qanastek/EMEA-V3 huggingface dataset:
Cross-resistance in vitro in viruses resistant to other protease inhibitors Atazanavir susceptibility was evaluated in 943 clinical isolates from patients without prior atazanavir exposure and exhibited a wide array of genotypic and phenotypic patterns.
Reżistenza inkroċjata in vitro f’ virusijiet reżistenti għal inibituri protease oħra Is- suxxettibbilità għal atazanavir ġiet evalwata f' 943 iżolat kliniku minn pazjenti li ma kellhomx esponiment preċedenti għal atazanavir u wrew firxa sħiħa ta ’ mudelli ġenotipiċi u fenotipiċi.
In vitro, there was a clear trend toward decreased susceptibility to atazanavir as isolates exhibited high resistance levels to
In vitro, kien hemm tendenza ċara lejn suxxettibbilità mnaqqsa għal atazanavir hekk kif l- iżolati wrew reżistenza kbira għal ħafna inibituri protease.
In general, susceptibility to atazanavir was retained (83% of isolates displayed < 2.5 fold change in EC50) among isolates resistant to no more than 2 protease inhibitors.
B' mod ġenerali, is- suxxettibbilità għal atazanavir inżammet (83% ta 'l- iżolati wrew bidla ta' < 2. 5 drabi fl- EC50) inżammet fost l- iżolati reżistenti għal mhux aktar minn 2 inibituri protease.
Eighteen percent of isolates had 4 or more of the following 6 substitutions considered critical substitutions for protease inhibitors: positions L10, M46, I54, V82, I84, and L90.
Tmintax fil- mija ta 'l- iżolati kellhom 4 jew aktar mis- sostituzzjonijiet segwenti kkunsidrati bħala sostituzzjonijiet kritiċi għall- inibituri protease: pożizzjonijiet L10, M46, I54, V82, I84, u L90.
These isolates expressed a median fold change in EC50 relative to wildtype of 12.0 for atazanavir.
Dawn l - iżolati wrew bidla medja fl- EC50 għall- wildtype ta '12. 0 għal atazanavir.
Therefore, viral isolates having at least 4 of these specific mutations would be considered resistant for atazanavir.
Għalhekk, iżolati virali li jkollhom mill- anqas 4 minn dawn il- bidliet speċifiċi jkunu kkunsidrati bħala reżistenti għal atazanavir.
Clinical results In antiretroviral naive patients Study 138 is an international randomised, open-label, multicenter, prospective trial of 883 antiretroviral treatment naïve patients comparing REYATAZ/ ritonavir (300 mg/ 100 mg once daily) to lopinavir/ ritonavir (400 mg/ 100 mg twice daily), each in combination with fixed dose tenofovir/ emtricitabine (300 mg/ 200 mg tablets once daily).
Riżultati kliniċi F' pazjenti li ma jkunux ħadu kura antiretrovirali qabel Studju 138 huwa prova prospettiva, multiċentri, open- label, randomizzata, internazzjonali ta '883 pazjent li ma ħadux kura antiretrovirali qabel, li tqabbel REYATAZ/ ritonavir (300 mg/ 100 mg darba kuljum) ma' lopinavir/ ritonavir (400 mg/ 100 mg darbtejn kuljum), kull waħda flimkien ma 'doża fissa ta' tenofovir/ emtricitabine (pilloli ta '300 mg/ 200 mg darba kuljum).
The mean baseline CD4 cell count was 214 cells/ mm3 (range:
L- għadd medju ta 'ċelloli CD4 fil - linja bażi kien ta' 214- il ċellola/ mm3 (medda:
2 to 810 cells/ mm3) and mean baseline plasma HIV-1 RNA was 4.94 log10 copies/ ml (range:
2 sa 810 ċelloli / mm3) u l- medja ta 'HIV- 1 RNA fil - plasma fil- linja bażi kienet ta' 4. 94 log10 kopji/ ml (medda:
2.6 to 5.88 log10 copies/ ml).
2. 6 sa 5. 88 log10 kopji/ ml).
The REYATAZ/ ritonavir arm has similar (non-inferior) antiviral efficacy compared to the lopinavir/ ritonavir arm, as assessed by the proportion of patients with HIV RNA < 50 copies/ ml at week 48:
Il- fergħa ta 'REYATAZ/ ritonavir kellha effikaċja antivirali simili (mhux inferjuri) meta mqabbla mal- fergħa ta' lopinavir/ ritonavir, kif evalwat mill- proporzjon ta 'pazjenti b' HIV RNA < 50 kopji/ ml f' ġimgħa 48:
78% of patients on REYATAZ/ ritonavir compared to 76% on lopinavir/ ritonavir (difference estimate of ATV/ RTV-LPV/ RTV:
78% tal- pazjenti fuq REYATAZ/ ritonavir meta mqabbel ma '76% fuq lopinavir/ ritonavir (stima tad - differenza ta' ATV/ RTV- LPV/ RTV:
1.7% [95% CI, -3.8%, 7.1%] according to the Confirmed Virologic Response (CVR) Non-Completer = Failure (NC = F) definition of response.
1. 7% [95% CI, - 3. 8%, 7. 1%] skond id- definizzjoni ta 'rispons tar - Rispons Viroloġiku Ikkonfermat (CVR) ta' Non- Completer = Failure (NC = F).
In a per protocol analysis which excluded non-completers (i. e. patients who discontinued before the week 48 HIV RNA assessment) and patients with major protocol deviations, the proportion of patients with HIV RNA < 50 copies/ ml at week 48 was 86% (338/ 392) for REYATAZ/ ritonavir and 89% (332/ 372) for lopinavir/ ritonavir (difference estimate of ATV/ RTV-LPV/ RTV: -3% [95% CI, -7.6%, 1.5%].
F' analiżi skond il- protokoll li ma inkludietx pazjenti li ma komplewx (jiġifieri pazjenti li waqfu qabel il- kejl ta 'l- HIV RNA f' ġimgħa 48) u pazjenti b' devjazzjonijiet kbar mill- protokoll, il- proporzjon ta' pazjenti b' HIV RNA < 50 kopji/ ml f' ġimgħa 48 kien ta '86% (338/ 392) għal REYATAZ/ ritonavir u 89% (332/ 372) għal lopinavir/ ritonavir (differenza fl- istima ta' ATV/ RTV- LPV/ RTV: - 3% [95% CI, - 7. 6%, 1. 5%].
Table 2:
16 Tabella 2:
Efficacy Outcomes at Week 48 (Study 138) for the CVR (NC=F) REYATAZ/ ritonavira (300 mg/ 100 mg once daily)
REYATAZ/ ritonavira (300 mg/ 100 mg darba kuljum)
analysis lopinavir/ ritonavirb (400 mg/ 100 mg twice daily)
lopinavir/ ritonavirb (400 mg/ 100 mg darbtejn kuljum)
Parameter
Parametru HIV RNA < 50 kopja/ ml,% c
HIV RNA < 50 copies/ ml,% c All patients Baseline Characteristics HIV RNA
Il- pazjenti kollha Karatteristiċi tal- Linja Bażi HIV RNA
< 100,000 copies/ ml ≥ 100,000 copies/ ml
< 100, 000 kopja/ ml
82 (n=217d) 74 (n=223)
81 (n=218)
81 (n=218) 72 (n=225)
74 (n=223 78 (n=58)
16 CD4 count
72 (n=225)
< 50 cells/ mm3 50 to < 100 cells/ mm3
< 50 ċellola/ mm3
100 to < 200 cells/ mm3 ≥ 200 cells/ mm3
100 sa < 200 ċellola/ mm3 ≥200 ċellola/ mm3
HIV RNA Mean Change from Baseline, log10 copies/ ml
Bidla Medja fl- HIV RNA mil- Linja Bażi, log10 kopji/ ml
CD4 Mean Change from Baseline, cells/ mm3 All patients Baseline Characteristics HIV RNA
Bidla Medja fil- CD4 mil- Linja Bażi, ċelloli/ mm Il- pazjenti kollha Karatteristiċi tal- Linja Bażi HIV RNA
< 100,000 copies/ ml ≥ 100,000 copies/ ml a
< 100, 000 kopja/ ml ≥100, 000 kopja/ ml a
REYATAZ/ RTV with tenofovir/ emtricitabine (fixed dose 300 mg/ 200 mg tablets once daily). b Lopinavir/ RTV with tenofovir/ emtricitabine (fixed dose 300 mg/ 200 mg tablets once daily). c Intent-to-treat analysis, with missing values considered as failures. d Number of patients evaluable.
REYATAZ/ RTV ma ’ tenofovir/ emtricitabine (pilloli ta 'doża fissa ta' 300 mg/ 200 mg darba kuljum). b Lopinavir/ RTV ma ’ tenofovir/ emtricitabine (pilloli ta 'doża fissa ta' 300 mg/ 200 mg darba kuljum). c Analiżi ta 'dawk bil- Ħsieb ta' kura, bil- valuri nieqsa kkunsidrati bħala fallimenti. d Numru ta 'pazjenti li setgħu jiġu evalwati.
In antiretroviral experienced patients Study 045 is a randomised, multicenter trial comparing REYATAZ (300 mg once daily) with ritonavir (100 mg once daily) to REYATAZ (400 mg once daily) with saquinavir soft gelatine capsules (1,200 mg once daily), and to lopinavir + ritonavir (400/ 100 mg fixed dose combination twice daily), each in combination with tenofovir (see sections 4.5 and 4.8) and one NRTI, in 347 (of 358 randomised) patients with virologic failure on two or more prior regimens containing at least one PI, NRTI, and NNRTI.
F' pazjenti li diġà ħadu kura antiretrovirali Studju 045 huwa studju b' aktar minn ċentru wieħed, fuq bażi każwali li jqabbel REYATAZ (300 mg darba kuljum) ma ’ ritonavir (100 mg darba kuljum) ma ’ REYATAZ (400 mg darba kuljum) ma ’ saquinavir f’ kapsuli tal- ġelatina ratba (1, 200 mg darba kuljum), u ma ’ lopinavir + ritonavir (400/ 100 mg flimkien f’ doża fissa kombinata, darbtejn kuljum), kull waħda flimkien ma ’ tenofovir (ara 4. 5 u 4. 8) u NRTI wieħed, f’ 347 (minn 358 fuq bażi każwali) pazjenti li kellhom falliment viroloġiku f' żewġ kuri jew iżjed mogħtija qabel li kien fihom għallinqas PI, NRTI u NNRTI wieħed.
For randomised patients, the mean time of prior antiretroviral exposure was 138 weeks for PIs, 281 weeks for NRTIs, and 85 weeks for NNRTIs.
F’ pazjenti fuq bażi każwali l- ħin medju ta ’ l- espożizzjoni preċedenti antiretrovirali kien ta ’ 138 ġimgħa għal PIs, 281 ġimgħa għal NRTIs, u 85 ġimgħa għal NNRTIs.
At baseline, 34% of patients were receiving a PI and 60% were receiving an NNRTI.
Bħala linja bażo, 34% tal- pazjenti ħadu PI u 60% ħadu NNRTI.
Fifteen of 120 (13%) patients in the REYATAZ + ritonavir treatment arm and 17 of 123 (14%) patients in the lopinavir + ritonavir arm had four or more of the PI substitutions L10, M46, I54, V82, I84, and L90.
Ħmistax mill- 120 (13%) pazjent li ħadu REYATAZ + ritonavir u 17 mill- 123 (14%) pazjent li ħadu lopinavir + ritonavir kellhom erba 'sostituzzjonijiet ta ’ L10, M46, I54, V82, I84, u L90 jew iżjed.
Thirty-two percent of patients in the study had a viral strain with fewer than two NRTI substitutions.
Tnejn u tletin fil- mija tal- pazjenti fl- istudju kellhom razza virali b’ inqas minn żewġ sostituzzjonijiet ta 'NRTI.
14 to 1,543 cells/ mm3) and the mean baseline plasma HIV-1 RNA level was 4.4 log10 copies/ ml (range:
Fil- linja bażi, il- medja ta ’ ammont ta ’ ċelluli CD4 kien 337 ċelluli/ mm3 (bejn 14 u 1, 543 ċelluli/ mm3) u l- medja tal- livell fil- plażma ta ’ l- HIV - 1 RNA kien 4. 4 log10 kopji/ ml (bejn 2. 6 u 5. 88 log10 kopji/ ml).
The population included in this study was moderately pretreated.
Il- grupp ta ’ nies li ħadu sehem f’ dan l - istudju ġew ikkurati minn qabel moderatament.
The primary endpoint was the time-averaged difference in change from baseline in HIV RNA through 48 weeks.
Il- punt finali primarju kien id- differenza fuq medja ta 'żmien fil- bidla tal- HIV RNA mil- linja bażi matul 48 ġimgħa.
Through 48 weeks of treatment, the decreases from baseline in HIV RNA levels (primary endpoint) were 1.93 log10 copies/ ml for REYATAZ + ritonavir and 1.87 log10 copies/ ml for lopinavir + ritonavir.
Matul it- 48 ġimgħa ta ’ kura, it- tnaqqis mil- linja bażi fil- livelli ta 'HIV RNA (il- punt finali primarju) kien ta ’ 1. 93 log10 kopji/ ml għal REYATAZ + ritonavir u 1. 87 log10 kopji/ ml għal lopinavir + ritonavir.
REYATAZ + ritonavir was similar (non-inferior) to lopinavir + ritonavir on this efficacy measure (time-averaged difference of 0.13, 97.5% confidence interval [-0.12, 0.39]).
REYATAZ + ritonavir kien simili (mhux inferjuri) għal lopinavir + ritonavir fuq din il - miżura ta 'effikaċja (id- differenza fuq medja ta' żmien ta '0. 13, intervall ta' kunfidenza ta '97. 5% [- 0. 12, 0. 39]).
Consistent results were obtained with the last observation carried forward method of analysis (time-averaged difference of 0.11, 97.5% confidence interval [-0.15, 0.36]).
Kien hemm riżultati konsistenti bil- metodu ta ’ analiżi fejn l- aħħar osservazzjoni ġiet mgħoddija 'l quddiem (differenza fuq medja ta' żmien ta ’ 0. 11, intervall ta ’ fiduċja 97. 5% [- 0. 15, 0. 36]).
The proportions of patients with HIV RNA < 400 copies/ ml in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 53% and 54%, respectively, by intent-to-treat analysis, with missing values considered as failures.
Il- proporzjon ta ’ pazjenti bl- HIV RNA < 50 kopji/ ml li
The proportions of patients with HIV RNA < 50 copies/ ml in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 36% and 42%, respectively.
17 ħadu REYATAZ + ritonavir u lopinavir + ritonavir arm kien rispettivament ta ’ 36% u 42%.
By as-treated analysis, excluding missing values, the proportions of patients with HIV RNA < 400 copies/ ml (< 50 copies/ ml) in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 55% (40%) and 56% (46%), respectively.
Skond l - analiżi hekk kif ikkurati, meta teskludi l- valuri nieqsa, il- proporzjon ta ’ pazjenti bl- HIV RNA < 400 kopji/ ml (< 50 kopji/ ml) li ħadu REYATAZ + ritonavir u oħrajn li ħadu lopinavir + ritonavir kien ta '55% (40%) u 56% (46%) rispettivament.
The mean increases from baseline in CD4 cell count were 110 cells/ mm3 and 121 cells/ mm3 in the REYATAZ + ritonavir and lopinavir + ritonavir arms, respectively.
Iż- żidiet medja fil- linja bażi ta ’ ammont ta ’ ċelluli CD4 kienu 110 ċelluli/ mm3 u 121 ċelluli/ mm3 għall- pazjenti li ħadu REYATAZ + ritonavir u lopinavir + ritonavir rispettivament.
Analyses of data through 96 weeks of treatment demonstrated durability of antiviral activity.
Analiżi tad- data matul is- 96 ġimgħa ta 'kura wrew id- dewmien ta' l- attività antivirali.
Mean HIV RNA changes from baseline at Week 96 (-2.29 log10 copies/ ml for REYATAZ + ritonavir and -2.08 log10 copies/ ml for lopinavir + ritonavir, time-averaged difference of 0.14, 97.5% confidence interval [-0.13, 0.41]) met criteria for non-inferiority based on observed cases.
Il- bidliet medji mil- linja bażi fl- HIV RNA fis- 96 Ġimgħa (- 2. 29 log10 kopji/ ml għal REYATAZ + ritonavir u - 2. 08 log10 kopji/ ml għal lopinavir + ritonavir, differenza fuq medja ta 'żmien ta' 0. 14, intervall ta 'kunfidenza ta' 97. 5% [- 0. 13, 0. 41]) issodisfaw il- kriterji ta 'mingħajr inferjorità ibbażati fuq każijiet osservati.
Consistent results were obtained with the last observation carried forward method of analysis.
Inkisbu riżultati konsisitenti bil- metodu ta 'analiżi fejn l- aħħar osservazzjoni ġiet mgħoddija' l quddiem.
The proportions of patients with HIV RNA < 400 copies/ ml (< 50 copies/ ml) for REYATAZ + ritonavir were 43% (32%) and for
Il- proporzjon ta ’ pazjenti b' HIV RNA < 400 kopja/ ml (< 50 kopja/ ml) għal REYATAZ + ritonavir kien ta '43% (32%) u għal lopinavir + ritonavir kien ta' 46% (35%).
Patients completing treatment while in response after 48 weeks were censored.
Pazjenti li komplew il - kura waqt ir- rispons wara 48 ġimgħa ġew iċċensurati.
By as-treated analysis, excluding missing values, the proportions of patients with HIV RNA < 400 copies/ ml (< 50 copies/ ml) for REYATAZ + ritonavir were 84% (72%) and for lopinavir + ritonavir were 82% (72%).
Skond l- analiżi hekk kif trattati, meta teskludi l - valuri nieqsa, il- proporzjon ta ’ pazjenti bl- HIV RNA < 400 kopji/ ml (< 50 kopji/ ml) għal REYATAZ + ritonavir kien ta '84% (72%) u għal lopinavir + ritonavir kien ta' 82% (72%).
It is important to note that at time of the 96-week analysis, 48% of patients overall remained on study.
Importanti li wieħed jinnota li fil- ħin ta 'l- analiżi tas- 96 ġimgħa, 48% tal- pazjenti totali baqgħu fl- istudju.
Through 48 weeks of treatment, two types of analyses were performed based on baseline genotypic mutations.
Matul 48 ġimgħa ta 'kura, saru żewġ tipi ta' analiżi bbażati fuq linja bażi ta 'mutazzjonijiet ġenotipiċi.
The first consisted in assessing the HIV RNA change from baseline in the subgroup of patients with < or ≥ of 4 of the following set of mutations:
Ta 'l- ewwel kien jikkonsisti fil- valutazzjoni ta' bidla fl- HIV RNA mil- linja bażi fil- grupp ta 'pazjenti bi < jew ≥ ta' 4 tas- sett li ġej ta 'mutazzjonijiet:
10, 20, 24, 32, 33, 36, 46, 48, 50, 54, 63, 71, 73, 82, 84 and 90.
10, 20, 24, 32, 33, 36, 46, 48, 50, 54, 63, 71, 73, 82, 84 u 90.
The second consisted in assessing the HIV RNA change from baseline in the subgroup of patients with < or ≥ of 4 of the following more specific set of mutations:
Tat- tieni kien jikkonsisti fil- valutazzjoni ta 'bidla fl- HIV RNA mil- linja bażi fil- grupp ta' pazjenti bi < jew ≥ ta '4 tas- sett aktar speċifiku li ġej ta' mutazzjonijiet:
In the analysis performed for patients with ≥ 4 protease gene mutations among the following set of mutations 10, 20, 24, 32, 33, 36, 46, 48, 50, 54, 63, 71, 73, 82, 84 and 90, the results significantly favoured the lopinavir + ritonavir arm.
Fl- analiżi li saret għal pazjenti b '≥ 4 mutazzjonijiet tal- ġeni protease fost is- sett li ġej ta' mutazzjonijiet 10, 20, 24, 32, 33, 36, 46, 48, 50, 54, 63, 71, 73, 82, 84 u 90, ir- riżultati kienu mxaqilbin b' mod sinifikanti favur lopinavir + ritonavir.
There were too few patients with ≥ 4 of the second more specific set of mutations (i. e.
Kien hemm ftit wisqpazjenti b' ≥ 4 tat- tieni sett aktar speċifiku ta 'mutazzjonijiet (i. e.
10, 46, 54, 82, 84, 90) to assess the comparability of the REYATAZ + ritonavir and lopinavir + ritonavir regimens, but reduced virologic activity may be anticipated among patients with this resistance profile.
10, 46, 54, 82, 84, 90) biex jiġi kkalkulat kif REYATAZ + ritonavir jitqabbel ma 'lopinavir + ritonavir, imma attività viroloġika imnaqqsa tista' tkun mistennija fost pazjenti b' dan il- profil ta 'reżistenza.
REYATAZ + saquinavir was shown to be inferior to lopinavir + ritonavir.
REYATAZ + saquinavir jidher li hu inferjuri għal lopinavir + ritonavir.
The pharmacokinetics of atazanavir were evaluated in healthy adult volunteers and in HIV-infected patients; significant differences were observed between the two groups.
Il- farmakokinetika ta ’ atazanavir ġiet evalwata f’ voluntiera adulti b’ saħħithom u f’ pazjenti infettati bl- HIV; ma dehru ebda differenzi sinjifikanti bejn iż- żewġ gruppi.
The pharmacokinetics of atazanavir exhibit a non-linear disposition.
Il- farmakokinetiċi ta ’ atazanavir juru dispożizzjoni mhux lineari.
In healthy subjects, the AUC of atazanavir from the capsules and oral powder were similar.
F’ suġġetti b’ saħħithom, l- AUC ta ’ atazanavir għall- kapsuli u għat- trab orali kienu l- istess.
Absorption: in HIV-infected patients (n=33, combined studies), multiple dosing of REYATAZ 300 mg once daily with ritonavir 100 mg once daily with food produced a geometric mean (CV%) for atazanavir, Cmax of 4466 (42%) ng/ ml, with time to Cmax of approximately 2.5 hours.
Assorbiment: f’ pazjenti infettati bl- HIV, (n=33 studji kombinati), wara li ngħataw ħafna dożi ta ’ REYATAZ 300 mg darba kuljum b' ritonavir 100 mg darba kuljum ma ’ l- ikel, il- medja ġeometrika (CV%) għal atazanavir, Cmax ta ’ 4466 (42%) ng/ ml, b’ ħin għal Cmax ta ’ madwar 2. 5 sigħat (Tmax).
The geometric mean (CV%) for atazanavir Cmin and AUC was 654 (76%) ng/ ml and 44185 (51%) ng• h/ ml, respectively.
Il - medja ġeometrika (CV%) għal atazanavir Cmin u AUC kienet 654 (76%) ng/ ml u 44185 (51%) ng• h/ ml, rispettivament.
Food effect: co-administration of REYATAZ and ritonavir with food optimizes the bioavailability of atazanavir.
Effetti ta ’ l- ikel: l- għoti fl- istess ħin ta ’ REYATAZ u ritonavir ma ’ l- ikel jottimizza l- bijodisponibbiltà ta ’ atazanavir.
Co-administration of a single 300-mg dose of REYATAZ and 100-mg dose of ritonavir with a light meal resulted in a 33% increase in the AUC and a 40% increase in both the Cmax and the 24-hour concentration of atazanavir relative to the fasting state.
L- għoti fl- istess ħin ta ’ doża waħda ta ’ 300 mg dose ta ’ REYATAZ u ta ’ doża ta ’ 100 - mg ta ’ ritonavir ma ’ ikla ħafifa rriżultat f’ żieda ta ’ 33% fl- AUC u f’ żieda ta ’ 40% kemm fis- Cmax kif ukoll fil- konċentrazzjoni ta ’ 24 siegħa ta ’ atazanavir fir- rigward ta ’ l- istat ta ’ sawm.
Co-administration with a high-fat meal did not affect the AUC of atazanavir relative to fasting conditions and the Cmax was within 11% of fasting values.
L- għoti fl- istess ħin ta ’ ikla b’ ammont kbir ta ’ xaħam ma affettwax l- AUC ta ’ atazanavir fir- rigward tal- kundizzjonijiet ta ’ sawm u s- Cmax kien fi ħdan il- 11% tal- valuri ta ’ sawm.
The 24-hour concentration following a high fat meal was increased by approximately 33% due to delayed absorption; the median Tmax increased from 2.0 to 5.0 hours.
Il- konċentrazzjoni ta ’ 24 siegħa wara ikla b’ ħafna xaħam żdiedet b’ madwar 33% minħabba assorbiment imdewwem; it- Tmax medjan żdied minn 2. 0 għal 5. 0 sigħat.
Administration of REYATAZ with ritonavir with either a light or a high-fat meal decreased the coefficient of variation of AUC and Cmax by approximately 25% compared to the fasting state.
L- għoti ta ’ REYATAZ ma ’ ritonavir jew ma ’ ikla ħafifa jew ma ’ ikla li kien fiha ħafna xaħam, il- koeffiċjent tal- varjazzjoni ta ’ AUC u Cmax naqas bejn wieħed u ieħor b’ 25% meta
To enhance bioavailability and minimise variability, REYATAZ is to be taken with food.
Biex tiżdied il- bijo- disponibilità u titnaqqas il- varjabilità, REYATAZ għandu jittieħed ma ’ l- ikel.
Distribution: atazanavir was approximately 86% bound to human serum proteins over a concentration range of 100 to 10,000 ng/ ml.
Tqassim: atazanavir jeħel b' rata ta 'bejn wieħed u ieħor 86% mal- proteini tad- demm uman f’ konċentrazzjoni li tvarja minn 100 sa 10, 000 ng/ ml.
Atazanavir binds to both alpha-1-acid glycoprotein (AAG) and albumin to a similar extent (89% and 86%, respectively, at 1,000 ng/ ml).
Atazanavir jingħaqad kemm mal- glikoproteina alpha- 1- acid (AAG) kif ukoll ma ’ l- albumina bl- istess ammont (rispettivament 89% u 86% f’ 1, 000 ng/ ml).
In a multiple-dose study in HIV-infected patients dosed with 400 mg of atazanavir once daily with a light meal for 12 weeks, atazanavir was detected in the cerebrospinal fluid and semen.
Fi studju ta 'aktar minn doża waħda f’ pazjenti nfettati bl- HIV mogħtija dożi ta ’ 400 mg, atazanavir darba kuljum ma ’ ikla ħafifa għal 12- il ġimgħa, atazanavir instab fil- likwidu ċerebro- spinali u fis- semen.
Metabolism: studies in humans and in vitro studies using human liver microsomes have demonstrated that atazanavir is principally metabolised by CYP3A4 isozyme to oxygenated metabolites.
Metaboliżmu: minn studji fil- bniedem u minn studji in vitro fejn intużaw mikrosomi epatiċi umani sar magħruf li atazanavir ġie metabolizzat prinċipalment bl- iżożimu ta 'CYP3A4 għal metaboliti ossiġenati.
Metabolites are then excreted in the bile as either free or glucuronidated metabolites.
Il- metaboliti joħorġu fil- bili kemm bħala metaboliti liberi jew bħala metaboliti glukuronidati.
Additional minor metabolic pathways consist of N-dealkylation and hydrolysis.
Passaġġi metaboliċi oħra huma N- dealkilazzjoni u idrolisi.
Two minor metabolites of atazanavir in plasma have been characterised.
Ġew ikkaratterizzati żewġ metaboliti minuri ta ’ atazanavir fil- plażma.
Neither metabolite demonstrated in vitro antiviral activity.
L- ebda metabolit in vitro ma wera attività antivirali.
18 Elimination: following a single 400-mg dose of 14C-atazanavir, 79% and 13% of the total radioactivity was recovered in the faeces and urine, respectively.
Kif jitneħħa: wara doża waħda ta ’ 400 mg ta ’ 14C- atazanavir, 79% u 13% tat- total tar- radjuattività ġie rkuprat rispettivament fil- purgar u fl- urina.
Unchanged drug accounted for approximately 20% and 7% of the administered dose in the faeces and urine, respectively.
Mill- mediċina mogħtija, madwar 20% u 7% tal- mediċina mhux mibdula ġiet irkuprata rispettivament fil- purgar u fl- urina.
Mean urinary excretion of unchanged drug was 7% following 2 weeks of dosing at 800 mg once daily.
Il- medja ta ’ mediċina mhux mibdula li ħarġet fl- urina kienet ta ’ 7% wara ġimagħtejn li ngħatat doża ta ’ 800 mg darba kuljum.
In HIV-infected adult patients (n=33, combined studies) the mean half-life within a dosing interval for atazanavir was 12 hours at steady state following a dose of 300 mg daily with ritonavir 100 mg once daily with a light meal.
F’ pazjenti adulti infettati bl- HIV (n= 33, studji kombinati), il- half- life medju fi ħdan intervall ta ’ dożaġġ għal atazanavir kien ta ’ 12- il siegħa wara li l- pazjenti ngħataw doża ta ’ 300 mg kuljum ma ’ ritonavir 100 mg darba kuljum ma ’ ikla ħafifa.
Special populations
Popolazzjonjiet speċjali
Impaired renal function: in healthy subjects, the renal elimination of unchanged atazanavir was approximately 7% of the administered dose.
Indeboliment fil- funzjoni renali: f’ nies f’ saħħithom, l- eliminazzjoni renali ta ’ atazanavir mhux mibdul kienet ta ’ madwar 7% tad- doża li ngħatat.
There are no pharmacokinetic data available on patients with renal insufficiency (see section 4.2); however, the impact of renal impairment on atazanavir elimination is anticipated to be minimal.
M’ hemmx tagħrif farmakokinetiku fuq pazjenti b’ insuffiċjenza renali (ara sezzjoni 4. 2); madankollu, l- impatt ta ’ ħsara renali fuq l- eliminazzjoni ta ’ atazanavir huwa mistenni li jkun wieħed minimu.
Impaired hepatic function: atazanavir is metabolised and eliminated primarily by the liver.
Indeboliment fil- funzjoni tal- fwied: atazanavir jiġi metabolizzat u eliminat prinċipalment mill- fwied.
The effects of hepatic impairment on the pharmacokinetics of atazanavir after a 300 mg dose with ritonavir have not been studied.
Għad ma ġewx studjati l- effetti ta ’ ħsara epatika fuq il- farmakokinetika ta ’ atazanavir wara doża ta ’ 300 mg ma ’ ritonavir.
Concentrations of atazanavir with or without ritonavir are expected to be increased in patients with moderately or severely impaired hepatic function (see sections 4.2, 4.3, and 4.4).
Il- konċentrazzjoni ta ’ atazanavir ma ’ jew mingħajr ritonavir mistennija tiżdied f’ pazjenti li jbatu minn ħsara moderata jew qawwija fil- funzjoni epatika (ara sezzjonijiet 4. 2, 4. 3 and 4. 4).
Age/ Gender: a study of the pharmacokinetics of atazanavir was performed in 59 healthy male and female subjects (29 young, 30 elderly).
Età/ Sess: sar studju fuq il- farmakokinetika ta ’ atazanavir fuq 59 persuna f’ saħħithom, nisa u rġiel (29 żgħażagħ, 30 anzjani).
There were no clinically important pharmacokinetic differences based on age or gender.
Ma kienx hemm differenzi klinikament importanti fil- farmakokinetika minħabba l- età jew is- sess.
Race: a population pharmacokinetic analysis of samples from Phase II clinical trials indicated no effect of race on the pharmacokinetics of atazanavir.
Razza: skond l- analiżi farmakokinetika fuq popolazzjoni minn kampjuni ta ’ provi kliniċi ta ’ Fażi II, ma dehrux effetti fuq il- farmakokinetika ta ’ atazanavir minħabba r- razza.
Infants, toddlers, children, and adolescents: the pharmacokinetics of atazanavir is being studied after multiple doses in paediatric patients, stratified by age.
Trabi, tfal żgħar li għadhom kemm telqu jimxu, tfal u adoloxxenti: il- farmakokinetika ta ’ atazanavir qed tiġi studjata wara doża ripetuta f’ pazjenti tfal imqassma skond l- età.
There are insufficient data at this time to recommend a dose (see section 4.2).
Għalissa m’ hemmx biżżejjed tagħrif biex tkun tista ’ tiġi rrakkomandata d- doża (ara sezzjoni 4. 2).
In repeat-dose toxicity studies, conducted in mice, rats, and dogs, atazanavir-related findings were generally confined to the liver and included generally minimal to mild increases in serum bilirubin and liver enzymes, hepatocellular vacuolation and hypertrophy, and, in female mice only, hepatic single-cell necrosis.
Fi studji dwar l- effetti tossiċi minn dożi ripetuti fi ġrieden, firien u klieb, l- effetti relatati ma ’ atazanavir li nstabu kienu l- iktar limitati għall- fwied u kienu jinkludi ġeneralment żidiet minimali għal moderati fil- livelli tas- serum bilirubin u ta ’ l- enżimi tal- fwied, vakwolazzjoni u ipertrofija epatoċellulari, u, fil- ġrieden nisa biss, nekrosi epatika ta ’ ċellula waħda.
Systemic exposures of atazanavir in mice (males), rats, and dogs at doses associated with hepatic changes were at least equal to that observed in humans given 400 mg once daily.
Il- preżenza sistematika ta ’ atazanavir fil- ġrieden (irġiel), firien, u klieb f’ dożi li għandhom x’ jaqsmu ma bidliet epatiċi kienet l - istess daqs dik osservata fil- bniedem wara li ngħata doża ta ’ 400 mg darba kuljum.
In female mice, atazanavir exposure at a dose that produced single-cell necrosis was 12 times the exposure in humans given 400 mg once daily.
Fil- ġrieden nisa, l - espożizzjoni għal atazanavir għal doża li pproduċiet nekrosi ta ’ ċellula waħda kienet 12- il- darba iktar
Serum cholesterol and glucose were minimally to mildly increased in rats but not in mice or dogs.
Fil- firien, iżda mhux fil- ġrieden jew fil - klieb, iż- żidiet fil- livelli tas- serum kolesterol u tal- glucose kienu minn minimi għal moderati.
During in vitro studies, cloned human cardiac potassium channel (hERG), was inhibited by 15% at a concentration (30 μ M) of atazanavir corresponding to 30-fold the free drug concentration at Cmax in humans.
Waqt studji in vitro, materjal kardijaku uman ikklonjat tal- potassju (hERG), kien impedut bi 15% f' konċentrazzjoni (30 μM) ta 'atazanavir li tikkorrispondi għal 30- darba l- konċentrazzjoni ta' droga libera Cmax fin- nies.
Similar concentrations of atazanavir increased by 13% the action potential duration (APD90) in rabbit Purkinje fibres study.
Konċentrazzjnijiet simili ta 'atazanavir żiedu bi 13% iż- żmien li fih tista' ssir azzjoni (APD90) fi studju ta 'fibri tal- fenek Purkinje.
Electrocardiographic changes (sinus bradycardia, prolongation of PR interval, prolongation of QT interval, and prolongation of QRS complex) were observed only in an initial 2-week oral toxicity study performed in dogs.
Bidliet elettrokardjografiċi (sinus bradycardia, titwil ta ’ l- intervall PR, titwil ta ’ l- intervall QR u titwil tal- kumpless QRS) kienu osservati biss fi studju inizjali tat- tossiċità orali ta ’ ġimagħtejn, li sar fil- klieb.
Subsequent 9-month oral toxicity studies in dogs showed no drug-related electrocardiographic changes.
Studji susseggwenti ta 'tossiċità orali fil - klieb li damu 9 xhur ma wrew ebda bidla elettrokardjografika relatata mad- drogi.
The clinical relevance of these non-clinical data is unknown.
Ir- relevanza klinika ta ’ dan it- tagħrif mhux kliniku mhijiex magħrufa.
Potential cardiac effects of this product in humans cannot be ruled out (see sections 4.4 and 4.8).
Mhux eskluż il- potenzjal ta ’ l- effetti kardijaċi ta ’ dan il- prodott fil- bniedem (ara sezzjonijiet 4. 4 u 4. 8).
The potential for PR prolongation should be considered in cases of overdose (see section4.9).
F’ każi ta ’ doża eċċessiva, it- titwil ta ’ l- intervall PR għandu jiġi ikkonsidrat (ara sezzjoni 4. 9).
In a fertility and early embryonic development study in rats, atazanavir altered oestrus cycling with no effects on mating or fertility.
Fi studji fuq il- fertilità u l- iżvilupp kmieni embrijoniku fil- firien, atazanavir biddel iċ- ċiklu ta ’ l - oestrus bla ma kellu effett fuq it- tgħammir u fuq il- fertilità.
No teratogenic effects were observed in rats or rabbits at maternally toxic doses.
Ma ġewx osservati effetti teratoġeniċi fil - firien jew fil- fniek f’ dożi tossiċi materni.
In pregnant rabbits, gross lesions of the stomach and intestines were observed in dead or moribund does at maternal doses 2 and 4 times the highest dose administered in the definitive embryo-development study.
Fil- fniek tqal ġew osservati leżjonijiet imdaqqsin fl- istonku u fl- intestini tal- fenka mejta jew moribonda b’ dożi materni darbtejn u 4 darbiet l- ogħla doża amministrata waqt l- istudju dwar l- iżvilupp definittiv ta ’ l- embriju.
In the pre- and postnatal development assessment in rats, atazanavir
Fil- valutazzjoni ta ’ l- iżvilupp, qabel u wara t- twelid, fil- firien, atazanavir ġab tnaqqis temporanju fil - piż korporali tal- frieħ, b’ doża tossika materna.
Systemic exposure to atazanavir at doses that resulted in maternal toxicity was at least equal to or slightly greater than that observed in humans given 400 mg once daily.
Il- preżenza sistematika ta ’ atazanavir f’ dożi li wasslu għal tossiċità materna, kienet millinqas daqs jew xi ftit iktar minn dik osservata fil- bniedem meta mogħtija doża ta ’ 400 mg darba kuljum.
Atazanavir was negative in an Ames reverse-mutation assay but did induce chromosomal aberrations in vitro in both the absence and presence of metabolic activation.
Atazanavir ħareġ negattiv f’ analiżi ta ’ mutazzjoni- riversa ta ’ Ames iżda kkaġuna aberazzjonijiet kromosomali in vitro fl- assenza u fil- preżenza t’ attivazzjoni metabolika.
In in vivo studies in rats, atazanavir did not induce micronuclei in bone marrow, DNA damage in duodenum (comet assay), or unscheduled DNA repair in liver at plasma and tissue concentrations exceeding those that were clastogenic in vitro.
Fi studji in vivo f’ firien, atazanavir ma kkaġunax mikronuklei fl- għadam tal- mudullun, ħsara tad- DNA fid- duwodenu (analiżi kometa), jew fejqan mhux mistenni ta ’ DNA fil- fwied għall- konċentrazzjonijiet tal- plażma u tat - tessuti li jeċċedu dawk li kienu klastoġeniċi in vitro.
In long-term carcinogenicity studies of atazanavir in mice and rats, an increased incidence of benign hepatic adenomas was seen in female mice only.
Minn studji fit- tul tal- karċinoġenità ta ’ atazanavir fil- ġrieden u fil- firien, kien hemm numru akbar ta ’ adenomi epatiċi beninni fil- ġrieden nisa biss.
The increased incidence of benign hepatic adenomas in female mice was likely secondary to cytotoxic liver changes manifested by single-cell necrosis and is considered to have no relevance for humans at intended therapeutic exposures.
L- inċidenza ikbar ta ’ adenomi epatiċi beninni fil- ġrieden nisa kienet x’ aktarx sekondarja għat- tibdil ċitotossiku fil- fwied li dehru b’ nekrosi f’ ċellula waħda u huma kkonsidrati li ma għandhom l- ebda relevanza fil- bniedem f’ dożi terapewtiċi intenzjonati.
There were no tumorigenic findings in male mice or in rats.
Ma kienx hemm evidenza tumoriġenika fil- ġrieden u fil- firien irġiel.
Atazanavir increased opacity of bovine corneas in an in vitro ocular irritation study, indicating it may be an ocular irritant upon direct contact with the eye.
Minn studju in vitro fuq l- irritazzjoni ta ’ l- għajnejn sar magħruf li atazanavir żied l- opaċità fl- għajnejn tal- barrin, u dan jindika li atazanavir jista ’ jkun irritanti fl- għajnejn meta jiġi f’ kuntatt dirett ma ’ l - għajnejn.
Capsule contents:
Il- kapsula fiha:
Crospovidone Lactose monohydrate Magnesium stearate
Crospovidone Lactose monohydrate Magnesium stearate
Capsule shells:
Il- qoxra tal- kapsula fiha:
Gelatine Indigocarmin (E132) Titanium dioxide (E171)
Gelatin Indigocarmin (E132) Titanium dioxide (E171)
Blue ink containing:
Shellac
Shellac Propylene glycol Ammonium hydroxide Indigocarmin (E132)
20 Propylene glycol Ammonium hydroxide Indigocarmin (E132)
White ink containing:
Linka bajda fiha:
Shellac Titanium dioxide (E171) Ammonium hydroxide Propylene glycol Simethicone
Shellac Titanium dioxide (E171) Ammonium hydroxide Propylene glycol Simethicone
Do not store above 25°C.
Taħżinx f’ temperatura ’ il fuq minn 25°C.
20 6.5 Nature and contents of container
6. 5 In- natura tal- kontenitur u ta ’ dak li hemm ġo fih
Each carton contains one high-density polyethylene (HDPE) bottle closed with child-resistant polypropylene closure.
Kull kartuna fiha flixkun wieħed ta 'polyethylene ta' densità għolja (HDPE) magħluq b' tapp tal - polypropylene li t- tfal isibu diffiċli biex jiftħu.
Each bottle contains 60 hard capsules.
Kull flixkun fih 60 kapsuli iebsin.
Each carton contains 60 x 1 capsules; 10 blister cards of 6 x 1 capsules each in Alu/ Alu perforated unit dose blisters.
Kull kartuna fiha 60 x 1 kapsula; 10 folji ta ’ 6 x 1 kapsula kull waħda f’ folji ta ’ Alu/ Alu ipperforat f’ doża ta ’ unità waħda.
Any unused product or waste material should be disposed of in accordance with local requirements.
Kull fdal tal- prodott li ma jkunx intuża jew skart li jibqa 'wara l- użu tal- prodott għandu jintrema kif jitolbu l- liġijiet lokali
BRISTOL-MYERS SQUIBB PHARMA EEIG Uxbridge Business Park Sanderson Road Uxbridge UB8 1DH United Kingdom
BRISTOL- MYERS SQUIBB PHARMA EEIG Uxbridge Business Park Sanderson Road Uxbridge UB8 1DH Renju Unit
02 March 2004 Date of latest renewal:
It Tnejn ta Marzu 2004 Data ta ’ l- aħħar tiġdid:
{month year}
[data]
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 din il- mediċina tinsab fuq il- website ta ’ l- Aġenzija Ewropea dwar il - Mediċini (EMEA): http: // www. emea. europa. eu /
REYATAZ 150 mg hard capsules
REYATAZ 150 mg kapsuli iebsin.
Each capsule contains 150 mg of atazanavir (as sulphate)
Kull kapsula fiha 150 mg ta 'atazanavir (bħala sulfat)
82.18 mg of lactose per capsule.
82, 18 mg ta 'lactose kull kapsula.
Hard capsule Opaque blue and powder blue capsule printed with white and blue inks, with "BMS 150 mg" on one half and with "3624" on the other half.
Kapsula iebsa Kapsula opaka blu u blu ċar stampata b’ inka bajda u blu, b ’ "BMS 150 mg" fuq nofs u bi "3624" fuq in- nofs l- ieħor.
22 Method of administration: for oral administration.
23 Kif jingħata: jittieħed mill- ħalq.
23 There have been reports of increased bleeding, including spontaneous skin haematomas and haemarthroses, in type A and B haemophiliac patients treated with protease inhibitors.
Hemm rapporti li pazjenti li jbatu minn emofilja tip A u B li ġew ikkurati b’ inibituri ta ’ proteasi kellhom iktar fsada, inkluż ematomi u emartrosi spontanja fil- ġilda.
In some patients additional factor VIII was given.
Xi pazjenti ngħataw fattur VIII
24 Relevant examples are cytomegalovirus retinitis, generalised and/ or focal mycobacterial infections, and Pneumocystis carinii pneumonia.
25 mikobatteriċi ffukati, u Pneumocystis carinii pneumonia.
25 Other interactions Interactions between atazanavir/ ritonavir and protease inhibitors, antiretroviral agents other than protease inhibitors, and other non-antiretroviral medicinal products are listed in the tables below (increase is indicated as “↑”, decrease as “↓”, no change as “↔”, twice daily as “ BID” and once daily as “ QD”).
26 Interazzjonijiet oħra L- interazzjonijiet bejn atazanavir/ ritonavir u inibituri protease, aġenti antiretrovirali li mhumiex inibituri protease, u prodotti mediċinali oħra li mhumiex antiretrovirali huma elenkati fit- tabella ta 'hawn isfel (żieda hija indikata bħala “ ↑ ”, tnaqqis bħala “ ↓ ”, l- ebda bidla bħala “ ↔ ”, darbtejn kuljum bħala “ BID ” u darba kuljum bħala “ QD ”).
(0.08, 0.21) (0.06, 0.18) (0.10, 0.27) with ddI+d4T
27
27 Co-administered medicinal
Antifungali
Medicinal
28
28 Co-administered medicinal
Prodotti mediċinali mogħtija Prodott
Sildenafil
31
Sildenafil is metabolised by CYP3A4.
Prodotti mediċinali mogħtija
Patients should be warned about these possible side effects.
Prodott AUC Cmax Cmin
HERBAL PRODUCTS
Rakkomandazzjonijie
John’ s wort (Hypericum perforatum):
fl- istess ħin (doża f’ mg)
Concomitant use of St.
mediċinali evalwat
Co-administration of REYATAZ/ ritonavir
(90% CI) (90% CI) (90% CI)
30 Co-administered medicinal
t dwar l- għoti fl- istess ħin
Medicinal
Barra minn hekk, f' każ ta 'rtirar tal - glukokortikojdi, jista ’ jkun hemm bżonn li jsir tnaqqis progressiv tad- doża fuq perjodu itwal.
Recommendations
DISFUNZJONI TA 'L- EREZZJONI Inibituri PDE5 Sildenafil
products (dose in mg)
Sildenafil huwa metabolizzat minn CYP3A4.
product assessed
Il- pazjenti għandhom jiġu mwissija dwar dawn l- effetti sekondarji li jista 'jkun hemm.
(90% CI) (90% CI) (90% CI)
PRODOTTI MILL - ĦXEJJEX
concerning
St.
co-administration
John’ s wort (Hypericum perforatum):
This effect may be due to an induction of CYP3A4.
L- użu konkomitanti ta 'St.
There is a risk of loss of therapeutic effect and development of resistance (see section 4.3).
John' s wort ma ’ REYATAZ/ ritonavir jista ’ jiġi mistenni li jirriżulta fi tnaqqis sinifikanti fil- livelli ta 'atazanavir fil - plasma.
with products containing St.
Dan l- effett jista ’ jkun minħabba induzzjoni ta ’ CYP3A4.
Co-administration warrants
fl- istess ħin (doża f’ mg)
(atazanavir 300 mg QD with ritonavir 100 mg QD)
(90% CI) (90% CI) (90% CI)
norbuprenorphine ↑ 2.05 ↑ 1.61 ↑ 2.01 The mechanism of interaction is CYP3A4 and UGT1A1 inhibition.
Il- mekkaniżmu ta 'interazzjoni huwa l- inibizzjoni ta' CYP3A4 u UGT1A1.
Concentrations of atazanavir were not significantly affected.
Il- konċentrazzjonijiet ta 'atazanavir ma kinux affettwati b' mod sinifikanti.
clinical monitoring for sedation and cognitive effects.
konoxxittivi.
A dose reduction of buprenorphine may be considered
Jista 'jiġi kkunsidrat tnaqqis fid - doża ta ’ buprenorphine
Methadone, stable maintenance dose (atazanavir 400 mg QD) SEDATIVES Benzodiazepines
Methadone, doża ta 'manteniment stabbli (atazanavir 400 mg QD)
No significant effect on methadone concentrations was observed.
Ma ġie osservat ebda effett sinifikanti fuq il- konċentrazzjonijiet tal - methadone.
Given that low dose ritonavir (100 mg twice daily) has been shown to have no significant effect on methadone concentrations, no interaction is expected if methadone is co-administered with REYATAZ and ritonavir, based on these data.
Minħabba li doża baxxa ta 'ritonavir (100 mg darbtejn kuljum) intweriet li m' għandha ebda effett sinifikanti fuq il - konċentrazzjonijiet tal- methadone, ma hija mistennija l- ebda interazzjoni jekk il- methadone jingħata fl- istess ħin ma' REYATAZ u ritonavir, skond din l- informazzjoni
No dosage adjustment is necessary if methadone is coadministered with REYATAZ and ritonavir.
M' hemmx bżonn ta 'aġġustament fid- doża jekk il- methadone jingħata fl- istess ħin ma' REYATAZ u ritonavir.
Midazolam and triazolam are extensively metabolized by CYP3A4.
Midazolam u triazolam jiġu metabolizzati b' mod estensiv minn CYP3A4.
Co-administration with REYATAZ/ ritonavir may cause a large increase in the concentration of these benzodiazepines.
L- għoti fl- istess ħin ma ’ REYATAZ/ ritonavir jista 'jikkawża żieda kbira fil- konċentrazzjoni ta' dawn il- benzodiazepines.
No drug interaction study has been performed for the co-administration of REYATAZ/ ritonavir with benzodiazepines.
Ma sarux studji dwar l- effett ta 'mediċini oħra fuq l- effett farmaċewtiku tal- prodott għall- għoti fl- istess ħin ta' REYATAZ/ ritonavir ma 'benzodiazepines.
Based on data for other CYP3A4 inhibitors, plasma concentrations of midazolam are expected to be significantly higher when midazolam is given orally.
Skond informazzjoni dwar inibituri oħra ta 'CYP3A4, il - konċentrazzjonijiet ta' midazolam fil- plasma huma mistennija li jkunu konsiderevolment ogħla meta midazolam jingħata mill- ħalq.
Data from concomitant use of parenteral midazolam with other protease inhibitors suggest a possible 3-4 fold increase in midazolam plasma levels.
Dejta mill - użu konkomitanti ta 'midazolam parenterali ma' inibituri protease oħra tissuġġerixxi żieda possibbli ta '3- 4 darbiet fil- livelli ta' midazolam fil - plasma.
If REYATAZ is
REYATAZ/ ritonavir m' għandux jingħata fl - istess ħin ma 'triazolam jew midazolam mogħti mill- ħalq (ara sezzjoni 4. 3), filwaqt li għandha tintuża kawtela meta jingħataw fl- istess ħin REYATAZ/ ritonavir ma' midazolam parenterali.
4.7 Effects on ability to drive and use machines
33 4. 7 Effetti fuq il- ħila biex issuq u tħaddem magni
Renal and urinary disorders:
34 addominali, stomatite aphthous, gass fl- istonku, ħalq xott
34 high drug exposures, jaundice due to indirect (unconjugated) hyperbilirubinaemia (without associated liver function test changes) or PR interval prolongations may be observed (see sections 4.4 and 4.8).
B’ dożi għoljin li jwasslu għal riskju għoli għall- mediċina, ġiet innotata suffejra minħabba iperbilirubinemja indiretta (mhux konjugata) (mhux konnessa ma ’ tibdil fit- test tal- funzjoni tal- fwied) jew titwil ta ’ l- intervall PR (ara sezzjonijiet 4. 4. or 4. 8).
Resistance Antiretroviral treatment naive patients In antiretroviral treatment naive patients, the I50L substitution, sometimes in combination with an A71V change, is the signature resistance substitution for atazanavir.
36 Pazjenti li qatt qabel ma ħadu kura antiretroviraliF’ pazjenti li qatt qabel ma ħadu kura antiretrovirali, is- sostituzzjoni I50L, kultant flimkien ma ’ bidla fl- A71V, hija sostituzzjoni ta ’ reżistenza firmatarja għal atazanavir.
Table 2:
37 Tabella 2:
36 CD4 count
72 (n=225)
The proportions of patients with HIV RNA < 50 copies/ ml in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 36% and 42%, respectively.
38 ħadu REYATAZ + ritonavir u lopinavir + ritonavir arm kien rispettivament ta ’ 36% u 42%.
38 Elimination: following a single 400-mg dose of 14C-atazanavir, 79% and 13% of the total radioactivity was recovered in the faeces and urine, respectively.
Kif jitneħħa: wara doża waħda ta ’ 400 mg ta ’ 14C- atazanavir, 79% u 13% tat- total tar- radjuattività ġie rkuprat rispettivament fil- purgar u fl- urina.
Shellac Propylene glycol Ammonium hydroxide Indigocarmin (E132)
41 Propylene glycol Ammonium hydroxide Indigocarmin (E132)
REYATAZ 200 mg hard capsules
REYATAZ 200 mg kapsuli iebsin.
Each capsule contains 200 mg of atazanavir (as sulphate)
Kull kapsula fiha 200 mg ta 'atazanavir (bħala sulfat)
109.57 mg of lactose per capsule.
109, 57 mg ta 'lactose kull kapsula.
Hard capsule Opaque blue capsule printed with white ink, with "BMS 200 mg" on one half and with "3631" on the other half.
Kapsula iebsa Kapsula opaka blu stampata b’ inka bajda, b ’ "BMS 200 mg" fuq nofs u b ’ "3631" fuq in- nofs l- ieħor.
42 Method of administration: for oral administration.
44 Kif jingħata: jittieħed mill- ħalq.
43 There have been reports of increased bleeding, including spontaneous skin haematomas and haemarthroses, in type A and B haemophiliac patients treated with protease inhibitors.
Hemm rapporti li pazjenti li jbatu minn emofilja tip A u B li ġew ikkurati b’ inibituri ta ’ proteasi kellhom iktar fsada, inkluż ematomi u emartrosi spontanja fil- ġilda.
In some patients additional factor VIII was given.
Xi pazjenti ngħataw fattur VIII addizzjonali.
In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced if treatment had been discontinued.
F’ iktar minn nofs il- każi rrapportati, il- kura b’ inibituri ta ’ proteasi tkompliet jew reġgħet
44 Relevant examples are cytomegalovirus retinitis, generalised and/ or focal mycobacterial infections, and Pneumocystis carinii pneumonia.
46 mikobatteriċi ffukati, u Pneumocystis carinii pneumonia.
45 Other interactions Interactions between atazanavir/ ritonavir and protease inhibitors, antiretroviral agents other than protease inhibitors, and other non-antiretroviral medicinal products are listed in the tables below (increase is indicated as “↑”, decrease as “↓”, no change as “↔”, twice daily as “ BID” and once daily as “ QD”).
47 Interazzjonijiet oħra L- interazzjonijiet bejn atazanavir/ ritonavir u inibituri protease, aġenti antiretrovirali li mhumiex inibituri protease, u prodotti mediċinali oħra li mhumiex antiretrovirali huma elenkati fit- tabella ta 'hawn isfel (żieda hija indikata bħala “ ↑ ”, tnaqqis bħala “ ↓ ”, l- ebda bidla bħala “ ↔ ”, darbtejn kuljum bħala “ BID ” u darba kuljum bħala “ QD ”).
(0.08, 0.21) (0.06, 0.18) (0.10, 0.27) with ddI+d4T
48
47 Co-administered medicinal
Antifungali
Medicinal
49
48 Co-administered medicinal
Prodotti mediċinali mogħtija Prodott
Sildenafil
52
50 Co-administered medicinal
t dwar l- għoti fl- istess ħin
4.7 Effects on ability to drive and use machines
54 4. 7 Effetti fuq il- ħila biex issuq u tħaddem magni
Renal and urinary disorders:
55 addominali, stomatite aphthous, gass fl- istonku, ħalq xott
54 high drug exposures, jaundice due to indirect (unconjugated) hyperbilirubinaemia (without associated liver function test changes) or PR interval prolongations may be observed (see sections 4.4 and 4.8).
B’ dożi għoljin li jwasslu għal riskju għoli għall- mediċina, ġiet innotata suffejra minħabba iperbilirubinemja indiretta (mhux konjugata) (mhux konnessa ma ’ tibdil fit- test tal- funzjoni tal- fwied) jew titwil ta ’ l- intervall PR (ara sezzjonijiet 4. 4. or 4. 8).
Resistance Antiretroviral treatment naive patients In antiretroviral treatment naive patients, the I50L substitution, sometimes in combination with an A71V change, is the signature resistance substitution for atazanavir.
57 Pazjenti li qatt qabel ma ħadu kura antiretroviraliF’ pazjenti li qatt qabel ma ħadu kura antiretrovirali, is- sostituzzjoni I50L, kultant flimkien ma ’ bidla fl- A71V, hija sostituzzjoni ta ’ reżistenza firmatarja għal atazanavir.
Table 2:
58 Tabella 2:
56 CD4 count
72 (n=225)
The proportions of patients with HIV RNA < 50 copies/ ml in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 36% and 42%, respectively.
59 ħadu REYATAZ + ritonavir u lopinavir + ritonavir arm kien rispettivament ta ’ 36% u 42%.
58 Elimination: following a single 400-mg dose of 14C-atazanavir, 79% and 13% of the total radioactivity was recovered in the faeces and urine, respectively.
Kif jitneħħa: wara doża waħda ta ’ 400 mg ta ’ 14C- atazanavir, 79% u 13% tat- total tar- radjuattività ġie rkuprat rispettivament fil- purgar u fl- urina.
Shellac Titanium dioxide (E171) Ammonium hydroxide Propylene glycol Simethicone
62 Shellac Titanium dioxide (E171) Ammonium hydroxide Propylene glycol Simethicone
60 Each carton contains 60 x 1 capsules; 10 blister cards of 6 x 1 capsules each in Alu/ Alu perforated unit dose blisters.
Kull kartuna fiha 60 x 1 kapsula; 10 folji ta ’ 6 x 1 kapsula kull waħda f’ folji ta ’ Alu/ Alu ipperforat f’ doża ta ’ unità waħda.