qanastek/EMEA-V3 huggingface dataset:
INTELENCE is expected to decrease plasma concentrations of these antiarrhythmics.
INTELENCE huwa mistenni li jnaqqas il- konċentrazzjonijiet fil- plażma ta ’ dawn l- antiarritmiċi.
Caution is warranted and therapeutic concentration monitoring, if available, is recommended for antiarrhythmics when co-administered with INTELENCE.
Hija rrakkomandata l- kawtela u monitoraġġ tal - konċentrazzjonijiet terapewtiċi, jekk disponibbli, huwa rrakkomandat għal antiaritmijaċi meta jittieħdu flimkien ma ’ INTELENCE.
ANTIBIOTICS
ANTIBIJOTIĊI
Based on the biliary elimination pathway of azithromycin, no drug interactions are expected between azithromycin and INTELENCE.
Ibbażat fuq il- passaġġ ta ’ eliminazzjoni biljari ta ’ azithromycin, mhux mistennija interazzjonijiet mediċinali bejn azithromycin u INTELENCE.
INTELENCE and azithromycin can be used without dose adjustments.
INTELENCE u azithromycin jistgħu jintużaw mingħajr aġġustament fid- doża.
Clarithromycin 500 mg b. i. d.
Clarithromycin 500mg b. i. d.
clarithromycin AUC ↓ 0.61 (0.53-0.69) clarithromycin Cmin ↓ 0.47 (0.38-0.57) clarithromycin Cmax ↓ 0.66 (0.57-0.77) 14-OH-clarithromycin AUC ↑ 1.21 (1.05-1.39) 14-OH-clarithromycin Cmin ↔ 1.05 (0.90-1.22) 14-OH-clarithromycin Cmax ↑ 1.33 (1.13-1.56) etravirine AUC ↑ 1.42 (1.34-1.50) etravirine Cmin ↑ 1.46 (1.36-1.58) etravirine Cmax ↑ 1.46 (1.38-1.56)
clarithromycin AUC ↓ 0. 61 (0. 53- 0. 69) clarithromycin Cmin ↓ 0. 47 (0. 38- 0. 57) clarithromycin Cmax ↓ 0. 66 (0. 57- 0. 77) 14- OH- clarithromycin AUC ↑ 1. 21 (1. 05- 1. 39) 14- OH- clarithromycin Cmin ↔ 1. 05 (0. 90- 1. 22) 14- OH- clarithromycin Cmax ↑ 1. 33 (1. 13- 1. 56) etravirine AUC ↑ 1. 42 (1. 34- 1. 50) etravirine Cmin ↑ 1. 46 (1. 36- 1. 58) etravirine Cmax ↑ 1. 46 (1. 38- 1. 56)
Clarithromycin exposure was decreased by etravirine; however, concentrations of the active metabolite, 14-OH-clarithromycin, were increased.
Espożizzjoni għal clarithromycin ġiet imnaqqsa b’ etravirine; iżda, konċentrazzjonijiet tal - metabolit attiv, 14- OH- clarithromycin, żdiedu.
Because 14-OH-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered; therefore alternatives to clarithromycin should be considered for the treatment of MAC.
Minħabba li 14- OH- clarithromycin għandu attivita` mnaqqsa kontra Mycobacterium avium complex (MAC), jista jagħti l - każ illi l- attivita` ġenerali kontra dan il- patoġen tinbidel; għalhekk għandhom jiġu kkunsidrati alternattivi għal clarithromycin għat - trattament ta ’ MAC
INTELENCE is expected to increase plasma concentrations of warfarin.
INTELENCE huwa mistenni li jżid il- konċentrazzjonijiet fil- plażma ta ’ warfarin.
It is recommended that the international normalised ratio (INR) be monitored when warfarin is combined with INTELENCE.
Huwa rrakkomandat li l - international normalised ratio (INR) jiġi monitorat meta warfarin huwa kkombinat ma ’ INTELENCE.
ANTICONVULSANTS
ANTIKONVULSANTI
Carbamazepine Phenobarbital Phenytoin
Carbamazepine Phenobarbital Phenytoin
Carbazamepine, phenobarbital and phenytoin are expected to decrease plasma concentrations of etravirine.
Carbazamepine, phenobarbital u phenytoin huma mistennija li jnaqqsu l - konċentrazzjonijiet fil- plażma ta ’ etravirine.
Combination not recommended.
Kombinazzjoni mhux irrakkomandata
ANTIFUNGALS
ANTIFUNGALI
Fluconazole Itraconazole Ketoconazole Posaconazole Voriconazole
Fluconazole Itraconazole Ketoconazole Posaconazole Voriconazole
Posaconazole is a potent inhibitor of CYP3A4 and fluconazole is a potent inhibitor of CYP2C9; both may increase plasma concentrations of etravirine.
Posaconazole huma impeditur qawwi ta ’ CYP3A4 u fluconazole huwa impeditur qawwi ta ’ CYP2C9; it- tnejn jistgħu jżidu l- konċentrazzjonijiet fil- plażma ta ’ etravirine.
Itraconazole and ketoconazole are potent inhibitors as well as substrates of CYP3A4.
Itraconazole u ketoconazole huma impedituri qawwija kif ukoll substrati ta ’ CYP3A4.
Concomitant systemic use of itraconazole or ketoconazole and INTELENCE may increase plasma concentrations of etravirine.
Użu sistemiku konkomitanti ta ’ itraconazole jew ketoconazole u INTELENCE jistgħu jżidu l- konċentrazzjonijiet fil- plażma ta ’ etravirine.
Simultaneously, plasma concentrations of itraconazole or ketoconazole may be decreased by INTELENCE.
B’ mod simultanju, il - konċentrazzjonijiet fil- plażma ta ’ itraconazole jew ketoconazole jistgħu jitnaqqsu b’ INTELENCE.
Voriconazole is a CYP2C19 substrate and CYP3A4 and CYP2C inhibitor.
Voriconazole huwa substrat ta ’ CYP2C19 u impeditur ta ’ CYP3A4 u CYP2C.
Concomitant use of voriconazole and INTELENCE may increase plasma concentrations of both drugs.
Użu konkomitanti ta ’ voriconazole u INTELENCE jistgħu jżidu l- konċentrazzjonijiet fil- plażma taż- żewġ mediċini.
INTELENCE and antifungals can be used without dose adjustments.
INTELENCE u antifungali jistgħu jintużaw mingħajr aġġustament fid- doża.
ANTIMYCOBACTERIALS
ANTIMIKOBATTERJALI
Rifampicin Rifapentine
Rifampicin Rifapentine
Rifampicin and rifapentine are expected to decrease plasma concentrations of etravirine.
Rifampicin u rifapentine huma mistennija li jnaqqsu l- konċentrazzjonijie fil - plażma ta ’ etravirine.
INTELENCE should be used in combination with a boosted protease inhibitor (PI).
INTELENCE għandu jintuża f’ kombinazzjoni ma ’ impeditur ta ’ protease (PI) ibbustjat.
Rifampicin is contraindicated in combination with boosted PIs.
Rifampicin huwa kontraindikat f’ kombinazzjoni ma ’ PIs ibbustjati.
rifabutin AUC ↓ 0.83 (0.75-0.94) rifabutin Cmin ↓ 0.76 (0.66-0.87) rifabutin Cmax ↓ 0.90 (0.78-1.03) 25-O-desacetyl-rifabutin AUC ↓ 0.83 (0.74-0.92) 25-O-desacetyl-rifabutin Cmin ↓ 0.78 (0.70-0.87) 25-O-desacetyl-rifabutin Cmax ↓ 0.85 (0.72-1.00) etravirine AUC ↓ 0.63 (0.54-0.74) etravirine Cmin ↓ 0.65 (0.56-0.74) etravirine Cmax ↓ 0.63 (0.53-0.74)
rifabutin AUC ↓ 0. 83 (0. 75- 0. 94) rifabutin Cmin ↓ 0. 76 (0. 66- 0. 87) rifabutin Cmax ↓ 0. 90 (0. 78- 1. 03) 25- O- desacetyl- rifabutin AUC ↓ 0. 83 (0. 74- 0. 92) 25- O- desacetyl- rifabutin Cmin ↓ 0. 78 (0. 70- 0. 87) 25- O- desacetyl- rifabutin Cmax ↓ 0. 85 (0. 72- 1. 00) etravirine AUC ↓ 0. 63 (0. 54- 074) etravirine Cmin ↓ 0. 65 (0. 56- 0. 74) etravirine Cmax ↓ 0. 63 (0. 53- 0. 74)
The combination of INTELENCE and rifabutin should be used with caution due to the risk of decrease in etravirine and rifabutin exposures.
Il- kombinazzjoni ta ’ INTELENCE ma ’ rifabutin għandha tintuża b’ kawtela minħabba r- riskju ta ’ tnaqqis ta ’ espożizzjoni ta ’ etravirine u rifabutin.
ANTIVIRALS
ANTIVIRALI
Not studied, but no interaction expected based on the renal elimination pathway of ribavirin.
Mhux studjat, imma mhux mistennija interazzjoni fuq bażi tal- mezz ta ’ eliminazzjoni renali ta ’ ribavirin.
The combination of INTELENCE and ribavirin can be used without dose adjustments.
Il- kombinazzjoni ta ’ INTELENCE u ribavirin tista ’ tintuża mingħajr aġġustament fid- doża
Not studied, etravirine is expected to increase plasma concentrations of diazepam.
Mhux studjat, etravirine huwa mistenni li jnaqqas il- konċentrazzjonijiet fil- plażma ta ’ diazepam.
Alternatives to diazepam should be considered.
Alternattivi għal diazepam għandhom jiġu kkunsidrati.
CORTICOSTEROIDS
KORTIKOSTEROJDI
Dexamethasone (systemic)
Dexamethasone (sistemiku)
Dexamethasone is expected to decrease plasma concentrations of etravirine
Dexamethasone huwa mistenni li jnaqqas il- konċentrazzjonijiet fil- plażma ta ’ etravirine
Systemic dexamethasone should be used with caution or alternatives should be considered, particularly for chronic use.
Dexamethasone sistemiku għandu jintuża b’ kawtela jew għandhom jiġu kkunsidrati alternattivi partikolarment għal użu kroniku.
ESTROGEN-BASED CONTRACEPTIVES
KONTRAĊETTIVI B’ BAŻI TA ’ ESTROGEN
Ethinylestradiol 0.035 mg q. d.
Ethinylestradiol 0. 035 mg q. d.
Norethindrone 1 mg q. d.
Norethindrone 1 mg q. d.
ethinylestradiol AUC ↑ 1.22 (1.13-1.31) ethinylestradiol Cmin ↔ 1.09 (1.01-1.18) ethinylestradiol Cmax ↑ 1.33 (1.21-1.46) norethindrone AUC ↔ 0.95 (0.90-0.99) norethindrone Cmin ↓ 0.78 (0.68-0.90) norethindrone Cmax ↔ 1.05 (0.98-1.12) etravirine AUC ↔ a etravirine Cmin ↔ a etravirine Cmax ↔ a
Ethinylestradiol AUC ↑ 1. 22 (1. 13- 1. 31) ethinylestradiol Cmin ↔ 1. 09 (1. 01- 1. 18) ethinylestradiol Cmax ↑ 1. 33 (1. 21- 1. 46) norethindrone AUC ↔ 0. 95 (0. 90- 0. 99) norethindrone Cmin ↓ 0. 78 (0. 68- 0. 90) norethindrone Cmax ↔ 1. 05 (0. 98- 1. 12) etravirine AUC ↔a etravirine Cmin ↔a etravirine Cmax ↔a
The combination of estrogen- and/ or progesterone-based contraceptives and INTELENCE can be used without dose adjustment.
Il- kombinazzjoni ta ’ kontraċettivi b’ bażi ta ’ estrogen u/ jew progesterone u INTELENCE jistgħu jintużaw mingħajr aġġustament fid - doża.
HMG CO-A REDUCTASE INHIBITORS
PRODOTTI MILL- ĦXEJJEX
atorvastatin AUC ↓ 0.63 (0.58-0.68) atorvastatin Cmin ND atorvastatin Cmax ↓ 1.04 (0.84-1.30) 2-OH-atorvastatin AUC ↑ 1.27 (1.19-1.36) 2-OH-atorvastatin Cmin ND 2-OH-atorvastatin Cmax ↑ 1.76 (1.60-1.94) etravirine AUC ↔ 1.02 (0.97-1.07) etravirine Cmin ↔ 1.10 (1.02-1.19) etravirine Cmax ↔ 0.97 (0.93-1.02)
atorvastatin AUC ↓ 0. 63 (0. 58- 0. 68) atorvastatin Cmin ND atorvastatin Cmax ↓ 1. 04 (0. 84- 1. 30) 2- OH- atorvastatin AUC ↑ 1. 27 (1. 19- 1. 36) 2- OH- atorvastatin Cmin ND 2- OH- atorvastatin Cmax ↑ 1. 76 (1. 60- 1. 94) etravirine AUC ↔ 1. 02 (0. 97- 1. 07) etravirine Cmin ↔ 1. 10 (1. 02- 1. 19) etravirine Cmax ↔ 0. 97 (0. 93- 1. 02)
The combination of INTELENCE and atorvastatin can be given without any dose adjustments, however, the dose of atorvastatin may need to be altered based on clinical response.
Il- kombinazzjoni ta ’ INTELENCE u atorvastatin tista ’ tingħata mingħajr aġġustament fid- doża, iżda d - doża ta ’ atorvastatin jista ’ jkollha bżonn tinbidel fuq bażi ta ’ rispons kliniku.
No interaction between pravastatin and INTELENCE is expected.
Mhux mistennija interazzjonijiet bejn pravastatin u INTELENCE.
Lovastatin, rosuvastatin and simvastatin are CYP3A4 substrates and co-administration with INTELENCE may result in lower plasma concentrations of the HMG Co-A reductase inhibitor.
Lovastatin, rosuvastatin u simvastatin huma substrati ta ’ CYP3A4 u t- teħid tagħhom flimkien ma ’ INTELENCE jista jwassal għal konċentrazzjonijiet fil- plażma iktar baxxi ta ’ l - impeditur ta ’ HMG Co- A reductase.
Fluvastatin, and rosuvastatin are metabolised by CYP2C9 and co-administration with INTELENCE may result in higher plasma concentrations of the HMG Co-A reductase inhibitor.
Fluvastatin u rosuvastatin huma metabolizzati minn CYP2C9 u t- teħid flimkien ma ’ INTELENCE jista ’ jwassal għal konċentrazzjonijiet fil- plażma iktar għoljin ta ’ l- impeditur ta ’ HMG Co- A reductase.
Dose adjustments for these HMG Co-A reductase inhibitors may be necessary.
Jista jkun hemm bżonn ta ’ aġġustament fid- dożi għal gawn l- impedituri HMG Co- A reductase.
H2-RECEPTOR ANTAGONISTS
ANTAGONISTI TAR- RIĊETTUR- H2
Ranitidine 150 mg b. i. d.
Ranitidine 150 mg b. i. d.
etravirine AUC ↓ 0.86 (0.76-0.97) etravirine Cmin ND etravirine Cmax ↓ 0.94 (0.75-1.17)
etravirine AUC ↓ 0. 86 (0. 76- 0. 97) etravirine Cmin ND etravirine Cmax ↓ 0. 94 (0. 75- 1. 17)
INTELENCE can be co-administered with H2-receptor antagonists without dose adjustments.
INTELENCE jista ’ jittieħed ma ’ antagonisti tar- riċettur- H2 mingħajr aġġustament fid - doża.
IMMUNOSUPPRESSANTS
IMMUNOSUPPRESSANTI
Cyclosporine Sirolimus Tacrolimus
Cyclosporine Sirolimus Tacrolimus
Etravirine is expected to decrease plasma concentrations of cyclosporine, sirolimus or tacrolimus.
Etravirine huwa mistenni li jnaqqas il- konċentrazzjonijiet fil- plażma ta ’ cyclosporine, sirolimus jew tacrolimus.
Co-administration with systemic immunosuppressants should be done with caution because plasma concentrations of cyclosporine, sirolimus or tacrolimus may be affected when co-administered with INTELENCE.
It- teħid flimkien ma ’ immunosuppressanti sistemiċi għandu jsir b’ kawtela minħabba li l - konċentrazzjonijiet fil- plażma ta ’ cyclosporine, sirolimus jew tacrolimus jistgħu jiġu affettwati meta jittieħdu ma ’ INTELENCE.
NARCOTIC ANALGESICS
ANALĠESIĊI NARKOTIĊI
Methadone individual dose ranging from 60 mg to 130 mg q. d.
Methadone Doża individwali fil - marġini bejn 60 mg u 130 mg q. d.
R(-) methadone AUC ↔ 1.06 (0.99-1.13) R(-) methadone Cmin ↔ 1.10 (1.02-1.19) R(-) methadone Cmax ↔ 1.02 (0.96-1.09) S(+) methadone AUC ↔ 0.89 (0.82-0.96) S(+) methadone Cmin ↔ 0.89 (0.81-0.98) S(+) methadone Cmax ↔ 0.89 (0.83-0.97) etravirine AUC ↔ a etravirine Cmin ↔ a etravirine Cmax ↔ a
R (-) methadone AUC ↔ 1. 06 (0. 99- 1. 13) R (-) methadone Cmin ↔ 1. 10 (1. 02- 1. 19) R (-) methadone Cmax ↔ 1. 02 (0. 96- 1. 09) S( +) methadone AUC ↔ 0. 89 (0. 82- 0. 96) S( +) methadone Cmin ↔ 0. 89 (0. 81- 0. 98) S( +) methadone Cmax ↔ 0. 89 (0. 83- 0. 97) etravirine AUC ↔a etravirine Cmin ↔a etravirine Cmax ↔a
No changes in methadone dosage were required based on clinical status during or after the period of INTELENCE co-administration.
Ma kienx hemm bżonn ta ’ bidliet fid- doża ta ’ methadone ibbażat fuq stat kliniku waqt jew wara l- perijodu ta ’ meta kienu qed jittieħed flimkien ma ’ INTELENCE.
PHOSPHODIESTERASE, TYPE 5 (PDE-5) INHIBITORS
IMPEDITURI PHOSPHODIESTERASE, TIP 5 (PDE- 5)
Sildenafil 50 mg single dose Vardenafil Tadalafil
Sildenafil 50 mg doża singola Vardenafil Tadalafil
sildenafil AUC ↓ 0.43 (0.36-0.51) sildenafil Cmin ND sildenafil Cmax ↓ 0.55 (0.40-0.75) N-desmethyl-sildenafil AUC ↓ 0.59 (0.52-0.68) N-desmethyl-sildenafil Cmin ND N-desmethyl-sildenafil Cmax ↓ 0.75 (0.59-0.96)
sildenafil AUC ↓ 0. 43 (0. 36- 0. 51) sildenafil Cmin ND sildenafil Cmax ↓ 0. 55 (0. 40- 0. 75) N- desmethyl- sildenafil AUC ↓ 0. 59 (0. 52- 0. 68) N- desmethyl- sildenafil Cmin ND N- desmethyl- sildenafil Cmax ↓ 0. 75 (0. 59- 0. 96)
Concomitant use of PDE-5 inhibitors with INTELENCE may require dose adjustment of the PDE-5 inhibitor to attain the desired clinical effect.
Bl- użu konkomitanti ta ’ impedituri ta ’ PDE- 5 ma ’ INTELENCE jista jkun hemm bżonn ta ’ aġġustament fid - doża tal- impeditur ta ’ PDE- 5 sabiex jiġi ottenut l- effett kliniku mixtieq.
PROTON PUMP INHIBITORS
IMPEDITURI TA ’ PROTON PUMP
9 a
9
Paroxetine 20 mg q. d.
Paroxetine 20 mg q. d.
paroxetine AUC ↔ 1.03 (0.90-1.18) paroxetine Cmin ↓ 0.87 (0.75-1.02) paroxetine Cmax ↔ 1.06 (0.95-1.20) etravirine AUC ↔ 1.01 (0.93-1.10) etravirine Cmin ↔ 1.07 (0.98-1.17) etravirine Cmax ↔ 1.05 (0.96-1.15)
paroxetine AUC ↔ 1. 03 (0. 90- 1. 18) paroxetine Cmin ↓ 0. 87 (0. 75- 1. 02) paroxetine Cmax ↔ 1. 06 (0. 95- 1. 20) etravirine AUC ↔ 1. 01 (0. 93- 1. 10) etravirine Cmin ↔ 1. 07 (0. 98- 1. 17) etravirine Cmax ↔ 1. 05 (0. 96- 1. 15)
INTELENCE can be co-administered with paroxetine without dose adjustments.
INTELENCE jista ’ jittieħed flimkien ma ’ paroxetine mingħajr aġġustament fid - doża
Comparison based on historic control.
Paragun ibbażat fuq kontroll storiku.
In drug-drug interaction studies, different formulations and/ or doses of etravirine were used which led to similar exposures and, therefore, interactions relevant for one formulation are relevant for the other.
Fi studji dwar interazzjonijiet bejn mediċina u oħra, intużaw formulazzjonijiet u/ jew dożi differenti ta ’ etravirine li wasslu għal espożizzjonijiet simili u, għalhekk, interazzjonijiet rilevanti għal formulazzjoni waħda huma rilevanti għal oħra.
Pregnancy There are no adequate and well-controlled studies with etravirine in pregnant women.
Tqala M’ hemmx studji adegwati u kontrollati tajjeb fuq etravirine f’ nisa tqal.
Placental transfer has been seen in pregnant rats, but it is not known whether placental transfer of INTELENCE also occurs in pregnant women.
Ġie nnotat trasferiment mill - plaċenta f’ firien tqal, izda mhux magħruf jekk trasferiment ta ’ INTELENCE mill- plaċenta jseħħx ukoll f’ nisa tqal.
Studies in animals do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/ foetal development, parturition or postnatal development (see section 5.3).
Studji li saru fuq bhejjem ma jurux effetti ħżiena diretti jew indiretti fuq it- tqala, fuq l- iżvilupp ta ’ l- embriju/ fetu, ħlas jew fuq żvilupp wara t- twelid (ara sezzjoni 5. 3).
INTELENCE should be used during pregnancy only if the potential benefit justifies the potential risk.
INTELENCE għandu jintuża fit- tqala biss jekk il- benefiċċju potenzjali jiġġustifika r- riskju potenzjali.
Breastfeeding It is not known whether etravirine is excreted in human milk.
Treddigħ Mhux magħruf jekk etravirine joħroġx fil- ħalib uman.
Because of both the potential for HIV transmission and the potential for adverse reactions in breast-fed infants, mothers should be instructed not to breast-feed if they are receiving INTELENCE.
Minħabba kemm il- potenzjal ta ’ trażmissjoni ta ’ HIV kif ukoll minħabba l- potenzjal ta ’ reazzjonijiet mhux mixtieqa fi trabi li jerdgħu, l- ommijiet għandhom jiġu avvżati biex ma jreddgħux jekk qed jirċievu INTELENCE.
Fertility No human data on the effect of etravirine on fertility are available.
Fertilita` Ma hemmx tagħrif fuq l- effett ta ’ etravirine fuq il- fertilita` fil- bniedem.
In rats, there was no effect on mating or fertility with etravirine treatment (see section 5.3).
Fil- firien, ma kienx hemm effetti fuq tgħammir jew fertilita` bi trattament ta ’ etravirine (ara sezzjoni 5. 3).
No studies on the effects of INTELENCE on the ability to drive or operate machines have been performed.
Ma sarux studji dwar l- effetti ta ’ INTELENCE fuq il- ħila biex issuq jew tħaddem magni.
Adverse drug reactions such as somnolence and vertigo have been reported in INTELENCE treated subjects at incidences similar to placebo (see section 4.8).
Reazzjonijiet avversi bħal ħedla tan- ngħas u sturdament ġew irrapurtati f’ individwi trattati b’ INTELENCE f’ inċidenza simili għal plaċebo (ara sezzjoni 4. 8).
There is no evidence that INTELENCE may alter the patient’ s ability to drive and operate machines, however, the adverse drug reaction profile should be taken into account.
M’ hemmx evidenza li INTELENCE jista ’ jibdel il - ħila tal- pazjent biex isuq jew iħaddem magni, iżda, għandu jiġi kkunsidrat il- profil tar- reazzjonijiet avversi tal- mediċina.
The safety assessment is based on all data from 1,203 patients in the ongoing Phase III placebo-controlled trials DUET-1 and DUET-2 in antiretroviral treatment-experienced HIV-1 infected adult patients, 599 of whom received INTELENCE (200 mg b. i. d.) (see section 5.1).
Il- valutazzjoni ta ’ sikurezza hija bbażata fuq it- tagħrif kollu meħud minn 1, 203 pazjenti fil- provi li għadhom għaddejjin ta ’ Fażi III kontrollati bil- plaċebo DUET- 1 u DUET- 2 f’ pazjenti adulti infettati b’ HIV- 1 u esperjenzati fi trattament antiretrovirali, 599 minnhom irċevew INTELENCE (200mg b. i. d.) (ara sezzjoni 5. 1).
In these pooled trials, the median exposure for patients in the INTELENCE arm was 30 weeks.
F’ dawn il- provi miġbura, l- espożizzjoni medja tal- pazjenti fil- fergħa ta ’ INTELENCE kienet ta ’ 30 ġimgħa.
The most frequently reported adverse drug reactions (ADRs) (incidence ≥ 10% in the INTELENCE arm) of all intensities occurring in the Phase III studies were rash (17.0% in the INTELENCE arm versus 9.4% in the placebo arm), diarrhoea (15.0% versus 20.4%) and nausea (13.9% versus 11.1%).
L- iktar reazzjonijiet avversi għall- mediċina (ADRs) li ġew irrapurtati frekwentement (inċidenza ≥ 10% fil- fergħa ta ’ INTELENCE) ta ’ kull intensita` li seħħew fl- istudji ta ’ Fażi III kienu raxx (17. 0% fil - fergħa ta ’ INTELENCE kontra 9. 4% fil - fergħa tal- plaċebo), dijarrea (15. 0% kontra 20. 4%) u nawsja (13. 9% kontra 11. 1%).
The rates of discontinuation due to any adverse reaction were 5.8% in patients receiving INTELENCE and 4.5% in patients receiving placebo.
Ir- rati ta ’ dawk li waqqfu t- trattament minħabba reazzjonijiet avversi kienu 5. 8% f’ pazjenti li kienu qed jirċievu INTELENCE u 4. 5% f’ pazjenti li kienu qed jirċievu plaċebo.
The most common ADR leading to discontinuation was rash (2.0% in the INTELENCE arm versus 0% in the placebo arm).
L- iktar ADR komuni li wassal għal waqfien mit- trattament kien raxx (2. 0% fil - fergħa ta ’ INTELENCE kontra 0% fil- fergħa tal- plaċebo).
Rash was most frequently mild to moderate, generally macular to maculopapular or erythematous, mostly occurred in the second week of therapy, and was infrequent after week 4.
10 Ir- raxx frekwentement kien ħafif għal moderat, ġeneralment bi tbajja għal bi tbajja u nfafet jew eritematuż, l- iktar li seħħew kien fit- tieni ġimgħa tat- terapija, u ma kienx frekwenti wara ġimgħa 4.
Rash was mostly self-limiting, and generally resolved within 1-2 weeks on continued therapy (see section 4.4).
Ir- raxx kien l- iktar limitat fih inniffsu, u ġeneralment għadda fi żmien 1- 2 ġimgħat fuq terapija kontinwata (ara sezzjoni 4. 4).
The incidence of rash was higher in women compared to men in the INTELENCE arm.
L- inċidenza tar- raxx kienet ogħla fin- nisa meta mqabbla mal- irġiel fil - fergħa ta ’ INTELENCE.
The clinical data are limited and
Ma kienx hemm differenza bejn is- sessi fil- qawwa jew waqfien tat- trattament minħabba raxx.
10 an increased risk of cutaneous reactions in patients with a history of NNRTI-associated cutaneous reaction cannot be excluded (see section 4.4).
It- tagħrif kliniku huwa limitat u ma jistax jiġi eskluż ir- riskju ogħla ta ’ reazzjonijiet fil- ġilda f’ pazjenti bi storja ta ’ reazzjonijiet fil- ġilda assoċċjati ma ’ NNRTI (ara sezzjoni 4. 4).
ADRs of moderate intensity or greater (≥ grade 2) reported in patients treated with INTELENCE are summarised in the table below (background regimen is indicated as “ BR”).
ADRs ta ’ intensita` moderata jew iżjed (≥ grad 2) irrapurtati f’ pazjenti trattati b’ INTELENCE huma elenkati fil- qosor fit- tabella hawn taħt (Reġimen fl- isfond huwa indikat bħala “ BR ”).
Laboratory abnormalities considered ADRs are included in a paragraph below the table.
ADRs li ġew ikkonsidrati mill- anormalitajiet tal- laboratorju huma inklużi f’ paragrafu taħt it- tabella.
The ADRs are listed by system organ class (SOC) and frequency.
L- ADRs huma elenkati skond is- sistema tal- klassifika tal- organi (SOC) u frekwenza.
Within each frequency grouping, ADRs are presented in order of decreasing seriousness.
F’ kull sezzjoni ta ’ frekwenza, l - ADRs huma mniżżlin f’ ordni ta ’ tnaqqis fis- serjeta` tagħhom.
Frequencies are defined as very common (≥ 1/ 10), common (≥ 1/ 100 to < 1/ 10) and uncommon (≥ 1/ 1,000 to < 1/ 100).
Il- frekwenzi huma definiti bħala komuni ħafna (≥ 1/ 10), komuni (≥ 1/ 100 sa < 1/ 10) u mhux komuni (≥ 1/ 1000 sa < 1/ 100).
Rare and very rare ADRs cannot be detected based on the number of patients included in the DUET trials.
ADRs li huma rari u rari ħafna ma jistgħux jiġu traċati ibbażat fuq in- numru ta ’ pazjenti inklużi fil- provi DUET.
DUET-1 and DUET-2 trials System Organ Class (SOC)
Provi DUET- 1 u DUET- 2 Sistema tal- klassifika tal- organi (SOC)
Frequency Category
Kategorija ta ’ Frekwenza
ADRs (INTELENCE + BR versus Placebo + BR)
ADRs (INTELENCE + BR kontra Plaċebo + BR)
myocardial infarction (0.5% vs 0.2%), atrial fibrillation (0.2% vs 0%), angina pectoris (0.3% vs 0.2%)
Infart mijokardijaku (0. 5% vs 0. 2%), fibrillazjoni atrijali (0. 2% vs 0%), angina pectoris (0. 3% vs 0. 2%)
thrombocytopaenia (1.3% vs 1.3%), anaemia (3.5% vs 3.6%)
Tromboċitopenija (1. 3% vs 1. 3%), anemija (3. 5% vs 3. 6%)
common uncommon
komuni mhux komuni
peripheral neuropathy (2.8% vs 1.8%), headache (2.7% vs 4.1%) convulsion (0.3% vs 0.5%), syncope (0.3% vs 0.3%), amnesia (0.2% vs 0.2%), tremor (0.2% vs 0.3%), somnolence (0.7% vs 0.5%), paraesthesia (0.7% vs 0.7%), hypoaesthesia (0.3% vs 0.2%), hypersomnia (0.2% vs 0%)
Newropatija periferali (2. 8% vs 1. 8%, uġigħ ta ’ ras (2. 7% vs 4. 1%) Konvulżjoni (0. 3% vs 0. 5%), sinkope (0. 3% vs 0. 3%), amnesija (0. 2% vs 0. 2%), tregħid (0. 2% vs 0. 3%), ħedla tan- ngħas (0. 7% vs 0. 5%), parasteżija (0. 7% vs 0. 7%), ipoestesija (0. 3% vs 0. 2%), ipersonja (0. 2% vs 0%).
Eye disorders Ear and labyrinth disorders
Disturbi fl- għajnejn Disturbi fl- widnejn u fis - sistema labirintika
uncommon uncommon
Mhux komuni Mhux komuni
blurred vision (0.7% vs 0%) vertigo (0.2% vs 0.5%)
Viżjoni imċajjpra (0. 7% vs 0%) Vertiġini (0. 2% vs 0. 5%)
uncommon
Mhux komuni
bronchospasm (0.2% vs 0%), exertional dyspnoea (0.5% vs 0.5%)
Bronkospażmu (0. 2% vs 0%), qtugħ ta ’ nifs waqt strapazz (0. 5% vs 0. 5%)
gastrooesophageal reflux disease (1.5% vs 1.0%), diarrhoea (5.2% vs 9.6%), vomiting (2.3% vs 2.0%), nausea (4.7% vs 3.5%), abdominal pain (3.0% vs 2.5%), flatulence (1.0% vs 1.0%), gastritis (1.0% vs 0.7%)
Mard ta ’ rifluss gastroesofagali (1. 5% vs 1. 0%), dijarrea (5. 2% vs 9. 6%), rimettar (2. 3% vs 2. 0%), nawsja (4. 7% vs 3. 5%) uġigħ addominali (3. 0% vs 2. 5%), gass fl- istonku (1. 0% vs 1. 0%), gastrite (1. 0% vs 0. 7%)
pancreatitis (0.7% vs 0.2%), haematemesis (0.2% vs 0%), stomatitis (0.2% vs 0.2%), constipation (0.3% vs 0.5%), abdominal distension (0.7% vs 1.0%), dry mouth (0.2% vs 0%), retching (0.2% vs 0%)
Pankreatite (0. 7% vs 0. 2%), ematemesi (0. 2% vs 0%), stomatite (0. 2% vs 0. 2%), stitikezza (0. 3% vs 0. 5%), nefħa addominali (0. 7% vs 1. 0%), ħalq xott (0. 2% vs 0%), tqalligħ (0. 2% vs 0%)
Renal and urinary disorders
Disturbi fil- kliewi u fis - sistema urinarja
renal failure (1.5% vs 1.5%)
Insuffiċjenza renali (1. 5% vs 1. 5%)
common uncommon
Komuni Mhux komuni
rash (9.0% vs 3.2%) swelling face (0.2% vs 0%), lipohypertrophy (0.3% vs 0.3%), night sweats (0.8% vs 0.8%), hyperhidrosis (0.5% vs 0.2%), prurigo (0.5% vs 0.5%), dry skin (0.3% vs 0.2%)
Raxx (9. 0% vs 3. 2%) Nefħa tal- wiċċ (0. 2% vs 0%), lipo- ipertrofija (0. 3% vs 0. 3%), tgħereq ħafna matul il- lejl (0. 8% vs 0. 8%), iperidrożi (0. 5% vs 0. 2%), prurigo (0. 5% vs 0. 5%), ġilda xotta (0. 3% vs 0. 2%)
Metabolism and nutrition disorders
11 Disturbi fil- metaboliżmu u n- nutrizzjoni
diabetes mellitus (1.0% vs 0.2%), hyperglycaemia (1.2% vs 0.5%), hypercholesterolaemia (3.5% vs 2.2%), hypertriglyceridaemia (4.7% vs 3.0%), hyperlipidaemia (1.5% vs 0.7%), dyslipidaemia (1.0% vs 0.3%)
Dijabete mellitus (1. 0% vs 0. 2%), ipergliċemija (1. 2% vs 0. 5%), iperkolesterolemija (3. 5% vs 2. 2%), ipertrigliċeridemija (4. 7% vs 3. 0%), iperlipidimja (1. 5% vs 0. 7%), dislipidimja (1. 0% vs 0. 3%)
anorexia (0.7% vs 0.8%)
Anoressija (0. 7% vs 0. 8%)
Vascular disorders General disorders and administration site conditions
Disturbi vaskulari Disturbi ġenerali u kondizzjonijiet ta ’ mnejn
common common uncommon
Mhux komuni
hypertension (2.8% vs 2.2%) fatigue (3.3% vs 4.0%) sluggishness (0.2% vs 0%)
Indolenza( 0. 2% vs 0%)
immune reconstitution syndrome (0.2% vs 0.2%), drug hypersensitivity (0.7% vs 0.7%)
Sindrome tar- rikostituzzjoni tas- sistema immuni (0. 2% vs 0. 2%), sensittivita` eċċessiva għall - mediċina (0. 7% vs 0. 7%)
hepatitis (0.2% vs 0.3%), hepatic steatosis (0.2% vs 0%), cytolytic hepatitis (0.3% vs 0%), hepatomegaly (0.2% vs 0.2%)
Epatite (0. 2% vs 0. 3%), stejatożi tal- fwied (0. 2% vs 0%), epatite ċitolitika (0. 3% vs 0%), epatomegalija (0. 2% vs 0. 2%)
gynaecomastia (0.2% vs 0%)
Ginekomastja (0. 2% vs 0%)
anxiety (1.2% vs 1.7%), insomnia (1.8% vs 2.2%) confusional state (0.2% vs 0.2%), disorientation (0.2% vs 0.3%), nightmares (0.2% vs 0.2%), sleep disorders (0.5% vs 0.3%), nervousness (0.2% vs 0.2%), abnormal dreams (0.2% vs 0.2%)
Ansjeta` (1. 2% vs 1. 7%), insomnja (1. 8% vs 2. 2%) Stat ta ’ konfużjoni (0. 2% vs 0. 2%), disorjentazzjoni (0. 2% vs 0. 3%), inkubi (0. 2% vs 0. 2%), disturbi fl - irqad (0. 5% vs 0. 3%), nervi (0. 2% vs 0. 2%), ħolm anormali (0. 2% vs 0. 2%)
Additional ADRs of at least moderate intensity observed in other trials were acquired lipodystrophy, angioneurotic oedema, erythema multiforme and haemorrhagic stroke, each reported in no more than 0.5% of patients.
ADRs addizzjonali ta’ mill- inqas intensita` moderata osservati fi provi oħrajn kienu lipodistrofija akkwistata, edima anġjonewrotika, eritema multiforme u puplesija emorraġika, kull wieħed irrapurtat f’ mhux iżjed minn 0. 5% tal- pazjenti.
Stevens-Johnson Syndrome has been reported rarely (< 0.1%) during clinical development with INTELENCE.
Is- sindromu Stevens- Johnson ġie rrappurtat rarament (< 0. 1%) waqt żvilupp kliniku b’ INTELENCE.
Laboratory abnormalities Treatment emergent clinical laboratory abnormalities (grade 3 or 4), considered ADRs, reported in ≥ 2% of patients in the INTELENCE arm versus the placebo arm, respectively, were increases in amylase (7.5% vs 7.9%), lipase (2.7% vs 1.7%), total cholesterol (5.8% vs 4.1%), low density lipoprotein (LDL) (5.2% vs 5.4%), triglycerides (7.0% vs 4.3%), glucose (2.5% vs 2.0%), alanine aminotransferase (ALT) (2.5% vs 1.7%), aspartate amino transferase (AST) (2.5% vs 1.7%) and decreases in neutrophils (3.7% vs 6.3%).
Anormalitajiet fil- laboratorju Anormalitajiet kliniċi li rriżultaw mit- trattament fil- laboratorju (grad 3 jew 4), ikkunsidrati bħala ADRs, irrapurtati f ’ ≥ 2% ta ’ pazjenti fil- fergħa INTELENCE versus il- fergħa plaċebo, rispettivament, kienu żidiet fl- amylase (7. 5% vs 7. 9%), lipase (2. 7% vs 1. 7%), kolesterol totali (5. 8% vs 4. 1%), lipoproteina ta ’ densita` baxxa (LDL) (5. 2% vs 5. 4%), trigliċeridi (7. 0% vs 4. 3%), glucose (2. 5% vs 2. 0%), alanine amino transferase (ALT) (2. 5% vs 1. 7%), aspartate amino transferase (AST) (2. 5% vs 1. 7%) u tnaqqis fin- newtrofili (3. 7% vs 6. 3%).
Lipodystrophy Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy) in HIV infected patients, including loss of peripheral and facial subcutaneous fat, increased intra-abdominal and visceral fat, breast hypertrophy and dorsocervical fat accumulation (buffalo hump) (see section 4.4).
Lipodistrofija Kombinazzjoni ta ’ terapija antiretrovirali ġiet assoċċjata ma ’ ridistribuzzjoni tax- xaħam tal- ġisem (lipodistrofija) f’ pazjenti infettati b’ HIV, inkluż telfien tax- xaħam periferali u taħt il- ġilda tal- wiċċ, żieda fix- xaħam intra- addominali u vixxerali, ipertrofija tas- sider u akkumulazzjoni ta ’ xaħam dorsoċervikali (ħotba tal- buflu) (ara sezzjoni 4. 4).
Immune reconstitution syndrome In HIV infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy, an inflammatory reaction to asymptomatic or residual opportunistic infections may arise (immune reconstitution syndrome) (see section 4.4).
Sindromu tar- rikostituzzjoni tas- sistema immuni F’ pazjenti infettati b’ HIV b’ defiċjenza qawwija tas- sistema immuni fiż- żmien meta tkun inbdiet it - terapija antiretrovirali kombinata, tista ’ tirriżulta reazzjoni infjammatorja għal infezzjonijiet asintomatiċi jew residwali (sindromu tar- rikostituzzjoni tas- sistema immuni) (ara sezzjoni 4. 4).
Osteonecrosis Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy.
Osteonekrożi Każijiet ta ’ osteonekrożi ġew irrapurtati, partikolarment f’ pazjenti b’ fatturi ta ’ riskju ġeneralment magħrufa, mard ta ’ HIV avvanzat jew espożizzjoni fit- tul għal terapija antiretrovirali kkombinata.
The frequency of this is unknown (see section 4.4).
Il - frekwenza ta ’ dan mhux magħruf (ara sezzjoni 4. 4).
Additional information on special populations Patients co-infected with hepatitis B and/ or hepatitis C virus In the pooled analysis for DUET-1 and DUET-2, the incidence of hepatic events tended to be higher in co-infected subjects treated with INTELENCE compared to co-infected subjects in the placebo group.
Informazzjoni addizzjonali fuq populazzjonijiet speċjali Pazjenti infettati wkoll b’ Epatite B u/ jew Epatite C Fl- analiżi miġbura għal DUET- 1 u DUET- 2, kien hemm tendenza għal żieda fl- inċidenza ta ’ avvenimenti epatiċi f’ individwi ko- infettati trattati b’ INTELENCE meta mqabbel ma ’ individwi ko -
INTELENCE should be used with caution in these patients (see also sections 4.4 and 5.2).
INTELENCE għandu jintuża b’ kawtela f’ dawn il- pazjenti (ara wkoll sezzjonijiet 4. 4 u 5. 2)
There is no specific antidote for overdose with INTELENCE.
Ma hemm l- ebda antidotu speċifiku għal doża eċċessiva b’ INTELENCE.
Treatment of overdose with INTELENCE consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient.
Trattament għal doża eċċessiva b’ INTELENCE jikkonsisti f’ miżuri ta ’ support ġenerali inkluż monitoraġġ tas- sinjali vitali u osservazzjoni ta ’ l- istat kliniku tal- pazjent.
If indicated, elimination of unabsorbed active substance is to be achieved by emesis or gastric lavage.
Jekk hu indikat, eliminazzjoni tas- sustanza attiva mhux assorbita għandha tintlaħaq permezz ta ’ emeżi jew ħasil gastriku.
Administration of activated charcoal may also be used to aid in removal of unabsorbed active substance.
Jista jingħata wkoll faħam attivat sabiex igħin fit- tneħħija tas- sustanza attiva mhux assorbita.
Since etravirine is highly protein bound, dialysis is unlikely to result in significant removal of the active substance.
Peress illi etravirine huwa marbut ħafna mal- proteina, huwa improbabbli li d- dijaliżi jwassal għal tneħħija sinjifikanti tas- sustanza attiva.
NNRTI (non-nucleoside reverse transcriptase inhibitor), ATC code: not yet assigned.
NNRTI (impeditur tan- non- nucleoside reverse transcriptase) Kodiċi ATC: għadu mhux assenjat
Mechanism of action Etravirine is an NNRTI of human immunodeficiency virus type 1 (HIV-1).
Mekkaniżmu ta ’ azzjoni Etravirine huwa NNRTI tal- virus ta ’ l- immunodefiċjenza umana tat- tip 1 (HIV- 1).
Etravirine binds directly to reverse transcriptase (RT) and blocks the RNA-dependent and DNA-dependent DNA polymerase activities by causing a disruption of the enzyme's catalytic site.
Etravirine jintrabat direttament mar- reverse transcriptase (RT) u jimblokka l- attivitajiet tad- DNA polymerase, li huma RNA- dipendenti u DNA- dipendenti billi jikkawża diżordni tas- sit katalitiku tal- enżimi.
Antiviral activity in vitro Etravirine exhibits activity against wild type HIV-1 in T-cell lines and primary cells with median EC50 values ranging from 0.9 to 5.5 nM.
Attivita` antivirali in vitro Etravirine jeżibixxi attivita` kontra wild type HIV- 1 f’ linji taċ- ċelluli- T u ċelluli primarji b’ medja ta ’ figuri ta ’ EC50 f’ marġini bejn 0. 9 u 5. 5nM.
Etravirine demonstrates activity against HIV-1 group M (subtypes A, B, C, D, E, F, and G) and HIV-1 group O primary isolates with EC50 values ranging from 0.3 to 1.7 nM and from 11.5 to 21.7 nM, respectively.
Etravirine juri attivita` kontra HIV- 1 grupp M (sottotipi A, B, C, D, E, F u G) u HIV- 1 grupp O iżolati primarji b’ figuri ta ’ EC50 f’ marġini bejn 0. 3 u 1. 7 nM u bejn 11. 5 u 21. 7 nM rispettivament.
Although etravirine demonstrates in vitro activity against wild type HIV-2 with median EC50 values ranging from 5.7 to 7.2 µM, treatment of HIV-2 infection with etravirine is not recommended in the absence of clinical data.
Għalkemm etravirine juri attivita` in vitro kontra wild type HIV- 2 b’ medja ta ’ figuri ta ’ EC50 f’ marġini bejn 5. 7 u 7. 2 µM, trattament tal- infezzjoni ta ’ HIV- 2 b’ etravirine m’ huwiex irrakkomandat fl- assenza ta ’ tagħrif kliniku.
Etravirine retains activity against HIV-1 viral strains resistant to nucleoside reverse transcriptase and/ or protease inhibitors.
Etravirine jibqa ’ jżomm attivita` kontra razzez virali ta ’ HIV- 1 li huma reżistenti għal impedituri tan- nucleoside reverse transcriptase u/ jew protease.
In addition, etravirine demonstrates a fold change (FC) in EC50 ≤ 3 against 60% of 6,171 NNRTI-resistant clinical isolates.
Barra minn hekk, etravirine juri bidla (FC) f ’ EC50 ta ’ ≤ 3 kontra 60% ta ’ 6171 iżolati kliniċi reżistenti għal NNRTI.
Resistance Etravirine efficacy in relation to NNRTI resistance at baseline has mainly been analysed with etravirine given in combination with darunavir/ ritonavir (DUET-1 and -2).
Reżistenza L- effikaċja ta ’ etravirine relatata ma ’ reżistenza ta ’ NNRTI fil- linja bażi ġiet prinċipalment analizzata b’ etravirine mogħti f’ kombinazzjoni ma ’ darunavir/ ritonavir (DUET- 1 u - 2).
Boosted protease inhibitors, like darunavir/ ritonavir, show a higher barrier to resistance compared to other classes of antiretrovirals.
Impedituri ta ’ protease ibbustjati bħal darunavir/ ritonavir, juru barriera ogħla għal reżistenza meta mqabbla ma ’ klassijiet oħrajn ta ’ antiretrovirali.
The breakpoints for reduced efficacy with etravirine (> 2 etravirine-associated mutations at baseline, see clinical results section) applies when etravirine is given in combination with a boosted protease inhibitor.
Il- breakpoints ta ’ effikaċja ridotta b’ etravirine (> 2 mutazzjonijiet assoċċjati ma ’ etravirine fil- linja bażi, ara sezzjoni tar- riżultati kliniċi) japplikaw meta etravirine jingħata f’ kombinazzjoni ma ’ impeditur ta ’ protease ibbustjat.
This breakpoint might be lower in antiretroviral combination therapy not including a boosted protease inhibitor.
Dan il- breakpoint jista jkun iktar baxx f’ terapija antiretrovirali kkombinata li ma tinkludix impeditur ta ’ protease ibbustjat.
In the Phase III trials DUET-1 and DUET-2, mutations that developed most commonly in patients with virologic failure to the INTELENCE containing regimen were V108I, V179F, V179I, Y181C and Y181I, which usually emerged in a background of multiple other NNRTI resistance-associated mutations (RAMs).
Fil- provi ta ’ Fażi III DUET- 1 u DUET- 2, mutazzjonijiet li żviluppaw l- iktar komuni f’ pazjenti b’ falliment viroloġiku għal reġimen li fih INTELENCE kienu V108I, V179F, V179I, Y181C u Y181I, li ġeneralment tfaċċaw fi sfond ta ’ mutazzjonijiet multipli oħrajn assoċċjati ma ’ reżistenza għal NNRTI (RAMs).
In all the other trials conducted with INTELENCE in HIV-1 infected patients, the following mutations emerged most commonly:
Fil- provi l- oħrajn kollha magħmula b’ INTELENCE f’ pazjenti infettati b’ HIV- 1, tfaċċaw il- mutazzjonijiet segwenti l- iktar komuni:
L100I, E138G, V179F, V179I, Y181C and H221Y.
L100I, E138G, V179F, V179I, Y181C u H221Y.
Cross-resistance Following virologic failure of an etravirine-containing regimen it is not recommended to treat patients with efavirenz and/ or nevirapine.
Cross- resistence Wara falliment viroloġiku ta ’ reġimen li fih etravirine mhux irrakkomandat li pazjenti jiġu trattati b’ efavirenz u/ jew nevirapine.
Clinical experience Treatment-experienced patients Pivotal studies The evidence of efficacy of INTELENCE is based on 24-week data from 2 ongoing Phase III trials DUET-1 and DUET-2.
13 Studji ċentrali L- evidenza tal- effikaċja ta ’ INTELENCE hi bbażata fuq tagħrif ta ’ 24- ġimgħa minn 2 provi tal- Fażi III DUET- 1 u DUET- 2 għaddejjin.
These trials were identical in design and similar efficacy for INTELENCE was seen in each trial.
Dawn il- provi kienu identiċi fid- disinn u dehret effikaċja simili għal INTELENCE f’ kull prova.
The results below are pooled data from the two trials.
Ir- riżultati hawn taħt huma tagħrif miġbur miż- żewġ provi.
Trial characteristics
Karatteristiċi tal- provi
- Design: randomized (1:1), double-blinded, placebo-controlled.
- Disinn: randomized (1: 1), double- blinded, kontrollati bil- plaċebo.
- Treatment:
- Trattament:
INTELENCE vs. placebo, in addition to a background regimen including
INTELENCE vs plaċebo, flimkien ma ’ reġimen fl- isfond li jinkludi
darunavir/ ritonavir (DRV/ rtv), investigator-selected N(t)RTIs and optional enfuvirtide (ENF).
darunavir / ritonavir (DRV/ rtv), N( t) RTIs magħżula mill- investigatur u enfuvirtide mhux ta ’ bilfors.
- Main inclusion criteria:
- Kriterji prinċipali ta ’ inklużjoni:
HIV-1 plasma viral load > 5000 HIV-1 RNA copies/ml at screening 1 or more NNRTI resistance-associated mutations (RAMs) at screening or from prior genotypic analysis (i.e., archived resistance)
Viral load ta ’ HIV- 1 > 5000 kopja / ml ta ’ HIV- 1 RNA waqt eżaminazzjoni 1 jew iżjed mutazzjonijiet assoċċjati ma ’ reżistenza (RAMs) għal NNRTI waqt eżaminazzjoni jew minn analiżi ġenotipika preċedenti (i. e. reżistenza arkivjata)
3 or more primary PI mutations at screening on a stable antiretroviral regimen for at least 8 weeks.
3 jew iżjed mutazzjonijiet ta ’ PI primarji waqt eżaminazzjoni Fuq reġimen antiretrovirali stabbli għal mill- inqas 8 ġimgħat.
- Stratification:
- Stratifikazzjoni:
Randomisation was stratified by the intended use of ENF in the BR, previous use
Ir- randomizzazzjoni ġiet stratifikata skond l- użu intiż ta ’ ENF fil- BR, użu
of darunavir and screening viral load.
preċedenti ta ’ darunavir u eżaminazzjoni tal- viral load.
- Virologic response was defined as achieving a confirmed undetectable viral load
- Rispons viroloġiku kien definit bħala li jilħaq viral load li ma jistax jitkejjel ikkonfermat
(< 50 HIV-1 RNA copies/ml).
(< 50 kopja/ ml ta ’ HIV- 1 RNA)
Summary of efficacy results
Sommarju tar- riżultati ta ’ effikaċja
DUET-1 and DUET-2 pooled 24-week data Baseline characteristics
Tagħrif miġbur minn DUET- 1 u DUET- 2 ġimgħa 24 Karatteristiċi linja bażi
Placebo + BR N=604
Plaċebo + BR N=604
Treatment difference (95% CI)
Medjan ta ’ HIV- 1 RNA fil- plażma
Median plasma HIV-1 RNA Median CD4 cell count Outcomes Confirmed undetectable viral load (< 50 HIV-1 RNA copies/ml)a n (%)
Għadd medjan ta ’ ċelluli CD4 Riżultati Viral load li ma jistax jitkejjel ikkonfermata (< 50 kopja/ ml ta ’ HIV- 1 RNA) a n (%)
4.8 log10 copies/ml 99 x 106 cells/l
99 x 106 ċelluli/ l
4.8 log10 copies/ml 109 x 106 cells/l
x 106 ċelluli/ l
17.8%
17. 8%
Overall
Ġenerali
353 (58.9%)
353 (58. 9%)
248 (41.1%)
248 (41. 1%)
(12.3%; 23.4%)d 4.8%
(12. 3%; 23. 4%) d 4. 8%
102 (66.7%)
102 (66. 7%)
99 (61.9%)
99 (61. 9%)
(5.8%; 15.4%)f 22.7%
(5. 8%; 15. 4%) f 22. 7%
Not de novo ENF
Mhux de novo ENF a
251 (56.3%)
251 (56. 3%)
149 (33.6%)
149 (33. 6%)
(16.4%; 29.1%) f a < 400 HIV-1 RNA copies/ml
< 400 kopja/ ml ta ’ HIV- 1 RNA
445 (74.3%)
445 (74. 3%)
317 (52.5%)
317 (52. 5%)
21.8%
21. 8%
n (%) (16.5%; 27.1%)d HIV-1 RNA log10 mean change
(16. 5%; 27. 1%) d n (%) Bidla medja ta ’ HIV- 1 RNA log10 - 0. 54 mill- linja bażi (log10 kopji/ ml) b Bidla medja tal- għadd taċ- ċelluli
-2.37
- 2. 37
-1.69
- 1. 69
-0.54
(- 0. 71; - 0. 37) c +19. 6
from baseline (log10 copies/ml)b CD4 cell count mean change from baseline (x 106/l)b Any AIDS defining illness and/or
CD4 mill- linja bażi (x 106 / l) b
+85.6
+85. 6
+66.8
+66. 8
(-0.71; -0.37)c +19.6 (8.4; 30.7)c -3.1%
Mard li jiddefinixxi AIDS u/ jew
death n (%) a
mewt n (%) a
22 (3.7%)
22 (3. 7%)
41 (6.8%)
41 (6. 8%)
(-5.6%; -0.6%)e
(- 5. 6%; - 0. 6%) e
Imputations according to the TLOVR algorithm (TLOVR = Time to Loss of Virologic Response). b Non-completer is failure (NC = F) imputation. c Treatment differences are based on Least Square Means from an ANCOVA model including the stratification factors.
Imputazzjonijiet skond l- alogaritmu TLOVR (TLOVR = Ħin għan- nuqqas ta ’ rispons viroloġiku). b Mhux komplut huwa imputazzjoni ta ’ falliment (NC=F). c Differenzi fit- trattament huma bbażati fuq Medja ta ’ l- Inqas Kwadrati minn mudell ANCOVA inkluż il- fatturi ta ’ stratifikazzjoni.
P-value < 0.0001 for mean decrease in HIV-1 RN A; P-value = 0.0060 for mean change in CD4 cell count. d Confidence interval around observed difference of response rates; P-value < 0.0001 from logistic regression model, including stratification factors. e Confidence interval around observed difference of response rates; P-value = not significant. f Confidence interval around observed difference of response rates; P-value from CMH test controlling for stratification factors = 0.427 for de novo, and < 0.0001 for not de novo.
14 d Intervall ta ’ kunfidenza madwar differenzi osservati tar- rati ta ’ rispons; Valur – P < 0. 0001 minn mudell ta ’ rigressjoni loġistika, inkluż fatturi ta ’ stratifikazzjoni. e Intervall ta ’ kunfidenza madwar differenzi osservati tar- rati ta ’ rispons; Valur – P = mhux sinjifikanti. f Intervall ta ’ kunfidenza madwar differenzi osservati tar- rati ta ’ rispons; Valur – P minn test CMH jikkontrolla l - fatturi ta ’ stratifikazzjoni = 0. 427 għal de novo, u < 0. 0001 għal mhux de novo.
Since there was a significant interaction effect between treatment and ENF, the primary analysis was done for 2 ENF strata (patients reusing or not using ENF versus patients using ENF de novo); results of this analysis (week 24 data) by ENF stratum are shown in the table above.
Peress illi kien hemm effett ta ’ interazzjoni sinjifikanti bejn it- trattament u ENF, l- analiżi primarja saret għal 2 strata ENF (pazjenti li reġgħu użaw jew mhux jużaw ENF kontra pazjenti li jużaw ENF de novo): riżultati ta ’ dawn l- analiżi (tagħrif f’ ġimgħa 24) bl- istratum ENF jidher fit- tabella hawn fuq.
A subgroup analysis of the virologic response (defined as a viral load < 50 HIV-1 RNA copies/ml) at week 24 by baseline viral load and baseline CD4 count (pooled DUET data) is presented in the table below.
Analiżi ta ’ sottogrupp tar- rispons viroloġiku (definit bħala viral load, < 50 kopja/ ml ta ’ HIV- 1 RNA) f’ ġimgħa 24 b’ viral load ta ’ linja bażi u għadd C4 ta ’ linja bażi (tagħrif DUET miġbur) huwa ppreżentat fit- tabella hawn taħt.
DUET-1 and DUET-2 pooled data Proportion of subjects with HIV-1 RNA < 50 copies/ml at week 24 Subgroups
Tagħrif miġbur DUET- 1 u DUET- 2 Proporzjon ta ’ individwi b’ HIV- 1 RNA < 50 kopja/ ml f’ ġimgħa 24 Sottogruppi HIV- 1 RNA fil- linja bażi
14 Baseline HIV-1 RNA < 30,000 copies/ml ≥ 30,000 and < 100,000 copies/ml ≥ 100,000 copies/ml Baseline CD4 count (x 106/l)
< 30, 000 kopja/ ml ≥ 30, 000 u < 100, 000 kopja/ ml ≥ 100, 000 kopja/ ml Għadd ta ’ CD4 fil- linja bażi (x106/ l)
76.4% 61.2% 44.3%
76. 4% 61. 2% 44. 3%
62.1% 39.4% 25.8%
62. 1% 39. 4% 25. 8%
< 50 ≥ 50 and < 200 ≥ 200 and < 350 ≥ 350
< 50 ≥ 50 u < 200 ≥ 200 u < 350 ≥ 350
39.0% 66.8% 70.6% 79.3%
39. 0% 66. 8% 70. 6% 79. 3%
23.4% 46.6% 54.4% 55.7%
23. 4% 46. 6% 54. 4% 55. 7%
Imputations according to the TLOVR algorithm (TLOVR = Time to Loss of Virologic Response)
Imputazzjonijiet skond l- alogaritmu TLOVR (TLOVR = Ħin għan- nuqqas ta ’ rispons viroloġiku)
Baseline genotype or phenotype and virologic outcome analyses In DUET-1 and DUET-2, the presence at baseline of 3 or more of the following mutations:
Analiżi tal- ġenotip jew fenotip tal- linja bażi u riżultat viroloġiku F’ DUET- 1 u DUET- 2, il- preżenza fil- linja bażi ta ’ 3 jew iżjed mis- segwenti mutazzjonijiet:
V90I, A98G, L100I, K101E, K101P, V106I, V179D, V179F, Y181C, Y181I, Y181V, G190A and G190S, (INTELENCE RAMs) was associated with a decreased virologic response to INTELENCE (see table below).
V90I, A98G, L100I, K101E, K101P, V106I, V179D, V179F, Y181C, Y181I, Y181V, G190A u G190S, (INTELENCE RAMs) kienet assoċċjata ma ’ tnaqqis tar- rispons viroloġiku għal INTELENCE (ara tabella hawn taħt).
These individual mutations occurred in the presence of other NNRTI RAMs.
Dawn il- mutazzjonijiet individwali seħħew fil- preżenza ta ’ NNRTI RAMs oħrajn.
V179F was never present without Y181C.
V179F qatt ma kien preżenti mingħajr Y181C.
Conclusions regarding the relevance of particular mutations or mutational patterns are subject to change with additional data, and it is recommended to always consult current interpretation systems for analysing resistance test results.
Konklużjonijiet dwar ir- rilevanza ta ’ mutazzjonijiet partikolari jew disinnji ta ’ mutazzjonijiet huma suġgetti għal bdil b’ tagħrif addizzjonali, u huwa rrakkomandat li wieħed dejjem jikkonsulta s- sistemi kurrenti ta ’ interpretazzjoni għal analiżi tar- riżultati ta ’ testijiet ta ’ reżistenza.
Proportion of subjects with < 50 HIV-1 RNA copies/ml at week 24 by baseline number of INTELENCE RAMs in the non-viral failure excluded population of pooled DUET-1 and DUET-2 trials
Proporzjon ta ’ individwi b < 50 kopja/ ml ta ’ HIV- 1 RNA f’ ġimgħa 24 skond in- numru fil- linja bażi ta ’ INTELENCE RAMs fil- popolazzjoni fejn hu eskluż falliment mhux virali ta ’ provi miġbura fi DUET - 1 u DUET- 2 Numru fil- linja bażi ta ’ INTELENCE RAMs *
Baseline number of
Fergħat ta ’ etravirine N=549
Reused/not used ENF
ENF użat mill- ġdid/ mhux użat
ranges 0 1 2 ≥3
Marġini kollha 0 1 2 ≥3
Placebo arms N=569
Fergħat tal- plaċebo N=569
All
Gamem kollha
ranges
36% (149/ 414)
36% (149/414)
64% (99/ 155)
64% (99/155)
* INTELENCE RAMs = V90I, A98G, L100I, K101E/ P, V106I, V179D/ F, Y181C/ I/ V, G190A/ S
* INTELENCE RAMs = V90I, A98G, L100I, K101E/P, V106I, V179D/F, Y181C/I/V, G190A/S Note: all patients in the DUET trials received a background regimen consisting of darunavir/rtv, investigator-selected NRTIs and optional enfuvirtide.
15 Nota: il- pazjenti kollha fil- provi DUET irċevew reġimen fl- isfond li jikkonsisti f’ darunavir/ rtv, NRTIs magħżula mill - investigatur u enfuvirtide mhux ta ’ bilfors.