as the International Congress on Antiphospholipid Antibodies and the International Society on Thrombosis and Haemostasis, suggests that DOACs can be considered for the treatment of an initial venous thrombosis in a patient who is single- or double-positive for aPL.11 However, these groups recommend against DOACs for patients with triple-positive aPL, arterial thrombosis, or recurrent venous thromboses. A recent meta-analysis of four important RCTs that compared DOACs with vitamin K antagonists (VKAs) was recently published.12 The amount of recurrent venous thrombosis in the DOAC group was numerically higher than the VKA group, but the result was not statistically significant. However, the risk of recurrent arterial thrombosis was significantly higher in the DOAC group.\n\nConclusion\n\nWe report the case of a 54-year-old woman with severe, uncontrolled RA who developed arterial and venous thromboses in the setting of RV and aPL. The incidence of RV is decreasing, but it remains an important extra-articular manifestation of RA with a high morbidity and mortality. Vigilance for this condition must be maintained, especially in patients with long-standing, seropositive RA. Earlier detection of this condition may lead to earlier treatment and better outcomes.\n\nDeclaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nEthical approval: Our institution does not require ethical approval for reporting individual cases or case series.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nInformed consent: Written informed consent was obtained from the patient(s) for their anonymized information to be published in this article.\n\nORCID iD: Jay Ghadiali https://orcid.org/0000-0002-2454-1552\n==== Refs\nReferences\n\n1 van der Woude D van der Helm-van Mil AHM . Update on the epidemiology, risk factors, and disease outcomes of rheumatoid arthritis. Best Pract Res Clin Rheumatol 2018; 32 (2 ): 174–187.30527425\n2 Smolen JS Aletaha D McInnes IB. Rheumatoid arthritis. Lancet 2016; 388 (10055 ): 2023–2038.27156434\n3 Turesson C O’Fallon WM Crowson CS , et al . Occurrence of extraarticular disease manifestations is associated with excess mortality in a community based cohort of patients with rheumatoid arthritis. J Rheumatol 2002; 29 (1 ): 62–67.11824973\n4 Ntatsaki E Mooney J Scott DGI , et al . Systemic rheumatoid vasculitis in the era of modern immunosuppressive therapy. Rheumatology 2014; 53 (1 ): 145–152.24108586\n5 Garcia D Erkan D. Diagnosis and management of the antiphospholipid syndrome. N Engl J Med 2018; 378 : 2010–2110.29791828\n6 Olech E Merrill JT. The prevalence and clinical significance of antiphospholipid antibodies in rheumatoid arthritis. Curr Rheumatol Rep 2006; 8 (2 ): 100–108.16569368\n7 de Groot K Harper L Jayne DRW , et al . Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized trial. Ann Intern Med 2009; 150 : 670–680.19451574\n8 Makol A Matteson EL Warrington KJ. Rheumatoid vasculitis: an update. Curr Opin Rheumatol 2015; 27 (1 ): 63–70 25405822\n9 Scott DGI Bacon PA . Intravenous cyclophosphamide plus methylprednisolone in treatment of systemic rheumatoid vasculitis. Am J Med 1984; 76 (3 ): 377–384.6142648\n10 Coffey CM Richter MD Crowson CS , et al . Rituximab therapy for systemic rheumatoid vasculitis: indications, outcomes, and adverse events. J Rheumatol 2020; 47 (4 ): 518–523.31203225\n11 Sayar Z Moll R Isenberg D , et al . Thrombotic antiphospholipid syndrome: a practical guide to diagnosis and management. Thromb Res 2021; 198 : 213–221.33485122\n12 Dufrost V Wahl D Zuily S. Direct oral anticoagulants in antiphospholipid syndrome: Meta-analysis of randomized controlled trials. Autoimmun Rev 2021; 20 (1 ): 102711.33197580\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "2050-313X", "issue": "9()", "journal": "SAGE open medical case reports", "keywords": "Rheumatoid vasculitis; antiphospholipid syndrome; cyclophosphamide; rheumatoid arthritis", "medline_ta": "SAGE Open Med Case Rep", "mesh_terms": null, "nlm_unique_id": "101638686", "other_id": null, "pages": "2050313X211015895", "pmc": null, "pmid": "34094564", "pubdate": "2021", "publication_types": "D002363:Case Reports", "references": "19451574;11824973;29791828;27156434;31203225;16569368;33197580;25405822;30527425;33485122;6142648;24108586", "title": "An arm and a leg: A case of rheumatoid vasculitis and antiphospholipid antibody syndrome.", "title_normalized": "an arm and a leg a case of rheumatoid vasculitis and antiphospholipid antibody syndrome" }

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{ "abstract": "OBJECTIVE\nRaynaud's phenomenon consists of vasospastic disease of the digital arteries after exposure to cold or stress. It causes an important reduction in the patient's quality of life when severe. The available treatments do not always offer favorable results.\n\n\nMETHODS\nA 3-year retrospective study was presented. A total of 15 patients with severe Raynaud's phenomenon who required infiltration with botulinum toxin type A participated in the study. In the first and follow-up visits (30 min, 7 days, 3 months, 6 months, and annual), the overall response by the patient was assessed as was the reduction in the number of weekly episodes of Raynaud's phenomenon, improvement in pain by means of the Visual Analogue Scale, and resolution of ulcers and necrosis as efficacy variables.\n\n\nRESULTS\nA total of 15 patients were included in the study. After 30 min of infiltration, the immediate results showed a very good perception of response in four patients. After 1 month of treatment, eight patients had obtained and maintained a very good response, persisting throughout the study. A statistically significant reduction in pain was obtained, as well as the number of weekly episodes of Raynaud's phenomenon. Of the seven patients with basal ulcers, five were completely healed at 3 months. Of the patients, 64.3% showed an overall satisfaction level of >8 at the end of treatment. No serious adverse events were observed.\n\n\nCONCLUSIONS\nBotulinum toxin is a useful treatment for severe Raynaud's phenomenon that is generally well tolerated. Its mechanism of action is not based exclusively on vasodilation. Further studies are necessary to define the ideal patient for this treatment, the most appropriate method of administration, and the number of units and frequency of the infiltrations.", "affiliations": "Department of Dermatology, Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Madrid, Spain.;Department of Dermatology, Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Madrid, Spain.;Department of Dermatology, Hospital Universitario del Sureste, Arganda del Rey, Madrid, Spain.;Department of Dermatology, Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Madrid, Spain.;Department of Rheumatology, Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Madrid, Spain.;Department of Radiology, Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Madrid, Spain.;Department of Dermatology, Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Madrid, Spain.;Department of Dermatology, Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Madrid, Spain.;Department of Dermatology, Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Madrid, Spain.", "authors": "Medina|Susana|S|https://orcid.org/0000-0003-3165-5387;Gómez-Zubiaur|Alba|A|https://orcid.org/0000-0003-3371-7676;Valdeolivas-Casillas|Nuria|N|https://orcid.org/0000-0002-8452-7541;Polo-Rodríguez|Isabel|I|https://orcid.org/0000-0001-9353-4367;Ruíz|Lucia|L|https://orcid.org/0000-0001-8618-1452;Izquierdo|Carmen|C|https://orcid.org/0000-0002-7367-2938;Guirado|Cristina|C|https://orcid.org/0000-0002-3421-3544;Cabrera|Alicia|A|;Trasobares|Lidia|L|https://orcid.org/0000-0003-2282-3764", "chemical_list": null, "country": "Turkey", "delete": false, "doi": "10.5152/eurjrheum.2018.18013", "fulltext": "\n==== Front\nEur J RheumatolEur J RheumatolEuropean Journal of Rheumatology2147-97202148-4279Medical Research and Education Association 10.5152/eurjrheum.2018.18013ejr-5-4-224Original ArticleBotulinum toxin type A in the treatment of Raynaud’s phenomenon: A three-year follow-up study Medina Susana 1https://orcid.org/0000-0003-3165-5387Gómez-Zubiaur Alba 1https://orcid.org/0000-0003-3371-7676Valdeolivas-Casillas Nuria 2https://orcid.org/0000-0002-8452-7541Polo-Rodríguez Isabel 1https://orcid.org/0000-0001-9353-4367Ruíz Lucia 3https://orcid.org/0000-0001-8618-1452Izquierdo Carmen 4https://orcid.org/0000-0002-7367-2938Guirado Cristina 1https://orcid.org/0000-0002-3421-3544Cabrera Alicia 1Trasobares Lidia 1https://orcid.org/0000-0003-2282-3764\n1 Department of Dermatology, Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Madrid, Spain\n2 Department of Dermatology, Hospital Universitario del Sureste, Arganda del Rey, Madrid, Spain\n3 Department of Rheumatology, Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Madrid, Spain\n4 Department of Radiology, Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Madrid, SpainAddress for Correspondence: Susana Medina; Department of Dermatology, Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Madrid, Spain. E-mail: susana.medina@salud.madrid.org12 2018 12 10 2018 5 4 224 229 15 4 2018 06 5 2018 © Copyright by 2018 Medical Research and Education Association2018Content of this journal is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.Objective\nRaynaud’s phenomenon consists of vasospastic disease of the digital arteries after exposure to cold or stress. It causes an important reduction in the patient’s quality of life when severe. The available treatments do not always offer favorable results.\n\nMethods\nA 3-year retrospective study was presented. A total of 15 patients with severe Raynaud’s phenomenon who required infiltration with botulinum toxin type A participated in the study. In the first and follow-up visits (30 min, 7 days, 3 months, 6 months, and annual), the overall response by the patient was assessed as was the reduction in the number of weekly episodes of Raynaud’s phenomenon, improvement in pain by means of the Visual Analogue Scale, and resolution of ulcers and necrosis as efficacy variables.\n\nResults\nA total of 15 patients were included in the study. After 30 min of infiltration, the immediate results showed a very good perception of response in four patients. After 1 month of treatment, eight patients had obtained and maintained a very good response, persisting throughout the study. A statistically significant reduction in pain was obtained, as well as the number of weekly episodes of Raynaud’s phenomenon. Of the seven patients with basal ulcers, five were completely healed at 3 months. Of the patients, 64.3% showed an overall satisfaction level of >8 at the end of treatment. No serious adverse events were observed.\n\nConclusion\nBotulinum toxin is a useful treatment for severe Raynaud’s phenomenon that is generally well tolerated. Its mechanism of action is not based exclusively on vasodilation. Further studies are necessary to define the ideal patient for this treatment, the most appropriate method of administration, and the number of units and frequency of the infiltrations.\n\nRaynaud’s phenomenonbotulinum toxinbotulinum toxin type A\n==== Body\nIntroduction\nRaynaud’s phenomenon is a vasospastic disorder of the digital arteries after exposure to cold or stress, accompanied by pain and ulcers (1–3), consequently altering the patient’s quality of life. Described by Maurice Raynaud in 1862, a primary form can be distinguished, as well as a form that is secondary or associated with systemic diseases (3).\n\nIn addition to general measures, such as patients avoiding tobacco and protecting themselves from the cold, drugs may be required in the treatment, and there is no current standardized therapeutic plan (3). Calcium antagonists are used as first-line treatment as they reduce the number and severity of weekly episodes (4). Other drugs, such as angiotensin II receptor blockers (5), phosphodiesterase inhibitors (6), prostaglandin analogs (7), and endothelin receptor antagonists, have been used in refractory cases (8, 9). Surgical treatment involving sympathectomy or arterial reconstruction may be necessary in certain patients who have incapacitating pain and ulcers with torpid evolution, but these techniques are not exempt from comorbidities and may not always offer satisfactory results (10).\n\nBotulinum toxin, a polypeptide produced by the Clostridium botulinum bacteria, is an acetylcholine release inhibitor in the peripheral nerve endings of the motor plate and sweat glands. The protein is formed by a light chain of 50 kDa and a heavy chain of 100 kDa linked by a disulfide bridge. The light chain is bound to synaptosomal-associated protein 25 of acetylcholine vesicles, to avoid its transport and exocytosis (11). It is used to treat blepharospasm, facial spasm, cervical dystonia, facial wrinkles, axillary hyperhidrosis, and anal fissures, among others. However, its use in severe Raynaud’s phenomenon is a recent therapeutic possibility (12).\n\nMethods\nWe performed a 3-year retrospective study involving, according to the inclusion and exclusion criteria shown in Table 1, patients with severe Raynaud’s phenomenon referred for dermatology consultations between December 2013 and March 2017 and who required treatment with botulinum toxin type A (Botox®; Allergan, Westport, Ireland). This treatment was given in the Dermatology Unit at Hospital Universitario Príncipe de Asturias de Alcalá de Henares (Madrid) and always administered by the same qualified medical staff.\n\nThe Pharmacy Committee and Clinical Research Ethics Committee approved the study protocol. Written informed consent was obtained from all the patients to participate in the study.\n\nA total of 15 patients were included in the study. Table 2 shows the demographic and clinical characteristics of the patients.\n\nThe infiltration protocol comprises the following steps (Figure 1): reconstitution of a vial containing 100 botulinum toxin units type A in 5 mL of saline serum to 0.9% (dilution: 20 IU/mL), marking of the infiltration sites, at the base of the lateral aspects of all the fingers, except the first as this is the least frequently affected and the one that is most at risk of suffering muscle weakness as a side effect, and injection of 4 and 8 IU of toxin per site using a 30 G needle, depending on the severity.\n\nFor the first four patients, there was an interval of 1 week before infiltration into the second hand, to evaluate the possible side effects. As the drug was tolerated well, it was decided that for the remaining cases, the drug would be infiltrated into both hands on the same day.\n\nFor the efficacy variables, we recorded the patient’s overall assessment of response (no response, mild response, moderate response, and very good response), as well as the reduction in the number of Raynaud episodes per week, improvement in pain (quantified using the Visual Analogue Scale (VAS) with scores between 0 and 10), and any resolution of ulcers and necrosis.\n\nData were recorded in both the first visit and during follow-up, with patient evaluation at 30 min, 7 days, 1 month, 3 months, 6 months, and a year from the infiltration. In addition, the patients’ overall level of satisfaction was registered at the end of the data collection period with scores between 0 (very unsatisfied) and 10 (totally satisfied).\n\nStatistical analysis was performed using the PASW Statistics 18. The non-parametric Wilcoxon test was used to analyze the quantitative variable of the number of weekly Raynaud’s phenomenon episodes and the qualitative variable of ordinal pain measured using VAS. The significance level was set at alpha ≤0.05.\n\nThe patients’ assessment of response and resolution of ulcers and necrosis were expressed descriptively.\n\nResults\nThe present study included a total of 15 (14 women and 1 man) patients. The average age of the patients was 46 (35–71) years. The follow-up period was 3 years for six patients, 2 years for four patients, and 1 year for four patients, with at least two winter periods after treatment for all the patients.\n\nThe immediate post-infiltration results are exemplified by some of the patients as well as the associated clinical images. After 30 min of infiltration with the toxin, five patients showed no change, three had mild response, two had moderate response, and four had very good response. One patient presented with purpuric coloration in all the fingers, together with a necrotic injury on the fifth finger of the left hand (Figure 2), accompanied by intense pain. After 6 h of treatment, there was a significant improvement in color, changing from a purpuric to a pinkish tone (Figure 2). In their initial visit, two patients presented with a significant limitation in the flexion and extension of the second finger in both hands (Figure 2). Half an hour after infiltration, they had full movement, accompanied by a total absence of pain and improved color (Figure 2). Four patients had a very painful ulcer in the pad of the second finger on the right hand. After infiltration, they reported that the pain had disappeared, and there was a subjective increase in temperature.\n\nOne patient died due to peritonitis. Owing to this reason, we will now refer to 14 patients.\n\nAt the 7-day visit, seven patients showed a very good response. After 1 month of treatment, eight patients had a very good response, one had a moderate response, two had a mild response, and three showed no response (Figure 3). Eight patients with a very good response maintained this with an annual dose, with the exception of two patients who required no further infiltrations, until 3 years of follow-up. Regarding the remaining six patients, three of them presented with moderate or mild response, and only one continued the treatment (annual infiltration) up to 2 years; the other three did not show a response, so treatment and monitoring were discontinued (Figure 3). Some patients experienced a significant improvement in mobility (reduced stiffness and numbness).\n\nThe average number of episodes per week of Raynaud’s phenomenon recorded at the first visit was 30 (range 3–60), and the pain assessment was 8 out of 10 (range 2–10). The number of episodes of Raynaud’s phenomenon significantly decreased in the first month post-treatment, with an average of 14 (range 0–60, p<0.009) (Figure 4). The pain intensity decreased to 2.7 (range 0–8, p<0.005), making this variable the earliest and most striking response (Figure 5). Only five patients continued to experience a reduction in pain in the 3- and 6-month visits. For the others, both the number of episodes and pain remained stable with respect to the data recorded 1 month after treatment, coinciding with summer.\n\nWith regard to ulcers, of the seven patients with basal ulceration, five were completely healed at 3 months, with no subsequent worsening, and two remained unchanged.\n\nOf the patients, 63% showed a satisfaction level of >8 at the end of treatment.\n\nWe documented no adverse systemic effects in our patients. Four patients reported a temporary decrease in strength lasting a few weeks, and two had pain at the injection site that resolved spontaneously after 2–3 days.\n\nDiscussion\nRaynaud’s phenomenon is triggered by stimuli, such as cold and stress, leading to an imbalance between the constriction and expansion of the small digital arteries. This leads to the appearance of pain, stiffness, numbness, a sensation of cold, and ulceration, with a consequent alteration in the quality of life of patients. Conventional treatments do not always control this process well, making it necessary to look for alternative therapies.\n\nIn 2004, Sycha et al. (13) published a pilot study involving two patients with severe Raynaud’s phenomenon who responded excellently to infiltration with botulinum toxin. Similar results have also been observed in previous studies (13–19).\n\nIn a study of 11 patients, Van Beek et al. (14) found an improvement in pain in the first 24–48 h, as well as a lower frequency of vasospasm episodes, which was maintained throughout 9.6 months of follow-up. The ulcers present in nine patients healed. The reported pain decreased from 9–10 to 0–2 (14).\n\nIn 2009, Neumeister et al. (16) published a study of 19 patients who were administered an infiltration of 50 to 100 IU of botulinum toxin type A per hand, reporting an 84% reduction in patient pain and improved flow in the Doppler study 30 min after the infiltration in 10 of the 14 patients treated, as well as ulcer healing in 60 days in all the patients. However, in a recent study, Bello et al. (20) could not demonstrate improvement in flow in the Doppler study after treatment with botulinum toxin in patients with Raynaud’s phenomenon secondary to systemic scleroderma (20).\n\nIn their prospective study published in 2011, Serri et al. (21) found that in 18 patients with scleroderma and Raynaud’s phenomenon, there is an improvement in pain measured using the QuickDASH scale, enhanced O2 partial pressure, and complete healing of ulcers (21).\n\nMotegi et al. (11), in a prospective study of 10 Japanese patients with scleroderma and Raynaud’s phenomenon, reported a decrease in the frequency of episodes and improved color, duration, and pain, as well as resolution of digital ulcers. In addition, they used thermography to measure changes in finger temperature after immersion in cold water (11).\n\nIn our study, 30 min after infiltration of the toxin, six patients already showed a response, and four of these were very good. This immediate response has been observed by other authors, with particular significance when it comes to a reduction in pain (13, 14, 16, 21, 22). On the other hand, the reduction in the number of weekly vasospasm episodes is significant 1 month after treatment, decreasing from an average of 30 to an average of 14 (p<0.009) (Figure 1). The average pain intensity decreased from 8 to 2.7 (p<0.005), making this variable the earliest and most striking response (Figure 2). In addition, five patients continued to improve beyond the first month, reaching the maximum response at 6 months. For the others, after 6 months, both the number of episodes and pain remained stable with respect to the data recorded 1 month after treatment.\n\nIt is known that cold and stress produce a norepinephrine-mediated stimulus of the adrenergic receptor in the pericytes and vascular smooth muscle cells, causing vasoconstriction. In patients with systemic scleroderma, the response of the alpha-adrenergic receptors is increased in the digital arteries, suggesting that norepinephrine intervenes in the genesis of Raynaud’s phenomenon (1, 2). On the other hand, norepinephrine, substance P, glutamate, and calcitonin gene-related peptide increase in the peripheral nerves of the affected skin, inducing severe pain and paresthesia in the fingers (22–26).\n\nThe reduced number of Raynaud’s phenomenon episodes, its decreased duration, and the improved pain, which may be immediate, are reported in several studies and were observed in the present study, as mentioned previously. The exact mechanism of action is unknown, but it seems that it does not only cause vasodilation due to the paralysis of the acetylcholine-mediated arterial muscles (27), as this mechanism does not explain the rapid response experienced by some patients. The blocking of norepinephrine release and the inhibition of alpha-adrenergic receptor expression in the vascular walls reduce vasoconstriction and pain (12).\n\nOn the other hand, in animal models, it has been demonstrated that botulinum toxin inhibits these pain-mediating neurotransmitters in the nociceptive sensory neurons, reducing the peripheral stimulus toward the spinal cord and its progression toward the cerebral cortex. To this, the blocking of ectopic sodium channels that are overexpressed and aberrant in ischemic and chronic pain processes must be added (16, 25). In line with previously published studies, in our study, the variable showing the best response was pain, with immediate improvement in five patients.\n\nThe improved mobility observed in some patients is in agreement with the reduced stiffness and numbness documented by Sycha et al. (13) it is likely that the reduced pain caused by the aforementioned inhibition of the neurotransmitters plays an important role in this process.\n\nSimilarly, the response of ulcers to the treatment, as well as the 4- to 8-week healing period, also agrees with published studies (12, 14–17, 21). The study by Motegi et al. (28) supports the resolution of ulcers with the demonstration of increased blood flow through angiography and dermoscopy tests.\n\nThe technique used on our patients, involving infiltration at the base of the fingers, is one of two proposals by Fregene et al. (15) These show no significant differences in efficacy, although there is a greater tendency to weakness in the intrinsic musculature, the more proximal the injection (palmar or wrist) (15). In addition, the infiltration on the lateral aspect of the base of the fingers was chosen because it is similar to the one used for the digital nerve block anesthesia of the fingers, targeting the neurovascular plexus.\n\nPatient satisfaction with the treatment is high, despite this technique requiring periodic infiltrations, which are very well tolerated in practically all cases.\n\nWe have not been able to establish a clear pattern associated with a better response. Some patients demonstrate an excellent response that is maintained over time, whereas others show no improvements. Regarding doses of 100–200 IU of botulinum toxin, they could be insufficient, as suggested by Motegi et al. (29) in a study in which a greater response is observed using a dose of 1000–2000 IU. Owing to these reasons, we consider multicentric, prospective, controlled studies to be necessary in order to establish the ideal candidate patient for the treatment, the most adequate doses, and the best injection pattern. A possible explanation for the variability in response is that certain patients may be immunologically resistant to botulinum toxin (3).\n\nIn conclusion, the present study establishes botulinum toxin as a safe, accessible, and effective therapeutic alternative for the treatment of severe Raynaud’s phenomenon, allowing non-responders to conventional treatments to maintain a good quality of life, through annual infiltrations prior to the winter period.\n\nEthics Committee Approval: Ethics committee approval was received for this study from the HUPA Ethical Committee (Decision Date: 06/2013; Decision No.CF 06/2013-DER).\n\nInformed Consent: Written informed consent was obtained from all the patients who participated in this study.\n\nPeer-review: Externally peer-reviewed.\n\nAuthor Contributions: Concept - S.M., I.P., C.I., L.R.; Design - S.M., I.P., C.I., L.R., N.V., C.G.; Supervision - S.M., I.P., C.I., L.R., L.T.; Resources - S.M., I.P., C.I., L.R., L.T.; Materials - S.M., I.P., C.I., L.R., C.G., A.C.; Data Collection and/or Processing - S.M., I.P., C.I., L.R., N.V., C.G.; Analysis and/or Interpretation - S.M., I.P., C.I., L.R., N.V., A.G.Z.; Literature Search - S.M., I.P., C.I., L.R., N.V., A.G.Z., A.C., C.G.; Writing Manuscript - S.M., A.G.Z.; Critical Review - S.M., I.P., C.I., L.R., A.G.Z., A.C., L.T.\n\nConflict of Interest: The authors have no conflict of interest to declare.\n\nFinancial Disclosure: The authors declared that this study has received no financial support.\n\nFigure 1 Infiltration sites at the base of the lateral aspects of all the fingers, except the first\n\nFigure 2 One patient presented with purpuric coloration in all the fingers, together with a necrotic injury on the fifth finger of the left hand (up, left). After 6 h of treatment, there was a significant improvement in color (up, right). Two patients presented with a significant limitation in the flexion and extension of the second finger in both hands (down, left). Half an hour after infiltration of the left hand, the fingers had full movement, accompanied by a total absence of pain and improved color (down, right)\n\nFigure 3 Patient evaluation at 30 min, 7 days, 1 month, 3 months, 6 months, and a year from the infiltration. Eight patients with a very good response maintained this with an annual dose, with the exception of two patients who required no further infiltrations\n\nFigure 4 Number of episodes of Raynaud’s phenomenon significantly decreased in the first month post-treatment\n\nFigure 5 The pain intensity significantly decreased in the first month of treatment, making this variable the earliest and most striking response\n\nTable 1 Inclusion and exclusion criteria\n\nInclusion criteria\tExclusion criteria\t\nSevere, primary, or secondary Raynaud’s phenomenon (intense and incapacitating pain)\tActive infection at the injection site\t\nPresence of ulcers and/or necrosis\tHypersensitivity to botulinum toxin or drug delivery vehicle\t\nDistal capillary filling of >8 s\tEarlier thoracic sympathectomy\t\nRefractory reaction to conventional medical treatments (calcium antagonists)\tPregnant or breastfeeding\t\nAbsence of obstructive disease confirmed by Doppler echocardiography\t\t\nTable 2 Demografic and clinical characteristics of the patients\n\nPatient ID\tSex\tAge (year)\tSmoker or ex-smoker\tRaynaud’s phenomenon type\tPrevious treatments\tUlcers and/or necrosis\tInfiltrated toxin units\t\n1\tF\t52\tNo\tSecondary LSS\tIloprost, nifedipine\tYes\tL: 48\nR: 48\t\n2\tF\t41\tYes\tSecondary LSS\tNifedipine\tNo\tL: 40\nR: 40\t\n3\tF\t51\tNo\tSecondary LSS\tNifedipine\tYes\tL: 52\nR: 48\t\n4\tF\t35\tNo\tSecondary LSS\tNifedipine, bosentan, iloprost, pentoxifylline\tYes\tL: 36\nR: 40\t\n5\tF\t41\tNo\tSecondary MCTD\tNifedipine\tYes\tL: 32\nR: 64\t\n6\tF\t37\tNo\tPrimary\tPentoxifylline, nifedipine\tNo\tL: 52\nR: 44\t\n7\tF\t48\tEx-smoker (10 years)\tSecondary LSS\tNifedipine\tNo\tL: 34\nR: 36\t\n8\tF\t46\tNA\tSecondary DSS\tAmlodipine\tNo\tL: 40\nR: 44\t\n9\tF\t71\tNA\tSecondary LSS\tDiltiazem\tNo\tL: 44\nR: 56\t\n10\tF\t52\tEx-smoker (1 year)\tSecondary LSS\tNifedipine\tNo\tL: 34\nR: 34\t\n11\tF\t54\tNA\tPrimary\tNifedipine\tNo\tL: 44\nR: 46\t\n12\tF\t41\tEx-smoker (10 years)\tSecondary DSS\tPentoxifylline, amlodipine\tYes\tL: 50\nR: 50\t\n13\tF\t44\tNA\tSecondary MCTD\tPentoxifylline, nifedipine\tNo\tL: 46\nR: 50\t\n14\tF\t43\tNA\tSecondary MCTD\tNifedipine\tNo\tL: 40\nR: 60\t\n15\tM\t69\tNA\tSecondary MCTD\tNifedipine\tNo\tL: 50\nR: 50\t\nDSS: diffuse systemic scleroderma; F: female; ID: identification; L: left; LSS: limited systemic scleroderma; MCTD: mixed connective tissue disease; M: male; NA: not available; R: right\n==== Refs\nReferences\n1 Herrick AL The pathogenesis, diagnosis and treatment of Raynaud phenomenon Nat Rev Rheumatol 2012 8 469 79 https://doi.org/10.1038/nrrheum.2012.96 22782008 \n2 Wigley FM Clinical practice Raynaud’s phenomenon N Engl J Med 2002 347 1001 8 https://doi.org/10.1056/NEJMcp013013 12324557 \n3 Neumeister MW The role of botulinum toxin in vasospactic disorders of the hand Hand Clin 2015 31 23 37 https://doi.org/10.1016/j.hcl.2014.09.003 25455354 \n4 Thompson AE Pope JE Calcium channel blockers for primay Raynaud’s phenomenon: a meta-analysis Rheumatology (Oxford) 2005 44 145 50 https://doi.org/10.1093/rheumatology/keh390 15546967 \n5 Matucci-Cerinic M Denton CP Frust DE Mayes MD Hsu VM Carpentier P Bosentan treatment of digital ulcers related to systemic sclerosis. Results from RAPIDS-2 randomised, double-blind placebo-controlled trial Ann Rheum Dis 2011 70 32 8 https://doi.org/10.1136/ard.2010.130658 20805294 \n6 Wigley FM Wise RA Seibold JR McCloskey DA Kujala G Medsger TA Jr Intravenous iloprost infusion in patients with Raynaud phenomenon secondary to systemic sclerosis. A multicentric placebo-controlled, double-blind study Ann Intern Med 1994 120 199 206 https://doi.org/10.7326/0003-4819-120-3-199402010-00004 7506013 \n7 Dziadzio M Denton CP Smith R Howell K Blann A Bowers E Losartan therapy for Raynaud phenomenon and scleroderma Arthitis Rheum 1999 42 2646 55 \n8 Nguyen VA Eisendle K Gruber I Hughe B Reider D Reider N Effect of the dual endothelin receptor antagonist bosentan on Raynaud’s phenomenon secondary to systemic sclerosis: a double-blind prospective, randomized, placebo controlled pilot study Rheumatology (Oxford) 2010 49 583 7 https://doi.org/10.1093/rheumatology/kep413 20040526 \n9 Merkel PA Herlyn K Martin RW Anderson JJ Mayes MD Bell P Measuring disease activity and functional status in patients with scleroderma and Raynaud’s phenomenon Arthritis Rheum 2002 46 2410 20 https://doi.org/10.1002/art.10486 12355489 \n10 Kostis SV Chung KC A systematic review of the outcomes of digital sympathectomy for treatment of chronic digital ischemia J Rheumatol 2003 30 1788 92 12913936 \n11 Motegi S Yamada K Toki S Uchiyama A Kubota Y Nakamura T Beneficial effect of botulinum toxin A on Raynaud’s phenomenon in Japanese patients with systemic sclerosis: A prospective, case series study J Dermatol 2016 43 56 62 https://doi.org/10.1111/1346-8138.13030 26173902 \n12 Setler P Therapeutic use of botulinum toxins: back-ground and history Clin J Pain 2002 18 Suppl S119 24 https://doi.org/10.1097/00002508-200211001-00002 12569958 \n13 Sycha T Graninger M Auff E Shinider P Botulinum toxin in the treatment of Raynaud phenomenon: A pilot study Eur J Clin Invest 2004 34 312 3 https://doi.org/10.1111/j.1365-2362.2004.01324.x 15086364 \n14 Van Beek AL Lim PK Gear AJ Pritzker MR Management of vasospastic disorders with botulinum toxin Plast Reconstr Surg 2007 119 217 26 https://doi.org/10.1097/01.prs.0000244860.00674.57 17255677 \n15 Fregene A Ditmars D Siddiqui A Botulinum toxin type A: A treatment option for digital ischemia in patients with Raynaud’s phenomenon Hand Surg Am 2009 34 446 52 https://doi.org/10.1016/j.jhsa.2008.11.026 \n16 Neumeister MW Chambers CB Herron MS Webb K Wietfeldt I Gillespie JN Botox therapy for ischemic digits Plast Reconstr Surg 2009 124 191 201 https://doi.org/10.1097/PRS.0b013e3181a80576 19568080 \n17 Neumeister MW Botulinum toxin type A in the treatment of Raynaud’s phenomenon J Hand Surg Am 2010 35 2085 92 https://doi.org/10.1016/j.jhsa.2010.09.019 21134617 \n18 Jenkins SN Neyman KM Veledar E Chen SC A pilot evaluating the efficacy of botulinum toxin A in the treatment of Raynaud phenomenon J Am Acad Dermatol 2013 69 834 5 https://doi.org/10.1016/j.jaad.2013.06.029 24124825 \n19 Iorio ML Masden DL Higgins JP Botulinum toxin A treatment of Raynaud’s phenomenon: A review Semin Arthritis Rheum 2012 41 599 603 https://doi.org/10.1016/j.semarthrit.2011.07.006 21868066 \n20 Bello RJ Cooney CM Melamed E Follmar K Yenokyan G Leatherman G The Therapeutic Efficacy of Botulinum Toxin in Treating Scleroderma-Associated Raynaud’s Phenomenon: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial Arthritis Rheumatol 2017 69 1661 9 https://doi.org/10.1002/art.40123 28426903 \n21 Serri J Legre R Veit V Guardia C Gay AM Intérêt de la toxine botulinique de type A dans le traitement des syndromes de Raynaud sévères secondaires à la sclérodermie systémique Ann Chir Plast Esthet 2013 58 658 62 https://doi.org/10.1016/j.anplas.2011.11.001 22204894 \n22 Aoki KR Review of a proposed mechanism for the antinociceptive action of botulinum toxin type A Neurotoxicology 2005 26 785 93 https://doi.org/10.1016/j.neuro.2005.01.017 16002144 \n23 Welch MJ Purkiss JR Foster KA Sensitivity of embryonic rat dorsal root ganglia neurons to clostridium botulinum neurotoxins Toxicon 2000 38 245 58 https://doi.org/10.1016/S0041-0101(99)00153-1 10665805 \n24 Lawrence GW Foran P Dolly JO Insights into a basis for incomplete inhibition by botulinum toxin A of Ca2+ evoked exocitosis from a permmeabilised chromaffin cells Toxicology 2002 181 249 53 https://doi.org/10.1016/S0300-483X(02)00453-5 12505320 \n25 Durham PL Cady R Regulation of calcitonin gene-related peptide secretion from trigeminal nerve cells by botulinum toxin type A: Implications for migraine therapy Headache 2004 44 35 42 https://doi.org/10.1111/j.1526-4610.2004.04007.x 14979881 \n26 Cui M Khanijou S Rubino J Aoki KR Subcutaneous administration of botulinum toxin A reduces formalin-induced pain Pain 2004 107 125 33 https://doi.org/10.1016/j.pain.2003.10.008 14715398 \n27 Stone AV Koman AL Callahan MF Eckman DM Smith BP Plate JF The effect of botulinum neurotoxin-A on blood flow in rats: A potencial mechanism for treatment of Raynaud phenomenon J Hand Surg 2012 37 795 802 https://doi.org/10.1016/j.jhsa.2012.01.021 \n28 Motegi SI Uehara A Yamada K Sekiguchi A Fujiwara C Toki S Efficacy of Botulinum Toxin B Injection for Raynaud’s Phenomenon and Digital Ulcers in Patients with Systemic Sclerosis Acta Derm Venereol 2017 97 843 50 https://doi.org/10.2340/00015555-2665 28358168 \n29 Motegi SI Sekiguchi A Saito S Ishibuchi H Kishi C Yasuda M Successful treatment of Raynaud’s phenomenon and digital ulcers in systemic sclerosis patients with botulinum toxin B injection: Assessment of peripheral vascular disorder by angiography and dermoscopic image of nail fold capillary J Dermatol 2018 45 349 52 https://doi.org/10.1111/1346-8138.14140 29164658\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "2147-9720", "issue": "5(4)", "journal": "European journal of rheumatology", "keywords": null, "medline_ta": "Eur J Rheumatol", "mesh_terms": null, "nlm_unique_id": "101656068", "other_id": null, "pages": "224-229", "pmc": null, "pmid": "30501848", "pubdate": "2018-12", "publication_types": "D016428:Journal Article", "references": "7506013;10616013;26173902;20040526;10665805;19258141;28426903;14715398;29164658;14979881;28358168;25455354;12324557;12355489;17255677;20805294;22204894;24124825;21868066;19568080;12913936;12569958;16002144;22782008;21134617;12505320;22386546;15546967;15086364", "title": "Botulinum toxin type A in the treatment of Raynaud's phenomenon: A three-year follow-up study.", "title_normalized": "botulinum toxin type a in the treatment of raynaud s phenomenon a three year follow up study" }

[ { "companynumb": "ES-ALLERGAN-1858012US", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "ONABOTULINUMTOXINA" }, "drugadditional": null, "drugadministrationroute": "030", "drugauthorizationnumb": "103000", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "POWDER FOR INJECTION", "drugdosagetext": "ACTUAL: 4 AND 8 UNITS OF TOXIN PER SITE USING A 30 G NEEDLE, DEPENDING ON THE SEVERITY", "drugenddate": null, "drugenddateformat": null, "drugindication": "RAYNAUD^S PHENOMENON", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BOTOX" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Peritonitis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MEDINA S, GOMEZ-ZUBIAUR A, POLO-RODRIGUEZ I, GUIRADO C, CABRERA A, TRASOBARES L, VALDEOLIVAS-CASILLAS N, RUIZ L, IZQUIERDO C. BOTULINUM TOXIN TYPE A IN THE TREATMENT OF RAYNAUD^S PHENOMENON: A THREE-YEAR FOLLOW-UP STUDY. EUROPEAN JOURNAL OF RHEUMATOLOGY. 2018?5(4):224-229", "literaturereference_normalized": "botulinum toxin type a in the treatment of raynaud s phenomenon a three year follow up study", "qualification": "1", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20181224", "receivedate": "20181219", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15741742, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" } ]

{ "abstract": "Women with congenital adrenal hyperplasia (CAH) may present with androgen excess that is difficult to control with conventional suppressive doses of glucocorticoids. Clinical management is challenging, and the woman is at great risk of developing steroid-induced complications.\n\n\n\nA 32-year-old woman with salt-wasting CAH due to 21-hydroxylase deficiency underwent right-sided adrenalectomy because of a large myelolipoma. Over the years, androgens became increasingly difficult to suppress on prednisolone 5 + 0 + 2.5 mg daily, and at age 39 years the left adrenal with an enlarging myelolipoma was removed. A month later serum testosterone levels had increased from 4.1 preoperatively to 18.3 nmol/L (reference 0.2-1.8 nmol/L), and adrenocorticotropin levels from 32 to 283 pmol/L (reference < 14 pmol/L). No adrenal parenchyma was visualized on computed tomography (CT). In the further search for the source of the markedly elevated testosterone, positron emission tomography (PET) was performed with 2 different tracers, 18fluorodeoxyglucose (18FDG) reflecting glucose metabolism and 11C-metomidate, an inhibitor of 11-β-hydroxylase targeting adrenocortical tissue.\n\n\n\n18FDG-PET/CT with cosyntropin stimulation showed ovarian/paraovarian hypermetabolism, suggestive of adrenal rest tumors. Further characterization with 11C-metomidate PET/CT showed uptakes localized to the ovaries/adnexa, behind the spleen, and between the right crus diaphragmaticus and inferior vena cava.\n\n\n\nAdrenal rest tumors can give rise to high androgen levels in spite of suppressive supraphysiological glucocorticoid doses. This case illustrates, for the first time, the value of 11C-metomidate PET as a sensitive method in documenting adrenal rest tumors, currently considered rare in women with CAH.", "affiliations": "Department of Endocrinology, Skåne University Hospital, Malmö, Lund University, Malmö, Sweden.;Department of Endocrinology, Metabolism and Diabetes, Karolinska University Hospital, Stockholm, Sweden.;Department of Endocrinology, Skåne University Hospital, Malmö, Lund University, Malmö, Sweden.;Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.;Department of Clinical Physiology and Nuclear Medicine, Skåne University Hospital, Lund, Sweden.", "authors": "Burman|Pia|P|;Falhammar|Henrik|H|;Waldenström|Erik|E|;Sundin|Anders|A|;Bitzén|Ulrika|U|", "chemical_list": "D002250:Carbon Radioisotopes; C000615233:Carbon-11; D012492:Salts; C084586:metomidate; D005045:Etomidate", "country": "United States", "delete": false, "doi": "10.1210/clinem/dgaa870", "fulltext": null, "fulltext_license": null, "issn_linking": "0021-972X", "issue": "106(2)", "journal": "The Journal of clinical endocrinology and metabolism", "keywords": "\n 18FDG PET/CT; 21-hydroxylase deficiency; adrenalectomy; cosyntropin; ovarian adrenal rest tumors; retroperitoneal adrenal rest tumors", "medline_ta": "J Clin Endocrinol Metab", "mesh_terms": "D000312:Adrenal Hyperplasia, Congenital; D000314:Adrenal Rest Tumor; D000328:Adult; D002250:Carbon Radioisotopes; D005045:Etomidate; D005260:Female; D006801:Humans; D009378:Neoplasms, Multiple Primary; D010051:Ovarian Neoplasms; D000072078:Positron Emission Tomography Computed Tomography; D012186:Retroperitoneal Neoplasms; D012492:Salts; D013548:Sweden; D014883:Water-Electrolyte Imbalance", "nlm_unique_id": "0375362", "other_id": null, "pages": "e675-e679", "pmc": null, "pmid": "33245336", "pubdate": "2021-01-23", "publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "11C-Metomidate PET/CT Detected Multiple Ectopic Adrenal Rest Tumors in a Woman With Congenital Adrenal Hyperplasia.", "title_normalized": "11c metomidate pet ct detected multiple ectopic adrenal rest tumors in a woman with congenital adrenal hyperplasia" }

[ { "companynumb": "SE-LUPIN PHARMACEUTICALS INC.-2021-23526", "fulfillexpeditecriteria": "2", "occurcountry": "SE", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "HYDROCORTISONE" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": "210209", "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MILLIGRAM, QD, 20+10+20 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "Androgens increased", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROCORTISONE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "HYDROCORTISONE" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": "210209", "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "30 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "Adrenal neoplasm", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "30", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROCORTISONE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "FLUDROCORTISONE" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.15 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "Androgens increased", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "0.15", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUDROCORTISONE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "FLUDROCORTISONE" }, "drugadditional": "4", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Adrenal neoplasm", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUDROCORTISONE" } ], "patientagegroup": null, "patientonsetage": "28", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Burman P, Falhammar H, Waldenstrom E, Sundin A, Bitzen U. 11C-Metomidate PET/CT Detected Multiple Ectopic Adrenal Rest Tumors in a Woman With Congenital Adrenal Hyperplasia. The Journal of Clinical Endocrinology + Metabolism. 2021;106(2):e675-e679", "literaturereference_normalized": "11c metomidate pet ct detected multiple ectopic adrenal rest tumors in a woman with congenital adrenal hyperplasia", "qualification": "1", "reportercountry": "SE" }, "primarysourcecountry": "SE", "receiptdate": "20211202", "receivedate": "20211202", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20139109, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220303" } ]

{ "abstract": "We conducted a multicenter, phase II trial to investigate the efficacy and safety of rituximab plus CVP (R-CVP) combination therapy for patients with previously untreated stage III or IV marginal zone lymphoma (MZL). The treatment consisted of rituximab 375 mg/m(2), cyclophosphamide 750 mg/m(2) and vincristine 1.4 mg/m(2) (maximum 2.0 mg) being given intravenously on day 1 and oral prednisolone 100 mg on days 1-5. The treatment was repeated every 3 weeks and this was continued for six or eight cycles. Forty-two patients were enrolled from 13 institutes in Korea. Among them, two patients were dropped after the first and second cycles of chemotherapy, respectively, without evaluation. The 40 patients received a total of 287 cycles of R-CVP chemotherapy. The overall response rate was 88% (95% CI, 77-98%) with 24 complete responses (60%). The median duration of response was 28.3 months. After a median follow-up of 38.2 months, the estimated 3-year progression-free survival and overall survival were 59% and 95%, respectively. There were 30/287 cycles (11%) and 5/287 cycles (2%) of grade 3 or 4 neutropenia and febrile neutropenia, respectively. The R-CVP regimen can be an effective and tolerable first-line immunochemotherapy regimen for advanced stage MZL.", "affiliations": "Division of Hematology/Oncology, Department of Internal Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, 75 Nowon Gil, Nowon-gu, Seoul 139-706, Republic of Korea.", "authors": "Kang|Hye Jin|HJ|;Kim|Won Seog|WS|;Kim|Seok Jin|SJ|;Lee|Je-Jung|JJ|;Yang|Deok-Hwan|DH|;Kim|Jin Seok|JS|;Lee|Se-Ryeon|SR|;Lee|Gyeong-Won|GW|;Kim|Hyo Jung|HJ|;Kim|Ho Young|HY|;Oh|Sung Yong|SY|;Kim|Hugh Chul|HC|;Eom|Hyeon-Seok|HS|;Chung|Jooseop|J|;Park|Jinny|J|;Suh|Cheolwon|C|;Ryoo|Baek-Yeol|BY|", "chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D005938:Glucocorticoids; D000069283:Rituximab; D014750:Vincristine; D003520:Cyclophosphamide; D011239:Prednisolone", "country": "Germany", "delete": false, "doi": "10.1007/s00277-011-1337-6", "fulltext": null, "fulltext_license": null, "issn_linking": "0939-5555", "issue": "91(4)", "journal": "Annals of hematology", "keywords": null, "medline_ta": "Ann Hematol", "mesh_terms": "D000328:Adult; D000368:Aged; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D003520:Cyclophosphamide; D018572:Disease-Free Survival; D004359:Drug Therapy, Combination; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D018442:Lymphoma, B-Cell, Marginal Zone; D008297:Male; D008875:Middle Aged; D011239:Prednisolone; D056910:Republic of Korea; D000069283:Rituximab; D015996:Survival Rate; D014750:Vincristine", "nlm_unique_id": "9107334", "other_id": null, "pages": "543-51", "pmc": null, "pmid": "21922208", "pubdate": "2012-04", "publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study", "references": null, "title": "Phase II trial of rituximab plus CVP combination chemotherapy for advanced stage marginal zone lymphoma as a first-line therapy: Consortium for Improving Survival of Lymphoma (CISL) study.", "title_normalized": "phase ii trial of rituximab plus cvp combination chemotherapy for advanced stage marginal zone lymphoma as a first line therapy consortium for improving survival of lymphoma cisl study" }

[ { "companynumb": "KR-ROCHE-652507", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "GIVEN ON DAYS 1 TO 5 OF EVERY CYCLE (REPEATED EVERY 3 WEEKS)", "drugenddate": null, "drugenddateformat": null, "drugindication": "B-CELL LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "GIVEN ON DAY 1 OF EVERY CYCLE; DOSE: 1.4 MG/M2 ( MAXIMUM 2.0 MG)", "drugenddate": null, "drugenddateformat": null, "drugindication": "B-CELL LYMPHOMA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "3", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": "103705", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INFUSION", "drugdosagetext": "ON DAY 1 OF EVERY CYCLE", "drugenddate": null, "drugenddateformat": null, "drugindication": "B-CELL LYMPHOMA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "3", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "375", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "GIVEN ON DAY 1 OF EACH CYCLE", "drugenddate": null, "drugenddateformat": null, "drugindication": "B-CELL LYMPHOMA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "3", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "750", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Rash", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Febrile neutropenia", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Asthenia", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hyperbilirubinaemia", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pyrexia", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neutropenia", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anaemia", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Peripheral sensory neuropathy", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Aspartate aminotransferase increased", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Abdominal pain", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Alanine aminotransferase increased", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Alopecia", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": ", KIM W, KIM S, LEE J-J, YANG D-H, KIM J, LEE S-R, LEE G, KIM H, KIM H, OH S, KIM H, EOM H-S, CHUNG J, PARK J, SUH C AND RYOO B-Y. PHASE II TRIAL OF RITUXIMAB PLUS CVP COMBINATION CHEMOTHERAPY FOR ADVANCED STAGE MARGINAL ZONE LYMPHOMA AS A FIRST-LINE THERAPY: CONSORTIUM FOR IMPROVING SURVIVAL OF LYMPHOMA (CISL) STUDY. ANNALS OF HEMATOLOGY 2012;91(4):543-551.", "literaturereference_normalized": "phase ii trial of rituximab plus cvp combination chemotherapy for advanced stage marginal zone lymphoma as a first line therapy consortium for improving survival of lymphoma cisl study", "qualification": "3", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20170410", "receivedate": "20120626", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 8636215, "safetyreportversion": 4, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" } ]

{ "abstract": "A unique case of primary refractory FLT3-itd mutated acute myeloid leukemia in an elderly patient, who achieved completed morphological remission, and FLT3-itd negativity, following 9 cycles of azacitadine in combination with escalating doses of donor lymphocyte infusions following relapse 18 months post reduced intensity HLAA mismatch Campath conditioning allogeneic stem cell transplant.", "affiliations": "Hematology and Stem Cell Transplantation Department, Heart of England NHS Trust, Birmingham, UK.;Hematology and Stem Cell Transplantation Department, Heart of England NHS Trust, Birmingham, UK.;Hematology and Stem Cell Transplantation Department, Heart of England NHS Trust, Birmingham, UK.;Hematology and Stem Cell Transplantation Department, Heart of England NHS Trust, Birmingham, UK.;Hematology and Stem Cell Transplantation Department, Heart of England NHS Trust, Birmingham, UK.;Hematology and Stem Cell Transplantation Department, Heart of England NHS Trust, Birmingham, UK.", "authors": "Horgan|Claire|C|;Kanellopoulos|Alexandros|A|;Paneesha|Shankara|S|;Kishore|Bhuvan|B|;Lovell|Richard|R|;Nikolousis|Emmanouil|E|", "chemical_list": null, "country": "Italy", "delete": false, "doi": "10.4081/hr.2019.7800", "fulltext": "\n==== Front\nHematol Rep\nHR\nHematology Reports\n2038-8322 2038-8330 PAGEPress Publications, Pavia, Italy \n\n30915202\n10.4081/hr.2019.7800\nCase Report\nA unique case of durable complete remission after salvage with azacitidine and DLI for high risk flt-3 positive acute myeloid leukemia, following relapse 18 months post allogeneic stem cell transplant\nHorgan Claire Kanellopoulos Alexandros Paneesha Shankara Kishore Bhuvan Lovell Richard Nikolousis Emmanouil Hematology and Stem Cell Transplantation Department, Heart of England NHS Trust, Birmingham, UK\nHematology and Stem Cell Transplantation Department, Heart of England NHS Trust, Bordesley Green East, Birmingham, B9 5SS, United Kingdom. +30.01214243699. manos.nikolousis@heartofengland. nhs.ukContributions: CH, manuscript writing; AK, review of manuscript; SP, review of manuscript; BK, review of manuscript; RL, review of manuscript; EN, writing and review of manuscript.\n\nConflict of interest: the authors declare no potential conflict of interest.\n\n\n25 2 2019 \n19 2 2019 \n11 1 780026 7 2018 15 11 2018 ©Copyright C. Horgan et al., 20192019Licensee PAGEPress, ItalyThis 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.A unique case of primary refractory FLT3-itd mutated acute myeloid leukemia in an elderly patient, who achieved completed morphological remission, and FLT3-itd negativity, following 9 cycles of azacitadine in combination with escalating doses of donor lymphocyte infusions following relapse 18 months post reduced intensity HLAA mismatch Campath conditioning allogeneic stem cell transplant.\n\nKey words\nAcute myeloid leukemiaFlt-3 mutationAzacitidineFunding: none.\n==== Body\nIntroduction\nAcute myeloid leukemia (AML) remains a therapeutic challenge. Despite ongoing research, the standard therapy for AML has not changed significantly in the past four decades. With the identification of cytogenetic and molecular abnormalities, several promising therapeutic agents are currently being investigated. FLT3 mutation is a well-recognized target seen in 30% of the cytogenetically normal AML. FLT3 mutated AML, particularly those individuals who harbor the most common type of FLT3 mutation, the internal tandem duplication (ITD), provides a particular challenge for clinicians treating the condition as it has traditionally been associated with poor outcomes, with a median overall survival of 13.1 months.1\n\nPatients with FLT3-itd mutated AML have been shown to benefit from allogeneic hematopoietic stem cell transplant (HSCT) to induce a potent antileukemic effect and overcome disease relapse in 1st clinical remission,2 however, at an increased risk of relapse post-transplant,3 and outcomes following transplant relapse have been particularly poor.4 Efforts to develop protein kinase inhibitors, inhibiting mutated forms of the FLT3 receptor, have led to successive generations of FLT3 inhibitors,5 providing new hope for individuals with FLT3-itd mutations. The RATIFY trial concluded that the FLT3 inhibitor midostaurin increased overall survival in younger adult patients, when used in combination with intensive induction and consolidation therapy,6 however, randomized trials evaluating intensive chemotherapy with other FLT3 inhibitors, including lestaurtinib and sorafenib, failed to show an improvement in response rate and overall survival.7-10 Despite this, recent case reports have suggested that the FLT3 inhibitor sorafenib, used in combination with azacitadine and donor lymphocyte infusions in patients with FLT3-itd mutated AML, who have relapsed post-transplant, can be an effective approach that warrants further evaluation in clinical trials.11\n\nCase Report\nA 68-year-old lady, who was diagnosed with AML de novo, FLT3-itd positive (high ITD: wild type ratio-the FLT3 mutant-towild type allelic ratio reflects the fraction of leukemia cells that harbor the mutation) normal karyotype on 12th February 2014, was referred for allogeneic stem cell transplantation in view of her high-risk disease. The patient had been previously well with no major comorbidities and had enjoyed regular exercise, particularly swimming, prior to diagnosis. Her disease was detected when a full blood count, sent by her GP as part of investigations for fatigue, demonstrated pancytopenia and a blast count of 30%.\n\nThe patient had unfortunately been refractory to one course of DA-chemotherapy she had received on AML-17 but had an excellent response to FLAG-IDA, achieving complete remission in the bone marrow after her 1st cycle. She had 1 brother, who was 66 years old and a heavy smoker and drinker, and since it was felt that he would not be an ideal candidate for a potential donor, an unrelated donor search was initiated following tissue typing.\n\nThe patient went on to complete a 2nd course of FLAG-IDA and was in complete remission when she underwent an HLAmismatched (mismatch at HLA-A locus) reduced intensity-conditioned Fludarabine/ Busulphan for 2 days/Alemtuzumab 50 mg over 2 days T-deplete matched unrelated donor allogeneic transplant, day 0=13/9/14. Most studies show an advantage of allo- HCT in first complete remission (CR1), with higher 3-5-year disease-free survival and lower relapse risk than with chemotherapy or autologous transplantation (auto- HCT). Allo-HCT proceeding early after reaching CR1 seems to improve survival, rather than after several courses of consolidation chemotherapy. CMV status was negative (recipient), positive (donor), and blood groups A negative and A positive for the recipient and donor respectively. Conditioning for the transplant was complicated by Enterobacter and E.coli bacteremias which resolved following treatment with meropenem, and the transplant itself was generally well tolerated with no major toxicities, apart from mild nausea and diarrhea. The patient engrafted neutrophils on day +18 and platelet engraftment on day +20 and was subsequently discharged on day +26 following treatment for a further febrile episode.\n\nThe post-transplant period was fairly unremarkable with the patient suffering from mild, grade 1, skin graft versus host disease (GVHD) according to NIH criteria, which started 6 weeks post transplant and responded to topical steroids, and clostridium difficile diarrhea 2 months post transplant which resolved with oral vancomycin. Her 3-month bone marrow aspirate and trephine demonstrated 100% donor chimerism in the whole sample and 99% in CD3+ T cells, and her ciclosporin was gradually tapered from January 2015. The patient continued to have ongoing diarrhea, between 3-4 episodes per day, and underwent a flexible sigmoidoscopy in February 2015, which showed inflammation but no evidence of gut GVHD on biopsy. She continued to remain well over subsequent months and after a slow taper, her ciclosporin was stopped on 31st June 2015. At 1-year post transplant, the patient was doing very well with only mild chronic skin GVHD (no sclerodermatous features, no mouth/eye/vaginal involvement) that was well-controlled with topical creams. Her lung function and echo at 1 year proved stable pulmonary and cardiac function respectively, and she was commenced on the vaccination program as per standard protocol. She continued to be monitored on a monthly basis and her clinical course over subsequent months remained uneventful.\n\nRelapse\nDespite this, when the patient attended clinic on 5/2/16 (18 months post transplant) she was alarmingly noted to have a significant reduction in Cher neutrophil count, so a viral screen for parvovirus, CMV, EBV, Adenovirus, HHV 6 and HHV 8 was sent and an urgent bone marrow arranged. Unfortunately, the bone marrow confirmed relapsed disease, with 20% blasts detected in the marrow flt-3 ITD positive and normal cytogenetics while a mixed chimerism was eatablished with 48% donor in the whole sample and 92% donor in the CD3+ T cell fraction. 2 months earlier she exhibited full chimera in both whole blood and T cells. She was commenced on azacitadine 75 mg/m2 for 7 days, with a plan to have her 1st donor lymphocyte infusion (DLI) after 2 cycles and access to AC220 and Crenolanib was applied for on a compassionate basis. Compassionate access to AC220 and Crenolanib was declined but she tolerated her 1st 2 cycles of azacitadine very well. Her chimerism post these 2 cycles was 53% and 91% for whole blood and T cells respectively, and she had her 1st DLI on 14/4/16 at a dose of 1×106 CD3+ cells/kg. During that time she remained cytopenic and required red cell and platelet transfusion.\n\nThe patient proceeded with cycles 3 and 4 azacitadine and received her 2nd DLI, at a dose of 5x106 CD3 cells/kg on 16/6/16. (table 1 for subsequent timeline of blood chimerism results). She proceeded with monthly cycles of azacitadine and had her 3rd DLI on 26/8/16 at a dose of 1×107 CD3 cells/kg (Table 1). On the 31st September 2016 the patient attended clinic complaining of ongoing gastrointestinal symptoms and, since these were attributed to her azacitadine, her dose was reduced by 50% and the 9th cycle was started 1 week later than scheduled. Unfortunately following this cycle, she developed gram-negative sepsis with E.coli requiring a brief intensive care admission for inotropic support. She recovered well and a bone marrow aspirate and trephine on 6/12/16, post 9 cycles of azacitadine and 3 doses of DLI, demonstrated complete morphological remission with FLT3-itd negativity. Following this, the patient has had no further treatment and continues to be monitored on a monthly basis in transplant clinic. She undergoes regular blood chimerism monitoring and her latest on 10/4/18, almost 4 years postoriginal transplant and over 2 years following relapse, continues to demonstrate 100% donor chimerism in both whole blood and CD3+ T cells.\n\nDiscussion\nFLT3-ITD mutations are associated with an inferior response to salvage therapy and a rapidly fatal progression at relapse both after chemotherapy and allogeneic stem cell transplantation.12 A number of FLT3 kinase inhibitors are in development and have been evaluated in patients with FLT3 mutated AML but none post allogeneic stem cell transplantation. Several mechanisms of resistance to FLT3-TKIs have been proposed and there is no evidence to a potent GvL effect in patients with high allelic ratio.13 Most prominently, the acquisition of mutations in the ATP-binding pocket of FLT3 inducing clinical resistance to FLT3 inhibitors has now been reported.14 We do not systemically evaluate the patients at relapse for the development of such mutation. An increasing allelic ratio with increasing rates of refractory disease has an obvious tendency to translate into decreasing CR rates. These findings underline the biological importance of specific FLT3 molecular characteristics in FLT3-ITDpositive AML.15\n\nThis unique case describes a patient with primary refractory FLT3-itd mutated AML with high ratio who relapsed 18 months post transplant and has achieved complete morphological remission, which has been sustained for 22 months since stopping therapy, with azacitadine and donor lymphocyte infusions only. To our knowledge, there are no other cases of this type, being FLT3-itd positive and refractory to DA initially, and subsequently have relapsed post transplant, who have achieved such long-lasting remission following treatment with this combination alone. The fact that relapse occurred more than 12 months post allogeneic stem cell transplant could have contributed to the positive outcome with the use of Azacitidine and DLI while low disease kinetics enabled the establishment of full donor chimerism and subsequent remission.\n\nThe combination of DLI and azacitadine has been explored in the treatment of AML relapse post transplant, but less that 20% of patients have achieved durable disease control,16 and the 1 patient reported in this data with the FLT3-itd mutation who achieved complete remission relapsed after 126 days.\n\nConclusions\nOur case highlights that a sustained complete remission with DLI and azacitadine alone is possible, even in patients who have high risk disease and offers hope to some individuals in this situation, particularly in scenarios when access to novel agents is restricted or not tolerated.\n\nAcknowledgements\nThe authors wish to thank all nursing staff and BMT coordinators on ward 19 at Heart of England NHS Trust.\n\nTable 1. Timeline of blood chimerism results and relation to treatment.\n\nDate\tTreatment stage\tChimerism whole blood, %\tChimerism CD3 T-cell fraction, %\t\n11/4/16\tPost 2× aza\t53\t91\t\n21/4/16\tPost 2× aza, 1× DLI\t81\t98\t\n16/6/16\tPost 4× aza, 2× DLI*\t62\t96\t\n15/7/16\tPost 5× aza, 2× DLI\t88\t99\t\n28/11/16\tPost 9× aza, 3× DLI\t100\t100\t\n24/2/17\tNo further treatment\t100\t100\t\n10/7/18\tNo further treatment\t100\t100\t\naza, azacitadine; DLI, donor lymphocyte infusion.\n\n*Second DLI given day prior to sample.\n==== Refs\nReferences\n1. Röllig C Bornhäuser M Thiede C \nLong-term prognosis of acute myeloid leukemia according to the new genetic risk classification of the European LeukemiaNet recommendations: evaluation of the proposed re-porting system\n. J Clin Oncol \n2011 ;29 : 2758 -65\n.21632498 \n2. Brunet S Labopin M Esteve J \nImpact of FLT3 internal tandem duplication on the outcome of rela-ted and unrelated hematopoietic transplantation for adult acute myeloid leukemia in first remission: a retro-spective analysis\n. J Clin Oncol \n2012 ;30 :735 -41\n.22291086 \n3. Medeiros BC Tian L Robenson S \nEuropean LeukemiaNet classification intermediate risk-1 cohort is associated with poor outcomes in adults with acute myeloid leukemia undergoing allogeneic hemato-poietic cell transplantation\n. Blood Cancer J \n2014 ;4 : e216 .24879117 \n4. Bejanyan N Weisdorf DJ Logan BR \nSurvival of patients with acute myeloid leukemia relapsing af-ter allogeneic hematopoietic cell transplantation: a center for international blood and marrow transplant re-search study\n. Biol Blood Marrow Transplant \n2015 ;21 :454 -9\n.25460355 \n5. Grunwald MR Levis MJ \nFLT3 tyrosine kinase inhibition as a paradigm for targeted drug development in acute myeloid leukemia\n. Semin Hematol \n2015 ;52 :193 -9\n.26111466 \n6. Stone RM Mandrekar S Laumann C \nMidostaurin, a multi-targeted kinase inhibitor, improves ove-rall survival when added to standard chemotherapy in adults age 18 – 60 with FLT3 mutant acute myeloid leukemia (AML): results from a randomized, prospective, placebo-controlled, doubleblind trial, CALGB 10603/RATIFY\n. Blood \n2015 ;126 .26160184 \n7. Levis M Ravandi F Wang ES \nResults from a randomized trial of salvage chemotherapy followed by lestaurtinib for patients with FLT3 mutant AML in first relapse\n. Blood \n2011 ;117 : 3294 -330\n.21270442 \n8. Knapper S Russell N Gilkes A \nA randomised assessment of adding the kinase inhibitor lestaurtinib to 1st-line chemotherapy for FLT3-mutated AML\n. Blood \n2017 ;129 :1143 -54\n.27872058 \n9. Serve H Krug U Wagner R \nSorafenib in combination with intensive chemotherapy in elderly pa-tients with acute myeloid leukemia: results from a randomized, placebo-controlled trial\n. J Clin Oncol \n2013 ;31 :3110 -8\n.23897964 \n10. Rollig C Serve H Huttmann A \nAddition of sorafenib versus placebo to standard therapy in patients aged 60 years or younger with newly diagnosed acute myeloid leukaemia (SO-RAML): a multicentre, phase 2, randomised controlled trial\n. Lancet Oncol \n2015 ;16 : 1691 -9\n.26549589 \n11. Campregher PV Pinto de Massos VR \nSuccessful treatment of post-transplant relapsed acute mye-loid leukemia with FLT3 internal tandem duplication using the combination of induction chemotherapy, donor lym-phocyte infusion, sorafenib and azacitidine. Report of three cases\n. Einstein (São Paulo) \n2017 ;15 :355 -8\n.28746590 \n12. Gilliland DG Griffin JD \nThe roles of FLT3 in hematopoiesis and leukemia\n. Blood \n2002 ;100 :1532 -42\n.12176867 \n13. Abu-Duhier FM Goodeve AC Wilson GA \nFLT3 internal tandem duplication mutations in adult acute myeloid leukaemia define a high-risk group\n. Br J Haematol \n2000 ;111 :190 -5\n.11091200 \n14. Rollig C Serve H Huttmann A \nStudy Alliance Leukaemia. Addition of sorafenib versus placebo to standard therapy in patients aged 60 years or younger with newly diagnosed acute myeloid leukaemia (SO-RAML): a multicentre, phase 2, randomised controlled trial\n. Lancet Oncol \n2015 ;16 :1691 -9\n.26549589 \n15. Kottaridis PD Gale RE Frew ME \nThe presence of a FLT3 internal tandem duplication in pa-tients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials\n. Blood \n2001 ;98 :1752 -9\n.11535508 \n16. Schroeder T Czibere A Platzbecker U \nAzacitidine and donor lymphocyte infusions as first salvage therapy for relapse of AML or MDS after allogeneic stem cell transplantation\n. Leukemia \n2013 ;27 :1229 -35\n.23314834\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "2038-8322", "issue": "11(1)", "journal": "Hematology reports", "keywords": "Acute myeloid leukemia; Azacitidine; Flt-3 mutation", "medline_ta": "Hematol Rep", "mesh_terms": null, "nlm_unique_id": "101556723", "other_id": null, "pages": "7800", "pmc": null, "pmid": "30915202", "pubdate": "2019-02-19", "publication_types": "D016428:Journal Article", "references": "24879117;22291086;21270442;21632498;26549589;23897964;11535508;23314834;25460355;11091200;27872058;28746590;12176867;26111466", "title": "A unique case of durable complete remission after salvage with azacitidine and DLI for high risk flt-3 positive acute myeloid leukemia, following relapse 18 months post allogeneic stem cell transplant.", "title_normalized": "a unique case of durable complete remission after salvage with azacitidine and dli for high risk flt 3 positive acute myeloid leukemia following relapse 18 months post allogeneic stem cell transplant" }

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A unique case of durable complete remission after salvage with azacitidine and DLI for high risk flt-3 positive acute myeloid leukemia, following relapse 18 months post allogeneic stem cell transplant.. 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{ "abstract": "Opsoclonus myoclonus syndrome (OMS) is a rare, neurological condition affecting 1 in 10 000 000 people annually. Opsoclonus, defined as involuntary rapid, multivectorial oscillations of the eyes, together with ataxia and myoclonus are usually present. OMS may be paraneoplastic: often associated with occult neuroblastoma in childhood and with breast carcinoma or small cell lung carcinoma in adults. Other aetiologies include viral or toxic agents. The pathogenesis is thought to be immune mediated. A 37-year-old woman with previous inflammatory cranial mononeuropathies was admitted for elective dilatation and curettage (D&C). Immediately after she complained of left-sided paraesthesia and later became disoriented, with incoherent speech, inability to obey commands, opsoclonus of the eyes and myoclonic jerks. Investigations including onconeuronal antibodies, cerebrospinal fluid analysis, and imaging were normal. She was treated with intravenous methylprednisolone with rapid improvement. Previous surgeries with anaesthesia were uncomplicated. The anaesthetic agents used for the D&C were fentanyl and propofol.", "affiliations": "Department of Neurosciences, Mater Dei Hospital, Attard, Malta.;Department of Neuroscience, Mater Dei Hospital, Msida, Malta.;Department of Neurology, Mater Dei Hospital, Msida, Malta.", "authors": "Aquilina|Annelise|A|;Dingli|Nicola|N|;Aquilina|Josanne|J|", "chemical_list": "D008775:Methylprednisolone", "country": "England", "delete": false, "doi": "10.1136/bcr-2017-219859", "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "2017()", "journal": "BMJ case reports", "keywords": "Anaesthesia; Neuroopthalmology", "medline_ta": "BMJ Case Rep", "mesh_terms": "D061605:Administration, Intravenous; D000328:Adult; D005260:Female; D006801:Humans; D008775:Methylprednisolone; D053578:Opsoclonus-Myoclonus Syndrome; D016896:Treatment Outcome", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "28432174", "pubdate": "2017-04-21", "publication_types": "D016428:Journal Article", "references": "19240003;20846945;22986354;23622330;23683453;24995204;25540528;25598905", "title": "Postintervention acute opsoclonus myoclonus syndrome.", "title_normalized": "postintervention acute opsoclonus myoclonus syndrome" }

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{ "abstract": "Methotrexate neurotoxicity can present with a wide spectrum of neurologic symptoms and brain magnetic resonance imaging (MRI) typically demonstrates cerebral edema, demyelination, multifocal white matter necrosis, and atrophy relatively selective for the deep cerebral white matter. Here, we report a case of subacute methotrexate neurotoxicity in a 40-year-old man with B cell acute lymphoblastic leukemia. Brain MRI showed cytotoxic lesion in the splenium of corpus callosum and left middle cerebellar peduncle. Patient significantly improved 24 hours after receiving oral dextromethorphan. Methotrexate neurotoxicity should be suspected in any symptomatic patient receiving high dose of methotrexate or intrathecal methotrexate therapy. Dextromethorphan should be considered in these patients as it can modulate the excitatory responses to homocysteine and its metabolite which are usually elevated in such patients.", "affiliations": "Department of Neurology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States.;Department of Neurology, University of Missouri, Columbia, Missouri, United States.", "authors": "Al-Awwad|Ahmad A|AA|0000-0001-8642-3730;Koriesh|Ahmed|A|", "chemical_list": null, "country": "Germany", "delete": false, "doi": "10.1055/s-0041-1732486", "fulltext": "\n==== Front\nAvicenna J Med\nAvicenna J Med\n10.1055/s-00051312\nAvicenna Journal of Medicine\n2231-0770\n2249-4464\nThieme Medical and Scientific Publishers Private Limited A-12, Second Floor, Sector -2, Noida-201301, Uttar Pradesh\n\n10.1055/s-0041-1732486\nAJM210036\nCase Report\nCytotoxic Lesion in the Splenium of Corpus Callosum Secondary to Subacute Methotrexate Neurotoxicity\nhttp://orcid.org/0000-0001-8642-3730\nAl-Awwad Ahmad A. 1\nKoriesh Ahmed 2\n1 Department of Neurology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States\n2 Department of Neurology, University of Missouri, Columbia, Missouri, United States\nAddress for correspondence Ahmad A. Al-Awwad, MD Neurology University of Oklahoma Health Sciences CenterOklahomaUnited Statesa.alawwad@yahoo.com\n9 2021\n04 8 2021\n1 8 2021\n11 3 160162\nSyrian American Medical Society. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).\n2021\nSyrian American Medical Society\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License, which permits unrestricted reproduction and distribution, for non-commercial purposes only; and use and reproduction, but not distribution, of adapted material for non-commercial purposes only, provided the original work is properly cited.\nMethotrexate neurotoxicity can present with a wide spectrum of neurologic symptoms and brain magnetic resonance imaging (MRI) typically demonstrates cerebral edema, demyelination, multifocal white matter necrosis, and atrophy relatively selective for the deep cerebral white matter. Here, we report a case of subacute methotrexate neurotoxicity in a 40-year-old man with B cell acute lymphoblastic leukemia. Brain MRI showed cytotoxic lesion in the splenium of corpus callosum and left middle cerebellar peduncle. Patient significantly improved 24 hours after receiving oral dextromethorphan. Methotrexate neurotoxicity should be suspected in any symptomatic patient receiving high dose of methotrexate or intrathecal methotrexate therapy. Dextromethorphan should be considered in these patients as it can modulate the excitatory responses to homocysteine and its metabolite which are usually elevated in such patients.\n\nKeywords\n\nmethotrexate neurotoxicity\nsplenium lesion\ndextromethorphan\n==== Body\npmcIntroduction\n\nMethotrexate (formerly amethopterin) is an antimetabolite used in the treatment of severe psoriasis, adult rheumatoid arthritis, and certain neoplastic diseases including acute lymphoblastic leukemia (ALL). 1 Methotrexate neurotoxicity (MNT) is a known adverse reaction that happens likely through disruption of central nervous system (CNS) folate homeostasis and/or direct neuronal damage. Brain magnetic resonance imaging (MRI) typically reveals diffusion restriction abnormalities with pathologic findings including cerebral edema, demyelination, multifocal white matter necrosis, and atrophy relatively selective for the deep cerebral white matter. 2 3\n\nCase Description\n\nA 40-year-old man with B cell ALL diagnosed 3 months prior to admission currently on consolidation therapy with pegaspargase and vincristine was admitted for management of neutropenic fever, severe holocranial headache, nausea, and encephalopathy. Physical exam on admission was remarkable for fever at 38.4 and low Glasgow Coma Scale of 11 with nonfocal neurologic exam. White blood count was low at 980 cell per cubic microliter with absolute neutrophil count of 350 cell per cubic microliter (normal > 4,000 and > 1,500, respectively). He was started on broad spectrum antibiotics and extensive infectious work-up was sent. He was also given filgrastim for severe neutropenia. Brain MRI with contrast did not show any abnormal contrast enhancement; however, it revealed diffusion restriction on diffusion-weighted imaging (DWI) sequence with correlating low signal on apparent diffusion coefficient (ADC) sequence at the splenium of corpus callosum as well as a small focus within the left middle cerebellar peduncle ( Fig. 1 ). Electroencephalogram, toxic metabolic panel, cytology, bacterial, and viral studies in serum and cerebrospinal fluid (CSF) were all unremarkable. Nevertheless, the patient’s mental status did not improve, in spite of supportive treatment. Fever and neutropenia both resolved on day 4 of admission; however, neurologic exam remains unchanged.\n\nFig. 1 Magnetic resonance imaging (MRI) shows axial diffusion-weighted imaging (DWI), apparent diffusion coefficient (ADC), and fluid-attenuated inversion recovery (FLAIR) sequences. Yellow arrows point to increased diffusion restriction with ADC correlation in the splenium of the corpus callosum (upper row) and left middle cerebellar peduncle (lower row). There are no corresponding changes on FLAIR in either cut.\n\nAs patient received three doses of 15 mg intrathecal methotrexate for ALL (last dose was 14 days prior to admission), subacute MNT was suspected. On day 6 of admission, dextromethorphan 60 mg every 12 hours was empirically started and the next day patient significantly improved and his neurologic exam was back to normal. He was monitored for another 24 hours then discharged home in good condition with total of 7 days of oral dextromethorphan 60 mg twice daily. Patient did not have any recurrent of his symptoms upon 1-month follow-up.\n\nDiscussion\n\nMNT is a well-known side effect that presents most frequently after prolonged low-dose oral, intrathecal, or high-dose methotrexate. It has been categorized as being acute, subacute, or chronic. 4 5 Acute MNT occurs within a few hours after methotrexate administration and patients usually exhibit signs of chemical meningitis including fever, somnolence, confusion, headache, nausea, vomiting, and dizziness. Subacute MNT is observed within days to weeks of methotrexate therapy where patient usually exhibit seizures or stroke-like symptoms including hemiparesis, hemisensory deficits, aphasia, and diplopia and some patients may experience fever and encephalopathy (similar to what was described in our case). 6 Chronic CNS toxicity occurs months to years after methotrexate therapy where patients develop cognitive dysfunction, behavioral abnormalities, and spasticity. Between all different types of MNT, the subacute form stands out as the most challenging one to be diagnosed. The association between sudden onset and acute progression of symptoms (frequently similar to the presentation of stroke) along with receiving methotrexate days or even weeks prior can be easily missed. Hence, MNT should be always on the differential for any patient with unexplained neurologic symptoms who received methotrexate therapy.\n\nThe pathogenesis of MNT is multifactorial, but CNS folate homeostasis likely plays a major role in it. Some studies suggested that acute toxicity is partly mediated by adenosine as methotrexate induces metabolic changes leading to increased extracellular adenosine. 7 Subacute and chronic toxicity, on the other hand, are probably mediated with homocysteine, S-adenosylmethionine/S-adenosylhomocysteine, and other excitatory amino acids. 8 There is usually an elevated level of homocysteine in CSF of patients who had received methotrexate. 6 9 Homocysteine is directly toxic to vascular endothelium and its metabolites are excitatory agonists of the N-methyl-D-aspartate (NMDA) receptor. 10 Dextromethorphan, a noncompetitive NMDA receptor antagonist, can modulate the excitatory responses to homocysteine and its metabolites and hence it has been used as a treatment of the neurological dysfunction associated with MNT and in some centers it is used as a prophylactic agent prior to methotrexate administration. 6 10 11\n\nOur patient’s MRI showed diffusion restriction on DWI with ADC correlation at the splenium of corpus callosum and the left middle cerebellar peduncle. These changes are consistent with cytotoxic edema. Cytotoxic cerebral edema refers to a type of cerebral edema in which water is trapped inside the cells resulting in their swelling. This intracellular edema mainly affects gray matter but also involves the white matter as astrocytes are also involved. 12 As cells swell due to inward shift of water, this will lead into decrease in diffusion, which will be identified as high signal on DWI and low signal on ADC. 12 Glutamate, a known neurotransmitter, plays major role in excitotoxicity by acting on aquaporins and NMDA receptors (among other receptors) leading into influx of water into both astrocytes and neurons resulting in cytotoxic edema appearance on MRI. 13 The elevated levels of homocysteine and its metabolites in patients treated with methotrexate can act as an excitatory agonists of NMDA receptors which can possibly explain the cytotoxic edema seen in such patients. The neurons, astrocytes, and oligodendrocytes of the corpus callosum have a higher density of receptors, including cytokine receptors, toxin receptors, and drug receptors comparing with other parts of the brain which makes the corpus callosum, and particularly the splenium, more vulnerable for cytotoxic edema. 13 14\n\nConflict of Interest None declared.\n\nFinancial Support None.\n\nStatement of Informed Consent Informed consent to publish this case was obtained from the patient and his wife.\n==== Refs\nReferences\n\n1 FDA methotrexate label. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/008085s066lbl.pdf. Accessed June 9, 2021\n2 Rollins N Winick N Bash R Booth T Acute methotrexate neurotoxicity: findings on diffusion-weighted imaging and correlation with clinical outcome AJNR Am J Neuroradiol 2004 25 10 1688 1695 15569732\n3 Ebner F Ranner G Slavc I MR findings in methotrexate-induced CNS abnormalities AJNR Am J Neuroradiol 1989 10 05 959 964 2505541\n4 Smith B Brain damage after intrathecal methotrexate J Neurol Neurosurg Psychiatry 1975 38 08 810 815 1058923\n5 Afshar M Birnbaum D Golden C Review of dextromethorphan administration in 18 patients with subacute methotrexate central nervous system toxicity Pediatr Neurol 2014 50 06 625 629 24742799\n6 Boogerd W vd Sande J J Moffie D Acute fever and delayed leukoencephalopathy following low dose intraventricular methotrexate J Neurol Neurosurg Psychiatry 1988 51 10 1277 1283 3225584\n7 Chan E S Cronstein B N Molecular action of methotrexate in inflammatory diseases Arthritis Res 2002 4 04 266 273 12106498\n8 Vezmar S Becker A Bode U Jaehde U Biochemical and clinical aspects of methotrexate neurotoxicity Chemotherapy 2003 49 (1-2)92 104 12714818\n9 Kishi S Griener J Cheng C Homocysteine, pharmacogenetics, and neurotoxicity in children with leukemia J Clin Oncol 2003 21 16 3084 3091 12915598\n10 Drachtman R A Cole P D Golden C B Dextromethorphan is effective in the treatment of subacute methotrexate neurotoxicity Pediatr Hematol Oncol 2002 19 05 319 327 12078863\n11 Fustino N J Juhl K Leister J Dextromethorphan administration on day 0 and day 7 for secondary prevention of methotrexate-induced neurotoxicity in childhood acute lymphoblastic leukemia: a retrospective case series J Pediatr Hematol Oncol 2020 doi: 10.1097/MPH.0000000000001714\n12 von K ummer R Dzialowski I Imaging of cerebral ischemic edema and neuronal death Neuroradiology 2017 59 06 545 553 28540400\n13 Starkey J Kobayashi N Numaguchi Y Moritani T Cytotoxic lesions of the corpus callosum that show restricted diffusion: mechanisms, causes, and manifestations Radiographics 2017 37 02 562 576 28165876\n14 Goursaud S Kozlova E N Maloteaux J M Hermans E Cultured astrocytes derived from corpus callosum or cortical grey matter show distinct glutamate handling properties J Neurochem 2009 108 06 1442 1452 19222709\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2231-0770", "issue": "11(3)", "journal": "Avicenna journal of medicine", "keywords": "dextromethorphan; methotrexate neurotoxicity; splenium lesion", "medline_ta": "Avicenna J Med", "mesh_terms": null, "nlm_unique_id": "101584155", "other_id": null, "pages": "160-162", "pmc": null, "pmid": "34646794", "pubdate": "2021-07", "publication_types": "D002363:Case Reports", "references": "2505541;12915598;31929386;19222709;15569732;1058923;12106498;28165876;28540400;12078863;3225584;24742799;12714818", "title": "Cytotoxic Lesion in the Splenium of Corpus Callosum Secondary to Subacute Methotrexate Neurotoxicity.", "title_normalized": "cytotoxic lesion in the splenium of corpus callosum secondary to subacute methotrexate neurotoxicity" }

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Cytotoxic Lesion in the Splenium of Corpus Callosum Secondary to Subacute Methotrexate Neurotoxicity. Avicenna J Med. 2021 Aug 4;11(3):160-162. doi: 10.1055/s-0041-1732486.", "literaturereference_normalized": "cytotoxic lesion in the splenium of corpus callosum secondary to subacute methotrexate neurotoxicity", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20211102", "receivedate": "20211102", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20023956, "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" }, { "companynumb": "US-ACCORD-243613", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": "037", "drugauthorizationnumb": "040716", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "THREE DOSES", "drugenddate": null, "drugenddateformat": null, "drugindication": "Acute lymphocytic leukaemia", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "15", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE" } ], "patientagegroup": null, "patientonsetage": "40", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Febrile neutropenia", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Headache", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Encephalopathy", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "Al-Awwad AA, Koriesh A. Cytotoxic Lesion in the Splenium of Corpus Callosum Secondary to Subacute Methotrexate Neurotoxicity. Avicenna J Med. 2021 Aug 4;11(3):160-162", "literaturereference_normalized": "cytotoxic lesion in the splenium of corpus callosum secondary to subacute methotrexate neurotoxicity", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20211027", "receivedate": "20211027", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20003360, "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": "Allergy and other immune-mediated diseases are more frequently reported in children who have undergone liver transplantation. Furthermore, autoantibodies are also prevalent, suggesting a state of immune dysregulation in these patients. Whether or not these processes occur simultaneously in the same individual has not been studied previously.\n\n\n\nA cohort of 43 children who had undergone liver transplantation for nonautoimmune liver disease at median age of 1.3 years was investigated for allergy and autoimmune disease. Sensitization to food and inhalant allergens was assessed, and autoantibodies were measured.\n\n\n\nThe prevalence of food allergy was 26% and that of respiratory allergy was 23%, whereas 33% and 26% of the subjects were sensitized to food and inhalant allergens, respectively. Autoimmune disease (ie, autoimmune hepatitis) occurred in a single individual (2%), whereas autoantibodies were present in 44% of the children. Food allergy and autoantibodies occurred concomitantly in 19% of the children, which was almost twice the frequency expected by chance (11%, P = 0.04). Respiratory allergy and the presence of autoantibodies were unrelated (12% concurrence versus the expected 10%, P = 0.73). In the logistic regression analysis, autoantibody formation was associated with discontinued immunosuppression and food allergy, with odds ratios of 13 (P = 0.01) and 7.1 (P = 0.03), respectively.\n\n\n\nIn contrast to respiratory allergy, food allergy and autoantibody formation occurred together in the same children who underwent liver transplantation at a frequency higher than would be expected by chance. This may reflect an underlying immune dysregulation that impairs immune tolerance to both food allergens and autoantigens.", "affiliations": "Department of Pediatric Gastroenterology, Hepatology and Nutrition, Institute of Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden.;Department of Infectious Diseases, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden.;Department of Infectious Diseases, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden.;Department of Pediatric Allergy and Pulmonology, Institute of Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden.;Department of Pediatric Gastroenterology, Hepatology and Nutrition, Institute of Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden.;Department of Infectious Diseases, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden.;Department of Infectious Diseases, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden.;Department of Pediatric Gastroenterology, Hepatology and Nutrition, Institute of Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden.", "authors": "Käppi|Timo|T|;Rabe|Hardis|H|;Lingblom|Christine|C|;Hesselmar|Bill|B|;Kullberg-Lindh|Carola|C|;Wold|Agnes E|AE|;Wennerås|Christine|C|;Saalman|Robert|R|", "chemical_list": "D000485:Allergens; D001323:Autoantibodies; D001324:Autoantigens; D016559:Tacrolimus", "country": "United States", "delete": false, "doi": "10.1097/TP.0000000000002751", "fulltext": null, "fulltext_license": null, "issn_linking": "0041-1337", "issue": "103(11)", "journal": "Transplantation", "keywords": null, "medline_ta": "Transplantation", "mesh_terms": "D000293:Adolescent; D000485:Allergens; D001323:Autoantibodies; D001324:Autoantigens; D001327:Autoimmune Diseases; D001656:Biliary Atresia; D002648:Child; D002675:Child, Preschool; D003430:Cross-Sectional Studies; D058625:End Stage Liver Disease; D005260:Female; D005500:Follow-Up Studies; D005512:Food Hypersensitivity; D006801:Humans; D007165:Immunosuppression Therapy; D007223:Infant; D016031:Liver Transplantation; D008297:Male; D016017:Odds Ratio; D011183:Postoperative Complications; D015995:Prevalence; D016559:Tacrolimus", "nlm_unique_id": "0132144", "other_id": null, "pages": "2338-2346", "pmc": null, "pmid": "30985574", "pubdate": "2019-11", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "High Frequency of Concomitant Food Allergy Development and Autoantibody Formation in Children Who Have Undergone Liver Transplantation.", "title_normalized": "high frequency of concomitant food allergy development and autoantibody formation in children who have undergone liver transplantation" }

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(10?15 NG/ML FOR 2 WEEKS AND TAPERED TO 3?5 NG/ML DURING THE FIRST 3 MONTHS)", "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": "15", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Seasonal allergy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Food allergy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Angioedema", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Conjunctivitis allergic", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulmonary sensitisation", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KAPPI T, RABE H, LINGBLOM C, HESSELMAR B, KULLBERG?LINDH C, WOLD AE ET AL. HIGH FREQUENCY OF CONCOMITANT FOOD ALLERGY DEVELOPMENT AND AUTOANTIBODY FORMATION IN CHILDREN WHO HAVE UNDERGONE LIVER TRANSPLANTATION. TRANSPLANTATION. 2019?103(11):2338?46", "literaturereference_normalized": "high frequency of concomitant food allergy development and autoantibody formation in children who have undergone liver transplantation", "qualification": "1", "reportercountry": "SE" }, "primarysourcecountry": "SE", "receiptdate": "20200706", "receivedate": "20200706", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17983887, "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": "SE-ASTELLAS-2020US022659", "fulfillexpeditecriteria": "1", "occurcountry": "SE", "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. 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HIGH FREQUENCY OF CONCOMITANT FOOD ALLERGY DEVELOPMENT AND AUTOANTIBODY FORMATION IN CHILDREN WHO HAVE UNDERGONE LIVER TRANSPLANTATION. TRANSPLANTATION. 2019?103(11):2338?46", "literaturereference_normalized": "high frequency of concomitant food allergy development and autoantibody formation in children who have undergone liver transplantation", "qualification": "1", "reportercountry": "SE" }, "primarysourcecountry": "SE", "receiptdate": "20200706", "receivedate": "20200706", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17983908, "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": "SE-ASTELLAS-2020US022652", "fulfillexpeditecriteria": "1", "occurcountry": "SE", "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. 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HIGH FREQUENCY OF CONCOMITANT FOOD ALLERGY DEVELOPMENT AND AUTOANTIBODY FORMATION IN CHILDREN WHO HAVE UNDERGONE LIVER TRANSPLANTATION. 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(10?15 NG/ML FOR 2 WEEKS AND TAPERED TO 3?5 NG/ML DURING THE FIRST 3 MONTHS)", "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": "8", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Bronchial obstruction", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Seasonal allergy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Abdominal pain", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Food allergy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Conjunctivitis allergic", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Asthma", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KAPPI T, RABE H, LINGBLOM C, HESSELMAR B, KULLBERG?LINDH C, WOLD AE ET AL. HIGH FREQUENCY OF CONCOMITANT FOOD ALLERGY DEVELOPMENT AND AUTOANTIBODY FORMATION IN CHILDREN WHO HAVE UNDERGONE LIVER TRANSPLANTATION. 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HIGH FREQUENCY OF CONCOMITANT FOOD ALLERGY DEVELOPMENT AND AUTOANTIBODY FORMATION IN CHILDREN WHO HAVE UNDERGONE LIVER TRANSPLANTATION. TRANSPLANTATION. 2019?103(11):2338?46", "literaturereference_normalized": "high frequency of concomitant food allergy development and autoantibody formation in children who have undergone liver transplantation", "qualification": "1", "reportercountry": "SE" }, "primarysourcecountry": "SE", "receiptdate": "20200706", "receivedate": "20200706", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17983952, "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": "SE-ASTELLAS-2020US022656", "fulfillexpeditecriteria": "1", "occurcountry": "SE", "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. (10?15 NG/ML FOR 2 WEEKS AND TAPERED TO 3?5 NG/ML DURING THE FIRST 3 MONTHS)", "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": "7", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Angioedema", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Food allergy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KAPPI T, RABE H, LINGBLOM C, HESSELMAR B, KULLBERG?LINDH C, WOLD AE ET AL. HIGH FREQUENCY OF CONCOMITANT FOOD ALLERGY DEVELOPMENT AND AUTOANTIBODY FORMATION IN CHILDREN WHO HAVE UNDERGONE LIVER TRANSPLANTATION. TRANSPLANTATION. 2019?103(11):2338?46", "literaturereference_normalized": "high frequency of concomitant food allergy development and autoantibody formation in children who have undergone liver transplantation", "qualification": "1", "reportercountry": "SE" }, "primarysourcecountry": "SE", "receiptdate": "20200706", "receivedate": "20200706", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17983930, "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": "SE-ASTELLAS-2020US022661", "fulfillexpeditecriteria": "1", "occurcountry": "SE", "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. (10?15 NG/ML FOR 2 WEEKS AND TAPERED TO 3?5 NG/ML DURING THE FIRST 3 MONTHS)", "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": "Food allergy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Angioedema", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Allergy to animal", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Conjunctivitis allergic", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KAPPI T, RABE H, LINGBLOM C, HESSELMAR B, KULLBERG?LINDH C, WOLD AE ET AL. HIGH FREQUENCY OF CONCOMITANT FOOD ALLERGY DEVELOPMENT AND AUTOANTIBODY FORMATION IN CHILDREN WHO HAVE UNDERGONE LIVER TRANSPLANTATION. TRANSPLANTATION. 2019?103(11):2338?46", "literaturereference_normalized": "high frequency of concomitant food allergy development and autoantibody formation in children who have undergone liver transplantation", "qualification": "1", "reportercountry": "SE" }, "primarysourcecountry": "SE", "receiptdate": "20200706", "receivedate": "20200706", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17983915, "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": "SE-ASTELLAS-2020US022664", "fulfillexpeditecriteria": "1", "occurcountry": "SE", "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. (10?15 NG/ML FOR 2 WEEKS AND TAPERED TO 3?5 NG/ML DURING THE FIRST 3 MONTHS)", "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": "11", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Angioedema", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Food allergy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KAPPI T, RABE H, LINGBLOM C, HESSELMAR B, KULLBERG?LINDH C, WOLD AE ET AL. HIGH FREQUENCY OF CONCOMITANT FOOD ALLERGY DEVELOPMENT AND AUTOANTIBODY FORMATION IN CHILDREN WHO HAVE UNDERGONE LIVER TRANSPLANTATION. TRANSPLANTATION. 2019?103(11):2338?46", "literaturereference_normalized": "high frequency of concomitant food allergy development and autoantibody formation in children who have undergone liver transplantation", "qualification": "1", "reportercountry": "SE" }, "primarysourcecountry": "SE", "receiptdate": "20200706", "receivedate": "20200706", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17983825, "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": "SE-ASTELLAS-2020US022654", "fulfillexpeditecriteria": "1", "occurcountry": "SE", "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. (10?15 NG/ML FOR 2 WEEKS AND TAPERED TO 3?5 NG/ML DURING THE FIRST 3 MONTHS)", "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": "17", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Angioedema", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Eosinophilic oesophagitis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Food allergy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulmonary sensitisation", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KAPPI T, RABE H, LINGBLOM C, HESSELMAR B, KULLBERG?LINDH C, WOLD AE ET AL. HIGH FREQUENCY OF CONCOMITANT FOOD ALLERGY DEVELOPMENT AND AUTOANTIBODY FORMATION IN CHILDREN WHO HAVE UNDERGONE LIVER TRANSPLANTATION. TRANSPLANTATION. 2019?103(11):2338?46", "literaturereference_normalized": "high frequency of concomitant food allergy development and autoantibody formation in children who have undergone liver transplantation", "qualification": "1", "reportercountry": "SE" }, "primarysourcecountry": "SE", "receiptdate": "20200706", "receivedate": "20200706", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17983941, "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": "SE-ASTELLAS-2020US022663", "fulfillexpeditecriteria": "1", "occurcountry": "SE", "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. (10?15 NG/ML FOR 2 WEEKS AND TAPERED TO 3?5 NG/ML DURING THE FIRST 3 MONTHS)", "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": "Angioedema", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Food allergy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KAPPI T, RABE H, LINGBLOM C, HESSELMAR B, KULLBERG?LINDH C, WOLD AE ET AL. HIGH FREQUENCY OF CONCOMITANT FOOD ALLERGY DEVELOPMENT AND AUTOANTIBODY FORMATION IN CHILDREN WHO HAVE UNDERGONE LIVER TRANSPLANTATION. TRANSPLANTATION. 2019?103(11):2338?46", "literaturereference_normalized": "high frequency of concomitant food allergy development and autoantibody formation in children who have undergone liver transplantation", "qualification": "1", "reportercountry": "SE" }, "primarysourcecountry": "SE", "receiptdate": "20200706", "receivedate": "20200706", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17983873, "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" } ]