qanastek/EMEA-V3 huggingface dataset:
The studies evaluated Agenerase oral solution and capsules at doses of 15 mg/ kg three times daily, 20 mg/ kg three times daily, 20 mg/ kg twice daily and 22.5 mg/ kg twice daily although the majority received 20 mg/ kg twice daily.
L- istudji evalwaw is- soluzzjoni orali u kapsuli ta 'Agenerase f’ dożi ta ’ 15mg/ kg tliet darbiet kuljum, 20mg/ kg tliet darbiet kuljum, 20mg/ kg darbtejn kuljum u 22. 5mg/ kg darbtejn kuljum għalkemm il- maġġoranza ingħataw 20mg/ kg darbtejn kuljum.
Those of at least 13 years of age and weighing at least 50 kg received 1200 mg Agenerase twice daily.
Dawk li kellhom almenu 13 il- sena u li kienu jiżnu almenu 50kg irċevew 1200mg Agenerase darbtejn kuljum.
Concomitant low dose ritonavir was not administered and the majority of the PI experienced subjects had prior exposure to at least one (78%) or two (42%) of the NRTIs co-administered with Agenerase.
37 ritonavir flimkien u l- maġġoranza tas- suġġetti b’ esperjenza PI kellhom esponiment minn qabel għal almenu wieħed (78%) jew tnejn (42%) tal- NRTI li ingħataw flimkien ma ’ Agenerase.
At Week 48, approximately 25% of those enrolled had plasma HIV-1 RNA < 10,000 copies/ ml and 9% < 400 copies/ ml with a median change from baseline in CD4+ cells of 26 cells/ mm3 (n=74).
F’ ġimgħa 48, bejn wieħed u ieħor 25% ta ’ dawk irreġistrati kellhom HIV- 1 RNA fil- plażma ta ’ < 10, 000 kopji/ ml u 9% kellhom < 400 kopji/ ml b’ bidla medja mill- linja bażi ta ’ ċelluli CD4+ ta ’ 26 ċellula/ mm3 (n=74).
There is no data on the efficacy of boosted Agenerase in children.
Ma hemmx informazzjoni fuq l- effikaċja ta ’ Agenerase aktar qawwi fit- tfal.
Concentrations of AAG have
Amprenavir huwa l- biċċa l- kbira mwaħħal ma ’ alpha- 1- acid glycoprotein (AAG), iżda xi ftit minnu jeħel ukoll ma ’ l- albumina.
37 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 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.
38 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 minn ma ’ din il- proteina.
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).
The primary route of elimination of amprenavir is via hepatic metabolism with less than 3% excreted unchanged in the urine.
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%.
The metabolites and unchanged amprenavir 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.
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.
38 A higher incidence of hepatocellular carcinoma was seen in all amprenavir male mouse treatment groups.
39 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.
Iżda din iż- żieda ma ’ ġietx mitqiesa bħala waħda importanti u statistikament differenti meta mqabbla ma ’ gruppi oħra ta ’ ġrieden irġiel li kienu qed jintużaw bħala kontroll.
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.
Il - proċess ta ’ kif jiżviluppaw dawn it- tumuri fil- fwied ma ġiex spjegat u lanqas ma huwa ċert jekk dawn għandhomx importanza għall- bniedem.
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 nekrożi fiċ- ċelluli tal- fwied.
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, PEG400).
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 PEG400 cannot be excluded.
Madanakollu ma ’ jistax jiġi eskluż li setà kien hemm reazzjoni anafilattika għal PEG 400.
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 u sorbitans, titanium dioxide, red printing ink.
Capsule contents: d-alpha tocopheryl polyethylene glycol 1000 succinate (TPGS), macrogol 400 (PEG 400), propylene glycol.
40 macrogol 400 (PEG 400), propylene glycol.
39 6.3 Shelf life
6. 3 Żmien kemm idum tajjeb il- prodott mediċinali
One or two white High Density Polyethylene (HDPE) bottles, each containing 240 capsules.
Flixkun jew tnejn magħmula mil- propilin ta ’ densità għolja (HDPE), kull wieħed fih 240 kapsula l - wieħed.
MARKETING AUTHORISATION NUMBERS
NUMRU TA ’ L- AWTORIZZAZZJONI GĦAT- TQEGĦID FIS- SUQ
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 15 mg/ ml oral solution.
Agenerase 15 mg/ ml, soluzzjoni orali
Agenerase oral solution contains 15 mg/ ml of amprenavir.
Soluzzjoni orali ta ’ Agenerase li fiha 15 mg/ ml ta ’ amprenavir.
The oral solution is clear, pale yellow to yellow with grape, bubblegum and peppermint flavouring.
Is- soluzzjoni orali hija ta ’ lewn ċar tagħti fl- isfar u għandha togħma ta ’ għeneb, bubblegum u peppermint.
Agenerase oral solution, in combination with other antiretroviral agents, is indicated for the treatment of protease inhibitor (PI) experienced HIV-1 infected adults and children above the age of 4 years.
4. 1 Indikazzjonijiet terapewtiċi
The choice of amprenavir should be based on individual viral resistance testing and treatment history of patients (see section 5.1).
L- għażla ta ’ amprenavir tiddependi fuq it- testijiet tar- reżistenza ta ’ l- individwu għall- vajrus u fuq l- istorja tal- kura tal- pazjent (ara 5. 1).
The benefit of Agenerase oral solution boosted with ritonavir has not been demonstrated either in PI naïve patients or in PI experienced patients.
Ma ġiex muri li s- soluzzjoni orali ta ’ Agenerase flimkien ma ’ ritonavir huwa ta ’ benefiċċju la f’ dawk il- pazjenti li m’ għandhomx esperjenza PI u lanqas f’ dawk li għandhom esperjenza PI.
Agenerase oral solution is administered orally and can be taken with or without food.
Is- soluzzjoni orali ta ’ Agenerase għandha tittieħed mill- ħalq u tistà tittieħed kemm ma ’ l- ikel kif ukoll waħidha.
Agenerase is also available as capsules.
Agenerase huwa disponibbli wkoll bħala kapsuli.
Amprenavir is 14% less bioavailable from the Agenerase oral solution than from the capsules; therefore, Agenerase capsules and Agenerase oral solution are not interchangeable on a milligram per milligram basis (see section 5.2).
Għalhekk, il- kapsuli rotob ta ’ Agenerase u s - soluzzjoni orali ta ’ Agenerase ma jistgħux jiġu mibdula ma ’ xulxin fuq bażi ta ’ milligramma għal milligramma (ara 5. 2).
Patients should discontinue Agenerase oral solution as soon as they are able to swallow the capsule formulation (see section 4.4).
Hekk kif il- pazjent ikun jistà jiblà il- kapsuli ta ’ Agenerase huwa għandu jieqaf milli jkompli jieħu is - soluzzjoni orali (ara 4. 4).
Patients of 4 years and older unable to swallow Agenerase capsules: the recommended dose of Agenerase oral solution is 17 mg (1.1 ml)/ kg three times a day, in combination with other antiretroviral agents, without exceeding a total daily dose of 2800 mg (see section 5.1).
42 ma ’ mediċini antiretrovirali oħra, mingħajr ma tinqabeż id- doża totali ta ’ 2800 mg kuljum (ara sezzjoni 5. 1).
The pharmacokinetic interactions between amprenavir and low doses of ritonavir or other protease inhibitors have not yet been evaluated in children.
Il- proprjetajiet farmakokinetiċi marbutin ma ’ l- użu ta ’ Agenerase flimkien ma ’ doża baxxa ta ’ ritonavir jew inibituri protease oħra ma ġewx valutati fit- tfal.
Additionally, as no dosing recommendations can be made regarding the concomitant use of Agenerase oral solution and low dose ritonavir, the use of this combination must be avoided in these patient populations.
Billi m’ hemmx doża li tistà tiġi rakkomandata meta jintużaw flimkien is- soluzzjoni orali ta ’ Agenerase u doża baxxa ta ’ ritonavir, din it- taħlita m’ għandiex tintuża f’ dawn il- pazjenti.
(see sections 4.3 and 5.3).
Tfal taħt l- 4 snin: l- użu tas- soluzzjoni orali ta ’ Agenerase fi tfal taħt l- 4 snin huwa kontra- indikat (ara 4. 3 u 5. 3).
(see section 5.2).
Anzjani: il- proprjetajiet farmakokinetiċi, l- effikaċja u s- sigurtà marbutin ma ’ l- użu ta ’ Agenerase ma ġewx studjati f’ pazjenti li għandhom ‘ il fuq minn 65 sena (ara 5. 2).
Renal impairment: although no dose adjustment is considered necessary for amprenavir, Agenerase oral solution is contraindicated in patients with renal failure (see section 4.3).
Indeboliment tal- Kliewi: għalkemm m’ hemmx bżonn ta ’ tibdil fid- doża ta ’ amprenavir, is- soluzzjoni orali ta ’ Agenerase hija kontra- indikata f’ pazjenti li jbatu minn insuffiċjenza tal- kliewi (ara 4. 3).
Agenerase oral solution is contraindicated in patients with hepatic impairment or failure (see section 4.3) (see Summary of Product Characteristics of Agenerase Capsules for prescribing information)
4. 3 Kontra- indikazzjonijiet
Hypersensitivity to the active substance or to any of the excipients
Sensittività eċċessiva għas- sustanzi attivi u għal xi sustanzi mhux attivi
Because of the potential risk of toxicity from the large amount of the excipient propylene glycol, Agenerase oral solution is contraindicated in infants and children below the age of 4 years, pregnant women, patients with hepatic impairment or failure and patients with renal failure.
Minħabba r- riskju ta ’ tossiċità li jeżisti kawża ta ’ l- ammont għoli ta ’ propylene glycol, li huwa sustanza mhux attiva, is- soluzzjoni orali ta ’ Agenerase hija kontra- indikata fi tfal li għandhom inqas minn 4 snin, f’ nisa tqal, f’ pazjenti li jbatu minn ħsara jew insuffiċjenza tal- fwied jew insuffiċjenza tal - kliewi.
Agenerase oral solution is also contraindicated in patients treated with disulfiram or other medicinal products that reduce alcohol metabolism (e. g. metronidazole) and preparations that contain alcohol (e. g. ritonavir oral solution) or additional propylene glycol (see section 4.4and 5.1).
Is- soluzzjoni orali ta ’ Agenerase hija kontra- indikata wkoll f’ dawk il- pazjenti li qed jieħdu kura permezz ta ’ disulfiram jew mediċini oħra li jnaqqsu il- metaboliżmu ta ’ l- alkoħol (eż. metronidazole) u preparazzjonijiet oħra li fihom l- alkoħol (eż. soluzzjoni orali ta ’ ritonavir) jew aktar propylene glycol (ara 4. 4 u 5. 1).
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 administred 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) jew vasospazmu periferali jew iskemija u iskemija ta ’ tessuti oħra tal- ġisem, inkluż iskemija ċerebrali jew mijokardjali (eż. derivati ta ’ ergot).
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).
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).
Patients should be advised that Agenerase, or any other current antiretroviral therapy does not cure HIV and that they may still develop opportunistic infections and other complications of HIV infection.
Il- pazjenti għandhom jiġu mgħarrfa li Agenerase, jew kull xorta ta ’ terapija antiretrovirali li teżisti bħalissa, ma tistax tfejjaq l- HIV u li xorta waħda jistgħu jiżviluppaw infezzjonijiet opportunistiċi jew kumplikazzjonijiet oħra marbuta ma ’ l- HIV.
On the basis of current pharmacodynamic data amprenavir should be used in combination with at least two other antiretrovirals.
43 Fuq it- tagħrif farmakodinamiku li jeżisti bħalissa, amprenavir għandu dejjem jintuża flimkien ma ’ ta ’ l- anqas żewġ mediċini antiretrovirali oħra.
Liver Disease:
Mard tal- Fwied: ir- rotta principali tal- metaboliżmu ta ’ amprenavir u ta ’ propylene glycol hija permezz tal- fwied.
The principal route of metabolism of amprenavir and the propylene glycol excipient is via the liver, Agenerase oral solution is contraindicated in patients with hepatic impairment or failure (see section 4.3).
Is- soluzzjoni orali ta ’ Agenerase hija kontra- indikata f’ pazjenti li jbatu minn indeboliment jew insuffiċjenza tal- fwied (ara 4. 3).
42 Patients taking the oral solution of Agenerase, particularly those with renal impairment or those with decreased ability to metabolise propylene glycol (e. g. those of Asian origin), should be monitored for adverse reactions potentially related to the high propylene glycol content (550 mg/ ml), such as seizures, stupor, tachycardia, hyperosmolarity, lactic acidosis, renal toxicity, haemolysis.
Dawn jistgħu jinkludu attakki ta ’ puplesija, sturdament, takikardija, hyperosmolarity, aċidożi lattika, tossiċità tal- kliewi u emolisi.
For patients with renal failure, hepatic impairment or failure, children and pregnant women, see section 4.3.
Għal informazzjoni dwar pazjenti li jsofru minn insuffiċjenza tal- kliewi, indeboliment jew insuffiċjenza tal- fwied, tfal u nisa tqal ara 4. 3.
The concomitant administration of Agenerase oral solution with disulfiram or other medicinal products that reduce alcohol metabolism (e. g. metronidazole), or preparations that contain alcohol (e. g. ritonavir oral solution) or additional propylene glycol is contraindicated (see sections 4.3and 4.5).
L- użu fl- istess waqt tas- soluzzjoni orali ta ’ Agenerase ma ’ disulfiram jew mediċini oħra li jnaqqsu il - metaboliżmu ta ’ l- alkoħol (eż. metronidazole) u preparazzjonijiet oħra li fihom l- alkoħol (eż. soluzzjoni orali ta ’ ritonavir) jew aktar propylene glycol huwa kontra- indikat (ara 4. 3 u 4. 5).
Medicinal products – interactions
Prodotti mediċinali - interazzjonijiet
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, quinidine 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.
The use of Agenerase concomitantly with halofantrine or lidocaine (systemic) is not recommended (see section 4.5).
Mhuwiex rakkomandat l- użu ta ’ Agenerase flimkien ma ’ halofantrine jew lidocaine (sistemiku) (ara sezzjoni 4. 5)
Anticonvulsants (carbamazepine, phenobarbital, phenytoin) should be used with caution.
Antikonvulżivi (carbamezapine, phenobarbital, phenytoin) għandhom jintużaw b’ kawtela.
Caution is advised when Agenerase is used concomitantly with delavirdine (see section 4.5).
Hu rrakkomandat tnaqqis fid- doża ta ’ rifabutin ta ’ almenu 50% meta jingħata flimkien ma 'Agenerase.
A reduction of rifabutin dosage of at least 50% is recommended when administered with Agenerase (see section 4.5).
Meta ritonavir jingħata miegħu jista 'jkun hemm bżonn aktar tnaqqis fid- doża (ara sezzjoni 4. 5).
Because of the potential for metabolic interactions with amprenavir, the efficacy of hormonal contraceptives may be modified, but there is insufficient information to predict the nature of the interactions.
44 Minħabba r- riskju ta ’ interazzjonijiet metaboliċi meta jingħataw ma ’ amprenavir, l- effikaċja tal - kontraċettivi ormonali tistà tinbidel, iżda m’ hemmx tagħrif biżżejjed biex wieħed jkun jistà jbassar x’ tip ta ’ effetti dawn jistgħu jkunu.
Therefore, when methadone is co-administered with amprenavir, patients should be monitored for opiate abstinence syndrome, in particular if low-dose ritonavir is also given.
Għalhekk meta dawn jiġu mogħtija flimkien, il- pazjenti għandhom jiġu osservati għas- sindromu ta ’ astininenza mill opiate, speċjalment jekk tkun ingħatat doża baxxa ta ’ ritonavir.
No recommendations can currently be made regarding adjustment of amprenavir dose when amprenavir is co-administered with methadone.
Bħalissa ma tistax tingħata informazzjoni dwar tibdil fid- doża ta ’ amprenavir meta dan jiġi mogħti fl- istess ħin mall- methadone.
43 Agenerase oral solution contains vitamin E (46 IU/ ml), therefore additional vitamin E supplementation is not recommended.
Is- soluzzjoni orali ta ’ Agenerase fiha il- vitamina E (46 IU/ ml) u għalhekk huwa rakkomandat li m’ għandiex tingħata aktar vitamina E.
Agenerase oral solution contains 1 mg potassium per ml.
Is- soluzzjoni orali ta ’ Agenerase fiha 1mg potassium kull ml.
This must be considered when prescribing to patients with reduced kidney function or patients on a controlled potassium diet.
Dan għandu jiġi kkunsidrat meta jingħata lil pazjenti b’ funzjoni mnaqqsa tal- kliewi jew pazjenti fuq dieta kkontrollata ta ’ potassium.
Agenerase oral solution also contains 4 mg sodium per ml.
Is- soluzzjoni orali ta ’ Agenerase fiha wkoll 4mg ta ’ sodium kull ml.
This must be taken into consideration when prescribing to patients on a controlled sodium diet.
Dan għandu jiġi kkunsidrat meta jingħata lil pazjenti fuq dieta kkontrollata ta ’ sodium.
New onset of diabetes mellitus, hyperglycaemia or exacerbations of existing diabetes mellitus have been reported in patients receiving antiretroviral therapy, including protease inhibitors.
Każijiet ġodda ta ’ dijabete, ipergliċemija jew taħrix ta ’ każi eżistenti ta ’ dijabete ġew irrapurtati f’ pazjenti li kienu qed jirċievu terapija antiretrovirali, inkluż bl- inibituri protease.
A connection between visceral lipomatosis and protease inhibitors and lipoatrophy and nucleoside reverse transcriptase inhibitors has been hypothesised.
Teżisti ipoteżi dwar rabtà possibli bejn il - visceral lipomatosis, l- inibituri protease, il- lipoatrophy u inibituri tan- nuklejosajd tar- rivers transkriptejż (NRTIs).
Clinical examination should include evaluation for physical signs of fat redistribution.
Waqt il- viżta l - pazjent għandu jiġi eżaminat għal sinjali fiżiċi li juru li hemm minn dan it- taqsim mod ieħor tax - xaħam tal- ġisem.
Consideration should be given to the measurement of fasting serum lipids and blood glucose.
Wieħed għandu wkoll jikkunsidra li jiġu mkejla il- livelli tal- lipidi fis- serum waqt is - sawm kif ukoll il- livell taz- zokkor fid- demm.
Haemophiliac patients
Pazjenti li jbatu minn emofilja
There have been reports of increased bleeding, including spontaneous skin haematomas and haemarthroses in haemophiliac patients type A and B treated with protease inhibitors.
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.
In more than half of the reported cases, treatment with protease inhibitors was continued, or reintroduced if treatment had been discontinued.
Ġie maħsub li jista jkun
A causal relationship has been evoked, although the mechanism of action has not been elucidated.
45 hemm rabta kawżali, għalkemm il- mod ta ’ kif dan setà seħħ ma ’ setax jigi spjegat.
44 Osteonecrosis
Ostejonekrożi:
Amprenavir is primarily metabolised in the liver by CYP3A4.
Amprenavir u ritonavir fil- biċċa l- kbira jiġu metabolizzati fil- fwied minn CYP3A4.
Similarly, amprenavir might also modify the pharmacokinetics of other medicinal products that share this metabolic pathway.
Bl- istess raġuni, amprenavir jistà jħalli effett fuq il- proprjetajiet farmakokinetiċi ta ’ mediċini oħra li bħalu jgħaddu minn dan l- istess proċess.
CYP3A4 substrates with narrow therapeutic index Agenerase must not be administered concurrently with medicinal products with narrow therapeutic windows containing active substances that are substrates of cytochrome P450 3A4 (CYP3A4).
Is- sustanzi li jaġixxi fuqhom CYP3A4 b’ therapeutic index zgħir Agenerase m’ għandux jingħata flimkien ma ’ prodotti mediċinali b’ marġinu terapewtiku dejjaq li fihom sustanzi attivi li jaġixxi fuqhom cytochrome P4503A4 (CYP3A4).
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).
Meta jingħataw flimkien 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).
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.
Herbal preparations containing St John’ s wort should therefore not be combined with Agenerase.
Jekk xi pazjent
If a patient is already taking St John’ s wort, check amprenavir and if possible viral levels and stop St John’ s wort.
46 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.
• Protease inhibitors (PIs)
● Inibituri protease (PIs):
45 Saquinavir: the AUC, Cmin and Cmax of saquinavir were decreased by 19% and 48% and increased by 21%, respectively, when given with amprenavir.
Saquinavir: l- AUC, Cmin u Cmax ta ’ saquinavir naqsu b’ 19% u 48% u żdiedu b’ 21% rispettivament meta ġie mogħti flimkien ma ’ amprenavir.
The AUC, Cmin and Cmax of amprenavir were decreased by 32%, 14% and 37%, respectively.
L - AUC, Cmin u Cmax ta ’ amprenavir naqsu bi 32%, 14% u 37% rispettivament.
Nelfinavir: the AUC, Cmin and Cmax of nelfinavir were increased by 15%, 14%, and 12% respectively when given with amprenavir.
Nelfinavir: l- AUC, Cmin u Cmax ta ’ nelfinavir żdiedu bi 15%, 14% u 12% rispettivament meta ġie mogħti flimkien ma ’ amprenavir.
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 co-administered with amprenavir capsules (600 mg twice daily) compared to values achieved after 1200 mg twice daily doses of amprenavir capsules.
Ritonavir: l- AUC u Cmin ta ’ amprenavir żdiedu b’ 64% u 508% rispettivament filwaqt li s- Cmax naqas bi 30% meta ritonavir (100 mg darbtejn kuljum) ġie mogħti flmkien ma ’ kapsuli ta ’ amprenavir (600 mg darbtejn kuljum) meta mqabbla ma ’ valuri milħuqa wara li ġiet mogħtija doża ta ’ 1200 mg ta ’ kapsuli ta ’ amprenavir darbtejn kuljum.
In clinical trials, doses of amprenavir 600 mg twice daily and ritonavir 100 mg twice daily have been used; confirming the safety and efficacy of this regimen.
Fi studji klinici li saru intużat doża ta ’ 600 mg amprenavir darbtejn kuljum flimkien ma ’ oħra ta ’ 100 mg ritonavir darbtejn kuljum.
Agenerase oral solution and ritonavir oral solution should not be co-administered (see section 4.3).
Is- soluzzjoni orali ta ’ Agenerase m’ għandha qatt tingħata flimkien mas- soluzzjoni orali ta ’ ritonavir (ara 4. 3)
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.
• Nucleoside analogue reverse transcriptase inhibitors (NRTIs):
47 ● Analogi ta ’ l- Inibituri nuklejosajd rivers transkriptejż (NRTIs):
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.
When amprenavir is combined with ritonavir, the effect of efavirenz is
Meta amprenavir jingħata flimkien ma ’ ritonavir, l- effetti ta ’ efavirenz jiġu kkumpensati mill- effett farmakokinetiku ta ’ ritonavir li jsaħħaħ dak ta ’ amprenavir.
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 the 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 ieħor flimkien ma ’ efavirenz fit- tfal.
No dose recommendations can be given for the co-administration of amprenavir and delavirdine.
M’ hemmx doża rakkomandabbli li tistà tintuża meta amprenavir u delavirdine jingħataw fl- istess waqt.
Rifabutin: co-administration of amprenavir with rifabutin resulted in a 193% increase in rifabutin AUC and an increase of rifabutin-related adverse events.
Rifabutin: meta amprenavir ingħata flimkien ma ’ rifabutin kien hemm żieda ta ’ 193% fl- AUC ta ’ rifabutin u żieda f’ reazzjonijiet avversi relatati ma ’ rifabutin.
The increase in rifabutin plasma concentration is likely to result from inhibition of rifabutin CYP3A4 mediated metabolism by amprenavir.
Iż- żieda fil- konċentrazzjoni ta ’ rifabutin fil- plażma x’ aktarx li tiġri minħabba li amprenavir jinibixxi il- metaboliżmu ta ’ rifabutin permezz ta ’
Clarithromycin: the AUC and Cmin of clarithromycin were unaltered and the Cmax decreased by 10% when given with amprenavir.
Clarithromycin: ma kien hemm l- ebda bidla fl- AUC u Cmin ta ’ clarithromycin, filwaqt li Cmax naqas b’ 10% meta ġie mogħti flimkien ma ’ amprenavir.
Ketoconazole / Itraconazole: the AUC and Cmax of ketoconazole were increased by 44% and 19% respectively when given with amprenavir.
Ketoconazole / Itraconazole: l- AUC u Cmax ta ’ ketoconazole żdiedu b’ 44% u 19% rispettivament meta ġie mogħti flimkien ma ’ amprenavir.
The AUC and Cmax of amprenavir were increased by 31% and decreased by 16% respectively.
L- AUC u Cmax ta ’ amprenavir żdied b’ 31% u naqas b’ 16% rispettivament.
Itraconazole concentrations are expected to increase in the same manner as ketoconazole.
Il- konċentrazzjonijiet ta ’ itraconazole huma mistennija li jiżdiedu bl- istess mod ta ’ ketoconazole.
No dose adjustment for any of the medicinal products is necessary when either ketoconazole or itraconazole is administered in combination with amprenavir.
M’ hemmx bżonn li jsir ċaqliq fid- doża ta ’ l- ebda waħda minn dawn il- prodotti mediċinali meta ketoconazole jew itraconazole jiġu mogħtija flimkien ma ’ amprenavir.
Agenerase oral solution is contraindicated in patients treated with metronidazole (see section 4.3).
Metronidazole: is- soluzzjoni orali ta ’ Agenerase hija kontra- indikata f’ dawk il- pazjenti li qed jingħataw metronidazole (ara 4. 3).
Patients should therefore be
L- importanza klinika ta ’ dawn ir- reazzjonijiet li jistgħu jseħħu mhix magħrufa u ma sarux studji fuqha.
47 monitored for toxic reactions associated with these medicinal products when these are administered in combination with Agenerase.
Kull pazjent għandu għalhekk jiġi mpoġġi taħt osservazzjoni għal kull effett tossiku marbut ma ’ dawn il- prodotti u li jistà jinqalà meta dawn jingħataw ma ’ Agenerase.
Agenerase oral solution contains propylene glycol (550 mg/ ml), which is primarily metabolised via alcohol dehydrogenase.
Alkoħol u sustanzi li jinibixxu l- metaboliżmu ta ’ l- alkoħol: is- soluzzjoni orali ta ’ Agenerase fiha propylene glycol (550 mg/ ml), li l- biċċa l- kbira minnu tiġi metabolizzata permezz ta ’ alcohol dehydrogenase.
Therefore, concomitant administration with disulfiram or other medicinal products that reduce alcohol metabolism (e. g. metronidazole) or preparations that contain alcohol (e. g. ritonavir oral solution) or propylene glycol is contraindicated (see sections 4.3 and 4.4).
Għalhekk l- użu fl- istess waqt ma ’ disulfiram jew mediċini oħra li jnaqqsu il - metaboliżmu ta ’ l- alkoħol (eż. metronidazole) u preparazzjonijiet oħra li fihom l- alkoħol (eż. soluzzjoni orali ta ’ ritonavir) jew aktar propylene glycol huwa kontra- indikat (ara 4. 3 u 4. 4).
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, felopidine, isradipine, nicardipine, nifedipine, nimodipine, nisolpidine u verapamil li possibilment tirriżulta f’ attività u effetti tossiċi aktar qawwija minn naħa ta’ dawn il- prodotti mediċinali.
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) lil pazjenti li qed jirċievu Agenerase.
Co- administration with Agenerase may substantially increase PDE5 inhibitor plasma concentrations and associated adverse events, including hypotension, visual changes and priapism (see section 4.4).
Meta Agenerase jingħata flimkien, jistà jkun hemm żieda konsiderevoli fil- konċentrazzjoni fil- plażma ta ’ inibituri ta ’ PDE5 u għal effetti mhux mixtieqa li jinkludu pressjoni baxxa, bdil fil- vista u prijapiżmu.
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%).
49 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%).
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).
Immunosuppressanti: monitoraġġ ta ’ spiss ta ’ konċentrazzjonijiet terapewtiċi ta ’ livelli ta ’ immunosuppressanti hu rakkomandat sakemm il- livelli jistabbilizzaw ruħhom għaliex konċentrazzjonijiet ta ’ cyclosporin, rapamycin u tacrolimus fil- plażma jistgħu jiżdiedu meta jingħataw flimkien ma ’ ampenavir (ara sezzjoni 4. 4).
48 Midazolam: midazolam is extensively metabolized by CYP3A4.
Midazolam jiġi mmetaboliżżat b’ mod estensiv minn CYP3A4.
Methadone and opiate derivatives: co-administration of methadone with amprenavir resulted in a decrease in the Cmxc and AUC of the active methadone enantiomer (R-enantiomer) of 25% and 13% respectively, whilst the Cmax, AUC and Cmin of the inactive methadone enantiomer (S-enantiomer) were decreased by 48%, 40% and 23% respectively.
Methadone u derivati opiate: meta ġie mogħti methadone flimkien ma ’ amprenavir kien hemm nuqqas fis- Cmax u AUC ta ’ l- active methadone enantiomer (R- enantiomer) ta ’ 25% u 13% rispettivament, filwaqt li Cmax, AUC u Cmin ta ’ l- inactive methadone enantiomer (S- enantiomer) naqsu b’ 48%, b’ 40% u bi 23% rispettivament.
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.
50 F’ paragun ma ’ grupp ta ’ kontroll storiku mhux imqabbel, 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 mqabbla m’ humiex ta ’ min joqgħod fuqhom.
Co-administration of 0.035 mg ethinyl estradiol plus 1.0 mg norethindrone resulted in a decrease of the amprenavir AUC and Cmin of 22% and 20% respectively, Cmax being unchanged.
Meta 0. 035 mg ethinyl estradiol u 1. 0 mg norethindrone ġie mogħti ma ’ amprenavir, kien hemm nuqqas fl- AUC u Cmin ta ’ amprenavir ta ’ 22% u 20% rispettivament, filwaqt li Cmax baqà l- istess.
The potential risk to humans is unknown.
M’ huwiex magħruf ir- riskju potenzjali fil- bniedem.
49 Lactation: amprenavir-related material was found in rat milk, but it is not known whether amprenavir is excreted in human milk.
Treddigħ: sustanzi relatati ma ’ amprenavir ġew misjuba fil- ħalib tal- ġrieden, iżda mhux magħruf jekk amprenavir joħroġx fil- ħalib ta ’ l- omm.
The systemic exposure to the dams associated with this finding was similar to exposure in humans, following administration of the recommended dose.
Id- doża fid- demm ta ’ l- ommijiet ġrieden f’ dan l- istudju kienet ekwivalenti għal dik li tintlaħaq fil- bniedem wara li jingħata doża normali.
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.
For many of these events it is unclear whether they are related to Agenerase, to concomitant treatment used in the management of HIV disease or to the disease process.
Il- kawża ta ’ ħafna minn dawn l- effetti ma kienitx ċara jekk kienux ġejjin minħabba Agenerase jew minħabba terapija oħra li kienet qed tingħata fl- istess ħin għall- kontrol tal- HIV jew inkella minħabba l- marda nnifisha.
Adverse reactions are listed below by MedDRA body system organ class and by frequency.
51 Dawn l- effetti mhux mixtieqa huma mniżżlin fil- lista t’ hawn taħt skond il- MedDRA body system organ class u skond kemm kienu frekwenti.
50 Symptoms of abnormal fat redistribution were infrequent in PROAB3001 with amprenavir.
Is- sintomi tat- lipodistrofijama kienux daqshekk komuni fl- istudju PROAB3001 li fih kien qed jingħata amprenavir.
In study PROAB3006, seven cases (3%) were reported in 245 NRTI-experienced subjects treated with amprenavir and in 27 (11%) of 241 subjects treated with indinavir, in combination with various NRTIs for a median duration of 56 weeks (p < 0.001).
Fl- istudju PROAB3006 kien hemm sebgħa każi (3%), minn total ta ’ 245 pazjent li kienu diġà ngħataw kura permezz tal- inibituri protease u li kienu qed jirċievu amprenavir, u 27 (11%) minn 241 pazjent li kienu qed jirċievu indinavir flimkien ma ’ diversi mediċini oħra tat- tip NRTIs għal medja ta ’ 56 ġimgħa (p < 0. 001).
Nervous system disorders
52 Disturbi fis- sistema nervuża
Headache Oral/ perioral paraesthesia, tremors, sleep disorders
Uġigh ta ’ ras parasteżija madwar jew ġewwa l- ħalq, rogħda, problemi ta ’ l- irqad
Almost all subjects with abnormal liver function tests were co-infected with Hepatitis B or C virus.
Kważi il- pazjenti kollha li kellhom it - testijiet tal- fwied mhux normali kienu nfettati wkoll bil- vajrus ta ’ l- epatite B jew C.
A higher incidence of rash was reported in patients treated with amprenavir in combination with efavirenz.
Il - każijiet ta ’ raxx kienu aktar frekwenti f’ dawk il- pazjenti li kienu qed jirċievu l- amprenavir flimkien ma ’ l- efavirenz.
Severe or life-threatening skin reactions have also occurred in patients treated with amprenavir (see section 4.4).
F’ xi pazjenti li kienu jircżċievu amprenavir, tfaċċaw effetti mhux mixtieqa tal- ġilda li kienu serji, jew li kienu ta ’ periklu għal ħajjithom.
51 General disorders and administration site conditions
Disturbi ġenerali u kondizzjonijiet ta ’ mnejn jingħata
4.9 Overdose
53 4. 9 Doża eċċessiva
However, since amprenavir is highly protein bound, dialysis is unlikely to be helpful in reducing blood levels of amprenavir.
Minħabba li amprenavir huwa l- parti kbira minnu mwaħħal mal- proteini tad- demm, l- użu tad- dijalisi sabiex jitbaxxa l- livell ta ’ amprenavir fid- demm ftit għandu użu.
Pharmacotherapeutic group: protease inhibitor; ATC Code:
Inibitur protease; Kodiċi ATC:
Mechanism of Action
Mekkaniżmu ta ’ Azzjoni
Amprenavir is a competitive inhibitor of HIV-1 protease.
Amprenavir huwa inibitur kompetitiv ta 'l- HIV- 1 protease.
Resistance
Reżistenza
When ART naïve patients were treated with the currently approved doses of fosamprenavir/ ritonavir, as for other ritonavir boosted PI regimens, the mutations described were rarely observed.
Meta pazjenti mingħajr esperjenza ta ’ ART ingħataw kura b’ dożi approvati bħalissa ta ’ fosamprenavir/ ritonavir, bħal sistemi oħra ta ’ kura PI imsaħħin b’ ritonavir, il- mutazzjonijiet deskritti kienu osservati rarament.
One resistance mutation was observed in each of 3 isolates:
54 Kienet osservata mutazzjoni ta ’ reżistenza waħda f’ kull waħda mit- tliet iżolati rispettivament:
Analyses based on genotypic resistance testing.
Analiżi bbażata fuq testijiet ta ’ reżistenza ġenotipika
There are currently data on cross-resistance between amprenavir and other protease inhibitors for all 4 fosamprenavir resistance pathways, either alone or in combination with other mutations.
Fuq bażi ta ’
Based on data from twenty-five antiretroviral naïve patients failing a fosamprenavir containing regimen (one of whom showed Baseline resistance to lopinavir and saquinavir and another to tipranavir) the resistance pathways associated with amprenavir produce limited cross-resistance to atazanavir/ ritonavir (three of 25 isolates), darunavir/ ritonavir (four of 25 isolates), indinavir/ ritonavir (one of 25 isolates), lopinavir/ ritonavir (three of 24 isolates), saquinavir (three of 24 isolates) and tipranavir/ ritonavir (four of 24 isolates)..
55 data minn ħamsa u għoxrin pazjent mingħajr esperjenza antiretrovirali li fallew fuq sistema ta ’ kura b’ fosamprenavir (fejn wieħed minnhom wera reżistenza tal- Lina Bażi għal lopinavir u saquinavir u ieħor għal tipranavir), il- passaġġi ta ’ reżistenza assoċċjati ma ’ amprenavir jipproduċu cross- resistance limitata għal atazanavir/ ritonavir (tlieta minn 25 iżolat), darunavir/ ritonavir (erba ’ minn 25 iżolat), indinavir/ ritonavir (wieħed minn 25 iżolat), lopinavir/ ritonavir (tlieta minn 24 iżolat), saquinavir (tlieta minn 24 iżolat) u tipranavir/ ritonavir (erba ’ minn 24 iżolat).
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 rivers transkriptejż minħabba li l- enżimi involuti huma differenti.
54 Results at week 16
Riżultati f’ ġimgħa 16
1 2 ≥ 3 Median number of PI
1 2 ≥3
primary mutations 1 Prior number of NRTIs
56 Numru medja ta ’ mutazzjonijiet primarji1 PI Numru ta ’ NRTI
The evidence of efficacy of unboosted Agenerase was based on two uncontrolled clinical studies involving 288 HIV infected children aged between 2 and 18 years, 152 of whom were PI experienced.
L- evidenza ta ’ effikaċja ta ’ Agenerase mhux qawwi kienet ibbażata fuq żewġ studji kliniċi mhux ikkontrollati b’ 288 tifel u tifla ta ’ bejn is- 2 u t- 18 il- sena infettati bl- HIV, li 152 minnhom kellhom esperjenza PI.
Concomitant low dose ritonavir was not administered and the majority of the PI experienced subjects had prior exposure to at least one (78%) or two (42%) of the NRTIs co-administered with Agenerase.
Ma ingħatatx doża baxxa ta ’ ritonavir flimkien u l- maġġoranza tas- suġġetti b’ esperjenza PI kellhom esponiment minn qabel għal almenu wieħed (78%) jew tnejn (42%) tal- NRTI li ingħataw flimkien ma ’ Agenerase.
55 5.2 Pharmacokinetic properties
5. 2 Tagħrif farmakokinetiku
At therapeutic dosages (1200 mg twice daily), the mean maximum steady state concentration (Cmax, ss) of amprenavir capsules is 5.36 µg/ ml (0.92-9.81) and the minimum steady state concentration (Cmin, ss) is 0.28 µg/ ml (0.12-0.51).
Meta jingħataw dożi terapewtiċi (1200 mg darbtejn kuljum), il- valur intermedju tal - konċentrazzjoni fi stat stabbli massima (Cmax, ss) tal- kapsuli huwa ta ’ 5. 36 µg/ ml (0. 92- 9. 81) filwaqt li dak tal - konċentrazzjoni fi stat stabbli minima (Cmin, ss) huwa ta ’ 0. 28 µg/ ml (0. 12- 0. 51).
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).
57 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).
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.
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 minn ma ’ din il- proteina.
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- enżima CYP3A4 taċ- citokromju P450.
56 Special populations:
Każijiet speċjali:
Renal impairment: patients with renal impairment have not been specifically studied.
58 Indeboliment tal- Kliewi: ma sarux studji partikulari fuq nies li għandhom ħsara fil- kliewi.
Agenerase oral solution should not be used in patients with hepatic impairment or failure (see section 4.3).
Is- soluzzjoni orali ta ’ Agenerase m’ għandiex tintuża f’ pazjenti li jbatu minn ħsara jew insuffiċjenza tal- fwied (ara 4. 3)
5.3 Preclinical safety data
5. 3 Tagħrif ta 'qabel l- użu kliniku dwar is- sigurtà tal- medicina
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- limfotiċi umani.
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- enżimi tal- fwied, żidiet fil- piż tal- fwied u effetti oħra mikroskopiċi bħal nekrożi fiċ- ċelluli tal- fwied.
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 il- metaboliżmu tagħhom għal kollox, li permezz tiegħu jkunu jistgħu ineħħu mill- ġisem amprenavir jew xi parti oħra kimika tal- formulazzjoni (bħal propylene glycol, PEG 400).