qanastek/EMEA-V3 huggingface dataset:
The mean AUC over a dosing interval of 12 hours is 18.46 µg. h/ ml (3.02- 32.95).
Il- valur intermedju tal - AUC fuq perjodu ta ’ 12- il siegħa huwa ta ’ 18. 46 µg. h/ ml (3. 02- 32. 95).
The 50 mg and 150 mg capsules have been shown to be bioequivalent.
Instab li l- kapsuli tal- 50 mg u dawk tal- 150 mg huma bijoekwivalenti.
The bioavailability of the oral solution at equivalent doses is lower than that of the capsules, with an AUC and Cmax approximately 14% and 19% lower, respectively (see section 4.2).
Fil- fatt l- AUC u Cmax huma madwar 14% u 19% anqas rispettivament (ara 4. 2).
The AUC and Cmin of amprenavir were increased by 64% and 508% respectively and the Cmax decreased by 30% when ritonavir (100 mg twice daily) was coadministered with amprenavir (600 mg twice daily) compared to values achieved after 1200 mg twice daily doses of amprenavir.
Dan meta pparagunat ma ’ livelli milħuqa wara doża ta ’ 1200 mg ta ’ amprenavir darbtejn kuljum.
While administration of amprenavir with food results in a 25% reduction in AUC, it had no effect on the concentration of amprenavir 12 hours after dosing (C12).
Filwaqt li meta amprenavir jingħata ma ’ l- ikel jkun hemm tnaqqis ta ’ 25% fl- AUC, ma jkun hemm l - ebda effett fuq il- konċentrazzjoni ta ’ amprenavir wara 12- il siegħa minn xħin tkun ingħatat id- doża (C12).
Therefore, although food affects the extent and rate of absorption, the steady-state trough concentration (Cmin, ss) was not affected by food intake.
Għalkemm l- ikel itellef l- ammont u r- rata ta ’ assorbiment, ma kien hemm l- ebda effett fuq l - konċentrazzjoni fi stat stabbli fl- iżjed punt baxx (Cmin, ss) meta ġie meħud l- ikel.
Distribution: the apparent volume of distribution is approximately 430 litres (6 l/ kg assuming a 70 kg body weight), suggesting a large volume of distribution, with penetration of amprenavir freely into tissues beyond the systemic circulation.
Dan il- valur jissuġġerixxi li l- volum ta ’ distribuzzjoni huwa akbar, b’ amprenavir jinfirex fit- tessuti tal- ġisem lil hinn sewwa miċ- cirkolazzjoni ġenerali.
The concentration of amprenavir in the cerebrospinal fluid is less than 1% of plasma concentration.
Il - konċentrazzjoni ta ’ amprenavir fil- fluwidu ċerebrospinali hija inqas minn 1% ta ’ dik fil- plażma.
In in vitro studies, the protein binding of amprenavir is approximately 90%.
Fi studji in vitro, il- kwantità ta ’ amprenavir li teħel mal- proteini tad- demm hija ta ’ madwar 90%.
Amprenavir is primarily bound to the alpha-1-acid glycoprotein (AAG), but also to albumin.
Amprenavir huwa l- biċċa l- kbira mwaħħal ma ’ alpha- 1- acid glycoprotein (AAG), iżda xi ftit minnu jeħel ukoll ma ’ l- albumina.
Concentrations of AAG have been shown to decrease during the course of antiretroviral therapy.
Ġie muri li l- konċentrazzjoni ta ’ l- AAG naqset waqt kura bil- mediċini antiretrovirali.
This change will decrease the total active substance concentration in the plasma, however the amount of unbound amprenavir, which is the active moiety, is likely to be unchanged.
Dan iċ- ċaqliq iġib miegħu tnaqqis fil- konċentrazzjoni totali fil- plażma tas- sustanza attiva, iżda x’ aktarx li l- kwantità ta ’ amprenavir mhux imwaħħal, li huwa l- forma attiva, ma tinbidilx.
While absolute free active substance concentrations remain constant, the percent of free active substance will fluctuate directly with total active substance concentrations at steady-state go from Cmax, ss to Cmin, ss over the course of the dosing interval.
Għalkemm il- konċentrazzjoni assoluta tas- sustanza attiva mhux imwaħħla tibqa kostanti, il- kwantità tas- sustanza attiva mhux imwaħħla tvarja skond kif tkun il- konċentrazzjoni totali tas- sustanza attiva fl - istat fiss u kif tinbidel mis- Cmax, ss sa Cmin, ss tul il- ħin li jgħaddi wara li tingħata d- doża.
This will result in a fluctuation in the apparent volume of distribution of total active substance, but the volume of distribution of free active substance does not change.
Dan iwassal sabiex ikun hemm ċaqliq fil- volum ta ’ distribuzzjoni apparenti tas- sustanza attiva kollha, iżda il - volum ta ’ distribuzzjoni tas- sustanza attiva mhux imwaħħla ma jinbidilx.
Clinically significant binding displacement interactions involving medicinal products primarily bound to AAG are generally not observed.
Ma ġewx osservati reazzjonijiet klinikament importanti ma ’ mediċini oħra li huma l- biċċa l- kbira mwaħħla ma ’ l- AAG u li jistgħu jikkawżaw problemi minħabba li xi mediċina tistà taqlà lill- oħra
Therefore, interactions with amprenavir due to protein binding displacement are highly unlikely.
Għalhekk ftit hemm probabbiltà li jseħħu reazzjonijiet mhux mixtieqa bejn amprenavir u mediċini oħra minħabba ċaqliq ta ’ wieħed lil ieħor minn fuq il- proteini tad- demm.
Metabolism: amprenavir is primarily metabolised by the liver with less than 3% excreted unchanged in the urine.
Metaboliżmu: amprenavir huwa l- biċċa l- kbira metabolizzat fil- fwied u l- ammont mhux metabolizzat li jispiċċa fl- awrina huwa ta ’ inqas minn 3%.
The primary route of metabolism is via the cytochrome P450 CYP3A4 enzyme.
Il- mod prinċipali ta ’ kif iseħħ dan il- metaboliżmu huwa permezz ta ’ l- enzima CYP3A4 taċ- ċitokromju P450.
Amprenavir is a substrate of and inhibits CYP3A4.
Amprenavir huwa substrat u inibitur ta ’ CYP3A4.
Therefore, medicinal products that are inducers, inhibitors or substrates of CYP3A4 must be used with caution when administered concurrently with Agenerase (see sections 4.3, 4.4 and 4.5).
Għalhekk mediċini li huma stimulanti, inibituri jew substrati ta ’ CYP3A4 għandhom jintużaw b’ attenzjoni kbira meta jingħataw flimkien ma ’ Agenerase (ara 4. 3, 4. 4, 4. 5).
Elimination: the plasma elimination half-life of amprenavir ranges from 7.1 to 10.6 hours.
Eliminazzjoni: il- half- life ta ’ l- eliminazzjoni ta ’ amprenavir mill- plażma tvarja bejn 7. 1 għal 10. 6 siegħat.
The plasma amprenavir half-life is increased when Agenerase capsules are co-administered with ritonavir.
Il- half- life ta ’ amprenavir fil- plażma tiżdied meta l- kapsuli ta ’ Agenerase jingħataw flimkien ma ’ ritonavir.
Following multiple oral doses of amprenavir (1200 mg twice a day), there is no significant active substance accumulation.
Wara li ngħataw aktar minn doża waħda ta ’ amprenavir permezz tal- ħalq (1200 mg darbtejn kuljum), ma kienx hemm akkumulazzjoni kbira tas- sustanza attiva.
The metabolites and unchanged amprenavir
Ir- rotta ta ’ mnejn jiġi eliminat mill- ġisem amprenavir huwa permezz ta ’ metaboliżmu fil- fwied u l- ammont mhux metabolizzat li jispiċċa fl- awrina huwa ta ’ inqas minn 3%.
18 account for approximately 14% of the administered amprenavir dose in the urine, and approximately 75% in the faeces.
Il- forom kollha li jirriżultaw wara l - metaboliżmu u l- amprenavir li jibqà mhux metabolizzat jagħmlu tajjeb għal madwar 14% tad- doża ta ’ amprenavir li tkun ingħatat u li tkun spiċċat fl- awrina, u għal madwar 75% fil- ħmieġ.
Special populations:
Każijiet speċjali:
Paediatrics: the pharmacokinetics of amprenavir in children (4 years of age and above) are similar to those in adults.
Użu fit- tfal: il- proprjetajiet farmakokinetiċi ta ’ amprenavir fit- tfal (minn erba ’ snin ‘ il fuq) jixbħu lil dawk fil- kbar.
Dosages of 20 mg/ kg twice a day and 15 mg/ kg three times a day with Agenerase capsules provided similar daily amprenavir exposure to 1200 mg twice a day in adults.
Dożi ta ’ 20 milligramma/ kg darbtejn kuljum u ta ’ 15 milligramma/ kg tliet darbiet kuljum ta ’ kapsuli ta ’ Agenerase kienu jixbħu ħafna d- doża ta ’ 1200 mg darbtejn kuljum fil- kbar għaliex jipprovdu bejn wieħed u ieħor l- istess livell ta ’ amprenavir.
Amprenavir is 14% less bioavailable from the oral solution than from the capsules; therefore, Agenerase capsules and Agenerase oral solution are not interchangeable on a milligram per milligram basis.
Għalhekk, il- kapsuli ta ’ Agenerase u s- soluzzjoni orali ta ’ Agenerase ma jistgħux jiġu mibdula ma ’ xulxin fuq bażi ta ’ milligramma għal milligramma.
Elderly: the pharmacokinetics of amprenavir have not been studied in patients over 65 years of age.
Użu fix- xjuħ: il- proprjetajiet farmakokinetiċi ta ’ amprenavir ma ’ ġewx studjati f’ pazjenti li l- età tagħhom hija minn 65 sena ‘ il fuq.
Renal impairment: patients with renal impairment have not been specifically studied.
Indeboliment tal- Kliewi: ma sarux studji partikulari fuq nies li għandhom ħsara fil- kliewi.
Less than 3% of the therapeutic dose of amprenavir is excreted unchanged in the urine.
Inqas minn 3% tad- doża effettiva ta ’ amprenavir tispiċċa fl- awrina mingħajr ma tinbidel.
The impact of renal impairment on amprenavir elimination should be minimal therefore, no initial dose adjustment is considered necessary.
L- impatt li tħalli ħsara fil- kliewi fuq l- eliminazzjoni ta ’ amprenavir għandu jkun mill- inqas u għalhekk ma jkunx hemm il - ħtieġa ta ’ xi ċaqliq fid- doża fil- bidu tal- kura.
Renal clearance of ritonavir is also negligible; therefore the impact of renal impairment on amprenavir and ritonavir elimination should be minimal.
L- ammont ta ’ kemm jitneħħa ritonavir permezz tal - kliewi huwa żgħir ħafna; għalhekk l- impatt li tħalli ħsara fil- kliewi fuq l- eliminazzjoni ta ’ amprenavir u ritonavir għandu jkun mill- inqas.
Hepatic impairment: the pharmacokinetics of amprenavir are significantly altered in patients with moderate to severe hepatic impairment.
Indeboliment tal- Fwied: ħsara moderata jew serja fil- fwied iġġib bidla sinjifikanti fil- proprjetajiet farmakokinetiċi ta ’ amprenavir.
The AUC increased nearly three-fold in patients with moderate impairment and four fold in patients with severe hepatic impairment.
L- AUC żdied b’ madwar tliet darbiet aktar f’ dawk il- pazjenti li kellhom ħsara moderata filwaqt li f’ dawk li kellhom ħsara serja żdied b’ erba darbiet aktar.
Clearance also decreased in a corresponding manner to the AUC.
L- ammont ta ’ clearance naqas ukoll bl- istess mod bħal AUC.
The dosage should therefore be reduced in these patients (see section 4.2).
Għalhekk f’ pazjenti bħal dawn id- doża għandha titnaqqas (ara 4. 2).
These dosing regimens will provide plasma amprenavir levels comparable to those achieved in healthy subjects given a 1200 mg dose twice daily without concomitant administration of ritonavir.
Din id- doża għandha tipprovdi livelli ta ’ amprenavir fil- plażma jixbħu lil dawk milħuqa f’ individwi b’ saħħithom li jirċievu 1200 mg darbtejn kuljum mingħajr ritonavir.
In long-term carcinogenicity studies with amprenavir in mice and rats, there were benign hepatocellular adenomas in males at exposure levels equivalent to 2.0-fold (mice) or 3.8-fold (rats) those in humans given 1200 mg twice daily of amprenavir alone.
Dan seħħ meta kien hemm livelli ta ’ mediċina li kienu għal darbtejn aktar (fil- ġrieden) u għal 3. 8 darbiet aktar (fil- firien) minn dawk li jintlaħqu fil- bnedmin meta jiġu mogħtija 1200 mg darbtejn kuljum ta ’ amprenavir waħdu.
In male mice altered hepatocellular foci were seen at doses that were at least 2.0 times human therapeutic exposure.
Fil - ġrieden irġiel seħħ tibdil fil- foci taċ- ċelluli tal- fwied meta ngħataw doża li kienet ta ’ l- anqas darbtejn aktar minn dik normali fil- bnedmin.
A higher incidence of hepatocellular carcinoma was seen in all amprenavir male mouse treatment groups.
Kien hemm inċidenza akbar ta ’ karċinoma taċ- ċelluli tal- fwied fil- gruppi kollha ta ’ ġrieden irġiel li ngħataw amprenavir.
However, this increase was not statistically significantly different from male control mice by appropriate tests.
Il -
The mechanism for the hepatocellular adenomas and carcinomas found in these studies has not been elucidated and the significance of the observed effects for humans is uncertain.
19 proċess ta ’ kif jiżviluppaw dawn it- tumuri fil- fwied ma ġiex spjegat u lanqas ma huwa ċert jekk dawn għandhomx importanza għall- bniedem.
However, there is little evidence from the exposure data in humans, both in clinical trials and from marketed use, to suggest that these findings are of clinical significance.
Mit- tagħrif miġbur mill- istudju fil- bniedem, kemm dak miġbur mill- istudji kliniċi kif ukoll minn dak miġbur wara li l- mediċina ġiet introdotta fis- suq, ma jidhirx li dawn is- sejbiet huma ta ’ mportanza fl- użu kliniku.
Amprenavir was not mutagenic or genotoxic in a battery of in vivo and in vitro genetic toxicity assays, including bacterial reverse mutation (Ames Test), mouse lymphoma, rat micronucleus, and chromosome aberration in human peripheral lymphocytes.
Dawn kienu jinkludu bacterial reverse mutation (Ames Test), tumuri malinni fil- glandola limfatika tal- ġrieden, rat micronucleus u chromosome aberration fil- limfoċiti umani.
In toxicological studies with mature animals, the clinically relevant findings were mostly confined to the liver and gastrointestinal disturbances.
Fi studji tossikoloġiċi li saru f’ annimali adulti s- sejbiet li saru u li huma ta ’ importanza klinika kienu kważi kollha problemi tal- fwied u gastro- intestinali.
Liver toxicity consisted of increases in liver enzymes, liver weights and microscopic findings including hepatocyte necrosis.
L- effetti tossiċi fil- fwied kienu jikkonsistu f’ żieda fl- enzimi tal- fwied, żidiet fil- piż tal- fwied u effetti oħra mikroskopiċi bħal nekrozi fiċ- ċelluli tal- fwied.
This liver toxicity can be monitored for and detected in clinical use, with measurements of AST, ALT and alkaline phosphatase activity.
Dan jistà jsir billi jiġu mkejla l- AST, l- ALT u l- attività ta ’ alkaline phosphatase.
However, significant liver toxicity has not been observed in patients treated in clinical studies, either during administration of Agenerase or after discontinuation.
Madankollu qatt ma ’ ġie muri li seħħet xi ħsara importanti fil- fwied f’ dawk il- pazjenti li ġew ikkurati waqt l- istudji kliniċi, kemm waqt l- użu ta ’ Agenerase kif ukoll wara li dan ġie mwaqqaf.
Amprenavir did not affect fertility.
Il- fertilità qatt ma sarilha ħsara permezz ta ’ amprenavir.
Local toxicity and sensitising potential was absent in animal studies, but slight irritating properties to the rabbit eye were identified.
Fl- istudji li saru fl- annimali ma kienx hemm tossiċità lokalizzata jew potenzjal għal sensibilizzazzjoni, għalkemm kien sinjali ta ’ irritazzjoni fl- għajnejn tal- fniek.
19 Toxicity studies in young animals, treated from four days of age, resulted in high mortality in both the control animals and those receiving amprenavir.
Fi studji tossikoloġiċi li saru f’ annimali żgħar, li ġew mogħtija l- mediċina minn meta kellhom erbat’ ijiem, kien hemm mortalità għolja kemm f’ dawk l- annimali li kienu qed jintużaw bħala kontroll kif ukoll f’ dawk li kienu qed jingħataw amprenavir.
These results imply that young animals lack fully developed metabolic pathways enabling them to excrete amprenavir or some critical components of the formulation (e. g. propylene glycol, PEG 400).
Dawn is- sejbiet juru li annimali żgħar ikunu għadhom ma żviluppawx għal kollox il- metaboliżmu tagħhom, li permezz tiegħu jkunu jistgħu ineħħu mill- ġisem amprenavir jew xi parti oħra kimika tal- formulazzjoni (bħal propylene glycol, PEG 400).
However, the possibility of anaphylactic reaction related to PEG 400 cannot be excluded.
Madanakollu ma ’ jistax jiġi eskluż li setà kien hemm reazzjoni anafilattika għal PEG 400.
In clinical studies, the safety and efficacy of amprenavir have not yet been established in children below four years of age.
Fi studji kliniċi għadu ma ’ ġiex stabbilit kemm huwa ta ’ periklu u effikaċi l- użu ta ’ amprenavir fi tfal taħt l - erbà snin.
In pregnant mice, rabbits and rats there were no major effects on embryo-foetal development.
Fi ġrieden, fniek u firien tqal ma ’ kienx hemm effetti kbar fuq il- fetu.
However, at systemic plasma exposures significantly below (rabbits) or not significantly higher (rat) than the expected human exposures during therapeutic dosing, a number of minor changes, including thymic elongation and minor skeletal variations were seen, indicating developmental delay.
Dawn jindikaw li kien hemm dewmien fl- iżvilupp.
A dose- dependent increase in placental weight was found in the rabbit and rat which may indicate effects on placental function.
Kien misjub li kien hemm żieda fil- piż tal- plaċenta fil- fenek u fil- far, li kienet marbuta skond ma ’ kemm tkun id- doża mogħtija.
It is therefore recommended that women of child-bearing potential taking Agenerase should practice effective contraception (e. g. barrier methods).
Għalhekk huwa rakkomandat li nisa li għad jistà jkollhom it- tfal u li qed jieħdu Agenerase għandhom jużaw metodu effettiv ta ’ kontraċezzjoni.
Capsule shell: gelatin, glycerol, d-sorbitol (E420) and sorbitans solution, titanium dioxide, red printing ink.
Qoxra tal- kapsula: gelatin, glycerol, taħlita likwida ta ’ d- sorbitol (E420) u sorbitans, titanium dioxide, red printing ink.
Capsule contents: d-alpha tocopheryl polyethylene glycol 1000 succinate (TPGS), macrogol 400 (PEG 400), propylene glycol.
Kontenut tal- kapsula: d- alpha tocopheryl polyethylene glycol 1000 succinate (TPGS), macrogol 400 (PEG 400), propylene glycol.
Not applicable.
Ma jgħoddx f’ dan il- kaz.
3 years.
Sentejn.
Keep the container tightly closed.
Żomm il- kontenitur magħluq sewwa.
White High Density Polyethylene (HDPE) bottles containing 480 capsules.
Fliexken bojod magħmula mil- propilin ta ’ densità għolja (HDPE) u fihom 480 kapsula l- wieħed.
Glaxo Group Ltd Glaxo Wellcome House Berkeley Avenue Greenford Middlesex UB6 0NN United Kingdom
Glaxo Group Ltd Glaxo Wellcome House Berkeley Avenue Greenford Middlesex UB6 0NN Renju Unit
20 October 2000 Date of last renewal:
20 ta ’ Ottubru 2000 Data ta ’ l- aħħar tiġdid:
17 November 2005
17 ta 'Novembru 2005
DATE OF THE REVISION OF THE TEXT
DATA TA ’ META ĠIET RIVEDUTA L- KITBA
Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http: / /www. emea. europa. eu.
Informazzjoni dettaljata dwar dan il- prodott tinsab fuq il- website ta ’ l- Aġenzija Ewropeja dwar il - Mediċini (EMEA) http: // www. emea. europa. eu /.
Agenerase 150 mg soft capsules.
Agenerase 150 mg, kapsuli rotob
Each capsule contains 150 mg amprenavir.
Kull kapsula fiha 150 mg ta ’ amprenavir.
Sorbitol (E420)
Sustanzi mhux attivi Sorbitol (E420)
Oblong, opaque, off-white to cream coloured, printed with ‘ GX CC2’.
Forma rettangolari, opaki b’ lewn abjad maħmuġ jkanġi għall- krema u stampati bl- ittri ‘ GX CC2 ’.
Adults and adolescents of 12 years of age and older (greater than 50 kg body weight): the recommended dose of Agenerase capsules is 600 mg twice daily with ritonavir, 100 mg twice daily, in combination with other antiretroviral agents.
Adulti u Adoloxxenti minn 12- il sena ‘ l fuq (piż tal- ġisem aktar minn 50kg): id- doża rakkomandata ta ’ kapsuli ta ’ Agenerase hija ta ’ 600 mg darbtejn kuljum flimkien ma ’ ritonavir, li jingħata f’ doża ta ’ 100 mg darbtejn kuljum, flimkien ma ’ mediċini antiretrovirali oħra.
22 Children (4 to 12 years) and patients less than 50 kg body weight: the recommended dose of Agenerase capsules is 20 mg/ kg body weight twice a day, in combination with other antiretroviral agents, without exceeding a total daily dose of 2400 mg (see section 5.1).
22 Tfal (minn 4 sa 12- il sena) u pazjenti li għandhom piż tal- ġisem inqas minn 50kg: id- doża rakkomandata ta ’ kapsuli ta ’ Agenerase hija ta ’ 20 mg għal kull kilogramm ta ’ piż tal- gisem darbtejn kuljum, flimkien ma ’ mediċini antiretrovirali oħra, mingħajr ma tinqabeż id- doża totali ta ’ 2400 mg kuljum (ara sezzjoni 5, 1).
Agenerase is not recommended in children below 4 years due to lack of data on safety and efficacy (see section 5.2).
Tfal taħt l- 4 snin: l- użu ta ’ Agenerase fi tfal taħt l- 4 snin m’ huwiex irrikmandat minħabba nuqqas ta ’ informazzjoni fuq sigurta ’ u effikaċja (ara 5. 2)
Agenerase must not be administered concurrently with medicinal products with narrow therapeutic windows that are substrates of cytochrome P450 3A4 (CYP3A4).
Agenerase m’ għandux jiġi mogħti ma ’ mediċini li għandhom meded terapewtiċi dojoq u li huma substrati taċ- ċitokromju P450 3A4 (CYP3A4).
Co-administration may result in competitive inhibition of the metabolism of these medicinal products and create the potential for serious and/ or life-threatening adverse events such as cardiac arrhythmia (e. g. amiodarone, bepridil, quinidine, terfenadine, astemizole, cisapride, pimozide), respiratory depression and / or prolonged sedation (e. g. oral triazolam and oral midazolam (for caution on parenterally administered midazolam, see section 4.5)) or peripheral vasospasm or ischaemia and ischaemia of other tissues, including cerebral or myocardial ischaemia (e. g. ergot derivatives).
It- teħid flimkien jista ’ jirriżulta f’ inibizjoni kompetitiva tal- metaboliżmu ta ’ dawn il- mediċini, li jista ’ jwassal għal possibbiltà ta ’ reazzjonijiet avversi li huma serji jew li jpoġġu l- ħajja tal- pazjent f’ periklu, bħal arritmija kardijaka (eż. amiodarone, bepridil, quinidine, terfenadine, astemizole, cisapride, pimozide) dipressjoni respiratorja u/ jew sedazzjoni fit- tul (eż triazolam mill- ħalq u midazolam mill- ħalq (ara sezzjoni 4. 5 għal kawtela ta ’ kif tuża midazolam fil- vina) vasospażmu periferali jew iskemija u iskemija ta ’ tessuti oħra tal- ġisem, inkluż iskemija ċerebrali jew mijokardjali (eż. derivati ta ’ ergot).
(see section 4.5).
Il- kumbinazzjoni ta ’ rifampicin u Agenerase flimkien ma ’ doża baxxa ta ’ ritonavir hija kontraindikata (ara sezzjoni 4. 5)
Herbal preparations containing St John’ s wort (Hypericum perforatum) must not be used while taking amprenavir due to the risk of decreased plasma concentrations and reduced clinical effects of amprenavir (see section 4.5).
23 Sustanzi mediċinali ppreparati mill- ħxejjex li fihom Fexfiexa tar- raba ’ (Hypericum perforatum) m’ għandhomx jintużaw fl- istess waqt li qed jintuża amprenavir minħabba r- riskju ta ’ tnaqqis fil - konċentrazzjoni tal- plażma u fl- effetti kliniċi ta ’ amprenavir (ara 4. 5).
23 4.4 Special warnings and precautions for use
4. 4 Twissijiet speċjali u prekawzjonijiet għall- użu
When amprenavir is administered as monotherapy, resistant viruses rapidly emerge (see section 5.1).
Meta dan jingħata waħdu malajr jitfaċċa vajrus reżistenti (ara 5. 1).
Agenerase capsules are contraindicated in patients with severe hepatic impairment when used in combination with ritonavir (see section4.3).
L- użu ta ’ Agenerase flimkien ma ’ ritonavir huwa kontra - indikat f’ dawk il- pazjenti li jbatu minn ħsara kbira fil- fwied (ara 4. 3).
Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased risk of severe and potentially fatal hepatic adverse events.
Pazjenti li huma morda bl - epatite B jew Ċ b’ mod kroniku, u li jingħataw taħlita ta ’ mediċini antivirali, jinsabu f’ riskju akbar li jsofru minn reazzjonijiet epatiċi avversi u li jistgħu jkunu fatali.
In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant product information for these medicinal products.
F’ każ ta ’ pazjenti li huma morda bl - epatite B jew Ċ b’ mod kroniku u li ser jingħataw taħlita ta ’ mediċini antivirali, wieħed għandu dejjem jikkonsulta l- informazzjoni li jsib ma dawn il- mediċini.
Concomitant use of Agenerase with ritonavir and fluticasone or other glucocorticoids that are metabolised by CYP3A4 is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects, including Cushing’ s syndrome and adrenal suppression (see section 4.5).
Mhuwiex rakkomandat l- użu ta ’ Agenerase flimkien ma ’ ritonavir u fluticasone u glukokortikojdi oħra li jiġu mmetaboliżżati minn CYP3A4 sakemm il- benefiċċju potenzjali tal- kura mhuwiex akbar mir - riskju ta ’ l- effetti tal- kortikosterojdi fid- demm, li jinkludi is- sindromu ta ’ Cushing u trażżin tal - glandola adrenali (ara sezzjoni 4. 5).
The HMG-CoA reductase inhibitors lovastatin and simvastatin are highly dependent on CYP3A4 for metabolism, thus concomitant use of Agenerase with simvastatin or lovastatin is not recommended due to an increased risk of myopathy, including rhabdomyolysis.
Il- mediċini lovastatin u simvastatin, li jinibixxu l’ HMG- CoA reductase, jiddependu ħafna fuq CYP3A4 biex jiġu metabolizzati; għalhekk l- użu tagħhom fl- istess waqt ma ’ Agenerase m’ huwiex rakkomandat minħabba riskju kbir ta’ mijopatija, inkluż rhabdomyolysis.
For some medicinal products that can cause serious or life-threatening undesirable effects, such as carbamazepine, phenobarbital, phenytoin, tricyclic antidepressants and warfarin (monitor International Normalised Ratio), concentration monitoring is available; this should minimise the risk of potential safety problems with concomitant use.
F’ dawk il- każi fejn qegħdin jintużaw mediċini li jistgħu jikkawżaw reazzjonijiet avversi li huma serji jew li jpoġġu l- ħajja tal- pazjent f’ periklu, bħal carbamezapine, phenobarbital,, tricyclic antidepressants u warfarin (wieħed għandu josserva l- International Normalised Ratio), wieħed għandu jżomm il - konċentrazzjoni taħt osservazzjoni; dan għandu jwassal biex ikun hemm tnaqqis fir- riskju li jiżviluppaw problemi relatati mas- sigurtà meta jingħataw dawn il- mediċini fl- istess ħin.
Anticonvulsants (carbamazepine, phenobarbital, phenytoin) should be used with caution.
24 Antikonvulżivi (carbamezapine, phenobarbital, phenytoin) għandhom jintużaw b’ kawtela.
Caution is advised when Agenerase is used concomitantly with delavirdine (see section 4.5).
Hi rrakkomandata l- kawtela meta Agenerase jintuża flimkien ma ’ inibituri ta ’ PDE5 (eż sildenafil u vardenafil) (ara sezzjoni 4. 5) Hi rrakkomandata l- kawtela meta Agenerase jintuża flimkien ma ’ delavirdine (ara sezzjoni 4. 5).
24 A reduction of rifabutin dosage of at least 50% is recommended when administered with Agenerase.
Hu rrakkomandat tnaqqis fid- doża ta ’ rifabutin ta ’ almenu 50% meta jingħata flimkien ma 'Agenerase.
Agenerase capsules contain vitamin E (109 IU/ 150 mg capsule), therefore additional vitamin E supplementation is not recommended.
Il- kapsuli ta ’ Agenerase fihom il- vitamina E (109IU/ 150mg kull kapsula) u għalhekk huwa rakkomandat li m’ għandiex tingħata aktar vitamina E.
A connection between visceral lipomatosis and protease inhibitors and lipoatrophy and nucleoside reverse transcriptase inhibitors has been hypothesised.
25 visceral lipomatosis, l- inibituri protease, il- lipoatrophy u inibituri nuklejosajd rivers transkriptejż.
Haemophiliac patients
Pazjenti li jbatu minn emofilija
In some
F’ pazjenti li jbatu mill- emofilja tip A u B, u li kienu jieħdu l- inibituri protease, ġew irrapportati każijiet fejn kien hemm żieda fil- fsada u li kienu jinkludu ematomi spontanji fil- ġilda u haemarthroses.
25 patients, additional factor VIII was given.
Xi wħud minn dawn il- pazjenti ingħataw aktar factor VIII.
Although the etiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV-disease and/ or long-term exposure to combination antiretroviral therapy (CART).
Għalkemm il- kawża tista ’ tkun minħabba ħafna fatturi, (li jinkludu l- użu ta ’ kortikosterojdi, il- konsum ta ’ alkoħol, immunosoppressjoni qawwija, indiċi ogħla ta ’ piż tal- ġisem), każijiet ta ’ ostejonekrożi nstabu li huwa partikolarment aktar komuni f’ pazjenti b’ HIVavvanzat u/ jew użu ta ’ terapija antiretrovirali kombinata (TARK) fit- tul.
Similarly, amprenavir and ritonavir might also modify the pharmacokinetics of other medicinal products that share this metabolic pathway.
Bl- istess raġuni kemm amprenavir, kif ukoll ritonavir, jistgħu jħallu effett fuq il - proprjetajiet farmakokinetiċi ta ’ dawk il- mediċini li bħalhom jgħaddu minn dan l- istess proċess.
Co-administration may result in competitive inhibition of the metabolism of these active substances thus increasing their plasma level and leading to serious and / or life-threatening adverse reactions such as cardiac arrhythmia (e. g. amiodarone, astemizole, bepridil, cisapride, pimozide, quinidine, terfenadine) or peripheral vasospasm or ischaemia (e. g. ergotamine, dihydroergotamine) (see section 4.3).
26 dan jista ’ jwassal għal inibizjoni kompetitiva tal- metaboliżmu ta ’ dawn is- sustanzi attivi u b’ hekk iżid il- livell tagħhom fil- plażma u jwassal għal reazzjonijiet avversi serji u / jew ta ’ periklu għas- saħħa bħal arritmja tal- qalb (eż amiodarone, astemizole, bepridil, cisapride, pimozide, quinidine, terfenadine) jew spażmu ta 'l- arterji periferali jew iskemija (eż ergotamine, dihydroergotamine).
These active substances include flecainide and propafenone (see section 4.3).
Dawn is- sustanzi attivi jinkludu fost oħrajn flecainide u propafenone.
26 Rifampicin Rifampicin is a strong CYP3A4 inducer and has been shown to cause an 82% decrease in amprenavir AUC, which can result in virological failure and resistance development.
Rifampicin Rifampicin huwa induttur qawwi ta ’ CYP3A4 u intwera li jikkawża tnaqqis ta '82% fl- AUC ta ’ amprenavir, li jista ’ jirriżulta f’ falliment viroloġiku u żvilupp ta ’ reżistenza.
St John’ s wort (Hypericum perforatum) Serum levels of amprenavir can be reduced by concomitant use of the herbal preparation St John’ s wort (Hypericum perforatum).
St. John’ s wort (Hypericum perforatum): il- livell ta ’ amprenavir fis- serum jistà jitnaqqas meta fl- istess ħin tingħata il- mediċina tal- ħxejjex Fexfiexa tar- raba ’ (Hypericum perforatum).
Herbal preparations containing St John’ s wort should therefore not be combined with Agenerase.
Mediċini tal- ħxejjex li fihom St. John’ s wort m’ għandhomx jingħataw ma ’ Agenerase.
If a patient is already taking St John’ s wort, check amprenavir and if possible viral levels and stop St John’ s wort.
Jekk xi pazjent ikun qiegħed jieħu St. John’ s wort, wieħed irid jiċċekja l- livell ta ’ amprenavir kif ukoll il- livell tal - vajrus, filwaqt li St. John’ s wort jitwaqqaf.
The dose of amprenavir may need adjusting.
Jistà jkun hemm bżonn ta ’ bidla fid- doża ta’ amprenavir.
The inducing effect may persist for at least 2 weeks after cessation of treatment with St John’ s wort (see section 4.3).
L- effett stimulanti jistà jdum għal ta ’ l- inqas ġimagħtejn wara li St. John’ s wort ikun twaqqaf.
Ritonavir: the AUC and Cmin of amprenavir were increased by 64% and 508% respectively and the Cmax decreased by 30% when ritonavir (100 mg twice daily) was coadministered with amprenavir capsules (600 mg twice daily) compared to values achieved after 1200 mg twice daily doses of amprenavir capsules.
Fi studji kliniċi li saru intużat doża ta ’ 600 mg amprenavir darbtejn
The amprenavir plasma Cmin values achieved with the combination of amprenavir (600 mg twice daily) in combination with Kaletra (400 mg lopinavir + 100 mg ritonavir twice daily) are approximately 40- 50% lower than when amprenavir (600 mg twice daily) is given in combination with ritonavir 100 mg
Il- valuri ta ’ Cmin fil- plażma għal amprenavir milħuqa permezz tat- taħlita ta ’ amprenavir (600 mg darbtejn kuljum) flimkien ma ’ Kaletra (400 mg lopinavir + 100 mg ritonavir darbtejn kuljum) huma bejn wieħed u ieħor 40- 50% anqas minn meta amprenavir (600 mg darbtejn kuljum) jiġi mogħti flimkien ma ’ 100 mg darbtejn kuljum ta ’ ritonavir.
Adding additional ritonavir to an amprenavir plus Kaletra regimen increase lopinavir Cmin values, but not amprenavir Cmin values.
Jekk jingħata aktar ritonavir ma ’ taħlita ta ’ amprenavir u Kaletra, jkun hemm żieda fil- valuri tas- Cmin ta ’ lopinavir iżda mhux f’ dawk ta ’ amprenavir.
No dose recommendation can be given for the co- administration of amprenavir and Kaletra, but close monitoring is advised because the safety and efficacy of this combination is unknown.
M’ hemmx doża rakkomandabbli li tista ’ tintuża meta jingħataw flimkien amprenavir u Kaletra iżda huwa għaqli li l- pazjent jinżamm taħt osservazzjoni minħabba li s- sigurtà u l- effikaċja ta’ din it- taħlita mhumiex magħrufa.
Abacavir: the AUC, Cmin, and Cmax of abacavir were unaltered when given with amprenavir.
Abacavir: l- AUC, Cmin u Cmax ta ’ abacavir ma nbidlux meta ġie mogħti flimkien ma ’ amprenavir.
The AUC, Cmin, and Cmax of amprenavir were increased by 29%, 27%, and 47%, respectively.
L - AUC, Cmin u Cmax ta ’ amprenavir żdiedu bi 29%, 27% u 47% rispettivament.
Efavirenz: efavirenz has been seen to decrease the Cmax, AUC, and Cmin, ss of amprenavir by approximately 40% in adults.
Efavirenz: ġie muri li efavirenz inaqqas is- Cmax, AUC u Cmin, ss ta ’ amprenavir b’ madwar 40% f’ pazjenti adulti.
Treatment with efavirenz in combination with amprenavir and saquinavir is not recommended as the exposure to both protease inhibitors would be decreased.
Taħlita ta ’ efavirenz flimkien ma ’ amprenavir u saquinavir m’ hijiex rakkomandata, minħabba li ż - żewġ inibituri protease ma ’ jilħaqx ikollhom ħin biżżejjed biex jagħmlu l- effett tagħhom.
No dose recommendation can be given for co-administration of amprenavir with another protease inhibitor and efavirenz in children.
M’ hemmx doża rakkomandabbli li tista tintuża meta jingħataw fl- istess waqt amprenavir u inibitur protease flimkien ma ’ efavirenz fit- tfal.
Nevirapine:
28 Nevirapine:
If these medicinal products are used concomitantly care is advised, and
Jekk dawn il- mediċini jintużaw flimkien, dan għandu jsir b’ attenzjoni.
28 close clinical and virological monitoring should be performed since it is difficult to predict the effect of the combination of amprenavir and ritonavir on delavirdine.
Fl- istess waqt għandu jkun hemm osservazzjoni mill- qrib tal- pazjent, flimkien ma ’ osservazzjoni viroloġika, minħabba li huwa diffiċli tbassar l- effett tat- taħlita ta ’ amprenavir u ritonavir fuq delavirdine.
Antibiotics/ antifungals
Antibijotiċi/ antifungals
The AUC, Cmin and Cmax of amprenavir were increased by 18%, 39%, and 15% respectively.
L- AUC, Cmin u Cmax ta ’ amprenavir żdiedu bi 18%, 39% u 15% rispettivament.
Ketoconazole / Itraconazole: the AUC and Cmax of ketoconazole were increased by 44% and 19% respectively when given with amprenavir alone.
Ketoconazole / Itraconazole: l- AUC u Cmax ta ’ ketoconazole żdiedu b’ 44% u 19% rispettivament meta ġie mogħti flimkien ma ’ amprenavir waħdu.
No dose adjustment for any of the medicinal products is necessary when either ketoconazole is or itraconazole administered in combination with amprenavir.
M’ hemmx bżonn li jsir ċaqliq fid- doża ta ’ l- ebda waħda minn dawn iż- żewġ prodotti mediċinali meta jew ketoconazole jew itraconazole jiġu mogħtija flimkien ma ’ amprenavir.
Patients should therefore be monitored for toxic reactions associated with these medicinal products when these are administered in combination with Agenerase.
29 għalhekk jiġi mpoġġi taħt osservazzjoni għal kull effett tossiku marbut ma ’ dawn il- prodotti u li jistà jinqalà meta dawn jingħataw ma ’ Agenerase.
Calcium-channel blockers: amprenavir may lead to increased serum concentrations of calcium channel blockers such as amlodipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine and verapamil, possibly resulting in enhanced activity and toxicity of these medicinal products.
Imblokkaturi tal- kanali tal- kalċju: l- użu ta ’ amprenavir jistà jwassal għal żieda fil- konċentrazzjoni fis - serum ta ’ imblokkaturi tal- kanali tal- kalċju bħal amlopidine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nimodipine, nisolpidine u verapamil, li possibilment jirriżulta f’ attività u effetti tossiċi aktar qawwija minn naħa ta’ dawn il- prodotti mediċinali.
29 Erectile dysfunction agents: based on data for other protease inhibitors caution should be used when prescribing PDE5 inhibitors (e. g. sildenafil and vardenafil) to patients receiving Agenerase.
Erectile Dysfunction Agents: fuq tagħrif miġbur dwar inibituri protease oħra, huwa għaqli li wieħed jippreskrivi b’ attenzjoni inibituri ta ’ PDE5 (eż sildenafil u vardenafil) f’ pazjenti li qed jirċievu Agenerase.
Fluticasone propionate (interaction with 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%).
Fluticasone propionate (effett ma ’ ritonavir): fi studju kliniku fejn kapsuli ta ’ ritonavir 100mg darbtejn kuljum ingħataw ma ’ fluticasone propionate 50μg erba ’ darbiet kuljum fl- imnieħer għal 7 ijiem f’ suġġetti b’ saħħithom, il- livelli ta ’ fluticasone propionate fil- plażma żdiedu b’ mod sinifikanti, filwaqt li l- livelli intrinsiċi ta ’ cortisol naqqsu bejn wieħed u ieħor bi 86% (90% confidence interval 82- 89%).
Since increased concentrations of HMG-CoA reductase inhibitors may cause myopathy, including rhabdomyolysis, the combination of these medicinal products with Agenerase is not recommended.
Minħabba li żieda fil- konċentrazzjoni fil- plażma ta ’ dawn il- mediċini tistà twassal għal mijopatija, inkluż rhabdomyolysis, huwa rakkomandat li dawn il- mediċini ma ’ jintużawx flimkien ma ’ Agenerase.
Immunosuppressants: frequent therapeutic concentration monitoring of immunosuppresant levels is recommended until levels have stabilised as plasma concentrations of cyclosporin, rapamycin and tacrolimus may be increased when co-administered with amprenavir (see section 4.4).
30 konċentrazzjonijiet ta ’ cyclosporin, rapamycin u tacrolimus fil- plażma jistgħu jiżdiedu meta jingħataw flimkien ma ’ ampenavir (ara sezzjoni 4. 4).
30 As compared to a non-matched historical control group, co-administration of methadone and amprenavir resulted in a 30%, 27% and 25% decrease in serum amprenavir AUC, Cmax and Cmin respectively.
F’ paragun ma ’ grupp ta ’ kontroll storiku mhux mqabbel, kien hemm tnaqqis ta ’ 30%, 27% u 25% fl - AUC, Cmax u Cmin ta ’ amprenavir fis- serum, meta dan ġie mogħti flimkien ma ’ methadone.
No recommendations can currently be made regarding adjustment of amprenavir dose when amprenavir is co-administered with methadone due to the inherent low reliability of non- matched historical controls.
Bħalissa ma tistà tingħata l- ebda rakkomandazzjoni dwar tibdil fid- doża ta ’ amprenavir, meta dan jiġi mogħti flimkien ma ’ methadone, minħabba l- fatt li kontrolli storiċi mhux imqabbla m’ humiex ta ’ min joqgħod fuqhom.
Oral anticoagulants: a reinforced monitoring of the International Normalised Ratio is recommended in case of administration of Agenerase with warfarin or other oral anticoagulants, due to a possible decrease or increase of their antithrombotic effect (see section 4.4).
Anti- koagulanti orali: monitoraġġ rinfurzat tal- Proporzjon Internazzjonali Normalizzathu rakkomandat f’ każi ta ’ l- għoti ta ’ Agenerase ma ’ warfarin jew xi anti- koagulanti oħra, minħabba l - possibiltà ta ’ xi tnaqqis jew żieda ta ’ l- effett anti- trombotiku tagħhom (ara sezzjoni 4. 4).
When ritonavir is co-administered, the effect on hormonal contraceptive concentrations cannot be predicted, therefore, alternative methods of contraception are also recommended.
Meta jingħata wkoll ritonavir, l- effett li jistà jkollu fuq il- konċentrazzjoni ta ’ dawn il- kontraċettivi ma jistax jiġi mbassar u għalhekk huwa għaqli li tintuża forma oħra ta ’ kontraċezzjoni.
Tricyclic antidepressants: careful monitoring of the therapeutic and adverse reactions of tricyclic antidepressants is recommended when they (for example desipramine and nortriptyline) are concomitantly administered with Agenerase (see section 4.4).
Monitoraġġ tajjeb ta ’ l- effetti terapewtiċi u l- effetti avversi ta ’ antidepressanti triċikliċi hu rakkomandat meta dawn (per eżempju desipramine u nortriptyline) jingħataw flimkien ma ’ Agenerase.
Pregnancy: there are no adequate data from the use of amprenavir in pregnant women.
Tqala: ma hemmx informazzjoni biżżejjed mill- użu ta ’ amprenavir f’ nisa tqal.
Studies in animals have shown reproductive toxicity (see section 5.3).
Studji f’ annimali urew tossiċità ripproduttiva (ara sezzjoni 5. 3).
This medicinal product should be used during pregnancy only after careful weighing of the potential benefits compared to the potential risk to the foetus.
31 Din il- mediċina għandha tintuża biss fit- tqala wara li jiġu meqjusa bir- reqqa l- vantaġġi u r- riskji li jistà jkun hemm għall- fetu.
Additionally, it is recommended that HIV infected women do not breast-feed their infants in order to avoid transmission of HIV.
Aktar minn hekk ommijiet infettati bl- HIV m’ għandhomx ireddgħu lit- trabi tagħhom sabiex ma jinxteridx il- vajrus tal- HIV.
The safety of Agenerase has been studied in adults and children of at least 4 years of age, in controlled clinical trials, in combination with various other antiretroviral agents.
Saru studji kliniċi dwar is- sigurtà ta ’ Agenerase, flimkien ma ’ mediċini antiretrovirali oħra, fl- adulti u fit- tfal li għandhom ta ’ l- inqas 4 snin.
Adverse events considered associated with the use of Agenerase are gastro-intestinal symptoms, rash and oral/ peri-oral
Effetti mhux mixtieqa li dehru ġejjin mill- użu ta ’ Agenerase kienu sintomi gastro- intestinali, raxx u parasteżija madwar jew ġewwa l- ħalq.
Most undesirable effects associated with Agenerase therapy were mild to moderate in severity, early in onset, and rarely treatment-limiting.
Ħafna mill- effetti mhux mixtieqa assoċjati ma ’ l- użu ta ’ Agenerase kienu ħfief jew moderati u żviluppaw kmieni waqt l- użu, għalkemm rari kienu ta ’ tfixkil għat- terapija.
In children, the nature of the safety profile is similar to that seen in adults.
Il- profil tas- sigurtà fit- tfal jixbaħ lil dik fil- kbar.
Uncommon:
32 Mhux komuni:
Elevated triglycerides, elevated amylase, abnormal fat redistribution, anorexia Hyperglycaemia, hypercholesterolaemia
ipergliċemija, livelli għoljin ta ’ kolesterol fid- demm
32 Gastrointestinal disorders
Disturbi gastro- intestinali
Skin and subcutaneous tissue disorders
Disturbi fil- ġilda u fittessuti ta ’ taħt il- ġilda
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).
Każijet ta ’ nekrożi fl- għadam ġew irrappurtati partikolarment f’ pazjenti b’ fatturi ta ’ riskju magħrufa, b’ HIVavvanzat u/ jew esponiment għal terapija antiretrovirali kombinata (CART) fit- tul.
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).
F’ pazjenti nfettati b’ HIV b’ defiċjenza serja ta ’ l- immunita ’ fiż- żmien tal- bidu ta ’ terapija antiretrovirali (CART), jista 'jkun hemm reazzjoni nfjammatorja għal infezzjonijiet mingħajr sintomi jew opportunistiċi residwi (ara sezzjoni 4. 4).
If overdose occurs, the patient should be monitored for evidence of toxicity (see section 4.8), and standard supportive treatment provided as necessary.
F’ każ bħal dan il- pazjent għandu jiġi osservat għal effetti tossiċi (ara 4. 8) u għandha tingħata kull għajnuna jew trattament meħtieġ.
Pharmacotherapeutic group; protease inhibitor; ATC Code:
Inibitur protease; Kodiċi ATC:
Amprenavir is a competitive inhibitor of HIV-1 protease.
Mekkaniżmu ta ’ Azzjoni Amprenavir huwa inibitur kompetitiv ta ’ l- HIV- 1 protease.
Amprenavir binds to the active site of HIV-1 protease and thereby prevents the processing of viral gag and gag-pol polyprotein precursors, resulting in the formation of immature non-infectious viral particles.
Amprenavir jintrabat mas- sit attiv tal - protease ta ’ HIV- 1 u b’ hekk ma jħallix l- ipproċessar tal- prekursuri virali tal- polyprotein gag u gag - pol, li tirriżulta fil- formazzjoni ta ’ partiċelli mhux infettivi immaturi tal- vajrus.
Resistance
34 Reżistenza
HIV-1 isolates with decreased susceptibility to amprenavir have been selected during in vitro serial passage experiments Reduced susceptibility to amprenavir was associated with virus that had developed I50V or I84V or V32I+I47V or I54M mutations.
Suxxettibiltà mnaqqsa għal amprenavir ġiet assoċjata ma ’ virus li kien żviluppa mutazzjonijiet ta ’ I50V jew I84V jew V32I+I47V jew I54M.
Additional mutations observed which may contribute to resistance were:
Mutazzjonijiet oħra osservati li jistgħu iwasslu għal reżistenza kienu:
34 b) PI-experienced patients
b) Pazjenti b’ esperjenza- PI
In the studies of PI-experienced patients, PRO30017 (amprenavir 600 mg / ritonavir 100 mg twice daily in sub-study A and B with 80 and 37 patients respectively), the following mutations emerged in patients with virological failure:
Fl- istudji ta ’ pazjenti b’ esperjenza- PI, PRO30017 (amprenavir 600mg/ ritonavir 100mg darbtejn kuljum f’ sub- studju A u B bi 80 u 37 pazjent rispettivament), ħarġu dawn il- mutazzjonijiet f’ pazjenti b’ falliment viroloġiku:
Analyses based on genotypic resistance testing.
35 Analiżi bbażata fuq testijiet ta ’ reżistenza ġenotipika
L10F/ I/ V, L33F, M36I, I54A/ L/ M/ S/ T/ V, I62V, V82A/ C/ F/ G, I84V and L90M and is associated with increased phenotypic resistance to fosamprenavir with ritonavir as well as reduced likelihood of virological response (resistance).
L10F/ I/ V, L33F, M36I, I54A/ L/ M/ S/ T/ V, I62V, V82A/ C/ F/ G, I84V u L90M u hija assoċċjata ma ’ żieda fir- reżistenza finotipika għal fosamprenavir ma ’ ritonavir kif ukoll bħala ċans anqas ta ’ rispons viroloġiku (reżistenza).
Analyses based on phenotypic resistance testing.
Analiżi bbażata fuq testijiet ta ’ reżistenza fenotipika
Clinically validated phenotypic interpretation systems may be used in association with the genotypic data to estimate the activity of amprenavir / ritonavir or fosamprenavir / ritonavir in patients with PI- resistant isolates.
Sistemi ta ’ interpretazzjoni fenotipika validata klinikament tista ’ tintuża flimkien ma ’ data ġenotipika biex tagħmel stima ta ’ l- attività ta ’ amprenavir / ritonavir jew fosamprenavir / ritonavir f’ pazjenti b’ iżolati reżistenti għal PI.
Conversely amprenavir retains activity against some isolates with resistance to other PIs and this retained activity would depend on the number and type of protease resistance mutations present in the isolates.
Għall- kuntrarju amprenavir jibqa ’ attiv kontra xi iżolati b’ reżistenza għal PI oħra u din l- attività miżmuma tiddependi fuq in- numru u t- tipi ta ’ mutazzjonijiet ta ’ reżistenza għal protease li hemm fl- iżolati.
35 The number of key PI-resistance mutations increases markedly the longer a failing PI-containing regimen is continued.
In- numru ta ’ tibdil importanti li jwasslu għal reżistenza kontra l- inibituri protease jiżdied b’ mod sinifikattiv aktar ma ddum tintuża kura bl- inibituri protease li ma tkunx qed tirnexxi.
Cross resistance between amprenavir and reverse transcriptase inhibitors, is unlikely to occur because the enzyme targets are different.
Mhux mistenni li jkun hemm reżistenza misluba bejn amprenavir u inibituri tar- rivers transkriptejż minħabba li l- enzimi involuti huma differenti.
The evidence of efficacy of Agenerase in combination with ritonavir 100 mg twice daily is based on study PRO30017, a randomized, open-label study, in which PI-experienced adults experiencing virological failure (viral load ≥ 1000 copies/ ml) received either Agenerase (600 mg twice daily) in combination with ritonavir (100 mg twice daily) and nucleoside analogues (NRTI) or a standard of care (SOC) PI, predominantly boosted with low-dose RTV.
L- evidenza ta ’ effikaċja ta ’ Agenerase flimkien ma 'ritonavir 100mg darbtejn kuljum hija ibbażata fuq studju PRO30017, studju randomised open- label fejn pazjenti b’ esperjenza PI li esperjenzaw falliment viroloġiku (viral load ≥1000 kopja/ ml) irċevew jew Agenerase (600mg darbtejn kuljum) flimkien ma ’
One hundred and sixty-three (163) patients with virus sensitive to Agenerase, at least one other PI, and at least one NRTI were included in PRO30017 substudy A.
Mija u tlieta u sittin (163) pazjent b’ virus sensittiv għal Agenerase, almenu PI ieħor, u almenu NRTI ieħor kienu inklużi fl- istudju sekondarju ta ’ PRO30017.
Results at week 16
Riżultati f’ ġimgħa 16
(2.34– 6.07)
4. 10 (2. 34– 6. 07)
primary mutations 1 Prior number of NRTIs
mutazzjonijiet 1 primarji PI Numru ta ’ NRTI
(range 0-2)
1. 0 (range 0- 2)