qanastek/EMEA-V3 huggingface dataset:
Co-administration of APTIVUS with low dose ritonavir, with active substances that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/ or life-threatening events is contraindicated.
L- għoti konġunt ta 'APTIVUS flimkien ma' doża baxxa ta ’ ritonavir, ma ’ sustanzi attivi li huma prinċipalment dipendenti fuq CYP3A għall- eliminazzjoni, u li l- konċentrazzjoni għolja tagħhom fil- plażma hija assoċjata ma ’ effetti serji u/ jew li tista ’ tikkaġuna l- mewt hu kontraindikat.
These active substances include antiarrhythmics (amiodarone, bepridil, quinidine), antihistamines (astemizole, terfenadine), ergot derivatives (dihydroergotamine, ergonovine, ergotamine, methylergonovine), gastointestinal motility agents (cisapride), neuroleptics (pimozide, sertindole) and sedatives/ hypnotics (triazolam) (see section 4.3).
Dawn is- sustanzi attivi jinkludu anti- arritmiċi (amiodarone, bepridil, quinidine), anti- ħistamini (astemizole, terfenadine), derivati ta 'ergot (dihydroergotamine, ergonovine, ergotamine, methylergonovine), mediċini li jmexxu fl- imsaren (cisapride), newrolettiċi (pimozide, sertindole) u sedativi/ ipnotiċi (triazolam) (ara sezzjoni 4. 3).
11 In addition, co-administration of APTIVUS with low dose ritonavir, with drugs that are highly dependent on CYP2D6 for clearance, such as the antiarrhythmics flecainide, propafenone and metoprolol given in heart failure, is contraindicated (see section 4.3).
Barra minn hekk, l- użu ta ’ APTIVUS flimkien ma ’ doża baxxa ta ’ ritonavir ma ’ mediċini oħrajn li jiġu prinċipalment eliminati permezz ta ’ CYP2D6, bħal l- anti- arritmiċi flecainide, propafenone u metoprolol li jingħata f’ falliment kardijaku, huwa kontra- indikat (ara sezzjoni 4. 3).
Some anti-infectives are not recommended (halofantrine, lumefantrine) as well as miscellaneous agents (tolterodine) (see section 4.4).
Xi mediċini li jaħdmu kontra l- infezzjonijiet m' humiex rakkomandati (halofantrine, lumefantrine) kif ukoll mediċini mixxellanji (tolterodine) (ara sezzjoni 4. 4).
Oral contraceptives/ oestrogens:
Kontraċettivi orali/ Oestrogens:
APTIVUS, co-administered with low dose ritonavir, decreases the AUC and Cmax of ethinyl-oestradiol by 50%, but does not significantly alter the pharmacokinetic behaviour of norethindrone.
APTIVUS, mogħti flimkien ma ’ doża baxxa ta ’ ritonavir, jikkaġuna tnaqqis ta ’ 50% fl- AUC u Cmax ta ’ ethinyl- oestradiol, iżda ma jbiddilx b’ mod sinifikanti l- fatturi farmakokinetici ta ’ norethindrone.
The concomitant administration with APTIVUS, co-administered with low dose ritonavir, is not recommended.
L- għoti konġunt ma 'APTIVUS, mogħti flimkien ma ’ doża baxxa ta ’ ritonavir, mhux rakkomandat.
Alternative or additional contraceptive measures are to be used when oestrogen based oral contraceptives are co-administered with APTIVUS and low dose ritonavir.
Miżuri alternattivi jew addizzjonali ta 'kontraċezzjoni għandhom jittieħdu meta kontraċettivi li jittieħdu mill- ħalq u li huma bbażati fuq oestrogen huma mogħtija flimkien ma' APTIVUS mogħti
Patients using oestrogens as hormone replacement therapy should be clinically monitored for signs of oestrogen deficiency (see section 4.4 and section 4.6).
Pazjenti li jieħdu oestrogens bħala terapija ormonali ta 'sostituzzjoni għandhom jiġu monitorati b' mod kliniku għal sinjali ta' tnaqqis ta 'oestrogen (ara sezzjoni 4. 4 u sezzjoni 4. 6).
Phosphodiesterase 5 (PDE5) inhibitors Sildenafil and vardenafil:
Sildenafil u vardenafil:
Particular caution should be used when prescribing the phosphodiesterase (PDE5) inhibitors sildenafil or vardenafil in patients receiving APTIVUS co-administered with low dose ritonavir.
Għandu jkun hemm attenzjoni partikolari meta l- impedituri ta 'phosphodiesterase (PDE5) sildenafil jew vardenafil jiġu preskritti lil pazjenti li qed jirċievu APTIVUS mogħti flimkien ma ’ doża baxxa ta ’ ritonavir.
Co-administration of APTIVUS and low dose ritonavir with PDE5 inhibitors is expected to substantially increase PDE5 concentrations and may result in an increase in PDE5 inhibitor-associated adverse events including hypotension, visual changes and priapism.
L- għoti flimkien ta 'APTIVUS, mogħti flimkien ma ’ doża baxxa ta ’ ritonavir, ma' impedituri ta 'PDE5 hi mistennija li żżid sostanzjalment il - konċentrazzjonijiet ta' PDE5 u tista 'tirriżulta f' effetti avversi relatati ma impedituri ta PDE5 li jinkludu pressjoni baxxa, bidliet fil- vista u prijapiżmu.
In a pharmacokinetic study performed in healthy male volunteers, co-administration of APTIVUS and low dose ritonavir with single dose tadalafil increased tadalafil exposure (AUC increased by 2.3 fold) at the first dose and did not change tadalafil exposure at steady-state.
Fi studju farmakokinetiku mwettaq fuq voluntieri rġiel b’ saħħithom, l- għoti ta ’ APTIVUS flimkien ma ’ doża baxxa ta ’ ritonavir b’ doża waħda ta ’ tadalafil żiedet l- espożizzjoni għal tadafil (AUC żiedet b’ 2. 3 darbiet) fl- ewwel doża u ma bidletx l- espożizzjoni ta ’ tadalafil fl- istadju fiss.
Therefore it is recommended to prescribe tadalafil after at least 7 days of APTIVUS/ ritonavir dosing.
Għalhekk huwa rakkomandat li jinkiteb tadalafil fuq riċetta tat- tabib wara ta ’ lanqas 7 ijiem ta ’ dożaġġ ta ’ APTIVUS/ ritonavir.
Narcotic analgesics (Methadone/ Meperidine):
Analġesiċi narkotiċi (Methadone/ Meperidine):
Co-administration of APTIVUS and low dose ritonavir with single dose methadone was demonstrated to decrease methadone pharmacokinetic parameters (AUC0-24h ratio of 0.47 with 90% CI [0.44; 0.51] and Cmax ratio of 0.45 with 90% CI [0.41; 0.49]), in a study conducted in fasted healthy subjects.
L- għoti konġunt ta ’ APTIVUS, mogħti flimkien ma ’ doża baxxa ta ’ ritonavir ma ’ doża waħda ta 'methadone, uriet li tnaqqas il- parametri farmakokinetiċi ta' methadone (proporzjon ta 'AUC0- 24h ta' 0. 47 b' 90% CI [0. 44; 0. 51] u l- proporzjon ta 'Cmax ta' 0. 45 b' 90% CI [0. 41; 0. 49]), fi studju li sar f' suġġetti sajmin b' saħħithom.
Therefore in such cases, patients should be monitored for opiate withdrawal syndrome.
Għalhekk f' każijiet bħal dawn il- pazjenti għandhom jiġu monitorati għal sindromi ta 'tiżmin ta' opiates.
Dosage of methadone may need to be increased.
Id- doża ta 'methadone għandha mnejn tkun trid tiġi miżjuda.
APTIVUS, co-administered with low dose ritonavir, is expected to decrease meperidine concentrations and increase normeperidine metabolite concentrations.
APTIVUS, mogħti flimkien ma ’ doża baxxa ta ’ ritonavir, hu mistenni li jnaqqas il- konċentrazzjonijiet ta 'meperidine u jżid il- konċentrazzjonijiet ta' metaboliti ta 'normeperidine.
Dosage increase and long-term use of meperidine with APTIVUS co-administered with low dose ritonavir are not recommended due to the increased concentrations of the metabolite normeperidine which has both analgesic activity and CNS stimulant activity (eg seizures).
Iż- żjieda fid- doża, u l- użu fit- tul ta ’ meperidine flimkien ma ’ APTIVUS, mogħti flimkien ma ’ doża baxxa ta ’ ritonavir, mhumiex rakkomandati, minħabba li dan iżid il- livell tal- metabolit normeperidine li għandu kemm attività analġeżika kif ukoll jaġixxi bħala stimulant għas- sistema nervuża ċentrali (CNS) (eż. puplesiji).
Immunosuppressants (cyclosporin, tacrolimus, sirolimus):
Mediċini immunosuppressivi (cyclosporin, tacrolimus, sirolimus):
Concentrations of cyclosporin, tacrolimus, or sirolimus cannot be predicted when co-administered with APTIVUS co-administered with low dose ritonavir, due to conflicting effect of APTIVUS, co-administered with low dose ritonavir, on CYP 3A and Pgp.
Konċentrazzjonijiet ta 'cyclosporin, tacrolimus, jew sirolimus ma jistgħux jiġu previsti meta jiġu amministrati konġuntivament ma' APTIVUS, mogħti flimkien ma ’ doża baxxa ta ’ ritonavir, minħabba l- effett konfliġġenti ta 'APTIVUS, mogħti flimkien ma ’ doża baxxa ta ’ ritonavir, fuq CYP 3A u Pgp.
More frequent concentration monitoring of these medicinal products is recommended until blood levels have been stabilised.
Monitoraġġ aktar ta 'spiss tal - konċentrazzjonijiet ta' dawn il- prodotti mediċinali hu rakkomandat sakemm il- livelli tad- demm ikunu ġew stabilizzati.
Warfarin and other oral anticoagulants:
Warfarin u antikoagulanti orali oħrajn:
Co-administration of APTIVUS with low dose ritonavir and warfarin may alter the metabolism of S-warfarin (initial inhibition and after 10 days a net induction was observed).
L għoti konġunt ta 'APTIVUS, flimkien ma ’ doża baxxa ta ’ ritonavir u warfarin jista ’ jibdel il- metaboliżmu ta ’ S- warfarin (kienet osservata inibizzjoni inizjali u wara 10 ijiem induzzjoni netta).
Consequently, APTIVUS co-administered with low dose ritonavir, may be associated with changes in INR (International Normalised Ratio) values, and may affect anticoagulation (thrombogenic effect) or increase the risk of bleeding.
Konsegwentement, APTIVUS mogħti flimkien ma ’ doża baxxa ta ’ ritonavir, jista 'jiġi assoċjat ma ’ bidliet fil- valuri ta' l- INR (International Normalised Ratio), u jista 'jaffettwa l- antikoagulazzjoni (effett tromboġeniku) jew iżid ir- riskju ta' fsada.
Close clinical and biological (INR measurement) monitoring is recommended when these medicinal products are combined.
Monitoraġġ kliniku u bioloġiku mill- qrib (kejl ta 'l- INR) hu rakkomandat meta dawn il- prodotti mediċi jiġu kkombinati.
Antacids:
Antacids:
When APTIVUS, co-administered with low dose ritonavir, was co-administered with 20 ml of aluminium- and magnesium-based liquid antacid, tipranavir AUC12h, Cmax and Cmin were reduced by 25-29%.
Meta APTIVUS mogħti flimkien ma ’ doża baxxa ta ’ ritonavir, ingħata ma ’ 20 ml ta ’ mediċina likwida ta ’ kontra l- aċidu fl- istonku, li fiha l- aluminju u l- manjesju, l- AUC12h, Cmax u Cmin ta ’ tipranavir tbaxxew b’ 25- 29%.
Dosing of APTIVUS, co-administered with low dose ritonavir, with antacids should be separated by at least a two hours time interval.
Għaldaqstant, l- għoti ta ’ doża ta ’ APTIVUS, flimkien ma ’ doża baxxa ta ’ ritonavir, u ta ’ antaċidi għandhom ikunu separati b’ mhux anqas minn sagħtejn minn xulxin.
12 Proton pump inhibitors:
Impedituri tat- tip proton pump:
In clinical pharmacokinetic studies of tipranavir/ ritonavir in combination with omeprazole (40 mg qd), no clinically important changes in tipranavir/ ritonavir plasma concentrations were observed and thus no tipranavir/ ritonavir dose adjustment is required.
Fi studji farmakokinetiċi kliniċi ta ’ tipranavir/ ritonavir flimkien ma ’ omeprazole (40 mg qd) ma ġewx osservati bidliet klinikament importanti fil- konċentrazzjonijiet tal- plażma ta ’ tipranavir/ ritonavir u għalhekk mhux meħtieġ li jkun hemm aġġustament fid- doża ta ’ tipranavir/ ritonavir.
Tipranavir/ ritonavir at steady state resulted in decreases in omeprazole AUC and Cmax by 71% and 73%, respectively.
Tipranavir/ ritonavir fi stadju fiss irriżulta fi tnaqqis fl- AUC u Cmax b’ 71% u 73% rispettivament.
Similar effects were observed for the S-enantiomer, esomeprazole.
Effetti simili kienu osservati fl- enantjomer S, esomeprazole.
Therefore, the combined use of tipranavir/ ritonavir with either omeprazole or esomeprazole is not recommended (see section 4.4).
Għalhekk l- użu kombinat ta ’ tipranavir / ritonavir jew ma ’ omeprazole jew esomeprazole mhux rakkomandat (ara sezzjoni 4. 4).
If unavoidable, upward dose adjustments for either omeprazole or esomeprazole may be considered based on clinical response to therapy.
Jekk dan ma jistax jiġi evitat, aġġustamenti ’ l fuq fid- doża ta ’ omeprazole jew esomeprazole għandu
There are no data available indicating that omeprazole or esomeprazole dose adjustments will overcome the observed pharmacokinetic interaction.
M’ hemmx tagħrif disponibbli li juri li aġġustamenti fid- dożi ta ’ omeprazole jew esomeprazole ser jegħlbu l- interazzjoni farmakokinetika osservata.
Recommendations for maximal doses of omeprazole or esomeprazole are found in the corresponding product information.
Rakkomandazzjonijiet għal dożi massimi ta ’ omeprazole jew esomeprazole jinsabu fl - informazzjoni korrispondenti għal prodott.
H2-receptor antagonists:
Antagonisti riċettaturi ta ’ H2:
No data are available for H2-receptor antagonists in combination with tipranavir and low dose ritonavir.
L- ebda tagħrif mhu disponibbli għal antagonisti riċettaturi H2 f’ kombinazzjoni ma ’ tipranavir u doża baxxa ta ’ ritonavir.
An increase in gastric pH that may result from H2-receptor antagonist therapy is not expected to have an impact on tipranavir plasma concentrations.
Żieda fil- pH gastriku li tista ’ tirriżulta minn terapija antagonista b’ riċettaturi H2 mhix mistennija li jkollha impatt fil- konċentrazzjonijiet tal- plażma ta ’ tipranavir.
Caution should be exercised when such drugs are combined with tipranavir and low dose ritonavir.
Kawtela għandha tiġi eżerċitata meta mediċini bħal dawn jingħataw flimkien ma ’ tipranavir u doża baxxa ta ’ ritonavir.
Theophylline:
Theophylline:
Based on data from the cocktail study where caffeine (CYP1A2 substrate) AUC was reduced by 43%, APTIVUS/ ritonavir is expected to decrease theophylline concentrations.
Skond dejta mill- istudju koktejl meta l- AUC ta ’ kaffeina (sottostrat ta ’ CYP1A2) tnaqqas b’ 43%, APTIVUS/ ritonavir, mistenni li jnaqqas il- konċentrazzjonijiet ta ’ theophylline.
Theophylline plasma concentrations should be monitored during the first two weeks of co- administration with APTIVUS/ ritonavir and the theophylline dose should be increased as needed.
Il - konċentrazzjonijiet tal- plażma ta ’ theophylline għandhom jiġu monitorati matul l- ewwel żewġ ġimgħat ta ’ l- għoti flimkien ta ’ APTIVUS/ ritonavir u d- doża ta ’ theophylline għandha tiżdied kif meħtieġ.
APTIVUS, co-administered with low dose ritonavir, is expected to increase desipramine concentrations.
APTIVUS, mogħti flimkien ma ’ doża baxxa ta 'ritonavir, mistenni jgħolli l- konċentrazzjonijiet ta ’ desipramine.
Dosage reduction and concentration monitoring of desipramine is recommended.
Huwa rakkomandat li jkun hemm tnaqqis fid- doża u monitoraġġ tal- konċentrazzjonijiet ta ’ desipramine.
Concomitant use of APTIVUS/ ritonavir and oral midazolam is contra-indicated (see section 4.3).
L- użu konkomitanti ta ’ APTIVUS/ ritonavir u midazolam mogħti mill- ħalq hu kontra - indikat (ara sezzjoni 4. 3).
Ritonavir is a potent inhibitor of CYP3A4 and therefore will affect drugs metabolised by this enzyme.
Ritonavir huwa impeditur qawwi ta ’ CYP3A4 u għalhekk jaffettwa mediċini metabolizzati b’ din l- enżima.
When co-administered with APTIVUS/ ritonavir at steady-state concentrations of intravenously administered single dose midazolam were increased 2.8 fold (AUC0-24h) and concentrations of orally administered midazolam were increased 10 fold.
Meta jingħata flimkien ma ’ APTIVUS/ ritonavir fi stadju fiss il- konċentrazzjonijiet mogħtija ġol vina ta ’ midazolam żdiedu 2. 8 darbiet (AUC0- 24h) u l- konċentrazzjonijiet ta ’ midazolam mogħti mill- ħalq żdiedu b’ 10 darbiet.
If APTIVUS/ ritonavir is administered with parenteral midazolam, close clinical monitoring for respiratory depression and/ or prolonged sedation should be instituted and dosage adjustment should be considered.
Jekk APTIVUS/ ritonavir jiġi mogħti b’ midazolam parenterali, għandu jiġi stabbilit monitoraġġ kliniku mill- qrib għal dipressjoni respiratorja u/ jew sedattiv prolongat u aġġustament fid- doża għandu jiġi kkonsidrat.
APTIVUS, co-administered with low dose ritonavir, may double the exposure of orally administered digoxin at first dose, while the net effect at steady state may rather consist in a slight decrease in digoxin exposure.
APTIVUS, mogħti flimkien ma ’ doża baxxa ta ’ ritonavir, jista ’ jirdoppja l- espożizzjoni għal digoxin mogħti mill- ħalq fl- ewwel doża, filwaqt li l- effett nett fi stadju fiss pjuttost jista ’ jikkonsisti minn tnaqqis żgħir għal espożizzjoni ta ’ digoxin.
Monitoring of digoxin serum concentrations is recommended until steady state has been obtained.
Monitoraġġ tal- konċentrazzjonijiet ta ’ digoxin fis- serum hu rakkomandat sakemm jintlaħaq l- istadju fiss.
In a pharmacokinetic study performed in healthy volunteers, concomitant use of low dose ritonavir (200 mg twice daily) with a single dose of trazodone led to an increased plasma concentration of trazodone (AUC increased by 2.4 fold).
Fi studju farmakokinetiku mwettaq fuq voluntiera b' saħħithom, l- użu konġunt ta 'doża baxxa ta' ritonavir (200 mg darbtejn kuljum) ma' doża waħda ta 'trazodone, rriżulta f' konċentrazzjonijiet ogħla ta' trazodone fil- plażma (AUC żdiedet b' 2. 4 drabi).
Adverse events of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir in this study.
Reazzjonijiet avversi ta 'nawsea, sturdamenti, pressjoni baxxa u sinkope ġew osservati wara l- għoti konġunt ta' trazodone u ritonavir f' dan l- istudju.
However, it is unknown whether the combination of tipranavir/ ritonavir might cause a larger increase in trazodone exposure.
Madankollu, mhux magħruf jekk il- kombinazzjoni ta 'tipranavir/ ritonavir tistax tirriżulta f' espożizzjoni ogħla ta' trazodone.
The combination should be used with caution and a lower dose of trazodone should be considered.
Il- kombinazzjoni għandha tintuża b' kawtela u doża aktar baxxa ta 'trazodone għandha tiġi kkonsidrata.
APTIVUS co-administered with low-dose ritonavir at steady-state resulted in approximately a 50% decrease in bupropion Cmax and AUC0-12h.
APTIVUS, mogħti flimkien ma ’ doża baxxa ta ’ ritonavir fi stadju fiss wassal għal tnaqqis ta ’ madwar 50% f’ Cmax u AUC0- 12h ta ’ bupropion.
This effect may be due to induction of bupropion metabolism.
Dan l- effett jista ’ jkun ikkawżat mill- induzzjoni tal- metaboliżmu ta ’ bupropion.
There was no relevant change in TPV Cmin.
Ma kien hemm ebda tibdil rilevanti f’ Cmin ta ’ TPV.
If the co- administration with bupropion is judged unavoidable, this should be done under close clinical monitoring for bupropion efficacy, without exceeding the recommended dosage, despite the observed induction.
Jekk l- għoti ma ’ bupropion huwa kkunsidrat li ma jistax jiġi evitat, dan għandu jsir taħt monitoraġġ kliniku mill- qrib għal effikaċja ta ’ bupropion, mingħajr ma tinqabeż id- doża rakkomandata, minkejja l- induzzjoni osservata.
The pharmacokinetic
Studju farmakodinamiku fuq l- interazzjoni f’ voluntiera b’ saħħithom wera li meta ngħataw loperamide u APTIVUS, mogħti flimkien ma ’ doża baxxa ta ’ ritonavir, ma kienx hemm xi bidla klinikament rilevanti fir- reazzjoni tas- sistema respiratorja għal carbon dioxide.
13 analysis showed that the AUC and Cmax of loperamide are reduced by 51% and 61%, respectively, and the Cmin of tipranavir by 26%.
L- analiżi farmakokinetika żvelat li l- AUC u Cmax ta ’ loperamide tbaxxiet b’ 51% u b ’ 61%, rispettivament, u Cmin ta 'tipranavir b' 26%.
The clinical relevance of these changes is unknown.
Ir- rilevanza klinika ta ’ dawn il- bidliet mhix magħrufa.
Fluticasone propionate (interaction with ritonavir):
Fluticasone propionate (interazzjoni ma 'ritonavir):
In a clinical study where ritonavir 100 mg capsules bid were co-administered with 50 µg intranasal fluticasone propionate (4 times daily) for 7 days in healthy subjects, the fluticasone propionate plasma levels increased significantly, whereas the intrinsic cortisol levels decreased by approximately 86% (90% confidence interval 82-89%).
13 kuljum) għal 7 t’ ijiem f' suġġetti f' saħħithom, il- livelli ta 'fluticasone propionate fil- plażma żdiedu b' mod sinifikattiv, filwaqt li l- livelli intrinsiċi ta' cortisol tnaqqsu b' madwar 86% (90% intervall ta 'kunfidenza 82- 89%).
Greater effects may be expected when fluticasone propionate is inhaled.
Effetti akbar huma mistennija meta fluticasone propionate jittieħed min- nifs.
Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate; this could also occur with other corticosteroids metabolised via the P450 3A pathway eg budesonide.
Effetti sistematiċi ta 'corticosteroid li jinkludu s- sindromu ta' Cushing u t- trażżin adrenali ġew rapportati f' pazjenti li qed jirċievu ritonavir u ħadu fluticasone propionate bin- nifs jew b' mod intranażali; dan jista 'jseħħ ukoll b' corticosteroids oħrajn metabolizzati permezz tal- passaġġ P450 3A eż. budesonide.
Consequently, concomitant administration of tipranavir, co-administered with low dose ritonavir, and these glucocorticoids is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects (see section 4.4).
Konsegwentement, l- użu konġunt ta 'tipranavir, mogħti flimkien ma' doża baxxa ta 'ritonavir, u dawn il- glucocorticoids mhux rakkomandat għajr meta s- siwi potenzjali tat- trattament jisboq ir- riskju ta' effetti sistematiċi ta 'corticosteroid (ara sezzjoni 4. 4).
A dose reduction of the glucocorticoid should be considered with close monitoring of local and systemic effects or a switch to a glucocorticoid, which is not a substrate for CYP3A4 (e. g. beclomethasone).
Għandu jiġi kkonsidrat tnaqqis fid- doża tal- glucocorticoid b' monitoraġġ mill- qrib ta 'effetti lokali u sistematiċi jew bidla għal glucocorticoid, li mhux sustrat għal CYP3A4 (e. g. beclomethasone).
Moreover, in case of withdrawal of glucocorticoids progressive dose reduction may have to be performed over a longer period.
Barra minn hekk, fil- każ li glucocorticoids jiġu revokati, it- tnaqqis fid- doża għandu mnejn irid isir fuq perijodu itwal.
The effects of high fluticasone systemic exposure on ritonavir plasma levels are as yet unknown.
L- effetti ta 'l- espożizzjoni sistematika għolja għal fluticasone fuq livelli ta' ritonavir fil- plażma għadhom mhumiex magħrufa.
There are no adequate data from the use of APTIVUS in pregnant women.
M’ hemmx tagħrif biżżejjed dwar l- użu ta ’ APTIVUS waqt it- tqala.
Tipranavir should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
Fit- tqala, tipranavir għandu jintuża biss jekk is- siwi potenzjali tiegħu jisboq ir- riskju potenzjali għall- fetu.
APTIVUS adversely interacts with oral contraceptives.
Hemm reazzjonijiet avversi bejn APTIVUS u kontraċettivi orali.
Therefore, an alternative, effective, safe method of contraception should be used during treatment.
Għaldaqstant, waqt il- kura, għandha tittieħed miżura ta ’ kontraċezzjoni alternattiva li tkun sikura u effettiva.
Consistent with the recommendation that HIV-infected mothers should not breast-feed their infants under any circumstances to avoid risking postnatal transmission of HIV, mothers should discontinue breast-feeding if they are receiving APTIVUS.
B' mod konsistenti mar- rakkomandazzjoni li ommijiet infettati bl- HIV m’ għandhomx ireddgħu lit- trabi tagħhom taħt l- ebda ċirkostanza biex jevitaw ir- riskju tat- tixrid ta ’ l- HIV wara t- tqala, l- ommijiet għandhom iwaqqfu l- irdigħ jekk qed jieħdu APTIVUS.
Patients should be informed that APTIVUS soft capsules contain small amounts of alcohol (7% ethanol, ie 100 mg per capsule or 200 mg per dose).
Il- pazjenti għandhom jiġu informati li l- kapsuli rotob ta 'APTIVUS fihom ammonti żgħar ta' alkoħol (7% ethanol, ie 100 mg kull kapsula jew 200 mg għal kull doża).
APTIVUS co-administered with low dose ritonavir, has been associated with reports of significant liver toxicity.
APTIVUS mogħti flimkien ma ’ doża baxxa ta ’ ritonavir, ġie assoċjat ma rapporti ta 'tossiċità sinifikanti tal- fwied.
In Phase III RESIST trials, the frequency of transaminase elevations was significantly increased in the APTIVUS/ ritonavir arm compared to the comparator arm.
Fil- provi RESIST ta 'Fażi III, il- frekwenza ta' żidiet fit- transaminase kibret b' mod sinifikanti fil- każ ta ’ APTIVUS/ ritonavir meta mqabbel mal- komparatur.
Close monitoring is therefore needed in patients treated with APTIVUS, co-administered with low dose ritonavir (see section 4.4).
Monitoraġġ mill- qrib hu għalhekk meħtieġ f' pazjenti trattati b' APTIVUS, mogħti flimkien ma ’ doża baxxa ta ’ ritonavir (ara sezzjoni 4. 4).
Limited data are currently available for the use of APTIVUS, co-administered with low dose ritonavir, in patients co-infected with hepatitis B or C.
Attwalment, hemm biss ċifri ristretti dwar l- użu ta 'APTIVUS, mogħti flimkien ma ’ doża baxxa ta ’ ritonavir, f' pazjenti ko- infettati b' epatite B jew Ċ.
APTIVUS should therefore be used with caution in patients co-infected with hepatitis B or C.
Għalhekk APTIVUS għandu jintuża b' kawtela f' pazjenti li huma ko- infettati b' epatite B jew Ċ.
Tipranavir, co-administered with low dose ritonavir has been studied in a total of 6308 HIV-positive adults as combination therapy in clinical studies, including compassionate use studies.
L- użu ta ’ tipranavir mogħti flimkien ma ’ doża baxxa ta ’ ritonavir kien studjat f’ total ta ’ 6308 pazjenti adulti li rriżultaw pożittivi għal HIV, f’ terapija kombinata, waqt studji kliniċi, li jinkludu studju ta ’ użu kompassjonali.
Of these 5219 patients received the dose of 500 mg/ 200 mg twice daily.
Minn dawn, 5219- il pazjent ngħataw dożi fissi ta ’ 500 mg/ 200 mg darbtejn kuljum.
909 adults in clinical trials, including 541 in
909 adulti, fi provi kliniċi li jinkludu 541 fil- provi ewlenin RESIST- 1 u RESIST- 2 ta 'Fażi III ġew trattati b’ 500 mg/ 200 mg darbtejn kuljum għal mill- anqas 48 ġimgħa.
14 the RESIST-1 and RESIST-2 Phase III pivotal trials, have been treated with 500 mg/ 200 mg twice daily for at least 48 weeks.
Il- karatteristiċi ta 'sigurtà klinika li ġejjin (epatotossiċità, iperlipidemija, każijiet ta' fsada, raxx) dehru fi frekwenza ogħla fost pazjenti trattati b' APTIVUS/ ritonavir meta mqabbla mal- komparatur ta '
The following clinical safety features (hepatotoxicity, hyperlipidaemia, bleeding events, rash) were seen at higher frequency among APTIVUS/ ritonavir treated patients when compared with the comparator arm treated patients in the RESIST trials, or have been observed with APTIVUS/ ritonavir administration.
14 pazjenti fil- provi ta 'RESIST, jew li ġew osservati bl- għoti b' APTIVUS/ ritonavir.
The clinical significance of these observations has not been fully explored.
It- tifsira klinika ta 'dawn l- osservazzjonijiet għadha ma ġietx mistħarrġa sew.
Hepatotoxicity:
Epatotossiċità:
After 48 weeks of follow-up, the frequency of Grade 3 or 4 ALAT and/ or ASAT abnormalities was higher in APTIVUS/ ritonavir patients compared with comparator arm patients (10% and 3.4%, respectively).
Wara 48 ġimgħa ta 'segwitu, il- frekwenza ta' abnormalitajiet ALAT u/ jew ASAT ta 'Grad 3 jew 4 kienet ogħla f' pazjenti fuq APTIVUS/ ritonavir meta mqabbla ma' pazjenti bil- komparatur (10% u 3. 4%, rispettivament).
Multivariate analyses showed that baseline ALAT or ASAT above DAIDS Grade 1 and co-infection with hepatitis B or C were risk factors for these elevations.
Analiżi multivarjati wrew li l- livell bażi ta 'riferiment ta' ALAT jew ASAT 'il fuq minn Grad 1 ta' DAIDS u ko- infezzjoni b' epatite B jew Ċ kienu fatturi ta 'predispożizzjoni għal dawn iż- żidiet.
Most patients were able to continue treatment with APTIVUS/ ritonavir.
Il- biċċa l- kbira tal- pazjenti setgħu jissoktaw bit- trattament b 'APTIVUS/ ritonavir.
Hyperlipidaemia:
Iperlipidemija:
Grade 3 or 4 elevations of triglycerides occurred more frequently in the APTIVUS/ ritonavir arm compared with the comparator arm.
Żidiet ta 'grad 3 jew 4 tat- triglycerides seħħew aktar ta' spiss bl- użu ta ’ APTIVUS/ ritonavir meta mqabbla ma ’ l- użu tal- komparatur.
At 48 weeks these rates were 25.2% of patients in the APTIVUS/ ritonavir arm and 15.6% in the comparator arm.
Fi- 48 ġimgħa dawn ir- rati kienu ta '25. 2% f' pazjenti fuq APTIVUS/ ritonavir u 15. 6% fil- każ tal- komparatur.
RESIST participants receiving APTIVUS/ ritonavir tended to have an increased risk of bleeding; at 24 weeks the relative risk was 1.98 (95% CI=1.03, 3.80).
Parteċipanti fl- istudju RESIST li kienu qed jirċievu APTIVUS/ ritonavir intwerew li jinsabu f' riskju akbar ta 'fsada; wara 24 ġimgħa r- riskju relattiv kien ta' 1. 98 (95% CI=1. 03, 3. 80).
At 48-weeks the relative risk decreased to 1.27 (95% CI=0.76, 2.12).
Mat- 48 ġimgħa r- riskju relattiv tnaqqas għal 1. 27 (95% CI=0. 76, 2. 12).
There was no pattern for the bleeding events and no difference between treatment groups in coagulation parameters.
Ma kienx hemm skema ta 'każijiet ta' fsada u ma kienx hemmx differenza bejn gruppi ta 'trattament f' parametri ta' koagulazzjoni.
Fatal and non-fatal intracranial haemorrhage (ICH) have been reported in patients receiving APTIVUS, many of whom had other medical conditions or were receiving concomitant medicinal products that may have caused or contributed to these events.
Emorraġiji intrakranjali fatali u mhux fatali (ICH) ġew rapportati f' pazjenti li qed jieħdu APTIVUS, li ħafna minnhom kellhom kundizzjonijiet mediċi oħra jew kienu qed jieħdu prodotti mediċinali flimkien ma 'dawn li setgħu rriżultaw jew ikkontribwixxu għal dawn l- każijiet.
No pattern of abnormal haematological or coagulation parameters has been observed in patients in general, or preceding the development of ICH.
L- ebda skema ta 'parametri ematoloġiċi anormali jew tal - koagulazzjoni ma ġiet osservata b' mod ġenerali fil- pazjenti jew qabel l- iżvilupp ta' ICH.
An increased risk of ICH has previously been observed in patients with advanced HIV disease/ AIDS such as those treated in the APTIVUS clinical trials.
Riskju ogħla ta 'ICH kien osservat qabel f' pazjenti li għandhom HIV/ AIDS bħal dawk trattati fil- provi kliniċi ta' APTIVUS.
An interaction study in women between APTIVUS, co-administered with low dose ritonavir, and ethinyl oestradiol/ norethindrone demonstrated a high frequency of non-serious rash.
Studju dwar l- interazzjoni fin- nisa bejn APTIVUS, mogħti flimkien ma ’ doża baxxa ta 'ritonavir, u ethinyl oestradiol/ norethindrone wera frekwenza għolja ta' raxx mhux serju.
In the RESIST trials, the risk of rash was similar between APTIVUS/ ritonavir and comparator arms (16.3% vs.
Fil- provi ta 'RESIST, ir- riskju ta' raxx kien simili bejn APTIVUS/ ritonavir u l- komparaturi (16. 3% vs.
12.5%, respectively; see section 4.4).
12. 5% rispettivament; ara sezzjoni 4. 4).
No cases of Stevens-Johnson Syndrome or Toxic Epidermal Necrolysis have been reported in the clinical development programme of APTIVUS.
Ma kien ebda każijiet irraportati tas- Sindromu ta 'Stevens- Johnson jew in- Nekrolisi Epidermali Tossika fil- programm ta' żvilupp kliniku ta 'APTIVUS.
The most frequent adverse reactions of any intensity (Grades 1-4) reported in the Phase III clinical studies in the APTIVUS/ ritonavir arms (n=749) are listed below by system organ class and frequency according to the following categories:
L- aktar effetti avversi ta ’ kull qawwa (Gradi 1- 4), li ġew rapportati waqt il- Fażi III ta ’ l- istudji kliniċi, fil- grupp trattatt permezz ta ’ APTIVUS/ ritonavir (n=749) huma elenkati hawn taħt skond l- organi li jeffettwaw u l- frekwenza:
Very common (≥ 1/ 10), common (≥ 1/ 100 to < 1/ 10)
Komuni ħafna (≥1/ 10), komuni (≥ 1/ 100 sa < 1/ 10)
Common: headache.
Komuni: uġigħ ta 'ras.
Very common: diarrhoea, nausea.
Komuni ħafna: dijarrea, nawsea.
Common: vomiting, flatulence, abdominal distension, abdominal pain, loose stools, dyspepsia.
Komuni: remettar, gass, infieħ ta ’ l- addome, uġigħ addominali, ippurgar merħi, dispepsja.
Skin and subcutaneous tissue disorders:
Disturbi tal- ġilda u tat- tessuti ta ’ taħt il- ġilda Komuni: raxx, prurite.
Common: rash, pruritus.
Komuni: ipertrigliċeridemija, iperlipidemija, anoreksja.
15 Metabolism and nutrition disorders:
15 Komuni: għeja
Clinically meaningful adverse reactions of moderate to severe intensity occurring in less than 1% (< 1/ 100) of adult patients in all Phase II and III trials treated with the 500 mg/ 200 mg tipranavir/ ritonavir dose (n=1397) are listed below by system organ class and frequency according to the following categories:
Reazzjonijiet avversi kliniċi notevoli ta 'intensità minn moderata sa gravi seħħew f' inqas minn 1% (< 1/ 100) tal- pazjenti adulti fil- provi kollha ta' Fażi II u III trattati bid- doża ta '500 mg/ 200 mg tipranavir/ ritonavir (n=1397), huma hawn isfel elenkati skond il- klassi tas- sistema ta' l- organi u l- frekwenza skond il- kategoriji li ġejjin:
Uncommon (≥ 1/ 1,000 to < 1/ 100), rare (≥ 1/ 10,000 to < 1/ 1,000)
Mhux komuni (≥ 1/ 1, 000 sa < 1/ 100), rari (≥1/ 10, 000 sa < 1/ 1, 000)
Uncommon: hepatic enzymes increased (ALAT, ASAT), lipase increased, liver function test abnormal (ALAT, ASAT), weight decreased.
Enżimi epatiċi mgħollija (ALAT, ASAT), lipase mgħolli, test tal- funzjoni tal- fwied abnormali (ALAT, ASAT), piż imnaqqas.
Uncommon: anaemia, neutropenia, thrombocytopenia.
Disturbi tad- demm u tas- sistema limfatika Mhux komuni: anemija, newtropenija, tromboċitopenija.
Uncommon: dizziness, neuropathy peripheral, somnolence.
Mhux komuni: sturdament, newropatija periferika, ngħas
Uncommon: dyspnoea.
Mhux komuni: dispnea.
Uncommon: gastrooesophageal reflux disease, pancreatitis.
Mhux komuni: mard ta 'rifluss gastroesofagali, pankreatite.
Renal and urinary disorders:
Disturbi tal- kliewi u tas- sistema urinarja:
Uncommon: renal insufficiency.
Mhux komuni: insuffiċjenza tal- kliewi.
Skin and subcutaneous tissue disorders:
Disturbi tal- ġilda u tat- tessuti ta ’ taħt il- ġilda:
Uncommon: exanthem, lipoatrophy, lipodystrophy acquired, lipohypertrophy.
Mhux komuni: eksantema, lipoatrofija, lipodistrofija miksuba, lipoipertrofija.
Musculoskeletal and connective tissue disorders:
Disturbi muskolo- skeletali u tat- tessut konnettiv:
Uncommon: muscle cramp, myalgia.
Mhux komuni: bugħawwieġ, milaġja.
Metabolism and nutrition disorders:
Disturbi tal- metaboliżmu u n- nutrizzjoni:
Uncommon: decreased appetite, diabetes mellitus, hyperamylasaemia, hypercholesterolaemia.
Mhux komuni: tnaqqis fl- aptit, diabetes mellitus, iperamilasemija, iperkolesterolemija.
Rare: dehydration, facial wasting, hyperglycaemia.
Rari: diżidrattazzjoni, telqien tal- muskoli tal- wiċċ, iperglicemija.
Uncommon: influenza like illness, malaise, pyrexia.
Mhux komuni: mard li jixbaħ l- influwenza, tħossok ma tiflaħx, deni.
Uncommon: hypersensitivity.
Mhux komuni: sensittività eċċessiva.
Hepatobiliary disorders:
Disturbi tal- fwied u tal- marrara:
Uncommon: cytolytic hepatitis, hepatic steatosis, hepatitis, toxic hepatitis.
Mhux komuni: epatite ċitolitika, steatosi epatika, epatite, epatite tossika.
Rare: hepatic failure (including fatal outcome), hyperbilirubinaemia.
Rari: insuffiċjenza tal- fwied (li tista ’ tikkaġuna l- mewt), iperbilirubinemija.
Uncommon: insomnia, sleep disorder.
Mhux komuni: nuqqas ta 'rqad, disturb fl- irqad.
Laboratory abnormalities
Abnormalitajiet tal- laboratorju
16 Frequencies of marked clinical laboratory abnormalities (Grade 3 or 4) reported in at least 2% of patients in the APTIVUS/ ritonavir arms in the phase III clinical studies (RESIST-1 and RESIST-2) after 48-weeks were increased ASAT (6.1%), increased ALAT (9.7%), increased amylase (6.0%), increased cholesterol (4.2%), increased triglycerides (24.9%), and decreased white blood cell count (5.7%).
Il- frekwenżi ta ’ riżultati abnormali tal- laboratorju li spikkaw (Grad 3 jew 4) ġew rapportati f ’ mill- anqas 2% tal- pazjenti fuq APTIVUS/ ritonavir li ħadu sehem fl- istudji kliniċi (RESIST- 1 u RESIST- 2) tal- Fażi III wara 48 ġimgħa wrew żjieda fl- ASAT (6. 1%), żjieda fl- ALAT (9. 7%), żjieda
Combination antiretroviral therapy, including regimens containing a protease inhibitor, is associated with redistribution of body fat in some patients, including loss of peripheral subcutaneous fat, increased intra-abdominal fat, breast hypertrophy and dorsocervical fat accumulation (buffalo hump).
It- terapija kombinata antiretrovirali, li tinkludi korsijiet li fihom impeditur tal- protease, hi assoċjata mad- distribuzzjoni mill- ġdid tax- xaħam f’ xi pazjenti li jinkludi t- telf ta ’ xaham subkutanju periferiku, żjieda fix- xaħam intra- addominali, ipertropija tas- sider u akkumulazzjoni ta ’ xaħam dorsoċervikali (ħotba tal- buflu).
Protease inhibitors are also associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance and hyperglycaemia.
L- impedituri ta ’ l- enżimi protease huma assoċjati wkoll ma ’ abnormaliajiet metaboliċi bħal ipertrigliċeridemija, iperkolesterolemija, reżistenza għall- insulina u ipergliċemija.
Increased CPK, myalgia, myositis and, rarely, rhabdomyolysis, have been reported with protease inhibitors, particularly in combination with nucleoside reverse transcriptase inhibitors.
Żjieda fis- CPK, majalġja, mijosite, u rarament, rabdomajoliżi, kienu ġew rapportati ma ’ l- użu ta ’ impedituri ta ’ l- enżima protease, b' mod partikolari meta ntużaw flimkien ma ’ impedituri ta ’ l- enżima reverse transcriptase.
In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise (see section 4.4).
Meta tinbeda t- terapija kombinanti antiretrovirali (CART), pazjenti infettati bl- HIV li għandhom sistema immunitarja batuta ħafna, jistgħu jiżviluppaw reazzjoni inflammatorja minħabba infezzjoni bla sintomi, jew minħabba li jkun hemm mikrobi opportunistiċi li jikkaġunaw infezzjoni (ara sezzjoni 4. 4).
Reactivation of herpes simplex and herpes zoster virus infections were observed in the RESIST trials.
Ġie osservat li kien hemm riattivazzjoni tal- virus ta ’ herpes simplex u herpes zoster fil- provi RESIST.
Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART).
Kienu rrapportati każijiet ta 'osteonekrosi, partikolarment f' pazjenti li ġeneralment għandhom fatturi ta' predispożizzjoni magħrufa, li huma morda b’ HIV avvanzat jew li kellhom espożizzjoni fuq tul ta 'żmien għat- terapija antiretrovirali kombinata (CART).
The frequency of this is unknown (see section 4.4).
Il- frekwenza ta 'din mhix magħrufa (ara sezzjoni 4. 4).
There is no known antidote for APTIVUS overdose.
M’ hemmx antidotu magħruf għal doża eċċesiva ta ’ APTIVUS.
Treatment of overdose should consist of general supportive measures, including monitoring of vital signs and observation of the patient ’ s clinical status.
It- trattament ta ’ doża eċċessiva għandu jikkonsisti f’ miżuri ġenerali ta ’ sostenn, li jinkludu l- monitoraġġ ta 'sinjali vitali kif ukoll ta ’ l- istat kliniku tal- pazjent.
If indicated, elimination of unabsorbed tipranavir should be achieved by emesis or gastric lavage.
Jekk ikun indikat, l- eliminazzjoni tat- tipranavir li ma jkunx assorbit, tista ’ tkun miksuba permezz ta ’ emeżi jew b’ ħasil ta ’ l- istonku.
Administration of activated charcoal may also be used to aid in removal of unabsorbed drug.
Jista ’ jintuża ukoll faħam attivat biex jgħin fit- tneħħija tal- mediċina mhux assorbita.
Since tipranavir is highly protein bound, dialysis is unlikely to be beneficial in significant removal of this medicine.
X’ aktarx li d- dijaliżi ma tkunx ta ’ għajnuna minħabba li tipranavir jeħel b’ mod qawwi mal- proteini.
Pharmacotherapeutic group: protease inhibitor, ATC code:
Impeditur tal- enżima protease, Kodiċi ATC:
J05AE09
J05A- E09
Mechanism of action:
Mod ta ’ kif jaħdem:
The human immunodeficiency virus (HIV-1) encodes an aspartyl protease that is essential for the cleavage and maturation of viral protein precursors.
Il- virus ta ’ l- immunodefiċjenza umana (HIV- 1) jikkodifika enżima aspartyl protease li hi essenzjali biex il- prekursuri tal- proteina virali jinqasmu u jimmaturaw.
Tipranavir is a non-peptidic inhibitor of the HIV-1 protease that inhibits viral replication by preventing the maturation of viral particles.
Tipranavir huwa impeditur ta ’ l- enżima HIV- 1 protease, mhux peptidiku, li jimpedixxi r- replikazzjoni tal- virus billi ma ’ jħallix il- partiċelli virali jimmaturaw.
Antiviral activity in vitro:
Attività anti- virali in vitro:
Tipranavir inhibits the replication of laboratory strains of HIV-1 and clinical isolates in acute models of T-cell infection, with 50% and 90% effective concentrations (EC50 and EC90) ranging from 0.03 to 0.07 µM (18-42 ng/ ml) and 0.07 to 0.18 µM (42-108 ng/ ml), respectively.
Tipranavir jimpedixxi r- replikazzjoni ta ’ razez tal- laboratorju ta ’ HIV- 1 u ta ’ kampjuni kliniċi elevati, waqt studji fuq mudelli ta ’ infezzjoni akuta taċ- ċelluli- T, b' valuri ta 50% u 90% ta ’ konċentrazzjonijiet effettivi (EC50 u EC90) fuq firxa bejn 0. 03 sa 0. 07 µM (18- 42 ng/ ml) u 0. 07 sa 0. 18 µM (42- 108 ng/ ml), rispettivment.
Tipranavir demonstrates antiviral activity in vitro against a broad panel of HIV-1 group M non-clade B isolates (A, C, D, F, G, H, CRF01 AE, CRF02 AG, CRF12 BF).
Tipranavir juri attività antivirali in vitro kontra firxa wiesa ’ ta 'HIV- 1 group M non- clade B isolates (A, C, D, F, G, H, CRF01 AE, CRF02 AG, CRF12 BF).
Group O and HIV-2 isolates have reduced susceptibility in vitro to tipranavir with EC50 values ranging from 0.164-1 µM and 0.233- 0.522 µM, respectively.
Grupp O u kampjuni iżolati ta 'HIV- 2 għandhom suxxettibilità mnaqqsa in vitro għal tipranavir b' valuri ta' EC50 li jvarjaw minn 0. 164- 1 µM u 0. 233- 0. 522 µM, rispettivament.
Protein binding studies have shown that the antiviral activity of tipranavir decreases on average 3.75-fold in conditions where human serum is present.
Studji fuq kif jeħel mal- proteini wera li l- attività antiretrovirali ta ’ tipranavir, tonqos b’ medja ta ’ 3. 75 darbiet meta jkun hemm serum uman.
The development of resistance to tipranavir in vitro is slow and complex.
L- iżvilupp ta ’ reżistenza kontra tipranavir in vitro iseħħ bil- mod u huwa kumpless.
L10F, I13V, V32I, L33F, M36I, K45I,
F’ esperiment partikolari li sar in vitro dwar ir- reżistenza, kampjun ta ’ HIV- 1 li kien reżistenti b’ 87
17 I54V/ T, A71V, V82L, I84V as well as a mutation in the gag polyprotein CA/ P2 cleavage site.
L10F, I13V, V32I, L33F, M36I, K45I, I54V/ T, A71V, V82L, I84V kif ukoll, mutazzjoni oħra fiż- żona ta ’ fejn tinqasam il- proteina magħrufa bħala gag polyprotein CA/ P2.
Reverse genetic experiments showed that the presence of 6 mutations in the protease (I13V, V32I, L33F, K45I, V82L, I84V) was required to confer > 10-fold resistance to tipranavir while the full 10-mutation genotype conferred 69-fold resistance to tipranavir.
Esperimenti ġenetiċi riversi wrew li l- preżenza ta ’ 6 mutazzjonijiet fil- protease (I13V, V32I, L33F, K45I, V82L, I84V) kienet meħtieġa biex tkun aktar minn 10 darbiet reżistenti għal tipranavir, filwaqt li meta jkun hemm ġenotip mimli bl- 10 mutazzjonijiet, ikun hemm reżistenza ta ’ 69 darba.
In vitro, there is an inverse correlation between the degree of resistance to tipranavir and the capacity of viruses to replicate.
In vitro, hemm korrelazzjoni inversa bejn il- qawwa tar- reżistenza kontra tipranavir u l- kapaċità tal- virus biex jirreplika.
Recombinant viruses showing ≥ 3-fold resistance to tipranavir grow at less than 1% of the rate detected for wild type HIV-1 in the same conditions.
Virusis rikombinanti li wrew ≥ 3 darbiet reżistenza għal tipranavir jikbru b’ inqas minn 1% tar- rata li jikbru biha HIV- 1 ta ’ tip selvaġġ fl- istess kundizzjonijiet.
Tipranavir resistant viruses which emerge in vitro from wild-type HIV-1 show decreased susceptibility to the protease inhibitors amprenavir, atazanavir, indinavir, lopinavir, nelfinavir and ritonavir but remain sensitive to saquinavir.
Viruses reżistenti għal tipranavir li joħorġu in vitro minn HIV- 1 ta ’ tip selvaġġ juru tnaqqis fis- suxxetibilità għall- impedituri ta 'l- enżima protease amprenavir, atazanavir, indinavir, lopinavir, nelfinavir u ritonavir imma jibqgħu sensittivi għal saquinavir.
Through a series of multiple stepwise regression analyses of baseline and on-treatment genotypes from all clinical studies, 16 amino acids have been associated with reduced tipranavir susceptibility and/ or reduced 48-week viral load response:
Permezz ta ’ serje ta ’ analiżi rigressivi fi stadji multipli tal- linja ta ’ referenza bażi u tal- ġenotipi li kienu ttrattati waqt l- istudji kliniċi, 16- il aċidu amminiku nstabu li kienu assoċjati ma ’ tnaqqis fis- suxxettibblità għal tipranavir u/ jew tnaqqis ta ’ 48 ġimgħa fl- għadd ta ’ viruses:
10V, 13V, 20M/ R/ V, 33F, 35G, 36I, 43T, 46L, 47V, 54A/ M/ V, 58E, 69K, 74P, 82L/ T, 83D and 84V.
10V, 13V, 20M/ R/ V, 33F, 35G, 36I, 43T, 46L, 47V, 54A/ M/ V, 58E, 69K, 74P, 82L/ T, 83D u 84V.
Clinical isolates that exhibited a ≥ 10-fold decrease in tipranavir susceptibility harboured eight or more tipranavir-associated mutations.
Il- kampjuni iżolati kliniċi li wrew tnaqqis ta '≥10 darbiet fis- suxxetabilità ta' tipranavir kellhom tmien mutazzjonijiet jew aktar assoċjati ma 'tipranavir.
In Phase II and III clinical trials, 276 patients with on-treatment genotypes have demonstrated that the predominant emerging mutations with APTIVUS treatment are L33F/ I/ V, V82T/ L and I84V.
Fil- provi kliniċi ta 'Fażi II u III, 276 pazjent b' ġenotipi ta' trattament urew li l- mutazzjonijiet emerġenti predominanti bit- trattament ta 'APTIVUS kienu L33F/ I/ V, V82T/ L and I84V.
Combination of all three of these is usually required for reduced susceptibility.
Il- kombinazzjoni tat- tlieta li huma hija ġeneralment meħtieġa għal tnaqqis fis- suxxetabilità.
Mutations at position 82 occur via two pathways: one from pre-existing mutation 82A selecting to 82T, the other from wild type 82V selecting to 82L.
Mutazzjonijiet f’ pożizzjoni 82 jiżvillupaw permezz ta ’ żewġ modi: waħda minn mutazzjoni eżistenti 82A għal 82T, u l- oħra mit- tip selvaġġ 82V għal 82L.
Cross-resistance:
Reżistenza inkroċjata:
Tipranavir maintains significant antiviral activity (< 4-fold resistance) against the majority of HIV-1 clinical isolates showing post-treatment decreased susceptibility to the currently approved protease inhibitors: amprenavir, atazanavir, indinavir, lopinavir, ritonavir, nelfinavir and saquinavir.
Tipranavir iżomm attività ta ’ kontra l- vajrus sinifikanti (reżistenza < 4 darbiet aktar) kontra l- maġġoranza tal- kampjuni kliniċi ta ’ HIV- 1 li juru tnaqqis fis- suxxettibblità ta ’ wara t- trattament għal impedituri protease li huma approvati attwalment: amprenavir, atazanavir, indinavir, lopinavir, ritonavir, nelfinavir u saquinavir.
Greater than 10-fold resistance to tipranavir is uncommon (< 2.5% of tested isolates) in viruses obtained from highly treatment experienced patients who have received multiple peptidic protease inhibitors.
Mhux komuni li jkun hemm aktar minn 10 darbiet reżistenza għal tipranavir (< 2. 5% tal- kampjuni ttestjati) ġo viruses meħuda minn pazjenti b’ esperjenza ta ’ ħafna terapiji li ngħataw aktar minn tip wieħed ta ’ impeditur tal - peptide protease.
Clinical pharmacodynamic data:
Dejta farmakodinamika klinikali:
The following clinical data is derived from analyses of 48-week data from ongoing studies (RESIST-1 and RESIST-2) measuring effects on plasma HIV RNA levels and CD4 cell counts.
Id- dejta li ġejja hija meħuda minn analiżi ta ’ tagħrif ta ’ 48 ġimgħa minn studji li għadhom għaddejjin (RESIST- 1 u RESIST- 2) dwar il- livelli ta ’ RNA ta ’ l- HIV fil- plażma kif ukoll fl- għadd ta ’ ċelluli CD4.
RESIST-1 and RESIST-2 are ongoing, randomised, open-label, multicentre studies in HIV-positive, triple-class experienced patients, evaluating treatment with APTIVUS co-administered with low dose ritonavir (500 mg/ 200 mg twice daily) plus an optimised background regimen (OBR) individually defined for each patient based on genotypic resistance testing and patient history.
Il- provi RESIST- 1 u RESIST- 2 li għadhom għadejjin, huma mingħajr ordni partikolari, bit- tikketta- miftuħa, multi- ċentrali u qed isiru fuq pazjenti li rriżultaw pożittivi għal HIV u b’ esperjenza ta ’ klassi- tripla, u dawn qed jivvalutaw it- trattament b’ APTIVUS mogħti flimkien ma ’ ritonavir b’ doża baxxa, (500 mg/ 200 mg darbtejn kuljum), kif ukoll trattament sekondarju ottimizzat (OBR) li huwa speċifiku għall- pazjent u bbażat skond ir- riżultati tat- testijiet dwar ir- reżistenza ġenotipika kif ukoll skond l- istorja medika tal- pazjent.
The comparator regimen included a ritonavir-boosted PI (also individually defined) plus an OBR.
Il- kors ta ’ trattament komparattiv jinkludi ritonavir mqawwi b’ PI (li jkun wkoll skond l- individwu) flimkien ma 'OBR.
The ritonavir-boosted PI was chosen from among saquinavir, amprenavir, indinavir or lopinavir/ ritonavir.
Ir- ritonavir mqawwi b' PI kien magħżul minn fost saquinavir, amprenavir, indinavir jew lopinavir/ ritonavir.