qanastek/EMEA-V3 huggingface dataset:
Oral anticoagulants: a reinforced monitoring of the International Normalised Ratio is recommended in case of administration of Telzir with ritonavir with warfarin or other oral anticoagulants, due to a possible decrease or increase of their antithrombotic effect.
Anti- koagulanti orali: monitoraġġ rinfurzat tal- Proporzjon Internazzjonali Normalizzat hu rakkomandat f’ każi ta ’ l- għoti ta ’ Telzir b’ ritonavir ma ’ warfarin jew xi anti- koagulanti oħra, minħabba l- possibiltà ta ’ xi tnaqqis jew żieda ta ’ l- effett anti- trombotiku tagħhom.
Co-administration of fosamprenavir 700 mg twice daily + ritonavir 100 mg twice daily with an oral contraceptive containing ethinyl estradiol (EE) 0.035 mg/ norethisterone (NE) 0.5 mg once daily decreased plasma EE AUC(0- τ) and Cmax by 37% and 28%, respectively, and decreased plasma NE AUC(0-τ), Cmax, and Cτ by 34%, 38%, and 26%, respectively.
Sterojdi: fosamprenavir 700mg darbtejn kuljum + ritonavir 100mg darbtejn kuljum flimkien ma ’ kontraċettiv orali li fih ethinyl estradiol (EE) 0. 035mg/ norethisterone (NE) 0. 5mg darba kuljum naqqsu l- EE AUC (0- τ) u s - Cmax fil- plażma b’ 37% u bi 28% rispettivament, u naqqsu l- NE AUC (0 - τ), Cmax u Cτ b’ 34%, 38% u 26% rispettivament.
Steady state plasma amprenavir pharmacokinetic (PK) parameters were not significantly affected by co-administration with this oral contraceptive; however, ritonavir AUC(0- τ) and Cmax were 45% and 63% higher, respectively, compared to historical data in female subjects dosed with fosamprenavir / ritonavir alone.
Il- parametri farmakokinetiċi (PK) ta ’ amprenavir fil - plażma fi stat fiss ma kienux daqshekk affettwati meta ingħataw flimkien ma ’ dan il- kontraċettiv orali; għalkemm l- AUC (0- τ) u s - Cmax ta ’ ritonavir kienu aktar għoljin b’ 45% u 65% rispettivament, meta mqabbla ma ’ data storika f’ suġġetti femminili li ngħataw fosamprenavir/ ritonavir waħidhom.
33 Paroxetine:
Paroxetine:
In animal studies at systemic plasma exposures (AUC) to amprenavir lower than therapeutic exposure in patients treated with Telzir, some developmental toxicity was observed (see section 5.3).
Fi studji fuq annimali b’ esponimenti sistemiċi ta ’ amprenavir fil- plażma( AUC) inqas minn esponimenti terapewtiċi f’ pazjenti li jkunu qed jieħdu Telzir, ġie osservat xi żvilupp ta ’ tossiċità (ara sezzjoni 5. 3).
In view of the low exposure in reproductive toxicity studies, the potential developmental toxicity of Telzir has not been fully determined.
Minħabba l - esponiment baxx fi studji dwar tossiċità fuq is- sistema riproduttiva, it- tossiċità potenzjali ta ’ Telzir fuq l- iżvilupp għada ma ġietx stabbilita għal kollox.
Lactation Amprenavir-related material was found in rat milk, but it is not known whether amprenavir is excreted in human milk.
Sustanzi relatati ma ’ amprenavir instabu fil- ħalib tal- firien, iżda mhux magħruf jekk amprenavir joħroġx fil- ħalib tal- bnedmin.
It should be noted that the Telzir oral suspension has not been evaluated clinically in adults and that the adverse reaction profile detailed in this section is based on the experience in adults with the Telzir film coated tablets.
Wieħed irid iżomm f’ rasu li s- sospensjoni orali Telzir ma ġietx valutata klinikament fl- adulti u li l - profil ta ’ reazzjonijiet ħżiena dettaljat f’ din is- sezzjoni hu bażat fuq l- esperjenza fl- adulti tal- pilloli Telzir miksijin b’ rita.
APV30003 in protease inhibitor experienced patients, fosamprenavir given in combination with low dose ritonavir either once daily (1400 mg / 200 mg) (n = 106) or twice daily (700 mg / 100 mg) (n = 106) in combination with two active reverse transcriptase inhibitors (RTIs).
APV30003 f’ pazjenti b’ esperjenza ta ’ impedituri protease, fosamprenavir flimkien ma ’ doża baxxa ta ’ ritonavir jew darba kuljum (1400 mg/ 200 mg) (n=106) jew darbtejn kuljum (700 mg/ 100 mg) (n=106) flimkien ma ’ żewġ impedituri attivi ta ’ reverse transcriptase (RTIs).
The adverse reaction profile was similar across all the respective adult studies: antiretroviral naïve (APV30002) and protease inhibitor experienced (twice daily dosing, APV30003) patient populations.
Il- profil ta ’ reazzjonijiet avversi kien simili għall- istudji kollha rispettivi fl- adulti: gruppi ta ’ pazjenti li m’ għandhomx esperjenza ta ’ trattament antiretrovirali (APV30002) u oħrajn b’ esperjenza ta ’ impedituri protease (doża ta ’ darbtejn kuljum, APV30003).
34 Adverse reactions are listed by MedDRA system organ class and absolute frequency.
Ir- reazzjonijiet avversi huma elenkati skond is- sistema MedRA, klassi ta ’ organi u frekwenza assoluta.
Very common (≥ 1/ 10), Common (≥ 1/ 100, < 1/ 10), Uncommon (≥ 1/ 1,000, < 1/ 100), Rare (≥ 1/ 10,000, < 1/ 1,000) or Very rare (< 1/ 10,000), including isolated reports.
Il- frekwenzi huma definiti bħala Komuni ħafna (≥1/ 10), Komuni (≥1/ 100, < 1/ 10), Mhux komuni (≥1/ 1, 000, < 1/ 100), Rari (≥1/ 10, 000, < 1/ 1, 000), jew Rari ħafna (≤1/ 10, 000) inklużi rapporti iżolati.
Most of the adverse events below were reported from two large clinical studies in adults, where the adverse events were of at least moderate intensity (Grade 2 or more) occurring in at least 1% of patients and reported by investigators as being attributable to the medicinal products used in the studies.
Ħafna mill- eventi avversi hawn taħt ġew irrapurtati minn żewġ studji kliniċi kbar fuq adulti, fejn l - effetti avversi kienu għall- inqas ta ’ intensità moderata (Grad 2 jew iżjed), li seħħew għall- inqas f’ 1% ta ’ pazjenti u li ġew rappurtati minn investigaturi li kienu attribwibbli għal prodotti mediċinali wżati f’ dawn l- istudji.
Headache, dizziness, oral paraesthesia
Uġigħ ta ’ ras, sturdament, parasteżija tal- ħalq
Rash (see text below “ rash/ cutaneous reactions”)
Raxx (ara l- kliem hawn taħt "raxx/ reazzjonijiet tal- ġilda ”)
Stevens Johnson syndrome
Rari Sindromu ta ’ Stevens Johnson
The rash generally will resolve spontaneously without the necessity of discontinuing treatment with the fosamprenavir with ritonavir.
Ġeneralment ir- raxx jgħaddi waħdu mingħajr il- bżonn li titwaqqaf il- kura ta ’ fosamprenavir b’ ritonavir.
Severe or life-threatening cases of rash, including Stevens-Johnson syndrome are rare.
Każijiet ta ’ raxx severi jew li jipperikolaw il- ħajja, inkluża s- sindromu Stevens- Johnson huma rari.
Fosamprenavir with ritonavir therapy should be definitively stopped in case of severe rash or in case of rash of mild or moderate intensity associated with systemic or mucosal signs (see section 4.4).
It - terapija b’ fosamprenavir ma ’ ritonavir trid tiġi imwaqqfa għall- kollox fil- każ ta ’ raxx severi jew fil - każ ta ’ raxx ħafif jew moderat assoċjat ma ’ sinjali sistemiċi jew mukużi (ara sezzjoni 4. 4).
35 Clinical chemistry abnormalities: clinical chemistry abnormalities (Grade 3 or 4) potentially related to treatment with fosamprenavir with ritonavir and reported in greater than or equal to 1% of adult patients, included: increased ALT (common), AST (common), serum lipase (common) and triglycerides (very common).
Anormalitajiet kliniċi ta ’ kimika: anormalitajiet kliniċi ta ’ kimika (Grad 3 jew 4) li setgħu kienu relatati ma ’ kura b’ fosamprenavir b’ ritonavir u li ġew rappurtati f’ 1% jew aktar ta ’ pazjenti adulti, kienu jinkludu: żieda ta ’ ALT (komuni), ta ’ AST (komuni), ta ’ serum lipase (komuni) u ta ’ trigliċeridi (komuni ħafna).
Rhabdomyolysis: an increase in CPK, myalgia, myositis, and rarely, rhabdomyolysis, have been reported with protease inhibitors, more specifically in association with nucleoside analogues.
Rabdomajoliżi: żieda ta ’ CPK, mijalġa, mijosite, u rarament ta ’ rabdomajoliżi ġiet rappurtata ma ’ impedituri protease, speċifikament aktar f’ assoċjazzjoni ma analogi nuklejosidi.
Osteonecrosis: 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).
Ostejonekrożi: Każijet ta ’ nekrożi fl- għadam ġew irrapurtati partikolarment f’ pazjenti b’ fatturi ta ’ riskju magħrufa, b’ HIVavvanzat u/ jew esponiment għal terapija antiretrovirali kombinata (CART) fit - tul.
Amprenavir is a competitive inhibitor of the HIV-1 protease.
L- attivita ’ antivirali in vitro osservata b’ fosamprenavir kienet minħabba l- preżenza ta ’ traċċi ta ’ amprenavir Amprenavir huwa impeditur kompetittiv tal- HIV- 1 protease.
Administration of fosamprenavir 700 mg twice daily with ritonavir 100 mg twice
L- għoti ta ’ ritonavir flimkien ma ’ fosamprenavir iżid l- AUC ta ’ amprenavir fil- plażma għal bejn wieħed u ieħor darbtejn u l- plażma Cτ, ss għal erba ’ sa sitt darbiet, imqabbel mal- valuri miksuba meta fosamprenavir jingħata waħdu.
36 daily results in plasma amprenavir concentrations (data from study APV30003 in antiretroviral experienced patients) which results in protein adjusted median ratios of Cmin/ IC50 and Cmin/ IC95 of 21.7 (range 1.19-240) and 3.21 (range 0.26-30.0), respectively.
L- għoti ta ’ 700 mg fosamprenavir darbtejn kuljum ma ’ 100 mg ritonavir darbtejn kuljum tirriżulta f’ konċentrazzjonijiet amprenavir fil- plażma (data mill- istudju APV30003 f’ pazjenti b’ esperjenza ta ’ kura antiretrovirali) li tirriżulta fil- medja ta ’ proporzjon aġġustata ta ’ proteina ta ’ Cmin/ IC50 u Cmin/ IC95 ta ’ 21. 7 (medda 1. 19- 240) u 3. 21 (medda 0. 26- 30. 0) rispettivament.
The relationship between in vitro anti-HIV-1 activity of amprenavir and the inhibition of HIV-1 replication in humans has not been defined.
Ir- relazzjoni bejn l- attività in vitro anti- HIV- 1 ta ’ amprenavir u l- impediment tar - replikazzjoni ta ’ HIV- 1 fil- bniedem għad ma ġietx definita.
Resistance
37 Reżistenza
b) ART-naïve or PI-naïve patients
a) Pazjenti mingħajr esperjenza ART jew PI
One resistance mutation was observed in each of 3 isolates:
Kienet osservata mutazzjoni ta ’ reżistenza waħda f’ kull waħda mit- tlett iżolati rispettivament:
37 In the studies of PI-experienced patients, APV30003 and its extension, APV30005 (fosamprenavir 700 mg / ritonavir 100 mg twice daily: n=107), the following mutations emerged in patients experiencing virological failure through 96 weeks:
Fl- istudji ta ’ pazjenti b’ esperjenza PI, APV30003 u l- estensjoni tiegħu, APV30005 (fosamprenavir 700 mg / ritonavir 100 mg darbtejn kuljum: n=107), ħarġu dawn il- mutazzjonijiet li ġejjin f’ pazjenti li esperjenzaw falliment viroloġiku matul 96 ġimgħa:
Genotypic interpretation systems may be used to estimate the activity of amprenavir / ritonavir or fosamprenavir / ritonavir in subjects with PI-resistant isolates.
Analiżi bbażata fuq testijiet ta ’ reżistenza ġenotipika Jistgħu jintużaw sistemi ta ’ interpretazzjonijiet ġenotipiċi biex tagħmel estimi ta ’ l- attivita ’ ta ’ amprenavir/ ritonavir jew fosamprenavir/ ritonavir f’ suġġetti b’ iżolati reżistenti għal PI.
The current (July 2006) ANRS AC-11 algorithm for fosamprenavir / ritonavir defines resistance as the presence of the mutations V32I+I47A/ V, or I50V, or at least four mutations among:
L- algoritmu kurrenti (Lulju 2006) ANRS AC- 11 għal fosamprenavir/ ritonavir jiddefinixxi reżistenza bħala l -
Each of these four genetic patterns associated with reduced susceptibility to amprenavir produces some cross-resistance to ritonavir but susceptibility to indinavir, nelfinavir and saquinavir is generally retained.
Kull wieħed min dawn l- erba ’ disinni ġenetiċi assoċċjati ma ’ suxxetibilita ’ mnaqqsa għal amprenavir tipproduċi cross- resistance għal ritonavir imma s- suxxetibilità għal indinavir, nelfinavir u saquinavir ġeneralment tibqa.
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).
Fuq bażi ta ’ data minn ħamsa u għoxrin pazjent mingħajr esperjenza antiretrovirali li fallew fuq sistema ta ’ kura b’ fosamprenavir (fejn wieħed minnhom wera reżistenza fil- Linja 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).
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.
The number of key PI-resistance mutations increases markedly the longer a failing PI-containing regimen is continued.
In- numru ta ’ mutazzjonijiet ċentrali ta ’ reżistenza- PI jiżdiedu sostanzjalment aktar ma ddum tintuża sistema ta ’ kura li fiha PI falluta.
Early discontinuation of failing therapies is recommended in order to limit the accumulation of multiple mutations, which may be detrimental to a subsequent rescue regimen.
Ikun aħjar jekk jittwafqu sistema ta ’ kura falluti kemm kmieni kemm jista ’ jkun biex tillimita l- akkumulazzjoni ta ’ ħafna mutazzjonijiet, li jistgħu ifixxklu sistemi ta ’ kura ta ’ salvataġġ li jiġu wara.
38 Clinical experience with fosamprenavir boosted with ritonavir is mainly based on three open label studies.
L- esperjenza klinika b’ fosamprenavir imsaħħah b’ ritonavir hi bażata l- aktar fuq tliett studji open- label.
Two studies performed in antiretroviral naïve patients, one in comparison to nelfinavir (study APV30002) and one in comparison to lopinavir / ritonavir (study ESS100732), and one study in antiretroviral experienced patients, in comparison to lopinavir / ritonavir (study APV30003).
Żewġ studji mwettqa f’ pazjenti li m’ għandhomx esperjenza ta ’ terapija antiretrovirali, wieħed f’ paragun ma nelfinavir (studju APV30002) u wieħed f’ paragun ma ’ lopinavir/ ritonavir (studju ESS100732), u studju f’ pazjenti b’ esperjenza antiretrovirali f’ paragun ma lopinavir/ ritonavir (studju APV30003).
In antiretroviral naïve patients in APV30002, fosamprenavir (1400 mg) given once daily in combination with low dose ritonavir (200 mg) as part of a triple regimen including abacavir (300 mg twice daily) and lamivudine (150 mg twice daily) showed similar efficacy over 48 weeks compared to nelfinavir (1250 mg) given twice daily in combination with abacavir plus lamivudine (300 and 150 mg twice daily).
F’ pazjenti li m’ għandhomx esperjenza ta ’ kura antiretrovirali fl- APV30002, fosamprenavir (1400 mg) darba kuljum flimkien ma ’ doża żgħira ta ’ ritonavir (200 mg) bħala parti minn kura trippla li tinkludi abacavir (300 mg darbtejn kuljum) u lamivudine (150 mg darbtejn kuljum) wera l- istess effikaċja matul 48 ġimgħa paragunat ma ’ nelfinavir (1250 mg) darbtejn kuljum flimkien ma ’ abacavir ma ’ lamivudine (300 u 150 mg darbtejn kuljum).
Non-inferiority was demonstrated between fosamprenavir with ritonavir and nelfinavir based on the proportions of patients achieving plasma HIV-1 RNA levels < 400 copies/ ml at 48 weeks (primary endpoint).
39 Intwera li ma kienx hemm inferjorità bejn fosamprenavir ma ’ ritonavir u nelfinavir ibbażata fuq il - proporzjon ta ’ pazjenti li laħqu livelli ta ’ HIV- 1 RNA fil- plażma ta ’ < 400 kopji/ ml fil- ġimgħa 48 (endpoint primarja).
CD4+ cell counts increased in both the fosamprenavir with ritonavir and nelfinavir groups, with median increases above baseline being similar in magnitude at Week 48 (+203 and +207 cells/ mm3, respectively).
L- għadd ta ’ ċelluli CD4+ żdied kemm fil- grupp fosamprenavir b’ ritonavir u kemm f’ dak nelfinavir, biż- żidiet medjani ’ l fuq mill- linja bażi jixxiebħu fid- daqs fil- Ġimgħa 48 (+ 203 u + 207 ċelluli/ mm3, rispettivament).
The data presented above demonstrates that the once daily regimen of fosamprenavir with ritonavir (1400/ 200 mg OD) in antiretroviral naïve patients showed similar efficacy compared to nelfinavir given twice daily.
It- tagħrif preżentat hawn fuq juri li f’ pazjenti li m’ għandhomx esperjenza ta ’ kura antiretrovirali, fosamprenavir ma ritonavir darba kuljum (1400 / 200mg OD) wera effikaċja simili meta mqabbel ma ’ nelfinavir darbtejn kuljum.
This study in view of its design (open label versus nelfinavir) did not provide a sufficiently robust efficacy demonstration in antiretroviral naïve patients to support the once daily regimen of fosamprenavir with ritonavir.
Dan l- istudju minħabba id- disinn tiegħu (tat- tip open label, kontra nelfinavir) ma weriex effikaċja robusta biżżejjed f’ pazjenti li m’ għandhomx esperjenza ta kura antiretrovirali biex isostni s- sistema ta ’ kura fosamprenavir ma ’ ritonavir darba kuljum.
As a conservative approach, based on enhanced amprenavir Ctrough levels, the twice daily dosing regimen of fosamprenavir with ritonavir was recommended for optimal therapeutic management of this population (see section 4.2).
Għalhekk b’ mod konservattiv, ibbażat fuq livelli għolja ta ’ amprenavir Ctrough, kura ta ’ fosamprenavir b’ ritonavir li tingħata darbtejn kuljum hija rakkomandata għall- aħjar trattament terapewtiku f’ dan il- qasam ta ’ pazjenti (ara sezzjoni 4. 2).
In a subsequent randomised open-label study (ESS100732) in antiretroviral naïve patients, fosamprenavir (700 mg) co-administered with low dose ritonavir (100 mg) in a twice daily regimen including abacavir / lamivudine (600 mg / 300 mg) fixed dose combination tablet once daily showed comparable efficacy over 48 weeks to lopinavir / ritonavir (400 mg / 100 mg) given twice daily in combination with abacavir / lamivudine (600 mg / 300 mg once daily).
Fi studju randomised open label li ġie wara (ESS100732) f’ pazjenti li m’ għandhomx esperjenza ta ’ kura antiretrovirali, fosamprenavir 700mg flimkien ma ’ doża baxxa ta ’ ritonavir (100mg) darbtejn kuljum flimkien ma ’ pillola b’ doża fissa ta ’ abacavir/ lamivudine (600mg/ 300mg) darba kuljum wriet fuq 48 ġimgħa effikaċja komparabbli ma ’ lopinavir/ ritonavir (400mg/ 100mg) darbtejn kuljum flimkien ma ’ abacavir/ lamivudine (600mg/ 300mg darba kuljum).
Non-inferiority was demonstrated between fosamprenavir co-administered with ritonavir and lopinavir / ritonavir based on the proportions of patients achieving plasma HIV-1 RNA levels < 400 copies/ ml at 48 weeks (primary endpoint).
Intweriet nuqqas ta ’ nferjorità bejn fosamprenavir flimkien ma ’ ritonavir u lopinavir/ ritonavir, ibbażat fuq il- proporzjon ta ’ pazjenti li jilħu livelli ta ’ HIV- 1 RNA fil- plażma ta ’ < 400 kopji / ml fit- 48 ġimgħa (endpoint primarju).
In the Time to loss of virological response (TLOVR) analysis for the ITT(E) population, the proportion of patients achieving < 400 copies/ ml was 73% (315 / 434) in the fosamprenavir with ritonavir group compared to 71% (317 / 444) of patients receiving lopinavir / ritonavir, with a 95% confidence interval of the difference of [-4,84%; 7; 05%].
Fl- analiżi ta ’ Żmien u t- telfa ta ’ effett viroloġiku (TLOVR) għall- popolazzjoni ITT( E), il- proporzjon ta ’ pazjenti fil- grupp ta ’ fosamprenavir ma ’ ritonavir li laħqu < 400 kopja/ ml kienet 73% (315/ 434) meta mqabbla ma ’ 71% (317/ 444) ta ’ pazjenti li ngħataw lopinavir/ ritonavir, b’ 95% intervall ta ’ kunfidenza tad- differenza ta ’ [- 4, 84%; 7; 05%].
Median increase in CD4 cell count was 176 cells/ mm3 in the fosamprenavir with ritonavir arm and 191 cells/ mm3 in the lopinavir / ritonavir arm respectively by Week 48.
Żieda fil- medja fil- livell ta ’ ċelloli CD4 kien ta ’ 173 ċellola/ mm³ fil- grupp ta ’ fosamprenavir ma ’ ritonavir u 191 ċellola/ mm³ fil- grupp ta ’ lopinavir/ ritonavir rispettivament sat- 48 Ġimgħa.
39 In a randomised open-label study (APV30003) in protease inhibitor experienced patients with virological failure (less than or equal to two PIs) the fosamprenavir with ritonavir (700 / 100 mg twice daily or 1400 / 200 mg once daily) did not demonstrate non-inferiority to lopinavir / ritonavir with regard to viral suppression as measured by the average area under the curve minus baseline (AAUCMB) for plasma HIV-1 RNA over 48 weeks (the primary end point).
Fi studju open- label randomised (APV30003) fuq pazjenti li kelhom l- impeditur protease b’ falliment viroloġiku (inqas minn jew ugwali għal żewġ PIs) fosamprenavir flimkien ma ’ ritonavir (700/ 100 mg darbtejn kuljum jew 1400/ 200 mg darba kuljum) ma wrewx nuqqas ta ’ non- inferjorità għal lopinavir/ ritonavir fir- rigward ta ’ soppressjoni virali kif imkejla mill- medja ta ’ l- erja ta ’ taħt il- kurva bil- linja bażi imnaqqsa (AAUCMB) għal HIV- 1 RNA fil- plażma matul 48 ġimgħa (l- endpoint primarju).
All patients in this study had failed treatment with a previous protease inhibitor regimen (defined as plasma HIV-1 RNA that never went below 1,000 copies/ ml after at least 12 consecutive weeks of therapy, or initial suppression of HIV-1 RNA which subsequently rebounded to ≥ 1,000 copies/ ml).
Il- kura b’ impeditur protease li ngħatat qabel (definita bħala HIV- 1 fil- plażma li qatt ma niżlet taħt l - 1000 kopji/ ml wara għall- inqas 12- il ġimgħa ta ’ terapija, jew soppressjoni inizjali ta ’ l- HIV- 1 RNA li wara reġgħet marret għal ≥kopji/ ml) ma rnexxiet fl- ebda pazjent.
The median durations of prior exposure to NRTIs were 257 weeks for patients receiving fosamprenavir with ritonavir twice daily (79% had ≥ 3 prior NRTIs) and 210 weeks for patients receiving lopinavir/ ritonavir (64% had ≥ 3 prior NRTIs).
40 pazjenti li kienu jieħdu fosamprenavir b’ ritonavir darbtejn kuljum (79% ħadu ≥3 NRTIs minn qabel) u ta ’ 210 ġimgħa għal pazjenti li kienu jieħdu lopinavir/ ritonavir (64% ħadu ≥3 NRTIs minn qabel).
The median durations of prior exposure to protease inhibitors were 149 weeks for patients receiving fosamprenavir with ritonavir twice daily (49% received ≥ 2 prior PIs) and 130 weeks for patients receiving lopinavir/ ritonavir (40% received ≥ 2 prior PIs).
It- tul medju ta ’ esponimenti ta ’ qabel għal impedituri protease kien ta ’ 149 ġimgħa għal pazjenti li kienu jieħdu fosamprenavir b’ ritonavir darbtejn kuljum (49% ħadu ≥2 PIs minn qabel) u ta ’ 130 ġimgħa għal pazjenti li kienu jieħdu lopinavir/ ritonavir (40% ħadu ≥ PIs minn qabel).
The mean AAUCMBs (log10 c/ ml) in the ITT (E) population (Observed analysis) at 48 weeks are described in the table below:
Il- medja ta ’ AAUCMBs (log10 c/ ml) fil- grupp ITT( E) (Analiżi osservata) wara 48 ġimgħa huma deskritti fit- tabella t’ hawn taħt:
Plasma HIV-1 RNA Average Area Under the Curve Minus Baseline (AAUCMB) Values (log10 copies/ ml) at week 48 by Randomisation Strata in APV30003 ITT (E) Population (Observed Analysis)
Plasma HIV- 1 RNA Il- Medja ta ’ l- Erja ta ’ Taħt il- Kurva bil- Linja Bażi Mnaqqsa (AAUCMB) Values (log10 copies/ ml) f’ ġimgħa 48 b’ Randomisation Strata f ’ APV30003 ITT (E) Popolazzjoni (Analiżi osservata)
Observed analysis Observed analysis FPV/ RTV BID LPV/ RTV BID
Analiżi osservata Analiżi osservata Analiżi osservata Diff. medja LPV/ RTV BID FPV/ RTV BID (97. 5% CI) Plażma HIV- 1 RNA
Observed analysis Mean Diff.
N=107
Plasma HIV-1 RNA stratum 1000 – 10,000
N=103
N=107 N=103 Mean (n) Mean (n)
stratum1
(97.5% CI) FPV/ RTV BID vs LPV/ RTV BID
FPV/ RTV BID vs
copies/ ml > 10.000 – 100,000
Medja (n) Medja (n) LPV/ RTV BID 1000 – 10, 000 - 0. 104 - 1. 43 (43) - 1. 53 (41) kopji/ ml (- 0. 550, 0. 342) > 10, 000 – 100, 000 0. 216 - 1. 81 (46) - 1. 59 (45) kopji/ ml (- 0. 213, 0. 664)
> 100,000 copies/ ml
1. 232 - 2. 61 (14) - 1. 38 (19) > 100, 000 kopji/ ml (0. 512, 1. 952)
1.232 (0.512, 1.952)
Popolazzjoni totali
-1.53 (105)
- 1. 53 (105)
-1.76 (103)
- 1. 76 (103)
0.244
0. 244
(-0.047, 0.536)
(- 0. 047, 0. 536) Spjegazzjoni:
40 In patients with high viral load at baseline (> 100,000 copies/ ml) 7/ 14 (50%) patients in the lopinavir / ritonavir group and 6/ 19 (32%) patients in the fosamprenavir with ritonavir group had plasma HIV-1 RNA < 400 copies/ ml.
F’ pazjenti b’ viral load għoli fil- linja bażi (> 100, 000 kopji/ ml) 7/ 14 (50%) ta ’ pazjenti fil- grupp ta ’ lopinavir / ritonavir u 6/ 19 (32%) ta ’ pazjenti fil- grupp ta ’ fosamprenavir b’ ritonavir kellhom plażma HIV- 1 RNA < 400 kopji/ ml.
The fosamprenavir with ritonavir twice daily regimen and the lopinavir / ritonavir twice daily regimen showed similar immunological improvements through 48 weeks of treatment as measured by median change from baseline in CD4+ cell count (fosamprenavir with ritonavir twice daily:
Il- kura b’ fosamprenavir ma ’ ritonavir darbtejn kuljum u dik ta ’ lopinavir/ ritonavir darbtejn kuljum, it - tnejn urew l- istess titjib immunoloġiku matul l- 48 ġimgħa ta ’ terapija kif imkejla b’ tibdil medjan mill - linja bażi ta ’ għadd ta ’ ċelluli CD4+ (fosamprenavir b’ ritonavir darbtejn kuljum:
The benefit in this age group has mainly been derived from the ongoing study, APV29005, an open label 48 week study evaluating the pharmacokinetic profiles, safety, and antiviral activity of fosamprenavir with ritonavir administered twice daily to HIV 1 protease inhibitor experienced and naive patients 2 to 18 years of age.
Il - benefiċċju f’ dan il- grupp ħareġ primarjament minn studju li għaddej bħalissa, APV29005, studju open label ta ’ 48 ġimgħa li jevalwa il- profili farmakokinetiċi, ta ’ sigurtà, u attività antivirali ta ’
APV29005 enrolled 25 patients aged 6 to 11 (the majority of whom were treated with fosamprenavir / ritonavir 18/ 3 mg/ kg twice daily or the adult tablet regimen) and 29 patients aged 12 to 18 (the majority of whom were treated with the adult tablet regimen).
APV29005 irreġistra 25 pazjent bejn is- 6 u l- 11 il- sena (li l- maġġoranza tagħhom ġew trattati b’ fosamprenavir/ ritonavir 18/ 3mg/ kg darbtejn kuljum jew bis- sistema ta ’ kura ta’ pilloli ta ’ l- adulti) u 29 pazjent bejn it- 12 u t- 18 il- sena (li l- maġġoranza tagħhom ġew trattati b’ sistema ta ’ kura ta ’ pilloli ta ’ l- adulti).
Overall, 27 (50%) were PI-naïve, 9 of whom were ART naïve, and 27 (50%) were PI-experienced.
Kollox ma 'kollox, 27 (50%) qatt ma ingħataw PI, li 9 minnhom kienu mingħajr esperjenza ART, u 27 (50%) kienu ingħataw PI.
Prior NRTI exposure was extensive, with median durations of 421 and 389 weeks for the PI naïve and experienced patients respectively.
L- espożizzjoni minn qabel għal NRTI kienet estensiva, b’ medja ta ’ tul ta ’ 421 ġimgħa u 389 ġimgħa għall- pazjenti li kienu ħadu kura u li qatt ma kienu ħadu kura b’ PI rispettivament.
Overall, patients enrolled with a median 4.6 HIV-1 RNA log10 copies/ ml (33% of whom had > 100,000 copies/ ml at baseline) and a median% CD4+ cell of 18% (39% of whom had% CD4+ of < 15% at baseline).
Kollox ma 'kollox, pazjenti irreġistrati b’ medja ta’ 4. 6 kopji/ ml ta' HIV- 1 RNA log 10 (fejn 33% minnhom kellhom > 100, 000 kopji/ ml fil- linja ta ’ bażi) u% medja ta ’ ċelluli CD4+ ta ’ 18% (37% minnhom kellhom% CD4+ ta ‘ < 15% fil- linja bażi.
The conversion of fosamprenavir to amprenavir appears to primarily occur in the gut epithelium.
Il- konverżjoni ta ’ fosamprenavir għal amprenavir tidher li sseħħ primarjament fl- epitilju ta ’ l- imsaren.
Telzir tablet and oral suspension formulations, both given fasted, delivered equivalent plasma amprenavir AUC∞ values and the Telzir oral suspension formulation delivered a 14% higher plasma amprenavir Cmax as compared to the oral tablet formulation.
Il- formulazzjonijiet ta ’ pilloli u sospensjoni orali Telzir, it- tnejn kemm huma meħudin waqt sawma, ipproduċew valuri ekwivalenti ta ’ AUC∞ ta ’ amprenavir fil- plażma u l- formulazzjoni ta ’ sospensjoni orali ta ’ Telzir ipproduċiet 14% aktar ta ’ Cmax ta ’ amprenavir fil- plażma meta mqabbla mal - formulazzjoni ta ’ pillola mill- ħalq.
However, the bioequivalence could not be demonstrated when the oral suspension was given with food.
Madankollu, il- bijoekwivalenza ma setgħatx tidher meta s - sospensjoni orali ingħatat ma ’ l- ikel.
Therefore for adult patients the Telzir oral suspension should be taken without food and on an empty stomach (see section 4.2).
Għalhekk f’ pazjenti adulti is- sospensjoni orali Telzir trid tittieħed mhux ma ’ l- ikel u fuq stonku vojt (ara sezzjoni 4. 2)
41 After single dose administration of fosamprenavir, amprenavir peak plasma concentrations are observed approximately 2 hours after administration.
Wara li tittieħed doża waħda ta ’ fosamprenavir, l- ogħla konċentrazzjonijiet ta ’ amprenavir fil- plażma iseħħu wara xi sagħtejn li tingħata.
After multiple dose oral administration of fosamprenavir 700 mg with ritonavir 100 mg twice daily, amprenavir was rapidly absorbed with a geometric mean (95% CI) steady state peak plasma amprenavir concentration (Cmax) of 6.08 (5.38-6.86) µg/ ml occurring approximately 1.5 (0.75-5.0) hours after dosing (tmax).
Wara t- teħid mill- ħalq ta ’ dożi multipli ta ’ 700 mg fosamprenavir ma ’ 100 mg ritonavir darbtejn kuljum, amprenavir ġie assorbit malajr ma ’ l- ogħla konċentrazzjoni (Cmax) ta ’ medja ġeometrika (95% CI) fl- istat fiss ta ’ amprenavir fil- plażma ta ’ 6. 08( 5. 38- 6. 86) μg/ ml li jkun hemm madwar 1. 5( 0. 75- 5. 0) sigħat wara t- teħid tad- doża (tmax).
The mean steady state plasma amprenavir trough concentration (Cmin) was 2.12 (1.77-2.54) µg/ ml and AUC0-tau was 39.6 (34.5– 45.3) h*µg/ ml.
Il- konċentrazzjoni medja fl- istat fiss ta ’ amprenavir fil- plażma fl - aktar livell baxx kienet 2. 12 (1. 77- 2. 54) μg/ ml u AUC0- tau kienet 39. 6 (34. 5- 45. 3) h* μg/ ml.
Administration of the fosamprenavir oral suspension formulation with a high fat meal (967 kcal, 67 grams fat, 33 grams protein, 58 grams carbohydrate) reduced plasma amprenavir AUC(0- ∞) by 28% and Cmax by 46% and delayed Tmax by 0.72 hours.
42 It- teħid ta ’ fosamprenavir fil- formolazzjoni ta ’ sospensjoni orali ma ’ ikla b’ ħafna xaħam (967 kcal, 67 gramma ta ’ xaħam, 33 gramma proteina, 58 gramma karboidrati) naqqas l- AUC (0- ∞) ta ’ amprenavir fil- plażma b’ madwar 28% u s- Cmax b ’ 46% u ttardja Tmax b’ 0. 72 siegħa.
For adult patients the fosamprenavir oral suspension should be taken without food and on an empty stomach.
Għal pazjenti adulti is - sospensjoni orali ta ’ fosamprenavir għandha tittieħed mingħajr ikel fuq stonku vojt.
In children and adolescents the fosamprenavir oral suspension should be taken with food.
Fi tfal u adolexxenti is- sospensjoni orali ta ’ fosamprenavir għandha tittieħed ma ’ l- ikel.
The dose recommendations for this population therefore take into account the observed food effect (see section 4.2).
Għaldaqstant ir - rakkomandazzjonijiet għad- doża għal din il- popolazzjoni jieħdu f’ kunsiderazzjoni l- effett osservat bl - ikel (ara sezzjoni 4. 2)
The apparent volume of distribution of amprenavir following administration of Telzir is approximately 430 l (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.
Jidher li l- volum tad- distribuzzjoni ta ’ amprenavir wara li jittieħed Telzir, huwa ta ’ madwar 430 1( 6 1/ kg jekk tieħu piż ta ’ ġisem ta ’ 70kg), li jissuġġerixxi li l- volum tad- distribuzzjoni huwa kbir, b’ amprenavir jippenetra liberament fit- tessuti tal- ġisem lil hinn sewwa miċ- cirkolazzjoni sistemika.
Concentrations of AAG have been shown to decrease during the course of antiretroviral therapy.
Ġie muri li l- konċentrazzjonijiet ta ’ AAG naqsu waqt kura b’ mediċini antiretrovirali.
CSF penetration of amprenavir is negligible in humans.
Il- penetrazzjoni CSF ta ’ amprenavir fis- CSF fil- bniedem hi ftit li xejn.
Fosamprenavir is rapidly and almost completely hydrolysed to amprenavir and inorganic phosphate as it is absorbed through the gut epithelium, following oral administration.
Fosamprenavir jiġi idrolizzat malajr u kważi kompletament f’ amprenavir u fosfat inorganiku waqt li jkun qed jiġi assorbit mill- epitelju ta ’ l- imsaren, wara li jittieħed mill- ħalq.
The primary route of metabolism is via the cytochrome P450 3A4 enzyme.
Ir- rotta ewlenija tal - metaboliżmu hi permezz ta ’ l- enzima ċitokromju P450 3A4.
Therefore medicinal products that are inducers, inhibitors or substrates of CYP3A4 must be used with caution when administered concurrently with Telzir with ritonavir (see sections 4.3 and 4.5).
Għalhekk prodotti mediċinali li huma indjusers jew huma impedituri jew substrati ta ’ CYP3A4 għandhom jintużaw b’ prekawzjoni meta jingħataw flimkien ma ’ Telzir b’ ritonavir (ara t- taqsimiet 4. 3 u 4. 5)
42 Elimination
Eliminazzjoni
The primary route of elimination of amprenavir is via hepatic metabolism with less than 1% excreted unchanged in the urine and no detectable amprenavir in faeces.
Ir- rotta ewlenija ta ’ mnejn jiġi eliminat amprenavir hi permezz ta ’ metaboliżmu fil- fwied u l- ammont mhux metabolizzat li jispiċċa fl- awrina huwa ta ’ inqas minn 1% u fil- purgar ma jkun hemm kważi xejn.
Metabolites account for approximately 14% of the administered amprenavir dose in the urine, and approximately 75% in the faeces.
Il - metaboliti fl- awrina jagħmlu tajjeb għal madwar 14% tad- doża ta ’ amprenavir li tkun ingħatat, u għal madwar 75% fil - purgar.
Compared to the historical adult population receiving fosamprenavir / ritonavir 700 / 100 mg twice daily, 12 to 18 year old subjects had 20% lower plasma APV AUC(0- 24), 23% lower Cmax, and 20% lower Cmin values.
43 12 u t- 18 il- sena kellhom valuri ta ’ AUC ta ’ APV aktar baxx fil- plażma b’ 20% (0- 24), Cmax aktar baxx bi 23% u Cmin aktar baxx b’ 20%.
Compared to the historical adult population receiving fosamprenavir with ritonavir 700 mg / 100 mg twice daily, a subset of five pediatric subjects ages 6 to < 24-months receiving fosamprenavir / ritonavir 45/ 7 mg/ kg twice daily demonstrated that despite an approximate 5-fold increase in fosamprenavir and ritonavir doses on a mg/ kg basis, plasma amprenavir AUC(0-τ) was approximately 48% lower, Cmax 26% lower, and Cτ 29% lower in the paediatric subjects.
Meta mqabbla ma ’ popolazzjoni adulta li fil- passat ħadu fosamprenavir ma 'ritonavir 700mg / 100mg darbtejn kuljum, grupp sekondarju ta' ħames suġġetti pedjatriċi ta ’ bejn is- 6 u < 24 xahar li ħadu fosamprenavir / ritonavir 45/ 7 mg/ kg darbtejn kuljum urew li għalkemm kien hemm żieda ta ’ bejn wieħed u ieħor 5 darbiet fid- doża ta ’ fosamprenavir u ritonavir fuq bażi ta ’ mg/ kg, l- AUC (0- τ) ta ’ amprenavir fil- plażma kien bejn wieħed u ieħor 48% aktar baxx, Cmax 26% aktar baxx u Cτ 29% aktar baxx f’ suġġetti pedjatriċi.
In subjects with mild hepatic impairment (Child-Pugh score of 5-6), the dosage regimen of fosamprenavir 700 mg twice daily with a reduced dosing frequency of ritonavir 100 mg once daily
F’ suġġetti b’ indeboliment tal- fwied ħafif (Child- Pugh score ta ’ 5- 6), is- sistema ta ’ dożaġġ ta ’ fosamprenavir 700 mg darbtejn kuljum flimkien ma ’ ritonavir 100mg bil- frekwenza tad- doża mnaqqsa għal darba kuljum waslet għal Cmax ta 'amprenavir ġol- plażma kemm kemm ogħla (17%), għal AUC (0- 12) ta ’ amprenavir ġol- plażma kemm kemm ogħla (22%), għall- livell simili ta ’ C12 ta' amprenavir totali fil- plażma u livell ta ’ C12 ta ’ amprenavir mhux marbut fil- plażma ta ’ bejn wieħed u ieħor 117% ogħla meta mqabbla ma ’ dawk ta ’ suġġetti b’ funzjoni tal- fwied normali li qegħdin jirċievu s- sistema ta ’ dożaġġ standard ta ’ fosamprenavir / ritonavir 700 mg / 100 mg darbtejn kuljum.
43 provided slightly higher plasma amprenavir Cmax (17%), slightly higher plasma amprenavir AUC(0-12) (22%), similar plasma total amprenavir C12 values and approximately 117% higher plasma unbound amprenavir C12 values compared to subjects with normal hepatic function receiving the standard fosamprenavir / ritonavir 700 mg / 100 mg twice daily regimen.
F’ suġġetti b’ indeboliment tal- fwied moderat (Child- Pugh score ta ’ 7- 9), huwa stmat li doża mnaqqsa ta ’ fosamprenavir 450 mg darbtejn kuljum flimkien ma ’ ritonavir 100mg bil- frekwenza tad- doża mnaqqsa għal darba kuljum twassal għal- livell simili ta ’ Cmax u AUC (0- 12) ta 'amprenavir ġol- plażma, imma twassal għal- livell ta ’ C12 ta ’ amprenavir totali fil- plażma ta ’ bejn wieħed u ieħor 35% iżjed baxx u livell ta ’ C12 ta ’ amprenavir mhux marbut fil- plażma ta ’ bejn wieħed u ieħor 88% ogħla min dik milqugħa f’ suġġetti b’ funzjoni tal- fwied normali li qed jirċievu s- sistema ta ’ dożaġġ standard ta ’ fosamprenavir / ritonavir 700 mg / 100 mg darbtejn kuljum.
In subjects with moderate hepatic impairment (Child-Pugh score of 7-9), a reduced dose of fosamprenavir 450 mg twice daily with a reduced dosing frequency of ritonavir 100 mg once daily is predicted to deliver similar plasma amprenavir Cmax and AUC(0-12), but approximately 35% lower plasma total amprenavir C12 values and approximately 88% higher plasma unbound amprenavir C12 values than achieved in subjects with normal hepatic function receiving the standard fosamprenavir with ritonavir 700 mg / 100 mg twice daily regimen.
F’ suġġetti b’ indebboliment sever tal- fwied (Child- Pugh score ta ’ 10- 13), doża mnaqqsa ta ’ fosamprenavir 300mg darbtejn kuljum bi frekwenza ta ’ dożaġġ ta ’ ritonavir imnaqqsa għal 100mg
In subjects with severe hepatic impairment (Child-Pugh score of 10-13), a reduced dose of fosamprenavir 300 mg twice daily with a reduced dosing frequency of ritonavir 100 mg once daily delivered 19% lower plasma amprenavir Cmax, 23% lower AUC(0-12), and 38% lower C12 values, but similar unbound plasma amprenavir C12 values than achieved in subjects with normal hepatic function receiving the standard fosamprenavir with ritonavir 700 mg / 100 mg twice daily regimen.
44 darba kuljum wassal 19% ta ’ amprenavir Cmax anqas fil- plażma, 23% anqas AUC (0- 12), u 38% anqas fil- valur ta ’ C12, imma valuri simili ta ’ C12 ta ’ amprenavir fil- plażma minn dawk f’ suġġetti b’ funzjoni normali tal- fwied li ħadu sistema ta ’ kura standard b’ fosamprenavir ma ’ ritonavir 700mg / 100mg darbtejn kuljum.
Fosamprenavir with ritonavir was generally well-tolerated in subjects with mild, moderate, or severe hepatic impairment, and these regimens had similar adverse event and clinical laboratory profiles as previous studies of HIV-1 infected subjects with normal hepatic function.
Il- biċċa l- kbira ta ’ suġġetti b’ indeboliment tal- fwied ħafif, moderat jew sever felħu għat- trattament b ’ fosamprenavir ma ’ ritonavir u dawn s- sistemi ta 'trattament urew profil ta ’ effetti avversi u profil kiniku tal- laboratorju simili għal dawk f’ studji li saru qabel f’ suġġetti bl- infezzjoni HIV- 1 b’ funzjoni tal- fwied normali.
In rabbits, systemic exposure at the high dose level was only 0.3 times human exposure at the maximum clinical dose and thus the development toxicity of fosamprenavir has not been fully determined.
Fil- fniek, esponiment sistemiku għal dożi għolja kien biss ta ’ 0. 3- il darba ta ’ l- esponiment tal- bniedem fl- ogħla dożi kliniċi u għalhekk it - tossiċità ta ’ waqt l- iżvilupp ta ’ fosamprenavir ma ġietx stabbilita għal kollox.
In rats exposed pre- and post-natally to fosamprenavir, pups showed impaired physical and functional development and reduced growth.
F’ firien li ħadu fosamprenavir qabel u wara t- twelid, iż- żgħar urew nuqqas ta ’ żvilupp fiżiku u funzjonali u kibru bil - mod.
The relevance of the hepatocellular findings in the rodents for humans is uncertain;
Fi studji fit- tul dwar karċinoġeniċità b’ fosamprenavir fi ġrieden u firien, kien hemm żiediet f’ adenomi epatoċellulari u kanċer epatoċellulari fi ġrieden meta kienu esposti għall- livelli ekwivalenti għal 0. 1 sa 0. 3 darbiet dawk fi bnedmin li ħadu 700mg ta ’ fosamprenavir u 100mg ritonavir darbtejn kuljum, u żidiet f’ adenomi epatoċellulari u adenomi follikulari tat- tirojde fi firien meta kienu esposti għall- livelli ekwivalenti għal 0. 3 sa 0. 6 darbiet dawk fi bnedmin li ħadu 700mg ta’ fosamprenavir u 100mg ta ’ ritonavir darbtejn kuljum.
44 however, there is no evidence from clinical trials or marketed use to suggest that these findings are of clinical significance.
Ma hijiex ċerta ir- rilevanza tas- sejbiet epatoċellulari f’ kull animal gerriemi għall- bnedmin; madankollu m’ hemm l- ebda evidenza minn studji kliniċi jew wara li jitqiegħed fis- suq li jissuġerixxi li dawn is- sejbiet fihom xi relevanza klinika.
The thyroid tumorigenic potential is regarded to be species-specific.
Studji b’ dożi ripetuti ta ’ fosamprenavir fil- firien ipproduċew effetti konsistenti ma ’ induzzjoni ta ’ enżima tal- fwied, li jippridisponi l- firien, imma mhux il- bniedem, għal neoplażmi tat- tirojde.
In rats only there was an increase in interstitial cell hyperplasia in males at exposure levels equivalent to 0.5-fold those in humans, and an increase in uterine endometrial adenocarcinoma in females at an exposure level equivalent to 1.1-fold those in humans.
Fil- firien biss kien hemm żieda fl- iperplasija fiċ- ċelloli interstitial fl- irġiel li kienu esposti għal livelli ekwivalenti għal 0. 5 darbiet dawk fil- bniedem, u żieda f’ adenokarċinoma ta ’ l- endometriju ta ’ l- utru fin- nisa meta kienu esposti għall- livelli ekwivalenti għal 1. 1 darbiet dawk fil- bniedem.
Hypromellose Sucralose Propylene glycol Methyl parahydroxybenzoate (E218) Propyl parahydroxybenzoate (E216) Polysorbate 80 Calcium chloride dihydrate Artificial grape bubblegum flavour Natural peppermint flavour Purified water
Hypromellose Sucralose Propylene glycol Methyl parahydroxybenzoate (E218) Propyl parahydroxybenzoate (E216) Polysorbate 80 Calcium chloride dihydrate Essenza artifiċjali ta ’ bubblegum ta ’ l- għeneb Essenza ta ’ peppermint naturali Ilma ippurifikat
Discard 28 days after first opening.
Għandu jintrema 28 jum wara li jinfetaħ.
HDPE bottle with a child resistant polypropylene closure containing 225 millilitres oral suspension.
Fliexken HDPE li jingħalqu b’ tapp tal- polypropylene li ma jistax jinfetaħ minn tfal u li jkun fihom 225 millilitri ta ’ sospensjoni orali.
A 10 ml graduated polypropylene dosing syringe and polyethylene adapter are provided in the pack.
Siringa tal- polypropylene immarkata sa ’ 10 ml għad- dożaġġ,, u adapter tal- polyethylene huma wkoll provduti mal- pakkett.
Glaxo Group Ltd Greenford Road
Glaxo Group Ltd Greenford Road Greenford Middlesex UB6 0NN Renju Unit
Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http: / /www. emea. europa. eu
Informazzjoni ddettaljata dwar dan il- prodott tinstab fuq il- website ta ’ l- Aġenzija Ewropeja dwar il - Medicini (EMEA) http: // www. emea. europa
46 ANNEX II
47 ANNESS ll
47 A MANUFACTURING AUTHORISATION HOLDERS RESPONSIBLE FOR BATCH RELEASE
DETENUR TA ’ L- AWTORIZZAZZJONI TAL- MANIFATTURA RESPONSABBLI GĦALL- HRUĠ TAL- LOTT
Film-coated tablets Glaxo Wellcome Operations, Priory Street, Ware, Hertfordshire SG12 0DJ, United Kingdom
Glaxo Wellcome Operations, Priority Street, Ware, Hertfordshire, SG12 ODJ, Renju Unit.
Oral suspension Glaxo Wellcome GmbH & Co KG, Industriestrasse 32-36, D-23843, Bad Oldesloe, Germany
KG, Industriestrasse 32- 36, 23843 Bad Oldesloe, Il- Ġermanja.
The printed package leaflet of the medicinal product must state the name and address of the manufacturer responsible for the release of the concerned batch.
Fuq il- fuljett ta` tagħrif tal- prodott mediċinali għandu jkun hemm l- isem u l- indirizz tal- manifattur responsabbli għall- ħruġ tal- lott konċernat.
Summary of Product Characteristics, section 4.2).
Sommarju tal- Karatteristiċi tal - Prodott, sezzjoni, 4. 2)
Not applicable.
Ma ’ jgħoddx f’ dan il- każ.
The MAH must ensure that the system of pharmacovigilance, as described in version 1 presented in Module 1.8.1 of the Marketing Authorisation Application, is in place and functioning before and whilst the product is on the market.
L- MAH għandu jassigura li s- sistema ta ’ farmakoviġilanza, kif deskritta f’ verżjoni 1 ippreżentata fil - Module 1. 8. 1 ta ’ l- Applikazzjoni għat- Tqegħid fis- Suq hija f’ postha u tiffunzjona qabel u waqt li l - prodott ikun fis- suq.
Risk Management Plan
Pjan ta ’ Immaniġġjar tar- Riskju
The MAH commits to performing the pharmacovigilance activities detailed in the Pharmacovigilance Plan as agreed in version 6.2 of the Risk Management Plan (RMP) presented in Module 1.8.2. of the Marketing Authorisation Application and any subsequent updates of the RMP agreed by the CHMP.
L- MAH jikkommetti li jwettaq l- attivitajiet ta ’ farmakoviġilanza ddettaljati fil- Pjan ta 'Farmakoviġilanza kif miftiehem f’ verżjoni 6. 2 tal- Pjan għall- Immaniġġjar tar- Riskju (RMP) ippreżentat f’ Module 1. 8. 2 ta ’ l- Applikazzjoni għat- Tqegħid fis- Suq u kull aġġornament ta ’ l- RMP iffissat mis- CHMP li jiġi wara.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the updated RMP should be submitted at the same time as the next Periodic Safety Update Report (PSUR).
Skond il- Ġwida tas- CHMP fuq is- Sistemi għall- Immaniġġjar tar- Riskju għall- prodotti mediċinali għall- użu fil- bniedem, l- RMP aġġornata għandha tiġi sottomessa fl- istess ħin mar- Rapport Perjodiku ta ’ l- Aġġornament għas- Sigurtà (PSUR).
In addition, an updated RMP should be submitted • When new information is received that may impact on the current Safety Specification, Pharmacovigilance Plan or risk minimisation activities • Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being reached • At the request of the EMEA
Barra minn hekk, RMP aġġornat għandu jkun sottomess • Meta tkun irċevuta informazzjoni ġdida li tistà tagħmel impatt fuq l- Ispeċifikazzjonijiet ta ’ Sigurtà kurrenti, il- Pjan ta ’ Farmakoviġilanza jew attivitajiet ta ’ tnaqqis ta ’ riskju. • F’ 60 ġurnata sa meta jrid tintlaħaq mira importanti (farmakoviġilanza jew tnaqqis ta ’ riskju) • Fuq talba ta ’ l- EMEA
49 ANNEX III
49 Rapporti Perjodiċi ta ’ l- Aġġornament tas- Sigurtà
LABELLING AND PACKAGE LEAFLET
Wara sottomissjoni ta ’ PSUR annwali f’ Diċembru ta ’ 2007 (li jkopri minn l- 20 ta ’ Ottubru 2006 sal - 21 ta ’ Ottubru 2007), l- MAH għandha tissottometti PSURs kull 6 xhur sakemm is- CHMP ma tagħtix istruzzjonijiet oħra.
51 PARTICULARS TO APPEAR ON THE OUTER PACKAGING
TIKKETTA
OUTER CARTON FOR TABLETS
52 TAGĦRIF LI GĦANDU JIDHER FUQ IL- PAKKETT TA ’ BARRA IL- PAKKETT TA ’ BARRA GĦALL- PILLOLI
Telzir 700 mg film-coated tablets Fosamprenavir
Telzir 700 mg Pilloli miksijin b’ rita Fosamprenavir
Each film-coated tablet contains 700 mg fosamprenavir as fosamprenavir calcium (equivalent to approximately 600 mg of amprenavir)
Kull pillola miksija b’ rita fiha 700 mg fosamprenavir bħala fosamprenavir calcium (ekwivalenti għal madwar 600 mg amprenavir)
Glaxo Group Ltd Greenford Middlesex UB6 0NN United Kingdom
Glaxo Group Ltd Greenford Road Greenford Middlesex UB6 0NN Renju Unit
53 PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING
54 TAGĦRIF LI GĦANDU JIDHER FUQ IL- PAKKETT LI JMISS MAL- PRODOTT
BOTTLE LABEL FOR TABLETS
TIKKETTA TA ’ FUQ IL- FLIXKUN GĦALL- PILLOLI
Read the package leaflet before use
Aqra l- fuljett ta ’ tagħrif qabel tibda l- użu
OUTER CARTON FOR ORAL SUSPENSION
TIKKETTA TA ’ FUQ IL- PAKKETT GĦAS- SOSPENSJONI ORALI
Telzir 50 mg/ ml oral suspension Fosamprenavir
Telzir 50 mg/ ml sospensjoni orali Fosamprenavir
Each ml of oral suspension contains 50 mg fosamprenavir as fosamprenavir calcium (equivalent to approximately 43 mg of amprenavir)
Kull ml ta ’ sospensjoni orali fih 50 mg fosamprenavir bħala fosamprenavir calcium (ekwivalenti għal madwar 43 mg amprenavir)
This product also contains preservatives: methyl parahydroxybenzoate (E218) and propyl parahydroxybenzoate (E216), see leaflet for further information
Methyl parahydroxybenzoate (E218) u propyl parahydroxybenzoate (E216), ara l- fuljett għal aktar tagħrif
Bottle with 225 ml oral suspension A 10 ml graduated dosing syringe and adapter are also provided in the pack
Flixkun ta ’ 225 ml sospensjoni orali Siringa immarkata ta ’ 10 ml għad- dożaġġ u adapter huma wkoll provduti fil- pakkett
Shake bottle vigorously before use
Ħawwad sew il- flixkun qabel użu
Discard 28 days after first opening
Armih wara 28 jum minn meta jkun infetaħ
Do not freeze
Tiffriżahx
57 PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING
58 TAGĦRIF LI GĦANDU JIDHER FUQ IL- PAKKETT LI JMISS MAL- PRODOTT
BOTTLE LABEL FOR ORAL SUSPENSION
TIKKETTA TA ’ FUQ IL- FLIXKUN GĦAS- SOSPENSJONI ORALI