qanastek/EMEA-V3 huggingface dataset:
The marketing authorisation holder is Gilead Sciences International.
Id- detentur tal- awtorizzazzjoni għat- tqegħid fis- suq huwa Gilead Sciences International.
The full EPAR for Vistide is available here.
L- EPAR sħiħ dwar Vistide jista ’ jiġi kkonsultat hawn.
VISTIDE 75 mg/ ml concentrate for solution for infusion.
Konċentrat ta ’ VISTIDE 75 mg/ ml għal soluzzjoni għall- infużjoni.
Each ml contains 75 mg cidofovir anhydrous.
Kull ml fih 75 mg cidofovir anhydrous.
Each vial contains 375 mg/ 5ml cidofovir anhydrous as the active substance.
Kull kunjett fih 375 mg/ 5ml cidofovir anhydrous bħala sustanza attiva.
Each vial contains approximately 2.5 mmol (or 57 mg) sodium per vial (5 ml) as a constituent of the excipients.
Kull kunjett fih bejn wieħed u ieħor 2. 5 mmol (jew 57 mg) sodju f’ kull kunjett (5 ml) bħala kostitwent tas- sustanzi mhux attivi.
The formulation is adjusted to pH 7.4.
Il- formulazzjoni hija aġġustata għal pH 7. 4.
VISTIDE is indicated for the treatment of CMV retinitis in patients with acquired immunodeficiency syndrome (AIDS) and without renal dysfunction.
VISTIDE huwa indikat għat- trattament ta ’ retinite b’ CMV f’ pazjenti li għandhom is- sindromu ta ’ l - immunodeffiċjenza akkwiżita (AIDS) u mingħajr tħassir fil- funzjoni tal- kliewi.
VISTIDE should be used only when other agents are considered unsuitable.
VISTIDE għandu jintuża biss meta aġenti oħrajn jitqiesu bħala mhux adattati.
The therapy should be prescribed by a physician experienced in the management of HIV infection.
It- terapija għandha tiġi preskritta minn tabib li għandu esperjenza fil- kura ta ’ infezzjonijiet bl- HIV.
Before each administration of VISTIDE, serum creatinine and urine protein levels should be investigated.
Qabel kull amministrazzjoni ta ’ VISTIDE għandhom jigu assessjati l- livelli tal- krejatinina fis- serum u tal- proteina fl- awrina.
VISTIDE must be administered with oral probenecid and intravenous saline as described below (see section 4.4 for appropriate recommendations, and under section 6.6 for information on obtaining probenecid).
VISTIDE għandu jingħata ma ’ probenecid mill- ħalq u salina li tingħata mill - ġol- vina kif deskritt taħt (ara sezzjoni 4. 4 għal rakkomandazzjonijiet xierqa, u ara sezzjoni 6. 6 għal informazzjoni fuq kif takkwista probenecid).
The recommended dosage, frequency, or infusion rate must not be exceeded.
Id- doża, il- frekwenza u r- rata ta ’ l- infużjoni m’ għandhomx ikunu aktar minn dawk irrakkomandati.
VISTIDE must be diluted in 100 millilitres 0.9% (normal) saline prior to administration.
VISTIDE għandu jiġi dilwit b’ 100 millilitru ta ’ salina (normali) 0. 9% qabel ma jingħata.
To minimise potential nephrotoxicity, oral probenecid and intravenous saline prehydration must be administered with each VISTIDE infusion.
Biex titnaqqas kemm jista ’ jkun il- possibiltà ta ’ tossicità għall- kliewi, il- pazjenti għandhom jingħataw probenecid mill- ħalq u għandhom ukoll jiġu idratati minn qabel permezz ta ’ salina li tingħata ġol- vina, kull darba li jingħataw infużjoni ta ’ VISTIDE.
Dosage in adults
Id- doża fl- adulti
Induction treatment.
Trattament biex tibda.
The recommended dose of cidofovir is 5 mg/ kg body weight (given as an intravenous infusion at a constant rate over 1 hour) administered once weekly for two consecutive weeks.
Id- doża rrakkomandata ta ’ cidofovir hija ta ’ 5mg għal kull kg tal- piż tal- ġisem (mogħti bħala infużjoni ġol- vina b’ rata kostanti fuq medda ta ’ siegħa), li tingħata darba fil- ġimgħa għal ġimgħatejn wara xulxin.
Maintenance treatment.
Trattament ta ’ manteniment.
Beginning two weeks after the completion of induction treatment, the recommended maintenance dose of cidofovir is 5 mg/ kg body weight (given as an intravenous infusion at a constant rate over 1 hour) administered once every two weeks.
Dan jinbeda ġimgħatejn wara li jitlesta t- trattament tal- bidu, u d- doża ta ’ manteniment b’ cidofovir rrakkomandata hija ta ’ 5 mg għal kull kg tal- piż tal- ġisem (li tingħata bħala infużjoni ġol- vina b’ rata kostanti fuq medda ta ’ siegħa) darba kull ġimgħatejn.
Suspension of maintenance treatment with cidofovir should be considered in accordance with local recommendations for the management of HIV-infected patients.
It- trattament ta ’ manteniment b’ cidofovir għandhu jigi sospiż skond ir- rakkomandazzjonijiet lokali għall- immaniġġar ta ’ pazjenti infettati bl- HIV.
2 Dosage in elderly The safety and efficacy of VISTIDE have not been established for the treatment of CMV disease in patients over 60 years of age.
Billi l- anzjani spiss ikollhom tnaqqis fil -
Since elderly individuals frequently have reduced glomerular function, particular attention should be paid to assessing renal function before and during administration of VISTIDE.
2 funzjoni tal- glomeruli, wieħed għandu joqgħod attent b ’ mod partikulari li l- funzjoni tal- kliewi tiġi eżaminata sew kemm qabel kif ukoll waqt l amministrazzjoni ta ’ VISTIDE.
Dosage in children and neonates VISTIDE is not recommended for use in children below 18 years of age due to a lack of data on safety and efficacy.
VISTIDE mhux rakkomandat għall- użu fit- tfal ta ’ taħt it- 18- il sena minħabba nuqqas ta ’ tagħrif dwar is- sigurta ’ u l- effikaċja tiegħu.
Dosage in renal insufficiency Renal insufficiency [creatinine clearance ≤ 55 ml/ min or ≥ 2+ proteinuria (≥ 100 mg/ dl)] is a contraindication for the use of VISTIDE (see section 4.3 and 4.4).
Insuffiċjenza fil- funzjoni tal- kliewi [clearance tal- krejatinina ≤ 55 ml/ min jew ≥ 2+ proteini fl- awrina (≥ 100 mg/ dl)] hija kontraindikata għal użu ta ’ VISTIDE (ara sezzjoni 4. 3 u sezzjoni 4. 4).
Dosage in hepatic insufficiency The safety and efficacy of VISTIDE have not been established in patients with hepatic disease and therefore it should be used with caution in this patient population.
Is- sigurtà u l- effikaċja ta ’ VISTIDE għadhom ma ġewx stabbiliti f’ pazjenti li jkollhom mard tal- fwied għalhekk hemm bżonn ta ’ iktar kawtela meta dan jintuża fil- popolazzjoni ta ’ dawn il- pazjenti..
Hypersensitivity to the active substance (cidofovir) or to any excipients.
Sensittività eċċessiva għas- sustanza attiva (cidofovir) jew għal xi sustanzi mhux attivi.
Cidofovir administration is contraindicated in patients unable to receive probenecid or other sulfa- containing medication (see section 4.4 Prevention of nephrotoxicity).
L- użu ta ’ Cidofovir huwa kontraindikat f’ pazjenti li ma jistgħux jieħdu probenecid (ara sezzjoni 4. 4 Prevenzjoni/ tnaqqis ta ’ tossicità għall- kliewi). u mediċini oħra li fihom il- komponent sulfa.
VISTIDE is contraindicated in patients with renal insufficiency (see section 4.2).
VISTIDE m’ għandux jintuża f’ pazjenti li għandhom insuffiċjenza tal- kliewi (ara sezzjoni 4. 2).
Concomitant administration of VISTIDE and other potentially nephrotoxic agents is contraindicated (see section 4.4).
L- użu ta ’ VISTIDE flimkiem ma mediċini li jistgħu jikkawżaw ħsara fil- kliewi huwa kontrindikat (ara sezzjoni 4. 4).
Direct intraocular injection of VISTIDE is contraindicated; direct injection may be associated with significant decreases in intraocular pressure and impairment of vision.
M’ għanda qatt tingħata injezzjoni diretta fl- għajnejn b’ VISTIDE; injezzjoni diretta fl- għajnejn tista ’ tkun assoċjata ma ’ tnaqqis sinifikanti fil- pressjoni ta ’ ġol- għajn u anki ma ’ tnaqqis fil- vista.
VISTIDE is formulated for intravenous infusion only and must not be administered by intraocular injection.
VISTIDE huwa ifformulat sabiex jintuża biss għall- infuażjonijiet ġol- vina, u m’ għandu qatt jingħata bħala injezzjoni ġol- għajn.
VISTIDE should be infused only into veins with adequate blood flow to permit rapid dilution and distribution.
VISTIDE għandu jiġi infuż biss ġo vini li jkollhom ċirkolazzjoni tajba tad - demm, biex b’ hekk jiġi ddilwit u mifrux malajr.
Renal insufficiency/ Haemodialysis Treatment with VISTIDE must not be initiated in patients with creatinine clearance ≤ 55 ml/ min, or ≥ 2+ Proteinuria (≥ 100 mg/ dl), as the optimum induction and maintenance doses for patients with moderate to severe renal impairment are not known.
It- trattament b’ VISTIDE m’ għandux jinbeda f’ pazjenti li jkollhom clearance tal- krejatinina ta ’ ≤55 ml/ min, jew ≥ 2+ ta ’ proteini fl- awrina (≥100 mg/ dl), billi l- aħjar dożi biex tibda t- trattament u biex tmantnih m’ humiex magħrufin fil- każ ta ’ pazjenti li għandhom indeboliment moderat għal sever tal- kliewi.
The efficacy and safety of cidofovir in such conditions has not been established.
L- effikaċja u s- sigurta ta ’ cidofovir taħt dawn il- kundizzjonijiet ma ġietx stabbilita.
High flux haemodialysis has been shown to reduce the serum levels of cidofovir by approximately 75%.
Dijaliżi tad- demm bi fluss mgħaġġel jidher li jnaqqas l- ammont ta ’ cidofovir fis- serum b’ xi 75%.
The fraction of the dose extracted during haemodialysis is 51.9 ± 11.0%.
Il - frazzjoni tad- doża li titneħħa permezz tad- dijaliżi tad- demm hija 51. 9 + 11. 0%.
Nephrotoxicity Dose-dependent nephrotoxicity is the major dose-limiting toxicity related to administration of cidofovir.
It- tossiċità fuq il- kliewi marbuta mad- doża, hija l- aktar ħaġa li tillimita d- doża ta ’ cidofovir li tista ’ tingħata.
The safety of cidofovir has not been evaluated in patients receiving other known potentially nephrotoxic agents (e. g. tenofovir, aminoglycosides, amphotericin B, foscarnet, intravenous pentamidine, adefovir and vancomycin).
Is- sigurta ’ ta ’ cidofovir f’ pazjenti li jkunu jieħdu xi mediċini oħrajn li huma magħrufin li jistgħu jagħmlu ħsara għall- kliewi (e. g. tenofovir, aminoglycosides, amphotericin B, foscarnet, pentamidine intrvenus, adefovir u vancomycin) għada ma gietx evalwata.
It is recommended to discontinue potentially nephrotoxic agents at least 7 days before starting cidofovir.
Huwa rrakkomandat li mediċini oħrajn li jistgħu jagħmlu ħsara għall- kliewi jitwaqqfu mill- inqas 7 ijiem qabel ma jinbeda cidofovir.
(See section 4.8).
(Ara sezzjoni 4. 8)
Patients treated at 3.0 mg/ kg, 5.0 mg/ kg or 10 mg/ kg without concomitant probenecid developed evidence of proximal tubular cell injury, including glycosuria, and decreases in serum phosphate, uric
Pazjenti li ngħataw 3. 0 mg/ kg, 5. 0 mg/ kg jew 10. 0 mg/ kg, mingħajr probenecid fl- istess ħin, kellhom sinjali ta ’ ħsara fiċ- ċelluli tal- proximal tubules, li kienu jinkludu l- preżenza taz- zokkor fl- awrina, u tnaqqis fil- livelli ta ’ phosphate, ta ’ uric acid u ta ’ bicarbonate fis- serum, u żieda fil- livell ta ’
3 acid and bicarbonate, and elevations in serum creatinine.
3 krejatinina fis- serum.
The signs of nephrotoxicity were partially reversible in some patients.
Dawn is- sinjali ta ’ ħsara fil- kliewi jidher li kienu parzjalment riversibli f’ xi ftit mill- pazjenti.
Concomitant use of probenecid is essential for reducing the pronounced nephrotoxicity of cidofovir to an extent that results in an acceptable benefit/ risk balance of cidofovir therapy.
L- użu ta ’ probenecid fl- istess żmien ta ’ kura huwa essenzjali sabiex titnaqqas it - tossiċita ’ fuq il- kliewi kkawżata minn cidofovir, sal- punt li jkun hemm bilanċ aċċettabli bein il - benefiċċji u r- riskji tat- terapija b’ cidofovir.
Prevention of nephrotoxicity Therapy must be accompanied by administration of oral probenecid and adequate intravenous saline prehydration (see 6.6 for information on obtaining probenecid) with each cidofovir dose.
It- terapija għandha tingħata flimkien ma ’ probenecid mill- ħalq u pre- idrazzjoni ġol- vina b’ saline (ara sezzjoni 6. 6 għal informazzjoni kif takkwista probenecid) ma kull doża ta ’ cidofovir. ma ’ kull doża ta ’ cidofovir.
All clinical trials relevant to clinical efficacy evaluation were performed using probenecid concomitantly with cidofovir.
Il- provi kliniċi kollha li għandhom x’ jaqsmu mal- valutazzjoni ta ’ l- effikaċa klinika saru bl- użu ta ’ probenecid fl- istess ħin ma ’ cidofovir.
Two grams of probenecid should be administered 3 hours prior to the cidofovir dose and one gram administered at 2 and again at 8 hours after completion of the 1 hour cidofovir infusion (for a total of 4 grams).
Żewġ grammi ta ’ probenecid għandhom jingħataw 3 sigħat qabel id- doża ta ’ cidofovir, u gramma waħda terġa ’ tingħata sagħtejn u mbagħad 8 sigħat (għal total ta ’ 4 grammi) wara li titlesta l- infużjoni ta ’ cidofovir li tkun ingħatat fuq medda ta ’ siegħa.
In order to reduce the potential for nausea and/ or vomiting associated with administration of probenecid, patients should be encouraged to eat food prior to each dose of probenecid.
Sabiex titnaqqas il- possibiltà ta ’ dardir u / jew riġġettar li jistgħu jkunu assoċjati ma ’ l - amministrazzjoni ta ’ probenecid, il- pazjenti għandhom ikunu mħeġġa biex jieklu xi ħaġa qabel kull doża ta ’ probenecid.
The use of an anti-emetic may be necessary.
Għandu mnejn ikun hemm bżonn li tintuża xi mediċina għal kontra d- dardir.
In patients who develop allergic or hypersensitivity symptoms to probenecid (e. g., rash, fever, chills and anaphylaxis), prophylactic or therapeutic use of an appropriate antihistamine and/ or paracetamol should be considered.
F’ pazjenti li jiżviluppaw sintomi t’ allerġija jew ta ’ sensittività eċċessiva għal probenecid (eż., raxx, deni, tkexkix ta ’ bard, u anafilassi), l- użu profilattiku jew terapewtiku ta ’ anti- istamina adattata u / jew paracetamol għandu jiġi kkunsidrat.
Cidofovir administration is contraindicated in patients unable to receive probenecid because of a clinically significant hypersensitivity to the active substance or medicinal product or to other sulfa- containing medicines.
L- użu ta ’ cidofovir huwa kontraindikat f’ pazjenti li ma jistgħux jieħdu probenecid minħabba li jkollhom sensittività eċċessiva u li tkun klinikament sinifikanti għas- sustanza attiva jew għall- prodott mediċnali jew għal mediċini oħrajn li fihom is- sulpha, l- amministrazzjoni ta ’ cidofovir għandha tiġi kkunsidrata biss jekk il- vantaġġi tat- terapija jitqiesu li huma akbar mir- riskji li jista jkun hemm.
Use of cidofovir without concomitant probenecid has not been clinically investigated.
Użu hekk waħdu ta ’ cidofovir mingħajr ma jingħata il- probenecid fl- istess ħin għadu ma ġiex studjat klinikament.
A probenecid desensitisation program is not recommended for use.
Trattament li permezz tiegħu wieħed jista jnaqqas is- sensittività ’ għalprobenecid mhux irrakkomandat.
In addition to probenecid, patients must receive a total of one litre of 0.9% (normal) saline solution intravenously immediately prior to each infusion of cidofovir.
Flimkien ma ’ probenecid, il- pazjenti għandhom jingħataw ukoll total ta ’ litru ta ’ taħlita ta ’ salina (normali) 0. 9% ġol- vina, eżatt qabel kull infużjoni ta ’ cidofovir.
Patients who can tolerate the additional fluid load may receive up to a total of 2 litres of 0.9% saline intravenously with each dose of cidofovir.
Dawk il- pazjenti li jistgħu jittolleraw tagħbija żejda ta ’ fluwidu jistgħu jingħataw sa total ta ’ 2 litri ta ’ salina 0. 9% ġol- vina ma ’ kull doża ta ’ cidofovir.
The first litre of saline solution should be infused over a 1 hour period immediately before the cidofovir infusion, and the second litre, if given, infused over a 1-3 hour period beginning simultaneously with the cidofovir infusion or starting immediately after the infusion of cidofovir.
L- ewwel litru ta ’ soluzzjoni salina għandha tiġi nfuża fuq perijodu ta ’ siegħa, immedjatament qabel l- infużjoni ta ’ cidofovir, u t- tieni litru, jekk jingħata, għandu jkun infuż fuq perijodu ta ’ bejn 1- 3 sigħat u għandu jinbeda fl- istess ħin ma ’ l- infużjoni ta ’ cidofovir jew immedjatament wara l- infużjoni ta ’ cidofovir.
Cidofovir therapy should be discontinued and intravenous hydration is advised if serum creatinine increases by ≥ 44 µmol/ l (≥ 0.5 mg/ dl), or if persistent proteinuria ≥ 2+ develops.
It- terapija b’ cidofovir għandha titwaqqaf u tajjeb ukoll li wieħed jiġi idratat minn ġol- vina kemm il - darba l- livell ta ’ krejatinina fis- serum jiżdied b ’ > 44 µmol/ l (> 0. 5mg/ dl), jew inkella jekk wieħed titfaċċalu l- proteina fl- awrina f’ ammonti ta ’ > 2+, u tippersisti f’ dan il- livell.
In patients exhibiting ≥ 2+ proteinuria, intravenous hydration should be performed and the test repeated.
F’ każ li l- pazjent ikun jidher li għandu livell ta ’ proteina fl- awrina ta ’ > 2 +, dan għandu l- ewwel jiġi idratat minn ġol- vina u mbagħad jerġa jsirlu t- test.
If following hydration, a ≥ 2+ proteinuria is still observed, cidofovir therapy should be discontinued.
Jekk wara li jkun ġie idratat jibqa jkun hemm livelli ta ’ proteini fl- awrina ta ’ > 2+, it- terapija b’ cidofovir għandha titwaqqaf.
Continued administration of cidofovir to patients with persistent ≥ 2+ proteinuria following intravenous hydration may result in further evidence of proximal tubular injury, including glycosuria, decreases in serum phosphate, uric acid and bicarbonate, and elevations in serum creatinine.
Jekk pazjenti li jibqgħu jingħataw cidofovir ikollhom ammont ta ’ proteina fl- awrina li jippersisti f ’ livelli ta ’ > 2+ minkejja li jkunu ġew idratati, jista ’ jiġri li toħroġ aktar evidenza ta ’ ħsara fil- proximal tubules tal- kliewi, li tinkludi zokkor fl- awrina, tnaqqis fil- livelli ta ’ phosphate, uric acid u bicarbonate fis- serum u żieda fil- livell tal- krejatinina fis - serum.
Interruption, and possibly discontinuation, is required for changes in renal function.
Twaqqif temporanju jew għal kollox tat- terapija huwa bżonnjuż għal bdil fil- funzjoni tal- kliewi.
For those patients who fully recover from cidofovir associated renal toxicity, the benefits-risk balance of reintroducing cidofovir has not yet been evaluated.
Għal dawk il- pazjenti li jirkupraw mit- tossiċita ’ assoċjata ma l- użu ta ’ cidofovir, il- bilanċ tal- benefiċċji u riskji li jerga ’ jinbeda cidofovir ma ġiex evalwat.
Patient Monitoring Proteinuria appears to be an early and sensitive indicator of cidofovir-induced nephrotoxicity.
Monitoraġġ tal- Pazjent Il- preżenza ta ’ proteina fl- awrina jidher li hi indikatriċi minn ta ’ l- ewwel u anki sensittiva ta ’ jekk hemmx ħsara fil- kliewi kawżata minn cidofovir.
Patients receiving cidofovir must have their serum creatinine and urine protein levels determined on specimens obtained within 24 hours prior to the administration of each dose of cidofovir.
Pazjenti li jkunu jieħdu cidofovir għandu jkollhom il - livelli tal- krejatinina fis- serum u l- livelli ta ’ proteina fl- awrina eżaminati permezz ta ’ kampjuni li jkunu nġabru fl- 24 siegħa ta ’ qabel kull doża ta ’ cidofovir li tkun ser tingħata.
Differential white blood cell counts should also be performed prior to each dose of cidofovir (see section 4.8).
Għadd differenzjali taċ - ċelloli tad- demm bojod għandu jsir ukoll qabel kull doża ta ’ cidofovir (ara sezzjoni 4. 8).
Ocular Events Patients receiving cidofovir should be advised to have regular follow-up ophthalmologic examinations for possible occurrence of Uveitis/ Iritis and Ocular Hypotony.
4 Episodji okulari Pazjenti li jirċievu cidofovir għandhom jiġu avżati sabiex isirulhom eżaminzzjonijiet oftalmoloġiċi regolari ta ’ follow- up għall- possibbiltà ta ’ l- okkorrenza ta ’ Uveite / Irite u Tnaqqis fil- pressjoni ta ’ ġol - għajn.
In case of Uveitis/ Iritis cidofovir should be discontinued if there is no response to treatment with a topical corticosteroid or the condition worsens, or if iritis/ uveitis reoccurs after successful treatment.
Fil- każ ta ’ Uveite / Irite, cidofovir għandu jitwaqqaf jekk ma jkun hemm ebda rispons għat - trattament b’ kortikosterojde topika jew jekk il- kundizzjoni tiggrava, jew jekk ikun hemm episodju mill- ġdid ta ’ iritis/ uveitis wara trattament li jkun sar b’ suċċess.
4 Other Cidofovir should be considered a potential carcinogen in humans (see section 5.3 Preclinical safety data).
Oħrajn Cidofovir għandu jitqies bħala sustanza li tista twassal għal- kanċer fil- bniedem (ara sezzjoni 5. 3 Studju qabel l- użu kliniku dwar is- sigurtà tal- mediċina).
Caution should be applied when considering cidofovir treatment of patients with diabetes mellitus due to the potential increased risk of developing ocular hypotony.
Wieħed għandu joqgħod attent meta jkun qed jiġi kkunsidrat l- użu ta ’ cidofovir f’ pazjenti li jkollhom iz- zokkor minħabba li f’ dan il- każ ikun hemm riskju akbar li l- pazjenti jiżviluppaw tnaqqis fil - pressjoni ta ’ ġol- għajn.
Male patients should be advised that cidofovir caused reduced testes weight and hypospermia in animals.
Pazjenti maskili għandhom jiġu avżati li cidofovir wassal għal tnaqqis fil- piż tat- testikoli u anki tnaqqis fl- ammonti ta ’ sperma fl- annimali.
Although not observed in clinical studies of cidofovir, such changes may occur in humans and cause infertility.
Għalkemm dan ma ġiex osservat fi studji kliniċi b’ cidofovir, xorta waħda jista jagħti l- każ li dan fil- fatt iseħħ tassew fil- bniedem, biex b’ hekk iwassal għal nuqqas ta ’ fertilità.
Appropriate precautions should continue to be employed to prevent transmission of HIV.
Prekawzjonijiet adegwati għandhom jiġu meħuda sabiex tipprevjeni it- trasmissjoni ta ’ HIV.
Probenecid increases the AUC of zidovudine.
Probenecid iżid l- AUC ta ’ zidovudine.
Patients receiving both drugs should be closely monitored for zidovudine induced haematological toxicity.
Pazjenti li jieħdu iż- żewġ mediċini għandhom ikunu mmonitorjati b’ attenzjoni għal tossiċita ’ fid- demm indotta minn zidovudine.
For other NRTI drugs administered concomitantly with probenecid, reference should be made to their respective prescribing information for any appropriate recommendations.
Għal mediċini NRTI mogħtija fl- istess żmien ma ’ probenecid, it- tagħrif dwar il- kitba tal- prodott għandha tkun ta ’ referenza għar- rakomandazzjonijiet.
Interactions of cidofovir/ probenecid and anti-HIV drugs or drugs used to treat common chronic viral infections in this population, such as HCV and HBV-related hepatitis, have not been investigated in clinical trials.
Interazzjonijiet ta ’ cidofovir, ta ’ probenecid, u ta ’ mediċini għal kontra l- HIV jew mediċini li jintużaw għall- kura ta ’ infezzjonijiet kroniċi virali komuni f’ din il- popolazzjoni, bħal epatite relatata ma ’ HCV u HBV, għadhom ma ġewx studjati permezz ta ’ studji kliniċi.
Probenecid is known to increase the exposure of many substances (e. g., paracetamol, acyclovir, angiotensin-converting enzyme inhibitors, aminosalicyclic acid, barbiturates, benzodiazepines, bumetanide, clofibrate, methotrexate, famotidine, furosemide, nonsteroidal anti-inflammatory agents, theophylline, and zidovudine).
Huwa fatt magħruf li probenecid iżid l- espożizzjoni ta ’ ħafna sustanzi (eż., paracetamol, acyclovir, aġenti li jinibixxu angiotensin- converting enzyme, aminosalicylic acid, barbiturati, benzodiazepines, bumetanide, clofibrate, methotrexate, famotidine, furosemide, aġenti mhux sterojdi għal kontra l - infjammazzjoni, theophylline, u zidovudine).
Therefore, when co-prescribing cidofovir/ probenecid with other agents, it is important for prescribers to consult the current probenecid SPC (or an appropriate drug reference source) and the respective prescribing information of the other co-administered products for full information regarding drug interactions and other features of that product.
Għalhekk, meta tagħti cidofovir/ probenecid ma’ aġenti oħra, huwa importanti li it- tobba jikkonsultaw l- iktar SmPC riċenti tal- probenicid (jew fonti ta ’ referenza adattata, bħal Formularju Nazzjonali) u informazzjoni rispettiva tal- prodotti l- oħra li jingħataw miegħu għal informazzjoni kompluta dwar fatturi oħra tal- prodott u interazzjonijiet ma ’ mediċini oħra.
Cidofovir is embryotoxic in rats and rabbits at subtherapeutic dose levels.
Cidofovir jagħmel ħsara lill- embriju kemm fil- far kif ukoll fil- fenek anki b’ dożi aktar baxxi minn dawk terapewtiċi.
A significantly increased foetal incidence of external, soft tissue and skeletal anomalies occurred in rabbits at 1.0 mg/ kg/ day, which was also maternally toxic.
Kien hemm żieda sinifikanti fl- inċidenza ta’ anomaliji esterni, u tat- tessuti r- rotob tal- ġisem, u anki skeletriċi, fil- fetu tal- fenek f’ dożi ta ’ 1. 0 mg/ kg/ jum, u saret ħsara anki lill- omm.
Pregnancy There are no studies of cidofovir in pregnant women.
Tqala Għad ma kienx hemm studji b’ cidofovir f’ nisa waqt it- tqala.
VISTIDE should not be used during pregnancy.
VISTIDE m’ għandux jintuża waqt it - tqala.
Women of childbearing potential should be advised to use effective contraception during and after treatment with cidofovir.
Nisa li jkunu għadhom f’ età li jista ’ jkollhom it- tfal għandhom jingħataw parir biex jagħmlu użu minn xi kontraċettiv effettiv kemm qabel kif ukoll wara t- trattament b’ cidofovir.
Lactation It is not known whether cidofovir is excreted in human milk.
5 Treddigħ Mhux magħruf jekk cidofovir joħroġx mal- ħalib tas- sider fil- bniedem.
Because many substances are excreted in human milk, nursing mothers should be instructed to discontinue cidofovir or discontinue nursing if they continue to receive cidofovir.
Billi ħafna sustanzi fil- fatt jispiċċaw anki fil- ħalib tas- sider fil- bniedem, allura ommijiet li jkunu qegħdin ireddgħu l- uliedhom għandhom jingħataw struzzjonijiet biex jew iwaqqfu cidofovir jew inkella jieqfu jreddgħu jekk ser jibqgħu jieħdu cidofovir.
Passage of the placenta barrier of cidofovir-related compound was observed in pregnant rats.
Fil- każ ta ’ firien waqt it- tqala kien osservat li xi sustanza li ġejja minn cidofovir qasmet il- barriera tal- plaċenta.
Excretion of cidofovir-related material into milk of lactating animals was not examined.
Il- ħruġ ta ’ materjal li għandu x’ jaqsam ma ’ cidofovir, fil - ħalib ta ’ annimali li jkunu qed jipproduċu l- ħalib fi żmien it- treddigħ, għadu ma ġiex studjat.
Refer to section 4.4 for further information
Irreferi għas- sezzjoni 4. 4 għal aktar tagħrif.
Adverse reactions such as asthenia may occur during cidofovir therapy.
Jista ’ jkun hemm reazzjonijiet avversi bħal astenja waqt it- trattament b’ cidofovir.
The physician is advised to discuss this issue with the patient, and based upon the condition of the disease and the tolerance of medication, give his recommendation in the individual case.
Tajjeb li t- tabib jiddiskuti din il- kwistjoni mal- pazjent, u mbagħad skond il- kundizzjoni tal- marda u skond kemm il - pazjent jittollera l- medikazzjoni, jagħti r- rakkomandazzjonijiet tiegħu, skond il- każ individwali.
The table below lists the adverse reactions identified through clinical trials or post-marketing surveillance by system organ class (SOC) and frequency.
It- tabella ta ’ hawn taħt turi il- lista tar- reazzjonijiet avversi identifikati minn studji kliniċi jew sorveljanza ta ’ wara t- tqegħid fis- suq elenkati bis- sistema tal- klassifika ta 'l- organi u l- frekwenza.
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
F' kull sezzjoni ta 'frekwenza, l- effetti mhux mixtieqa huma ppreżentati skond is- serjetà tagħhom.
Frequencies are defined as: very common (≥ 1/ 10), common (≥ 1/ 100 to < 1/ 10), uncommon (≥ 1/ 1000 to < 1/ 100) or not known (cannot be estimated from the available data).
Il- frekwenzi huma definiti bħala: komuni ħafna( ≥ 1/ 10), komuni (≥ 1/ 100 għal < 1/ 10), mhux komuni (≥ 1/ 1000 għal < 1/ 100) jew mhux magħruf (ma jistax jiġi stmat mit- tagħrif disponibbli).
Adverse reactions identified from post-marketing experience are included in italics.
Reazzjonijiet avversi identifikati fl- istudji ta ’ wara it- tqegħid fis- suq huma inklużi b’ ittri korsivi.
Adverse reactions possibly or probably related to cidofovir based on clinical trial experience and post-marketing surveillance
Reazzjonijiet avverso probabilment jew possibilment relatati ma cidofovir, hekk kif inhuma ibbażati fuq esperjenza fi studji kliniċi u sorveljanza ta ’ wara l- ħruġ tal- prodott fis- suq.
System Organ Class Blood and lymphatic system disorders
Sistema tal- klassifika tal- organi Disturbi tad- demm u tas- sistema limfatika
Adverse reactions
Reazzjonijiet avversi tal- mediċina
Very common Nervous system disorders
Komuni ħafna Disturbi fis- sistema nervuża
Very common Eye disorders
Komuni ħafna Disturbi fl- għajnejn
Headache
Uġiegħ ta ’ ras
Common Ear and labyrinth disorders
Komuni Disturbi fil- widnejn u fis- sistema labirintika
Iritis, uveitis, hypotony of the eye (see Section 4.4)
Irite, uveite, Tnaqqis fil- pressjoni ta ’ ġol - għajn.
Not known Respiratory, thoracic and mediastinal disorders
Mhux magħruf Disturbi respiratorji, toraċiċi u medjastinali
Hearing impaired
Disturbi tas- smigħ
Common Gastrointestinal disorders
Komuni Disturbi gastro- intestinali
Very common Not known Skin and subcutaneous tissue disorders
Komuni ħafna Mhux magħruf Disturbi fil- ġilda u fit- tessuti ta ’ taħt il- ġilda
Nausea, Vomiting Pancreatitis
Dardir, Rimettar Pankreatite
Very common Renal and urinary disorders
Komuni ħafna Disturbi fil- kliewi u fis- sistema urinarja
Proteinuria, blood creatinine increased (see Section 4.4)
Ħruġ ta ’ proteini fl- awrina, żieda fil- livell tal- krejatinina (ara Sezzjoni 4. 4)
Renal failure Fanconi syndrome acquired
Falliment tal- kliewi Sindromi ta ’ Fanconi syndrome akkwiżita
General disorders and administration site conditions Very common Common
Disturbi ġenerali u kondizzjonijiet ta 'mnejn jingħata Komuni ħafna Komuni
Asthenia, fever Chills
Astenja, deni Tkexkix ta ’ bard
Reports of renal failure (plus events possibly caused by renal failure, e. g. blood creatinine increased, proteinuria, glycosuria) received during post-marketing surveillance include some which were fatal.
Żieda fil- livell tal- krejatinina fid- demm, ħruġ ta ’ proteini fl- awrina, zokkor fl- awrina) kienu rrappurtati waqt is- sorvelljanza ta ’ wara l- ħruġ tal- prodott fis- suq u jinkludu wkoll uħud li kienu fatali.
Cases of acute renal failure have been reported after only one or two doses of cidofovir.
Każijiet ta ’ falliment tal- kliewi akut ġew irrappurtati wara doża ta ’ darba jew darbtejn ta ’ cidofovir.
The finding of any glycosuria, proteinuria/ aminoaciduria, hypouricemia, hypophosphatemia and/ or hypokalemia, should prompt for the consideration of cidofovir-related Fanconi syndrome.
Għandha tkun ikkunsidrata is- sindromu ta ’ Fanconi relatata ma ’ cidofovir, meta jinstab fl- awrina xi zokkor, proteini/ amino aċidi, livelli baxxi ta ’ aċidu uriku, livelli baxxi ta ’ fosfati, u/ jew ipokalemija.
6 The following table lists adverse reactions possibly or probably related to probenecid based on clinical trial experience:
It- tabella segwenti turi l- lista ta ’ reazzjonijiet avversi li huma possibilment jew probabbilment relatati ma ’ probenecid, hekk kif inhuma bbażati fuq esperjenza ta ’ studji kliniċi:
System Organ Class Nervous system disorders
Sistema tal- klassifika tal- organi Disturbi fis- sistema nervuża
Very common Skin and subcutaneous tissue disorders
Komuni ħafna Disturbi fil- ġilda u fit- tessuti ta ’ taħt il- ġilda
Nausea, vomiting
Dardir, rimettar
Fever Asthenia, chills
Deni Astenja, tkexkix ta ’ bard
In addition probenecid may also cause other adverse
Madanakollu probenecid jista wkoll jikkawża reazzjonijiet avversi oħra, inklużi anoressija, uġiegħ fil - ħanek, fwawar, alopeċja, sturdament, anemija u pollakijurja.
Hypersensitivity reactions, with dermatitis, pruritus, urticaria and, rarely, anaphylaxis, and Stevens-Johnson syndrome have occurred.
Reazzjonijiet ta ’ sensittivita ’ eċċessiva, b’ dermatite, ħakk, urtikarja u – rarament anafilassi, u sindromi Stevens- Johnson ġraw.
There have been reports of leukopenia, hepatic necrosis, nephrotic syndrome, and aplastic anaemia.
Kien hemm rapporti ta ’ lewkopenja, nekrożi tal- fwied, sindromi nefrotika u anemija aplastika.
Haemolytic anaemia has also occurred, and may be associated with G6DP deficiency.
Anemija emolitika ġrat ukoll, u tista tiġi assoċċjata ma ’ nuqqas ta ’ G6DP.
Therefore, when co- prescribing probenecid with cidofovir, it is important for prescribers to consult the current probenecid SmPC (or an appropriate drug reference source) for full information on the safety profile and other features of that product.
Għalekk, meta jingħata probenecid ma ’ cidofovir, huwa importanti li it- tabib li jgħatih jikkonsulta l- iktar SmPC riċenti tal- probenicid (jew sors ieħor akkreditabbli ta ’ informazzjoni dwar il- mediċina, eż / Formularju Nazzjonali) u informazzjoni rispettiva tal- prodotti l- oħra li jingħataw miegħu għall- informazzjoni kompluta dwar is - sigurta ’ u aspetti oħra tal- prodott.
Two cases of cidofovir overdose have been reported.
Ġew irrapportati żewġ każijiet ta ’ doża eċċessiva b’ cidofovir.
In both cases, the overdose occurred during the first induction dose and no additional cidofovir therapy was administered.
Fiż- żewġ każijiet, id- doża eċċessiva seħħet waqt l- ewwel doża tal- bidu, u mbagħad ma ngħatatx aktar terapija b’ cidofovir.
One patient received a single dose of 16.4 mg/ kg and the other patient received a single dose of 17.3 mg/ kg.
Wieħed mill - pazjenti kien ingħata doża waħda ta ’ 16. 4 mg/ kg, u l- ieħor kien ingħata doża waħda ta ’ 17. 3 mg/ kg.
Both patients were hospitalised and received prophylactic oral probenecid and vigorous hydration for 3 to 7 days.
It - tnejn li huma kellhom jinżammu l- isptar fejn ingħataw trattament profilattiku b’ probenecid mill- ħalq, filwaqt li ġew idratati b’ mod vigoruż għal 3 – 7 t’ ijiem.
One of these patients experienced a minor transient change in renal function, while the other patient had no change in renal function (see section 4.4).
Wieħed minn dawn il- pazjenti kellu tibdil ħafif tal- mument fil- funzjoni tal- kliewi, filwaqt li l- ieħor ma kellu l- ebda tibdil fil- funzjoni tal- kliewi (ara sezzjoni 4. 4)
Antiviral for systemic use, ATC Code:
Aġent antivirali għall- użu sistemiku, Kodiċi ATC:
General Cidofovir is a cytidine analogue with in vitro and in vivo activity against human cytomegalovirus (HCMV).
Cidofovir huwa analogu ta ’ cytidine b’ effett kontra human cytomegalovirus (HCMV) kemm in vitro kif ukoll in vivo.
HCMV strains resistant to ganciclovir may still be susceptible to cidofovir.
Razzez ta ’ HCMV li huma reżistenti għal ganciclovir xorta jistgħu jkunu suxxettibbli għal cidofovir.
Mechanism of action Cidofovir suppresses HCMV replication by selective inhibition of viral DNA synthesis.
Cidofovir irażżan il- proċess li bih l- HCMV isawwar kopja tiegħu nnifsu, u dan billi jinibixxi b’ mod selettiv is- sinteżi tad- DNA tal- virus.
Biochemical data support selective inhibition of HSV-1, HSV-2 and HCMV DNA polymerases by cidofovir diphosphate, the active intracellular metabolite of cidofovir.
Tagħrif biokimiku jindika li dan jiġri permezz ta ’ inibizzjoni selettiva ta ’ polymerases tad- DNA f’ HSV- 1, HSV- 2 u HCMV permezz ta ’ cidofovir diphosphate, li hija s- sustanza ffurmata fil- metaboliżmu ta ’ cidofovir ġewwa ċ- ċelluli.
Cidofovir diphosphate inhibits these viral polymerases at concentrations that are 8- to 600-fold lower than those needed to inhibit human cellular DNA polymerases alpha, beta, and gamma.
Cidofovir diphosphate jinibixxi dawn il- polymerases tal- virus anki f’ konċentrazzjonijiet li huma minn 8 sa 600 darba aktar baxxi minn dawk li hemm bżonn biex jinibixxi d- DNA polymerases alpha, beta u gamma fiċ- ċelluli tal- ġisem tal- bniedem.
Incorporation of cidofovir into viral DNA results in reductions in the rate of viral DNA synthesis.
L- inkorporazzjoni ta ’ cidofovir fid- DNA tal- virus tirriżulta fi tnaqqis fir- rata ta ’ sinteżi tad- DNA ta ’ l- istess virus.
Cidofovir enters cells by fluid-phase endocytosis and is phosphorylated to cidofovir monophosphate and subsequently to cidofovir diphosphate.
Cidofovir jidħol fiċ- ċelluli permezz ta ’ endoċitożi f’ fażi fluwida u jiġi fosforilat għal cidofovir monophosphate u wara għal cidofovir diphosphate.
Prolonged antiviral effects of cidofovir are related to the half-lives of its metabolites; cidofovir diphosphate persists inside cells with a half-life of 17-65 hours and a cidofovir phosphate-choline adduct has a half-life of 87 hours.
Effetti fit- tul ta ’ cidofovir kontra l- virus huma relatati mal- half- lives tas- sustanzi li jiġu ffurmati b’ riżultat tal- metaboliżmu tiegħu; Cidofovir diphosphate jippersisti ġoċ- ċelluli, b’ half- life ta ’ 17 – 65 siegħa filwaqt li is- sustanza magħquda ta ’ phosphate- choline għandha half- life ta ’ 87 siegħa.
7 Antiviral activity Cidofovir is active in vitro against HCMV, a member of the herpesviridae family.
Cidofovir huwa attiv in vitro kontra l- HCMV, li jifforma parti mil- familja herpesviridae.
Antiviral activity is seen at concentrations significantly below those which cause cell death.
L- effett ta ’ kontra l- virus jidher anki f’ konċentrazzjonijiet ferm anqas li jwasslu għall- mewt ta ’ ċelluli li jkunu f’ saff wieħed.
The in vitro sensitivity to cidofovir is shown in the following table:
Is- sensittività in vitro għal cidofovir tidher fil- lista li jmiss.
Cidofovir Inhibition of Virus Multiplication in Cell Culture
Inibizzjoni tal- virus minn cidofovir Tkattir f’ koltura taċ- ċelluli
Virus wild-type CMV isolates ganciclovir-resistant CMV isolates foscarnet-resistant CMV isolates
Virus tipi ta ’ CMV iżolati mis- salvaġġ Tipi ta ’ CMV reżistenti għal ganciclovir Tipi ta ’ CMV reżistenti għal foscarnet
IC50 (µM) 0.7 (± 0.6) 7.5 (± 4.3) 0.59 (± 0.07)
IC50 (µM) 0. 7 (± 0. 6) 7. 5 (± 4. 3) 0. 59 (± 0. 07)
In vivo activity against HCMV was confirmed with controlled clinical studies of cidofovir for the treatment of CMV retinitis in patients with AIDS, which demonstrated statistically significant delays in time to CMV retinitis progression for patients on cidofovir when compared to control patients.
L- attività in vivo ta ’ kontra l- HCMV fil- bniedem, ġiet konfermata permezz ta ’ studji kliniċi kkontrollati li fihom cidofovir intuża għat- trattament ta ’ retinite kkawżata mil- HCMV f’ pazjenti bl - AIDS, u fejn intwera li f’ pazjenti li kienu fuq cidofovir kellhom dewmien statistikament sinifikanti sa ma żviluppaw retinite kkawżżata mis- CMV, meta mqabbla ma ’ pazjenti tal- kontroll.
The median times to retinitis progression in the two efficacy studies (GS-93-106 and GS-93-105), were 120 days and not reached for the treatment arms vs.
Iż- żmien medjan sa ma kien hemm progressjoni għal retinite fiż- żewġ studji ta ’ l- effikaċja (l- istudji GS- 93- 106 u GS - 93- 105) kien ta ’ 120 jum u ma kienx milħuq f’ dawk li ħadu t- trattament vs.
22 days and 21 days for the untreated (deferred treatment) arms, respectively.
22 jum u 21 jum għal dawk li ma ħadux trattament (trattament diferit), rispettivament.
In study GS-93-107 conducted in patients who had relapsed after treatment with other agents, the median time to retinitis progression was 115 days.
Fl- istudju GS- 93- 107 li sar fuq pazjenti li rkadew wara trattament b’ aġenti oħrajn, iż- żmien medjan sa ma kien hemm progressjoni għal retinite kien ta ’ 115- il jum.
Viral resistance Following in vitro selection of ganciclovir-resistant HCMV isolates, cross-resistance between ganciclovir and cidofovir was seen with ganciclovir-selected mutations in the HCMV DNA polymerase gene but not with mutations in the UL97 gene.
Reżistenza tal- virus Wara li ġew magħżula in vitro iżolati ta ’ HCMV fil- bniedem li huma reżistenti għal ganciclovir, ħareġ li kien hemm cross resistance bejn ganciclovir u cidofovir minħabba mutazzjonijiet ġenetiċi magħżula b’ ganciclovir fil- ġene tal- polymerase tad- DNA tal- HCMV imma mhux minħabba mutazzjonijiet ġenetiċi fil- ġene UL97.
No cross-resistance between foscarnet and cidofovir was seen with foscarnet-selected mutants.
Ma kienx hemm cross resistance bejn foscarnet u cidofovir f’ mutanti magħżula b’ foscarnet.
Cidofovir-selected mutants had a mutation in the DNA polymerase gene and were cross-resistant to ganciclovir, but susceptible to foscarnet.
Mutanti magħżulin b’ cidofovir kellhom tibdil ġenetiku fil- ġene tal- polymerase tad- DNA u kien hemm cross resistance għal ganciclovir, iżda kienu suxxettibbli għal foscarnet.
The major route of elimination of cidofovir was by renal excretion of unchanged drug by a combination of glomerular filtration and tubular secretion.
Cidofovir jiġi eliminat prinċipalment billi l- mediċina, mhux mibdula, titneħħa mill- ġisem permezz tal - kliewi b’ taħlita ta’ filtrazzjoni minn ġol- glomeruli u ta ’ tnixxija minn ġot- tubules tal- kliewi.
In patients with normal renal function, 80 to 100% of the intravenous dose was recovered in the urine over 24 hours as unchanged cidofovir.
F’ pazjenti b’ funzjoni normali tal- kliewi, 80 – 100% tad- doża li ngħatat fil- vina reġgħet ġiet irkuprata fl- awrina bħala cidofovir mhux mibdul, fuq medda ta ’ 24 siegħa.
No metabolites of cidofovir have been detected in serum or urine of patients.
Ma nstabux sustanzi li kienu ġejjin mill - metaboliżmu ta ’ cidofovir la fis- serum u lanqas fl- awrina tal- pazjenti.
At the end of a one-hour infusion of cidofovir 5 mg/ kg administered with concomitant oral probenecid, the mean (± SD) serum concentration of cidofovir was 19.6 (± 7.18) mcg/ ml.
8 Fi tmiem infużjoni fuq medda ta ’ siegħa ta ’ cidofovir 5mg/ kg u li magħha ngħata wkoll probenecid mill- ħalq, il- konċentrazzjoni medja (± SD) ta’ cidofovir fis- serum kienet ta’ 19. 6 (± 7. 18) mcg/ ml.
The mean values of total serum clearance, volume of distribution at steady-state and terminal elimination half-life were 138 (± 36) ml/ hr/ kg, 388 (± 125) ml/ kg and 2.2 (±0.5) hour, respectively.
Il - valuri medji tat- tneħħija totali mis- serum, tal- volum tad- distribuzzjoni meta jkun intlaħaq stat fiss, u l - half- life fil- fażi terminali ta ’ l- eliminazzjoni kienu 138 (± 36) ml/ siegħa/ kg, 388 (± 125) ml/ kg u 2. 2 (± 0. 5) siegħa, rispettivament.
Dose-independent kinetics were demonstrated with single doses of cidofovir given over the dose range 3 to 7.5 mg/ kg.
Meta ntużaw dożi singoli ta ’ cidofovir li kienu jvarjaw minn 3 – 7. 5 mg/ kg intwera li kien hemm kinetiċi li kienu indipendenti mid- doża.
In vitro protein binding In vitro protein binding of cidofovir to plasma or serum protein was 10% or less over the cidofovir concentration range 0.25 to 25 mcg/ ml.
Irbit mal- proteini in vitro Fuq medda ta ’ konċentrazzjonijet ta ’ cidofovir li tvarja minn 0. 25 – 25 mcg/ ml kien jidher li l- irbit ta ’ cidofovir ma ’ proteini fil- plażma jew fis- serum kien ta ’ 10% jew inqas.
8 5.3 Preclinical safety data
Tagħrif ta 'qabel l- użu kliniku dwar is- sigurtà tal- mediċina 5. 3
Preclinical animal studies demonstrated that nephrotoxicity was the major dose-limiting toxicity of cidofovir.
Fi studji fuq l- annimali qabel l- użu kliniku ntwera li t- tossiċità għall- kliewi kienet dik li l- aktar tillimita d- doża ta ’ cidofovir.
Evidence for a nephroprotective effect for probenecid was shown in a 52-week study conducted in cynomolgus monkeys administered cidofovir 2.5 mg/ kg once weekly intravenously with 1 g of probenecid given orally.
Fi studju mifrux fuq 52 ġimgħa u li sar fuq xadini tal- ġenus cynomolgus, fejn dawn ingħataw cidofovir 2. 5 mg/ kg ġol- vina darba fil- ġimgħa flimkien ma ’ 1g probenecid li ngħata mill- ħalq, ħarġet evidenza li turi li probenecid fil- fatt għandu l- effett li jipproteġi l- kliewi.
Carcinogenesis In a 26-week intravenous toxicity study, a significant increase in incidence of mammary adenocarcinomas was seen in female rats and of Zymbal’ s gland carcinomas in male and female rats at subtherapeutic plasma levels of cidofovir.
Karċinoġenesi Fi studju fuq it- tossiċità meta jingħata fil- vina li dam 26 ġimgħa, kien hemm żieda sinifikanti fl - inċidenza ta ’ adenokarċinoma tas- sider f’ firien femminili u ta ’ karċinoma tal- glandola ta ’ Zymbal f’ firien kemm femminili kif ukoll maskili meta ntużaw livelli ta ’ cidofovir fil- plażma li kienu inqas minn dawk terapewtiċi.
In a separate study, once weekly subcutaneous injections of cidofovir for 19 consecutive weeks resulted in mammary adenocarcinomas in female rats at doses as low as 0.6 mg/ kg/ week.
Fi studju separat, fejn ingħataw injezzjonijiet ta ’ cidofovir taħt il- ġilda darba fil- ġimgħa, għal 19- il ġimgħa konsekuttiva, dawn irriżultaw f’ adenokarċinoma tas- sider f’ firien femminili, saħansitra b’ dożi baxxi ta ’ 0. 6 mg/ kg/ ġimgħa.
In both studies, tumours were observed within 3 months of dosing.
Fiż- żewġ studji, it- tumuri feġġew fl- ewwel 3 xhur minn meta nbdew id- dożi.
No tumours were observed in cynomolgus monkeys administered cidofovir intravenously once weekly for 52 weeks at doses up to 2.5 mg/ kg/ week.
Ma ġewx osservati tumuri f’ xadini tal- ġenus cynomolgus li ngħataw cidofovir fil- vina darba f’ ġimgħa għal 52 ġimgħa f’ dożi li kienu jaslu sa 2. 5mg/ kg/ ġimgħa.
Mutagenicity and reproductive toxicology Studies have shown that cidofovir is clastogenic in vitro at 100 µg/ ml and is embryotoxic in rats and rabbits.
Mutaġeniċita u tossikoloġija riproduttiva Studji wrew li cidofovir huwa klastoġeniku f’ konċentrazzjoni ta’ 100 µg/ ml in vitro, u jagħmel ħsara lill- embriju kemm fil- firien kif ukoll fil- fniek.
No mutagenic response was elicited by cidofovir at dose levels up to 5 mg/ plate, in the presence and absence of metabolic activation by rat liver S-9 fraction, in microbial assays involving Salmonella typhimurium for base pair substitutions or frameshift mutations (Ames) and Escherichia coli for reverse mutations.
F’ analiżi mikrobiċi li kienu jinvolvu Salmonella typhimurium għal sostituzzjonijiet base pair jew mutazzjonijiet frameshift (Ames) u Escherichia coli għall- mutazzjonijiet reverse, ma rriżultawx reazzjonijiet mutaġeniċi meta cidovovir intuża f’ konċentrazzjonijiet li waslu sa 5 mg/ plattina, kemm bl- attivazzjoni metabolika permezz tal- frazzjoni S- 9 tal- fwied tal- far kif ukoll mingħajrha.
An increase in formation of micronucleated polychromatic erythrocytes was observed in vivo in mice receiving a high, toxic intraperitoneal dose of cidofovir (≥ 2000 mg/ kg).
Kien hemm żieda fl- ammont ta ’ eritroċiti polikromatiċi mikronuklejati, in vivo, fi ġrieden li ngħataw doża għolja u tossika ta ’ cidofovir ġol- peritonew (≥ 2000 mg/ kg).
Cidofovir induced chromosomal aberrations in human peripheral blood lymphocytes in vitro without metabolic activation (S-9 fraction).
Cidofovir ikkaġuna aberrazzjonijiet tal- kromosomi f’ limfoċiti ġewwa s- sistema ċirkolatorja tal - bniedem, in vitro, mingħajr ma kellu bżonn ikollu attivazzjonni metabolika (bil- frazzjoni S- 9).
At the 4 cidofovir levels (12.5 to 100 µg/ ml) tested, the percentage of damaged metaphases and number of aberrations per cell increased in a concentration-dependent manner.
Fl- 4 livelli ta ’ cidofovir (12. 5 – 100 µg/ ml) li ġew ittestjati, il- persentaġġ ta ’ metafasijiet li saritilhom ħsara u n- numru t ’ aberrazzjonijiet għal kull ċellula żdiedu b’ mod li jidher li kien marbut mal - konċentrazzjoni ta ’ cidofovir.
No adverse effects on fertility or general reproduction were seen following once weekly intravenous injections of cidofovir in male rats for 13 consecutive weeks at doses up to 15 mg/ kg/ week.
Ma kien hemm l- ebda effett fuq il- fertilità jew fuq ir- riproduzzjoni in ġenerali, wara li firien maskili ingħataw injezzjonijiet ta ’ cidofovir fil- vina darba fil- ġimgħa, għal 13 il- ġimgħa konsekuttivi, f’ dożi li kienu jaslu sa 15mg/ kg/ ġimgħa.
Female rats dosed intravenously once weekly at 1.2 mg/ kg/ week or higher for up to 6 weeks prior to mating and for 2 weeks post mating had decreased litter sizes and live births per litter and increased early resorptions per litter.
Meta firien femminili ngħataw dożi ta ’ 1. 2 mg/ kg/ ġimgħa jew aktar, fil- vina, darba fil- ġimgħa, sa 6 ġimgħat qabel ma tgħammru u għal ġimgħatejn wara li kienu tgħammru, ġara li kellhom boton iżgħar u wkoll tnaqqis fin- numru ta ’ firien żgħar li twieldu ħajjin u kien hemm żieda fir- resorptions għal kull boton.
Peri- and post-natal development studies in which female rats received subcutaneous injections of cidofovir once daily at doses up to 1.0 mg/ kg/ day from day 7 of gestation through day 21 postpartum (approximately 5 weeks) resulted in no adverse effects on viability, growth, behaviour, sexual maturation or reproductive capacity in the offspring.
Fi studji fuq l- iżvilupp taż- żgħar waqt il- perijodu immedjatament qabel jew wara t- twelid jew sa ftit ġimgħat wara t- twelid, fejn firien femminili ngħataw injezzjonijiet ta ’ cidofovir taħt il- ġilda, darba kuljum, f’ dożi li kienu jaslu sa 1. 0 mg/ kg/ jum, mis- 7 jum tat- tqala sal- 21 jum wara l- ħlas (bejn wiehed u ieħor 5 ġimgħat), ma irriżultawx effetti mhux mixtieqa fuq il- vijabilità, l- iżvilupp, l- imġieba, l- maturazzjoni sesswali jew il- ħila riproduttiva