qanastek/EMEA-V3 huggingface dataset:
In vitro studies have shown that both emtricitabine and tenofovir can be fully phosphorylated when combined together in cells.
Studji in vitro urew li kemm emtricitabine kif ukoll tenofovir jistgħu jiġu fosforilati għal kollox meta magħqudin flimkien f’ ċelloli.
Emtricitabine triphosphate and tenofovir diphosphate competitively inhibit HIV-1 reverse transcriptase, resulting in DNA chain termination.
Emtricitabine triphosphate u tenofovir diphosphate jinibixxu HIV- 1 reverse transcriptase b’ mod kompetittiv, u dan jirriżulta f’ terminazzjoni tal- katina tad- DNA.
Both emtricitabine triphosphate and tenofovir diphosphate are weak inhibitors of mammalian DNA polymerases and there was no evidence of toxicity to mitochondria in vitro and in vivo.
Kemm emtricitabine triphosphate u tenofovir diphosphate huma inibituri dgħajfa ta ’ polymerases tad - DNA tal- mammali u ma kien hemm ebda evidenza ta ’ tossiċità għal mitokondrija in vitro u in vivo.
Antiviral activity in vitro: efavirenz demonstrated antiviral activity against most non-clade B isolates (subtypes A, AE, AG, C, D, F, G, J, and N) but had reduced antiviral activity against group O viruses.
Attività antivirali in vitro: efavirenz wera attività antivirali kontra ħafna mill- iżolati non- clade B (subtipi A, AE, AG, C, D, F, G, J, u N) iżda ma naqqasx l- attività antivirali kontra l- virusijiet ta ’ grupp O.
Emtricitabine displayed antiviral activity against HIV-1 clades A, B, C, D, E, F, and G.
Emtricitabine wera attività antivirali kontra HIV- 1 clades A, B, C, D, E, F, u G.
Tenofovir displayed antiviral activity against HIV-1 clades A, B, C, D, E, F, G, and O.
Tenofovir wera attività antivirali kontra HIV- 1 clades A, B, C, D, E, F, G, u O.
Both emtricitabine and tenofovir showed strain specific activity against HIV-2 and antiviral activity against HBV.
Kemm emtricitabine kif ukoll tenofovir urew attività speċifika tar- razza kontra HIV- 2 u attività antivirali kontra HBV.
In combination studies evaluating the in vitro antiviral activity of efavirenz and emtricitabine together, efavirenz and tenofovir together, and emtricitabine and tenofovir together, additive to synergistic antiviral effects were observed.
Fi studji ta ’ kombinazzjoni li jevalwaw l- attività antivirali in vitro ta ’ efavirenz u emtricitabine flimkien, efavirenz u tenofovir flimkien, u emtricitabine u tenofovir flimkien, ġew osservati addittivi għal effetti antivirali sinerġistiċi.
25 Resistance: resistance to efavirenz can be selected in vitro and resulted in single or multiple amino acid substitutions in HIV-1 RT, including L100I, V108I, V179D, and Y181C.
Reżistenza: ir- reżistenza għal efavirenz tista ’ tkun in vitro magħżula u rriżultat f’ sostituzzjonijiet ta ’ aċidu amminiku singolu jew aktar minn wieħed f’ HIV- 1 RT, inkluż L100I, V108I, V179D, u Y181C.
K103N was the most frequently observed RT substitution in viral isolates from patients who experienced rebound in viral load during clinical studies of efavirenz.
26 K103N kienet l- aktar sostituzzjoni RT osservata b’ mod frekwenti f’ iżolati virali minn pazjenti li esperjenzaw rikaduta fl- għadd virali matul l- istudji kliniċi ta ’ efavirenz.
Substitutions at RT positions 98, 100, 101, 108, 138, 188, 190 or 225 were also observed, but at lower frequencies, and often only in combination with K103N.
Sostituzzjonijiet fil - pożizzjonijiet RT 98, 100, 101, 108, 138, 188, 190 jew 225 ġew osservati wkoll, madankollu fi frekwenzi aktar baxxi, u spiss biss f’ kombinazzjoni ma ’ K103N.
Cross-resistance profiles for efavirenz, nevirapine and delavirdine in vitro demonstrated that the K103N substitution confers loss of susceptibility to all three NNRTIs.
Profili ta ’ kross- reżistenza għal efavirenz, nevirapine u delavirdine in vitro urew li s- sostituzzjoni K103N tagħti nuqqas ta ’ suxxettibbiltà għat- tliet NNRTIs kollha.
The potential for cross-resistance between efavirenz and NRTIs is low because of the different binding sites on the target and mechanism of action.
Il- potenzjal għal kross- reżistenza bejn efavirenz u NRTIs huwa wieħed baxx minħabba s- siti differenti ta ’ twaħħil fuq il- mira u l- mekkaniżmu ta ’ azzjoni.
The potential for cross-resistance between efavirenz and PIs is low because of the different enzyme targets involved.
Il- potenzjal għal kross- reżistenza bejn efavirenz u PIs huwa wieħed baxx minħabba l- miri differenti ta ’ l- enzimi involuti.
Resistance to emtricitabine or tenofovir has been seen in vitro and in some HIV-1 infected patients due to the development of an M184V or M184I substitution in RT with emtricitabine or a K65R substitution in RT with tenofovir.
Reżistenza għal emtricitabine jew tenofovir intweriet in vitro u f’ xi pazjenti infettati bl - HIV- 1 minħabba l- iżvilupp ta ’ sostituzzjoni ta ’ M184V jew M184I f’ RT b’ sostituzzjoni ta ’ emtricitabine jew ta ’ K65R f’ RT b’ tenofovir.
No other pathways of resistance to emtricitabine or tenofovir have been identified.
Ebda mogħdijiet ta ’ reżistenza oħrajn għal emtricitabine jew tenofovir ma ġew identifikati.
Emtricitabine-resistant viruses with the M184V/ I mutation were cross-resistant to lamivudine, but retained sensitivity to didanosine, stavudine, tenofovir and zidovudine.
Virusijiet reżistenti għal emtricitabine bil- mutazzjoni M184V/ I kienu kross- reżistenti għal lamivudine, madankollu żammew is- sensittività għal didanosine, stavudine, tenofovir u zidovudine.
The K65R mutation can also be selected by abacavir or didanosine and results in reduced susceptibility to these agents plus lamivudine, emtricitabine and tenofovir.
Il- mutazzjoni K65R tista ’ tkun magħżula wkoll b’ abacavir jew didanosine u tirriżulta f’ suxxettibbiltà mnaqqsa għal dawn is- sustanzi flimkien ma ’ lamivudine, emtricitabine u tenofovir.
Tenofovir disoproxil fumarate should be avoided in patients with HIV-1 harbouring the K65R mutation.
Tenofovir disoproxil fumarate għandu jkun evitat f’ pazjenti b’ HIV- 1 li għandhom mutazzjoni K65R.
Both the K65R and M184V/ I mutation remain fully susceptible to efavirenz.
Kemm il- mutazzjoni ta ’ K65R kif ukoll ta ’ M184V/ I tibqa ’ suxxettibbli għal kollox għal efavirenz.
Patients with HIV-1 expressing three or more thymidine analogue associated mutations (TAMs) that included either an M41L or an L210W substitution in RT showed reduced susceptibility to tenofovir disoproxil fumarate.
Pazjenti b ’ HIV- 1 li jesprimu tliet mutazzjonijiet analogue assoċjati ta ’ thymidine (TAMs) jew aktar inkluż jew sostituzzjoni M41L jew L210W f’ RT urew suxxettibbiltà mnaqqsa għal tenofovir disoproxil fumarate.
In vivo resistance (antiretroviral-naïve patients): extremely limited resistance data from patients treated with Atripla are currently available.
Reżistenza in vivo (pazjenti li qatt ma jkunu ħadu trattament antiretrovirali qabel): dejta estremament limitata ta ’ reżistenza minn pazjenti trattati b’ Atripla m’ hija disponibbli fil- preżent.
However, in a 144-week open-label randomised clinical study (GS-01-934) in antiretroviral-naïve patients, where efavirenz, emtricitabine and tenofovir disoproxil fumarate were used as individual formulations (or as efavirenz and the fixed combination of emtricitabine and tenofovir disoproxil fumarate (Truvada) from week 96 to 144), genotyping was performed on plasma HIV-1 isolates from all patients with confirmed HIV RNA > 400 copies/ ml at week 144 or early study drug discontinuation (see section on Clinical experience).
Madankollu, fi studju kliniku każwali bit- tikketta mikxufa ta ’ 144 ġimgħa (GS- 01- 934) f’ pazjenti li qatt ma jkunu ħadu trattament antiretrovirali qabel, fejn efavirenz, emtricitabine u tenofovir disoproxil fumarate ntużaw bħala formulazzjonijiet individwali (jew bħala efavirenz u l- kombinazzjoni fissa ta ’ emtricitabine u tenofovir disoproxil fumarate (Truvada) minn ġimgħa 96 sa 144), il- genotyping sar fuq iżolati ta ’ HIV- 1 fil- plażma mill- pazjenti kollha b’ HIV RNA kkonfermat ta ’ > 400 kopja/ ml f’ ġimgħa 144 jew twaqqif kmieni tal- mediċina studjata (ara sezzjoni dwar l- Esperjenza Klinika).
As of week 144:
Minn ġimgħa 144:
• The M184V/ I mutation developed in 2/ 19 (10.5%) isolates analysed from patients in the efavirenz + emtricitabine + tenofovir disoproxil fumarate group and in 10/ 29 (34.5%) isolates analysed from the efavirenz + lamivudine/ zidovudine group (p-value < 0.05, Fisher’ s Exact test comparing the emtricitabine + tenofovir disoproxil fumarate group to the lamivudine/ zidovudine group among all subjects). • No virus analysed contained the K65R mutation. • Genotypic resistance to efavirenz, predominantly the K103N mutation, developed in virus from 13/ 19 (68%) patients in the efavirenz + emtricitabine + tenofovir disoproxil fumarate group and in virus from 21/ 29 (72%) patients in the efavirenz + lamivudine/ zidovudine group.
• Il- mutazzjoni M184V/ I żviluppat fi 2/ 19 (10. 5%) iżolati analizzati minn pazjenti fil- grupp ta ’ efavirenz + emtricitabine + tenofovir disoproxil fumarate u f’ 10/ 29 (34. 5%) iżolati analizzati fil- grupp ta ’ efavirenz + lamivudine/ zidovudine (valur p ta ’ < 0. 05, it- Test Eżatt ta ’ Fisher li qabbel il- grupp ta ’ emtricitabine + tenofovir disoproxil fumarate mal- grupp ta ’ lamivudine/ zidovudine fost il- pazjenti kollha). • L- ebda virus li kien analizzat ma kien fih il- mutazzjoni K65R. • Reżistenza ġenotipika għal efavirenz, fil- biċċa l- kbira l- bidla ta ’ K103N, żviluppat f’ virus f’ 13/ 19 (68%) tal- pazjenti fil- grupp ta ’ efavirenz + emtricitabine + tenofovir disoproxil fumarate u f’ virus f’ 21/ 29 (72%) tal- pazjenti fil- grupp efavirenz + lamivudine/ zidovudine.
A summary of resistance mutation development is shown in Table 5.
Sommarju ta ’ l- iżvilupp tal- mutazzjonijiet tar- reżistenza qed jintwera f’ Tabella 5.
26 Table 5:
27 Tabella 5:
Development of resistance in study GS-01-934 through week 144
Żvilupp tar- reżistenza fl- istudju GS- 01- 934 sa ġimgħa 144
zidovudine
lamivudine /
tenofovir disoproxil fumarate (N=244)
tenofovir disoproxil fumarate (N=244)
(N=243)
zidovudine (N=243)
week 144 1
Analiżi tar- reżistenza sa ġimgħa 144
G190A/ S Y188C/ H V108I P225H
Ġenotipi waqt it- terapija Reżistenza għal efavirenz1 K103N K101E G190A/ S Y188C/ H V108I P225H M184V/ I K65R
(10.5%) (5%) (5%)
19 (100%) 13 (68%) 8 (42%) 3 (16%) 2 (10. 5%) 1 (5%) 1 (5%) 0 2 (10. 5%) 0
4 2 1 2
29 21 18 * 3 4 2 1 2 10 * 0
(14%) (7%) (3%) (7%)
(100%) (72%) (62%) (10%) (14%) (7%) (3%) (7%) (34. 5%)
* p-value < 0.05, Fisher’ s Exact test comparing efavirenz + emtricitabine + tenofovir disoproxil fumarate group to efavirenz + lamivudine/ zidovudine group among all patients.
* valur p < 0. 05, Test Eżatt ta ’ Fisher li qabbel il- grupp ta ’ efavirenz + emtricitabine + tenofovir disoproxil fumarate mal- grupp ta ’ efavirenz + lamivudine/ zidovudine fost il - pazjenti kollha.
1 Other efavirenz resistance mutations included A98G (n=1), K103E (n=1), V179D (n=1), and M230L (n=1).
1 Mutazzjonijiet oħra tar- reżistenza għal efavirenz kienu jinkludu A98G (n=1), K103E (n=1), V179D (n=1), u M230L (n=1).
2 Thymidine analogue associated mutations included D67N (n=1) and K70R (n=1).
2 Mutazzjonijiet assoċjati ma ’ analogi ta ’ thymidine kienu jinkludu D67N (n=1) u K70R (n=1).
Please refer to the Summary of Product Characteristics for the individual components for additional information regarding in vivo resistance with these medicinal products.
Jekk jogħġbok irreferi għas- Sommarju tal- Karatteristiċi tal- Prodott għall- komponenti individwali għal aktar informazzjoni dwar ir- reżistenza in vivo ma ’ dawn il- prodotti mediċinali.
In a 144-week open-label randomised clinical study (GS-01-934) antiretroviral treatment-naïve HIV-1 infected patients received either a once-daily regimen of efavirenz, emtricitabine and tenofovir disoproxil fumarate or a fixed combination of lamivudine and zidovudine (Combivir) administered twice daily and efavirenz once daily (please refer to the Summary of Product Characteristics for Truvada).
Fi studju kliniku każwali bit- tikketta mikxufa ta ’ 144 ġimgħa (GS- 01- 934) li fih, pazjenti infettati bl - HIV- 1 li qatt ma kienu ħadu trattament antiretrovirali qabel irċevew jew kors ta ’ darba kuljum ta ’ efavirenz, emtricitabine u tenofovir disoproxil fumarate jew kombinazzjoni fissa ta ’ lamivudine u zidovudine (Combivir) mogħti darbtejn kuljum u efavirenz darba kuljum (jekk jogħġbok irreferi għas - Sommarju tal- Karatteristiċi tal- Prodott għal Truvada).
Patients who completed 144 weeks of treatment with either treatment arm in study GS-01-934 were given the option to continue in an open-label extended phase of the study with Atripla on an empty stomach.
Pazjenti li temmew 144 ġimgħa ta ’ trattament b’ fergħa ta ’ trattament wieħed jew ieħor fi studju GS- 01- 934 ingħataw l- għażla li jkomplu f’ fażi estiża (b’ tikketta mikxufa) ta ’ l- istudju b’ Atripla fuq stonku vojt.
Preliminary 24-week data are available from a total of 286 patients who changed to Atripla:
Tagħrif preliminari ta ’ 24 ġimgħa huwa disponibbli minn total ta ’ 286 pazjent li qalbu għal Atripla:
160 had previously received efavirenz, emtricitabine and tenofovir disoproxil fumarate, and 126 had previously received Combivir and efavirenz.
160 kienu rċievew efavirenz, emtricitabine u tenofovir disoproxil fumarate qabel, u 126 kienu rċievew Combivir u efavirenz qabel.
The majority of patients from both initial treatment groups maintained virologic suppression after changing to Atripla.
Il- maġġoranza tal- pazjenti miż- żewġ gruppi tat- trattament inizjali żammew soppressjoni viroloġika wara li bidlu għal Atripla.
In 91% of the patients the HIV-1 RNA plasma concentrations remained < 50 copies/ ml and in 97% < 400 copies/ ml, after 24 weeks of Atripla treatment (intention to treat analysis (ITT), missing=failure).
F ’ 91% tal- pazjenti, il- konċentrazzjonijiet ta ’ HIV- 1 RNA fil- plażma baqgħu < 50 kopji/ ml u f’ 97% < 400 kopja/ ml, wara 24 ġimgħa ta ’ trattament b’ Atripla (analiżi b’ intenzjoni li tiġi ttrattata (ITT), nieqsa=ma ħadimx).
Study AI266073 was a 48-week open-label randomised clinical study in HIV infected patients comparing the efficacy of Atripla to antiretroviral therapy consisting of at least two nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs) with a protease inhibitor or non-nucleoside reverse transcriptase inhibitor; however not a regimen containing all Atripla components (efavirenz, emtricitabine and tenofovir disoproxil fumarate).
L- istudju AI266073 kien studju kliniku każwali bit- tikketta mikxufa mifrux fuq 48 ġimgħa fuq pazjenti infettati bl- HIV li jqabbel l- effikaċja ta ’ Atripla ma ’ terapija antiretrovirali magħmula minn mill- inqas żewġ nucleoside jew nucleotide reverse transcriptase inhibitors (NRTIs) b’ inibitur tal - protease jew b’ non- nucleoside reverse transcriptase inhibitor; madankollu mhux reġim li fih il -
Atripla was administered on an empty stomach (see section 4.2).
Atripla ngħatat fuq stonku vojt (ara sezzjoni 4. 2).
Patients had never experienced virological failure on a previous antiretroviral therapy, had no known HIV-1 mutations that confer resistance to any of the three components within Atripla, and had been virologically suppressed for at least three months at baseline.
Il- pazjenti qatt ma kienu esperjenzaw falliment viroloġiku fuq terapija antiretrovirali preċedenti, ma kellhom l- ebda mutazzjonijiet magħrufa ta ’ l- HIV- 1 li jagħtu reżistenza għal xi wieħed mit- tliet komponenti f’ Atripla, u kienu ġew viroloġikament imrażżna għal mill- anqas tliet xhur fil- linja bażi.
Forty-eight
Il- pazjenti jew qalbu għal Atripla (N= 203) jew komplew fuq ir- reġimen ta ’ trattament antiretrovirali oriġinali tagħhom (N= 97).
27 week data showed that high levels of virologic suppression, comparable to the original treatment regimen, were maintained in patients who were randomised to change to Atripla (see Table 6).
Id- dejta fil- ġimgħa tmienja u erbgħin uriet li livelli għoljin ta ’ trażżin viroloġiku, komparabbli mar- reġim ta ’ trattament oriġinali, inżammu f’ pazjenti li ntgħażlu b’ mod każwali biex jaqilbu għal Atripla (ara t- Tabella 6).
Table 6:
Tabella 6.
48-week efficacy data from study AI266073 in which Atripla was administered to virologically suppressed patients on combination antiretroviral therapy
Dejta ta ’ l- effikaċja fuq 48 ġimgħa mill- istudju AI266073 li fih Atripla ingħata lil pazjenti mrażżna viroloġikament fuq terapija antiretrovirali ta ’ kombinazzjoni
Treatment group
Grupp ta ’ trattament
Stayed on original treatment regimen
ta ’ trattament oriġinali
Difference between Atripla and original treatment regimen
reġim ta ’ trattament oriġinali
patients with HIV-1 RNA < 50 copies/ ml PVR (KM)
pazjenti b’ HIV- 1 RNA < 50 kopja/ ml PVR (KM)
85.5%
85. 5%
8.9% (-7.7% to 25.6%)
8. 9% (- 7. 7% sa 25. 6%)
M=Excluded M=Failure
M=Esklużi M=Ma rnexxewx
179/ 181 (98.9%) 179/ 203 (88.2%)
179/ 181 (98. 9%) 179/ 203 (88. 2%)
85/ 87 (97.7%) 85/ 97 (87.6%)
85/ 87 (97. 7%) 85/ 97 (87. 6%)
1.2% (-2.3% to 6.7%) 0.5% (-7.0% to 9.3%)
1. 2% (- 2. 3% sa 6. 7%) 0. 5% (- 7. 0% sa 9. 3%)
Modified LOCF
LOCF modifikat
190/ 203 (93.6%)
190/ 203 (93. 6%)
94/ 97 (96.9%)
94/ 97 (96. 9%)
-3.3% (-8.3% to 2.7%)
- 3. 3% (- 8. 3% sa 2. 7%)
patients with HIV-1 RNA < 200 copies/ ml PVR (KM)
pazjenti b’ HIV- 1 RNA < 200 kopja/ ml PVR (KM)
98.4%
98. 4%
-0.5% (-3.2% to 2.2%)
- 0. 5% (- 3. 2% sa 2. 2%)
M=Excluded
M=Esklużi
0% (-2.4% to 4.2%)
0% (- 2. 4% sa 4. 2%)
M=Failure
M=Ma rnexxewx
181/ 203 (89.2%)
181/ 203 (89. 2%)
87/ 97 (89.7%)
87/ 97 (89. 7%)
-0.5% (-7.6% to 7.9%)
- 0. 5% (- 7. 6% sa 7. 9%)
Pure virologic response assessed using the Kaplan Meier (KM) method M:
Rispons viroloġiku pur ivvalutat bil- metodu Kaplan Meier (KM) M:
Missing Modified LOCF:
Neqsin LOCF modifikat:
Post-hoc analysis where patients who failed virologically or discontinued for adverse events were treated as failures; for other drop-outs, the LOCF (last observation carried forward) method was applied
Analiżi post- hoc fejn il- pazjenti li ma rnexxewx viroloġikament jew li twaqqfitilhom il- kura minħabba episodji avversi kienu kkunsidrati bħala li ma rnexxewx; għal pazjenti oħrajn li ma komplewx, intuża l - metodu LOCF (l- aħħar osservazzjoni miġjuba ’ l quddiem)
When the two strata were analysed separately, response rates in the stratum with prior PI-treatment were numerically lower for patients switched to Atripla [92.4% versus 94.0% for the PVR (sensitivity analysis) for Atripla and SBR patients respectively; a difference (95%CI) of -1.6% (-10.0%, 6.7%)].
Meta ż- żewġ strata kienu analizzati separatament, ir- rati tar- rispons fl- istratum b’ kura bil- PI fil- passat kienu numerikament iktar baxxi għal pazjenti li qalbu għal Atripla [92. 4% kontra 94. 0% għall- PVR (analiżi tas- sensittività) għal Atripla u pazjenti SBR (stayed on their baseline regimen) rispettivament; differenza (95% CI) ta ’ - 1. 6% (- 10. 0%, 6. 7%)].
In the prior-NNRTI stratum, response rates were 98.9% vs 97.4% for Atripla and SBR patients respectively; a difference (95%CI) of 1.4% (-4.0%, 6.9%).
Fl- istratum ta ’ qabel NNRTI, ir- rati tar- rispons kienu 98. 9% vs 97. 4% għal Atripla u għal pazjenti SBR rispettivament; differenza (95% CI) ta ’ 1. 4% (- 4. 0%, 6. 9%).
No data are currently available from clinical studies with Atripla in treatment-naïve patients or in heavily pretreated patients.
Ebda dejta klinika m’ hija disponibbli attwalment minn studji kliniċi b’ Atripla f’ pazjenti li qatt ma ħadu t- trattament qabel jew f’ pazjenti li ħadu trattament qawwi qabel.
There is no clinical experience with Atripla in patients who are experiencing virological failure in a first-line antiretroviral treatment regimen or in combination with other antiretroviral agents.
Ma hemm ebda esperjenza klinika b’ Atripla f’ pazjenti li jkunu qegħdin jesperjenzaw falliment viroloġiku f’ reġim ta ’ trattament antiretrovirali first- line jew f’ kombinazzjoni ma ’ sustanzi antiretrovirali oħrajn.
Patients coinfected with HIV and HBV: limited clinical experience in patients co-infected with HIV and HBV suggests that treatment with emtricitabine or tenofovir disoproxil fumarate in antiretroviral combination therapy to control HIV infection also results in a reduction in HBV DNA (3 log10 reduction or 4 to 5 log10 reduction, respectively) (see section 4.4).
Pazjenti ko- infettati b’ HIV u b’ HBV: esperjenza klinika limitata f’ pazjenti ko- infettati b’ HIV u b’ HBV tissuġġerixxi li trattament b’ emtricitabine jew b’ tenofovir disoproxil fumarate f’ terapija ta ’ kombinazzjoni antiretrovirali biex jikkontrolla infezzjoni tal- HIV jirriżulta wkoll fi tnaqqis f’ HBV DNA (tnaqqis ta ’ 3 log10 jew tnaqqis 4 sa 5 log10, rispettivament) (ara sezzjoni 4. 4).
5.2 Pharmacokinetic properties
29 5. 2 Tagħrif farmakokinetiku
The separate pharmaceutical forms of efavirenz, emtricitabine and tenofovir disoproxil fumarate were used to determine the pharmacokinetics of efavirenz, emtricitabine and tenofovir disoproxil fumarate, administered separately in HIV infected patients.
Il- forom farmaċewtiċi separati ta ’ efavirenz, emtricitabine u tenofovir disoproxil fumarate intużaw biex jiġu stabbiliti l- farmakokinetiċi ta ’ efavirenz, emtricitabine u tenofovir disoproxil fumarate, mogħtija separatament f’ pazjenti infettati bl- HIV.
The bioequivalence of one Atripla film-coated tablet with one efavirenz 600 mg film-coated tablet plus one emtricitabine 200 mg hard capsule plus one tenofovir disoproxil 245 mg film-coated tablet (equivalent to 300 mg tenofovir disoproxil fumarate) administered together, was established following single dose administration to fasting healthy subjects in study GS-US-177-0105 (see Table 7).
Il- bijoekwivalenza ta ’ pillola waħda miksija b’ rita ta ’ Atripla ma ’ pillola waħda miksija b’ rita ta ’ efavirenz 600 mg flimkien ma ’ kapsula iebsa waħda ta ’ emtricitabine 200 mg u pillola miksija b’ rita ta ’ tenofovir disoproxil 245 mg (ekwivalenti għal 300 mg tenofovir disoproxil fumarate) mogħtija flimkien, ġiet stabbilita wara għoti ta ’ doża waħda lil suġġetti b’ saħħithom sajmin fl- istudju GS- US- 177- 0105 (ara Tabella 7).
28 Table 7:
Tabella 7:
Summary of pharmacokinetic data from study GS-US-177-0105
Sommarju tat- tagħrif farmakokinetiku mill- istudju GS- US- 177- 0105
fumarate (n=45) GMR (%)
fumarate (n=45) GMR (%)
Reference (90%CI) Test 98.79
Referenza (90% CI) Test 98. 79
Reference (90%CI) Test Reference (90%CI) 88.84
Referenza (90% CI) Test Referenza (90% CI) 88. 84
91.46
91. 46
2,264.3
2, 264. 3
2,308.6
2, 308. 6
(92.28,
(92. 28,
2,130.6
2, 130. 6
2,384.4
2, 384. 4
325.1
325. 1
352.9
352. 9
(84.64,
(84. 64,
(26.8)
(26. 8)
(30.3)
(30. 3)
105.76) 95.84
105. 76) 95. 84
(25.3)
(25. 3)
(20.4)
(20. 4)
93.94) 97.98
93. 94) 97. 98
(34.2)
(34. 2)
(29.6)
(29. 6)
98.83) 99.29
98. 83) 99. 29
125,623.6 132,795.7
AUC0- l- aħħar 125, 623. 6 132, 795. 7
(90.73,
(90. 73,
10,682.6 10,874.4
10, 682. 6 10, 874. 4
(94.90,
(94. 90,
1,948.8
1, 948. 8
1,969.0
1, 969. 0
(91.02,
(91. 02,
(ng·h/ ml)
(25. 7) (27. 0) (ng· h/ ml)
(25.7) (27.0)
(18. 1) (14. 9)
101.23) 95.87
(32. 9)
(18.1) (14.9)
(32. 8)
101.16) 97.96
101. 23) 95. 87
(32.8)
101. 16) 97. 96
108.32) 100.45
108. 32) 100. 45
AUCinf
146, 074. 9 155, 518. 6 AUCinf
146,074.9 155,518.6
10, 854. 9 11, 054. 3
(89.63,
2, 314. 0
10,854.9 11,054.3
2, 319. 4
(94.86,
(89. 63,
2,319.4
(94. 86,
(93.22,
(93. 22,
(ng·h/ ml)
(33. 1) (34. 6) (ng· h/ ml)
(33.1) (34.6)
(17. 9) (14. 9)
102.55)
(29. 2)
(17.9) (14.9)
(30. 3)
101.16)
102. 55)
(29.2)
101. 16)
(30.3)
108. 23)
108.23)
14. 5 14. 6
T1/ 2 (h)
17. 8
180.6 182.5 (45.3) (38.3)
(45. 3) (38. 3) (h)
14.5 14.6 (53.8) (47.8)
(53. 8) (47. 8)
Test: single fixed-dose combination tablet taken under fasted conditions.
Test: pillola ta ’ kombinazzjoni ta ’ doża fissa waħda taħt kundizzjonijiet ta ’ sawm.
Reference: single dose of a 600 mg efavirenz tablet, 200 mg emtricitabine capsule and 300 mg tenofovir disoproxil fumarate tablet taken under fasted conditions.
Referenza: doża waħda ta ’ pillola ta ’ efavirenz ta ’ 600 mg, kapsula ta ’ 200 mg emtricitabine u pillola ta ’ 300 mg tenofovir disoproxil fumarate meħudin f’ kundizzjonijiet ta ’ sawm.
GMR=geometric least-squares mean ratio, CI=confidence interval
Il- valuri għat- Test u Referenza huma medji (% koeffiċjent ta ’ varjazzjoni) GMR: proporzjon medju ta ’ l- inqas kwadri ġeometriku, CI=intervall ta ’ kunfidenza
Absorption: in HIV infected patients, peak efavirenz plasma concentrations were attained by 5 hours and steady-state concentrations reached in 6 to 7 days.
Assorbiment: f’ pazjenti infettati bl- HIV, l- ogħla konċentrazzjonijiet ta ’ plażma ta ’ efavirenz intlaħqu fi żmien 5 sigħat u konċentrazzjonijiet ta ’ stat fiss intlaħqu fi żmien 6 jew 7 jiem.
In 35 patients receiving efavirenz 600 mg once daily, steady-state peak concentration (Cmax) was 12.9 ± 3.7 µM (29%) [mean ± standard deviation (S. D.) (coefficient of variation (%CV))], steady-state Cmin was 5.6 ± 3.2 µM (57%), and AUC was 184 ± 73 µM• h (40%).
F’ 35 pazjent li kienu qed jirċievu efavirenz 600 mg darba kuljum, il- konċentrazzjoni massima fi stat fiss (Cmax) kienet 12. 9 ± 3. 7 µM (29%) [medja ± devjazzjoni standard (S. D.) (koeffiċjent ta ’ varjazzjoni (% CV))], Cmin stat fiss kien 5. 6 ± 3. 2 µM (57%), u AUC kien 184 ± 73 µM• h (40%).
Emtricitabine is rapidly absorbed with peak plasma concentrations occurring at 1 to 2 hours post-dose.
Emtricitabine jiġi assorbit malajr b’ konċentrazzjonijiet massimi tal- plażma jseħħu siegħa jew sagħtejn wara d- doża.
Following multiple dose oral administration of emtricitabine to 20 HIV infected patients, steady-state Cmax was 1.8 ± 0.7 µg/ ml (mean ± S. D.) (39%CV), steady-state Cmin was 0.09 ± 0.07 µg/ ml (80%) and the AUC was 10.0 ± 3.1 µg• h/ ml (31%) over a 24 hour dosing interval.
Wara għoti orali ta ’ aktar minn doża waħda ta ’ emtricitabine lil 20 pazjent infettat bl - HIV, Cmax ta ’ stat fiss kien 1. 8 ± 0. 7 µg/ ml (medju ± S. D.) (39% CV), Cmin ta ’ stat fiss kien 0. 09 ± 0. 07 µg/ ml (80%) u l- AUC kien 10. 0 ± 3. 1 µg• h/ ml (31%) fuq intervall ta ’ dożaġġ ta ’ 24 siegħa.
Following oral administration of a single 300 mg dose of tenofovir disoproxil fumarate to HIV-1 infected patients in the fasted state, maximum tenofovir concentrations were achieved within one hour and the Cmax and AUC (mean ± S. D.) (%CV) values were 296 ± 90 ng/ ml (30%) and 2,287 ± 685 ng• h/ ml (30%), respectively.
Il- valuri (% CV) kienu 296 ± 90 ng/ ml (30%) u 2, 287 ± 685 ng• h/ ml (30%), rispettivament.
The oral bioavailability of tenofovir from tenofovir disoproxil fumarate in fasted patients was approximately 25%.
Il- bijodisponibilità orali ta ’ tenofovir minn tenofovir disoproxil fumarate f’ pazjenti sajmin kienet madwar 25%.
Atripla has not been evaluated in the presence of food.
Atripla ma ġietx evalwata fil- preżenza ta ’ l- ikel.
Administration of efavirenz capsules with a high fat meal increased the mean AUC and Cmax of efavirenz by 28% and 79%, respectively, compared to administration in a fasted state.
30 Għoti ta ’ pilloli ta ’ efavirenz ma ’ ikla b’ ħafna xaħam żied l- AUC medju u Cmax ta ’ efavirenz bi 28% u b’ 79%, rispettivament, meta mqabbla ma ’ l- għoti fi stat ta ’ sawm.
Compared to fasted administration, dosing of tenofovir disoproxil fumarate and emtricitabine in combination with either a high fat meal or a light meal increased the mean AUC and Cmax of tenofovir by 35% and 15%, respectively without affecting emtricitabine exposures.
Meta mqabbel ma ’ l- għoti fi stat ta ’ sawm, id- doża ta ’ tenofovir disoproxil fumarate u emtricitabine f’ kombinazzjoni ma ’ ikla b’ ħafna xaħam jew ma ’ ikla ħafifa żiedet l- AUC u Cmax medju ta ’ tenofovir b’ 35% u bi 15% rispettivament mingħajr ma ġew affettwati l- espożizzjonijiet ta ’ emtricitabine.
Atripla is recommended for administration on an empty stomach since food may increase efavirenz exposure and may lead to an increase in the frequency of adverse reactions (see sections 4.4 and 4.8).
Atripla hija rrakkomandata sabiex tingħata fuq stonku vojt minħabba li l- ikel jista ’ jżid l- espożizzjoni ta ’ efavirenz u jista ’ jwassal għal żieda fil- frekwenza ta ’ reazzjonijiet avversi (ara sezzjonijiet 4. 4 u 4. 8).
It is anticipated that tenofovir exposure will be approximately 35% lower following administration of Atripla on an empty stomach as compared to the individual component tenofovir disoproxil fumarate when taken with food.
Huwa mistenni li l- espożizzjoni ta ’ tenofovir tkun bejn wieħed u ieħor 35% inqas wara għoti ta ’ Atripla fuq stonku vojt meta mqabbel mal- komponenti individwali tenofovir disoproxil fumarate meta meħud ma ’ l- ikel.
Forty-eight week data from a clinical study (AI266073) showed maintenance of virologic suppression for patients who had stable virologic suppression on combination
Dejta mill- ġimgħa tmienja u erbgħin minn studju kliniku (AI266073) uriet iż - żamma ta ’ trażżin viroloġiku għal pazjenti li kellhom trażżin viroloġiku stabbli fuq terapija antiretrovirali ta ’ kombinazzjoni u sussegwentament qalbu għal Atripla b’ rakkomandazzjoni għal amministrazzjoni ta ’ Atripla fuq stonku vojt.
Distribution: efavirenz is highly bound (> 99%) to human plasma proteins, predominantly albumin.
Distribuzzjoni: efavirenz jeħel tajjeb ħafna (> 99%) ma ’ proteini tal- plażma umana, il- biċċa l- kbira albumina.
In vitro binding of emtricitabine to human plasma proteins is < 4% and independent of concentrations over the range of 0.02 to 200 µg/ ml.
It- twaħħil in vitro ta ’ emtricitabine mal- proteini tal- plażma umana huwa < 4% u indipendenti minn konċentrazzjonijiet fuq il- medda ta ’ 0. 02 sa 200 µg/ ml.
Following intravenous administration the volume of distribution of emtricitabine was approximately 1.4 l/ kg.
Wara għoti ġol- vini, il- volum tad - distribuzzjoni ta ’ emtricitabine kien bejn wieħed u ieħor 1. 4 l/ kg.
After oral administration, emtricitabine is widely distributed throughout the body.
Wara għoti orali, emtricitabine huwa distribwit b’ mod mifrux madwar il- ġisem kollu.
The mean plasma to blood concentration ratio was approximately 1.0 and the mean semen to plasma concentration ratio was approximately 4.0.
Il- proporzjon tal- konċentrazzjoni medja tal - plażma għad- demm kienet madwar 1. 0 u l- proporzjon tal- konċentrazzjoni medja semen għal plażma kienet madawar 4. 0.
In vitro binding of tenofovir to human plasma or serum protein is < 0.7% and 7.2%, respectively over the tenofovir concentration range 0.01 to 25 µg/ ml.
It- twaħħil in vitro ta ’ tenofovir mal- plażma umana jew mal- proteina tas- serum hija < 0. 7% u 7. 2%, rispettivament fuq il- medda 0. 01 sa 25 µg/ ml tal- konċentrazzjoni ta ’ tenofovir.
Following intravenous administration the volume of distribution of tenofovir was approximately 800 ml/ kg.
Wara għoti ġol- vini, il - volum ta ’ distribuzzjoni ta ’ tenofovir kien madwar 800 ml/ kg.
After oral administration, tenofovir is widely distributed throughout the body.
Wara għoti orali, tenofovir huwa distribwit b’ mod mifrux madwar il- ġisem kollu.
Biotransformation: studies in humans and in vitro studies using human liver microsomes have demonstrated that efavirenz is principally metabolised by the cytochrome P450 system to hydroxylated metabolites with subsequent glucuronidation of these hydroxylated metabolites.
Bijotrasformazzjoni: studji fl- umani u studji in vitro li jużaw mikrosomi tal- fwied uman urew li efavirenz huwa metabolizzat b’ mod ewlieni mis- sistema ta ’ cytochrome P450 għal metaboliti idrossillati b’ glukuronidazzjoni sussegwenti tal- metaboliti idrossilati.
These metabolites are essentially inactive against HIV-1.
Dawn il- metaboliti huma essenzjalment inattivi kontra HIV- 1.
The in vitro studies suggest that CYP3A4 and CYP2B6 are the major isoenzymes responsible for efavirenz metabolism and that it inhibits P450 isoenzymes 2C9, 2C19, and 3A4.
L- istudji in vitro jissuġġerixxu li CYP3A4 u CYP2B6 huma l - isoenzimi maġġuri responsabbli għall- metaboliżmu ta ’ efavirenz u li jinibixxi l- isoenzimi 2C9, 2C19, u 3A4 ta ’ P450.
In in vitro studies efavirenz did not inhibit CYP2E1 and inhibited CYP2D6 and CYP1A2 only at concentrations well above those achieved clinically.
Fi studji in vitro, efavirenz ma inibixxix CYP2E1 iżda inibixxa CYP2D6 u CYP1A2 biss f’ konċentrazzjonijiet ’ l fuq sewwa minn dawn miksuba klinikament.
Efavirenz plasma exposure may be increased in patients with homozygous G516T genetic variant of the CYP2B6 isoenzyme.
L- espożizzjoni tal- plażma ta ’ efavirenz tista ’ tiżdied f’ pazjenti b’ varjant ġenetiku G516T omozigotiku ta ’ l- isoezim CYP2B6.
The clinical implications of such an association are unknown; however, the potential for an increased frequency and severity of efavirenz-associated adverse events cannot be excluded.
L- implikazzjonijiet kliniċi ta ’ assoċjazzjoni tali m’ humiex magħrufin; madankollu, il- potenzjal għal frekwenza u severità ikbar ta ’ episodji avversi assoċjati ma ’ efavirenz ma jistax jiġi eskluż.
Efavirenz has been shown to induce P450 enzymes, resulting in the induction of its own metabolism.
Efavirenz intwera li jinduċi enzimi ta ’ P450, li jirriżulta fl- induzzjoni tal- metaboliżmu tiegħu stess.
In uninfected volunteers, multiple doses of 200 to 400 mg per day for 10 days resulted in a lower than predicted extent of accumulation (22 to 42% lower) and a shorter terminal half-life of 40 to 55 hours (single dose half-life 52 to 76 hours).
F’ voluntiera m’ huwiex affettwati, dożi multipli ta ’ 200 sa 400 mg kuljum għal 10 t- ijiem irriżultaw f’ firxa ta ’ akkumulazzjoni inqas milli mistenni (22 sa 42% inqas) u half- life terminali inqas ta ’ 40 sa 55 siegħa (half- life ta ’ doża waħda ta ’ 52 sa 76 siegħa).
There is limited metabolism of emtricitabine.
Hemm ftit metaboliżmu ta ’ emtricitabine.
The biotransformation of emtricitabine includes oxidation of the thiol moiety to form the 3'-sulphoxide diastereomers (approximately 9% of dose) and conjugation with glucuronic acid to form 2'-O-glucuronide (approximately 4% of dose).
Il- bijotrasformazzjoni ta ’ emtricitabine tinkludi l - ossidazzjoni tal- moiety tat- thiol sabiex jiġu ffurmati 3 '- sulphoxide diastereomers (bejn wieħed u ieħor 9% tad- doża) u flimkien ma ’ aċidu glukuroniku biex jifforma 2' - O- glucuronide (bejn wieħed u ieħor 4% tad- doża).
In vitro studies have determined that neither tenofovir disoproxil fumarate nor tenofovir are substrates for the CYP450 enzymes.
Studji in vitro stabbilixxew li la tenofovir disoproxil fumarate u lanqas tenofovir m’ huma substrati għall- enzimi ta ’ CYP450.
Neither emtricitabine nor tenofovir inhibited in vitro drug metabolism mediated by any of the major human CYP450 isoforms involved in drug biotransformation.
La emtricitabine u lanqas tenofovir ma inibixxew il - metaboliżmu tal- mediċina in vitro medjata minn xi isoforma ta ’ CYP450 umana maġġuri f’ bijotrasformazzjoni tal- mediċina.
Also, emtricitabine did not inhibit uridine 5'-diphosphoglucuronyl transferase, the enzyme responsible for glucuronidation.
Barra minn hekk, emtricitabine ma inibixxix uridine 5 '- diphosphoglucuronyl transferase, l- enzim responsabbli għall- glukuronidazzjoni.
Elimination: efavirenz has a relatively long terminal half-life of at least 52 hours after single doses (see also data from bioequivalence study described above) and 40 to 55 hours after multiple doses.
31 Eliminazzjoni: efavirenz għandu half- life terminali relattivament twila ta ’ mill- anqas 52 siegħa wara dożi singoli (ara wkoll id- dejta mill- istudju ta ’ bijoekwivalenza deskritt fuq) u 40 sa 55 siegħa wara dożi multipli.
Approximately 14 to 34% of a radiolabelled dose of efavirenz was recovered in the urine and less than 1% of the dose was excreted in urine as unchanged efavirenz.
Bejn wieħed u ieħor 14 sa 34% tad- doża radjutikkettjata ta ’ efavirenz ġiet irkuprata fl - awrina u inqas minn 1% tad- doża inħarġet fl- awrina bħala efavirenz mhux mibdul.
Following oral administration, the elimination half-life of emtricitabine is approximately 10 hours.
Wara għoti orali, il- half- life ta ’ eliminazzjoni hija madwar 10 sigħat.
Emtricitabine is primarily excreted by the kidneys with complete recovery of the dose achieved in urine (approximately 86%) and faeces (approximately 14%).
Emtricitabine jinħareġ primarjament mill- kliewi b’ irkupru sħiħ tad- doża miksub fl- awrina (bejn wieħed u ieħor 86%) u ippurgar (bejn wieħed u ieħor 14%).
Thirteen percent of the emtricitabine dose was recovered in urine as three metabolites.
Tlettax fil- mija tad- doża ta ’ emtricitabine ġie rkuprat fl- awrina bħala tliet metaboliti.
The systemic clearance of emtricitabine averaged 307 ml/ min.
It- tneħħija sistematika ta ’ emtricitabine kellha medja 307 ml/ min.
Following oral administration, the elimination half-life of tenofovir is approximately 12 to 18 hours.
Wara amministrazzjoni orali, il- half- life ta ’ l- eliminazzjoni ta ’ tenofovir hija madwar 12 sa 18- il siegħa.
Tenofovir is primarily excreted by the kidney by both filtration and an active tubular transport system with approximately 70 to 80% of the dose excreted unchanged in urine following intravenous administration.
Tenofovir jinħareġ primarjament mill- kilwa kemm mill- filtrazzjoni kif ukoll mis- sistema ta ’ trasport tubulari attiva b’ bejn wieħed u ieħor 70 sa 80% tad- doża eliminata mhux mibdula fl- awrina wara għoti ġol- vini.
Renal
L- eliminazzjoni apparenti ta ’ tenofovir kellha medja ta ’ bejn wieħed u ieħor 307 ml/ min.
30 clearance has been estimated to be approximately 210 ml/ min, which is in excess of the glomerular filtration rate.
L- eliminazzjoni mill- kliewi kienet stmata bħala bejn wieħed u ieħor 210 ml/ min, li hija aktar mir- rata ta ’ filtrazzjoni glomerulari.
This indicates that active tubular secretion is an important part of the elimination of tenofovir.
Dan jindika li s- sekrezzjoni tubulari attiva hija parti importanti mill- eliminazzjoni ta ’ tenofovir.
Age, gender and ethnicity: the pharmacokinetics of emtricitabine and tenofovir are similar in male and female patients.
Età, sess u etniċità: il- farmakokinetiċi ta ’ emtricitabine u tenofovir huma simili f’ pazjenti nisa u rġiel.
Although limited data suggest that females as well as Asian and Pacific Island patients may have higher exposure to efavirenz, they do not appear to be less tolerant of efavirenz.
Għalkemm tagħrif limitat jissuġġerixxi li pazjenti nisa kif ukoll Asjatiċi u mill- Gżira Paċifika jista ’ jkollhom espożizzjoni ikbar għal efavirenz, ma jidhirx li huma inqas tolleranti għal efavirenz.
Pharmacokinetic studies have not been performed with efavirenz, emtricitabine or tenofovir in the elderly (over 65 years).
Għadhom ma sarux studji farmakokinetiċi b’ efavirenz, emtricitabine jew tenofovir fuq l- anzjani (aktar minn 65 sena).
Pharmacokinetic studies with Atripla have not been performed in infants and children (see section 4.2).
Għadhom ma sarux studji farmakokinetiċi b’ Atripla fuq trabi u tfal (ara sezzjoni 4. 2).
Renal impairment: the pharmacokinetics of efavirenz, emtricitabine and tenofovir disoproxil fumarate after co-administration of the separate pharmaceutical forms or as Atripla have not been studied in HIV infected patients with renal impairment.
Indeboliment renali: il- farmakokinetiċi ta ’ efavirenz, emtricitabine u tenofovir disoproxil fumarate wara l- għoti fl- istess ħin ta ’ forom farmaċewtiċi separati jew bħala Atripla għadhom ma ġewx studjati f’ pazjenti infettati bl- HIV b’ indeboliment renali.
Pharmacokinetic parameters were determined following administration of single doses of the individual preparations of emtricitabine 200 mg or tenofovir disoproxil 245 mg to non-HIV infected patients with varying degrees of renal impairment.
Il- parametri farmakokinetiċi ġew stabbiliti wara għoti ta ’ dożi singoli tal- preparazzjonijiet individwali ta ’ emtricitabine 200 mg jew tenofovir disoproxil 245 mg lil pazjenti mhux infettati bl- HIV bi gradi varji ta ’ indeboliment renali.
The degree of renal impairment was defined according to baseline creatinine clearance (normal renal function when creatinine clearance > 80 ml/ min; mild impairment with creatinine clearance=50 to 79 ml/ min; moderate impairment with creatinine clearance=30 to 49 ml/ min and severe impairment with creatinine clearance=10 to 29 ml/ min).
Il- grad ta ’ indeboliment renali ġie definit skond l- eliminazzjoni ta ’ kreatinina tal- linja bażi (funzjoni renali normali meta l- eliminazzjoni tal- kreatinina > 80 ml/ min; indeboliment ħafif b’ eliminazzjoni tal- kreatinina =50 sa 79 ml/ min; indeboliment moderat b’ eliminazzjoni tal- kreatinina =30 sa 49 ml/ min u indeboliment sever b’ eliminazzjoni tal- kreatinina =10 sa 29 ml/ min).
The mean (%CV) emtricitabine exposure increased from 12 µg• h/ ml (25%) in subjects with normal renal function to 20 µg• h/ ml (6%), 25 µg• h/ ml (23%) and 34 µg• h/ ml (6%) in patients with mild, moderate and severe renal impairment, respectively.
L- espożizzjoni medja (% CV) ta ’ emtricitabine żdiedet minn 12 µg• h/ ml (25%) f’ suġġetti b’ funzjoni renali normali għal 20 µg• h/ ml (6%), 25 µg• h/ ml (23%) u 34 µg• h/ ml (6%) f’ pazjenti b’ indeboliment renali, ħafif, moderat u sever, rispettivament.
The mean (%CV) tenofovir exposure increased from 2,185 ng• h/ ml (12%) in patients with normal renal function, to 3,064 ng• h/ ml (30%), 6,009 ng• h/ ml (42%) and 15,985 ng• h/ ml (45%) in patients with mild, moderate and severe renal impairment, respectively.
L- espożizzjoni medja (% CV) ta ’ tenofovir żdiedet minn 2, 185 ng• h/ ml (12%) f’ pazjenti b’ funzjoni renali normali, għal 3, 064 ng• h/ ml (30%), 6, 009 ng• h/ ml (42%) u 15, 985 ng• h/ ml (45%) f’ pazjenti b’ indeboliment renali, ħafif, moderat u sever, rispettivament.
In patients with end-stage renal disease (ESRD) requiring haemodialysis, between dialysis drug exposures substantially increased over 72 hours to 53 µg• h/ ml (19%) of emtricitabine, and over 48 hours to 42,857 ng• h/ ml (29%) of tenofovir.
F’ pazjenti b’ mard renali ta ’ l- aħħar fażi (ESRD) li jeħtieġu emodijaliżi, l- espożizzjonijiet tal- mediċina bejn id- dijaliżi żdiedu tul 72 siegħa għal 53 µg• h/ ml (19%) ta ’ emtricitabine, u aktar minn 48 siegħa għal 42, 857 ng• h/ ml (29%) ta ’ tenofovir.
The pharmacokinetics of efavirenz have not been studied in patients with renal impairment.
Il- farmakokinetiċi ta ’ efavirenz ma ġewx studjati f’ pazjenti b’ indeboliment renali.
However, less than 1% of an efavirenz dose is excreted unchanged in the urine, so the impact of renal impairment on exposure to efavirenz is likely to be minimal.
Madankollu, inqas minn 1% tad- doża ta ’ efavirenz hija eliminata mhux mibdula fl- awrina, għalhekk l- impatt ta ’ l - indeboliment renali fuq l- espożizzjoni għal efavirenz x’ aktarx li jkun minimu.
Atripla is not recommended for patients with moderate or severe renal impairment (creatinine clearance < 50 ml/ min).
32 Atripla m’ huwiex rakkomandat għal pazjenti b’ indeboliment renali moderat jew sever (eliminazzjoni tal- kreatinina < 50 ml/ min).
Patients with moderate or severe renal impairment require dose interval adjustment of emtricitabine and tenofovir disoproxil fumarate that cannot be achieved with the combination tablet (see sections 4.2 and 4.4).
Pazjenti b’ indeboliment renali moderat jew sever jeħtieġu aġġustament fl - intervall tad- doża ta ’ emtricitabine u tenofovir disoproxil fumarate li ma jkunx jista ’ jintlaħaq bil - pillola ta ’ kombinazzjoni (ara sezzjonijiet 4. 2 u 4. 4).
Hepatic impairment: the pharmacokinetics of Atripla have not been studied in HIV infected patients with hepatic impairment.
Indeboliment epatiku: il- farmakokinetiċi ta ’ Atripla ma ġewx studjati f’ pazjenti infettati bl- HIV b’ indeboliment epatiku.
Atripla should be administered with caution to patients with mild-to-moderate liver disease (see sections 4.3 and 4.4).
Atripla għandu jingħata b’ kawtela lil pazjenti b’ mard tal- fwied ħafif għal moderat (ara sezzjonijiet 4. 3 u 4. 4).
Atripla must not be used in patients with severe hepatic impairment (see section 4.3).
Atripla ma għandux jintuża f’ pazjenti b’ indeboliment tal- fwied sever (ara sezzjoni 4. 3).
In the single patient studied with severe hepatic impairment (CPT, Grade C), half-life of efavirenz was doubled indicating a potential for a much greater degree of accumulation.
Fl- uniku pazjent studjat b’ indeboliment tal- fwied sever (CPT, Grad C), il- half- life ta ’ efavirenz ġie rduppjat u dan jindika potenzjal għal grad ferm akbar ta ’ akkumulazzjoni.
31 The pharmacokinetics of emtricitabine have not been studied in non-HBV infected patients with varying degrees of hepatic insufficiency.
Il- farmakokinetiċi ta ’ emtricitabine ma ġewx studjati f’ pazjenti mhux infettati bl- HBV bi gradi varji ta ’ insuffiċjenza epatika.
In general, emtricitabine pharmacokinetics in HBV infected patients were similar to those in healthy subjects and in HIV infected patients.
B’ mod ġenerali, il- farmakokinetiċi ta ’ emtricitabine f’ pazjenti infettati bl - HBV kienu simili għal dawk f’ suġġetti b’ saħħithom u f’ pazjenti infettati bl- HIV.
A single 300 mg dose of tenofovir disoproxil fumarate was administered to non-HIV infected patients with varying degrees of hepatic impairment defined according to CPT classification.
Doża singola ta ’ 300 mg ta ’ tenofovir disoproxil fumarate ingħata lil pazjenti mhux infettati bl- HIV bi gradi varji ta ’ indeboliment tal- fwied definiti skond il- klassifikazzjoni tas- CPT.
Tenofovir pharmacokinetics were not substantially altered in subjects with hepatic impairment suggesting that no dose adjustment of tenofovir disoproxil fumarate is required in these subjects.
Il- farmakokinetiċi ta ’ Tenofovir ma ġewx mibdula sostanzjalment f’ suġġetti b’ indeboliment epatiku u dan jissuġġerixxi li ebda aġġustament fid- doża ta ’ tenofovir disoproxil fumarate ma huwa meħtieġ f’ dawn is- suġġetti
Malformations were observed in 3 of 20 foetuses/ newborns from efavirenz-treated cynomolgus monkeys given doses resulting in plasma efavirenz concentrations similar to those seen in humans.
Kienu osservati malformazzjonijiet fi 3 minn 20 fetu/ wild ġdid minn xadini cynomolgus ittrattati b’ efavirenz li ngħataw dożi li rriżultaw f’ konċentrazzjonijiet ta ’ efavirenz fil- plażma simili għal dawk li dehru fil- bnedmin.
Anencephaly and unilateral anophthalmia with secondary enlargement of the tongue were observed in one foetus, micro-ophthalmia was observed in another foetus, and cleft palate was observed in a third foetus.
Anenċefalija u anoftalmija unilaterali bi tkabbir sekondarju ta ’ l- ilsien kienu osservati f’ fetu wieħed, mikro- oftalmija kienet osservata f’ fetu ieħor, u palat mixquq kien osservat fit - tielet fetu.
Efavirenz induced foetal resorptions in rats.
Efavirenz induċa l- assorbiment tal- fetu fil- firien.
No malformations were observed in foetuses from efavirenz-treated rats and rabbits.
L- ebda malformazzjonijiet ma kienu osservati fil- feti minn firien u fniek ittrattati b’ efavirenz.
Conventional reproductive/ developmental toxicity studies with emtricitabine and tenofovir disoproxil fumarate revealed no special hazard for humans.
Studji konvenzjonali dwar l- effett tossiku fuq is- sistema riproduttiva u l- iżvilupp b’ emtricitabine u tenofovir disoproxil fumarate ma wrew l- ebda periklu speċjali għall- bnedmin.
Carcinogenicity studies using efavirenz showed an increased incidence of hepatic and pulmonary tumours in female mice, but not in male mice.
Studji tal- karċinoġeniċità bl- użu ta ’ efavirenz urew inċidenza akbar ta ’ tumuri epatiċi u pulmonari fi ġrieden nisa, iżda mhux fi ġrieden irġiel.
The mechanism of tumour formation and the potential relevance for humans are not known.
Il- mekkaniżmu tal- formazzjoni ta ’ tumuri u r- rilevanza potenzjali għall- bnedmin mhumiex magħrufa.
Carcinogenicity studies using efavirenz in male mice and in male and female rats were negative.
Studji tal- karċinoġeniċità bl- użu ta ’ efavirenz fi ġrieden irġiel u f’ firien irġiel u nisa kienu negattivi.
While the carcinogenic potential in humans is unknown, these data suggest that the clinical benefit of efavirenz outweighs the potential carcinogenic risk to humans.
Filwaqt li l- potenzjal karċinoġeniku fil- bnedmin mhux magħruf, din id- dejta tissuġġerixxi li l- benefiċċju kliniku ta ’ efavirenz jegħleb ir- riskju karċinoġeniku potenzjali għall- bnedmin.
Tenofovir disoproxil fumarate did not show any carcinogenic potential in a long-term oral carcinogenicity study in rats.
Tenofovir disoproxil fumarate ma wera l- ebda potenzjal karċinoġeniku fi studji dwar il - karċinoġeniċità orali fuq tul ta ’ żmien fil- firien.