SKEDULERINGSTATUS: S4EIENDOMSNAAM (EN DOSEERVORM):

TRENVIR (Tablette)SAMESTELLING:Elke filmbedekte tablet bevat emtrisitabien 200 mg, tenofovir disoproksielfumaraat 300 mg en efavirens 600 mg.Onaktiewe bestanddele sluit natriumkroskarmellose, rooi ysteroksied, mikrokristallyne sellulose, hipromellose, mieliestysel, magnesiumstearaat, natriumlaurielsulfaat, hidroksielpropielsellulose, opadrie pienk en opadrie bruin in.WAARSKUWING:GEVALLE VAN MELKSUURASIDOSE EN ERGE HEPATOMEGALIE MET STEATOSE, WAARVAN SOMMIGE NOODLOTTIG WAS, IS MET DIE GEBRUIK VAN NUKLEOSIED ANALOË ALLEEN OF IN KOMBINASIE MET ANDER ANTIRETROVIRALE MIDDELS GEMELD (SIEN "WAARSKUWINGS"). TRENVIR IS NIE AANGEDUI VIR DIE BEHANDELING VAN CHRONIESE INFEKSIE MET DIE HEPATITIS B VIRUS (HBV) NIE. DIE VEILIGHEID EN EFFEKTIWITEIT VAN TRENVIR IS NIE IN PASIËNTE MET HBV EN MIV GESAMENTLIKE INFEKSIE VASGESTEL NIE. ERGE AKUTE OPFLIKKERINGS VAN HEPATITIS B INFEKSIE IS GEMELD IN INDIVIDUE WIE BEHANDELING MET EMTRISITABIEN (200 mg) OF TENOFOVIR GESTAAK HET. PASIËNTE MET GESAMENTLIKE MIV EN HBV INFEKSIE BENODIG NOUKEURIGE MONITERING VAN HULLE LEWERFUNKSIE VIR TEN MINSTE VERSKEIE MAANDE; HIERDIE BEHOORT BEIDE KLINIESE EN LABORATORIUM OPVOLG IN TE SLUIT. TOEPASLIKE INISIËRING VAN ANTI-HEPATITIS B TERAPIE MAG NODIG WEES (SIEN "WAARSKUWINGS").

FARMAKOLOGIESE KLASSIFIKASIE:A 20.2.8 Antimikrobiale (chemoterapeutiese) middels. Antivirale middels.FARMAKOLOGIESE WERKING:Meganisme van werking:Emtrisitabien: Emtrisitabien, ‘n NRTI, is ‘n sintetiese nukleosied analoog van sitidien. Sellulêre ensieme fosforileer emtrisitabien tot emtrisitabien 5'-trifosfaat. Emtrisitabien 5'-trifosfaat kompeteer met die natuurlike substraat, deoksisitidien 5'-trifosfaat en word in nuutvormende virale DNA ingebou wat tot ketting terminasie aanleiding gee. Gevolglik word die aktiwiteit van MIV-1 omgekeerde transkriptase geïnhibeer. Emtrisitabien 5'-trifosfaat inhibeer soogdier DNA polimerase α, β, ε en mitochondriale DNA polimerase γ swak.Tenofovir disoproksielfumaraat: Tenofovir disoproksielfumaraat, ‘n NRTI, ook bekend as tenofovir DF, ‘n asikliese nukleosiedfosfonaat diëster analoog van adenosienmonofosfaat, benodig aanvanklike diëster hidrolise vir omskakeling na tenofovir. Sellulêre ensieme is verantwoordelik vir daaropvolgende fosforilasies om tenofovirdifosfaat te vorm. Tenofovirdifosfaat inhibeer die aktiwiteit van MIV-1 omgekeerde transkriptase deur kompetisie met die natuurlike substraat deoksiadenosien 5'-trifosfaat. Na invoeging in DNA word die DNA ketting getermineer. Tenofovirdifosfaat inhibeer soogdier DNA polimerase α, β en mitochondriale DNA polimerase γ swak.Efavirens:Efavirens, ‘n selektiewe nie-nukleosied omgekeerde transkriptase inhibeerder (NNRTI) van MIV-1, diffundeer tot binne die sel waar dit naasliggend tot die aktiewe setel van omgekeerde transkriptase bind. Gevolglik vind ‘n strukturele verandering in die ensiem plaas en word die funksie daarvan geïnhibeer. Efavirens is ‘n nie-kompeterende inhibeerder van MIV-1 omgekeerde transkriptase met verwysing na die primêre, templaat of nukleosied trifosfate, alhoewel daar ook ‘n geringe mate van kompeterende inhibisie teenwoordig is. Efavirens inhibeer nie MIV-2 omgekeerde transkriptase of menslike sellulêre DNA polimerases alfa, beta, gamma of delta nie.Farmakodinamika:Antivirale aktiwiteit:Emtrisitabien en tenofovir disoproksielfumaraat: Kombinasie studies wat die in vitro antivirale aktiwiteit van emtrisitabien en tenofovir gesamentlik geëvalueer het, het sinergistiese antivirale effekte getoon. Emtrisitabien: Limfoblastoïede sellyne, die MAGI-CCR5 sellyn en perifere bloed mononukleêre selle is gebruik om die in vitro aktiwiteit van emtrisitabien teen laboratorium en kliniese isolate van MIV te evalueer. Die IK50- (50 % inhibitoriese konsentrasie) waardes vir emtrisitabien het tussen 0,0013 – 0,64 μM (0,0003 – 0,158 μg/ml) gevarieer. Additiewe tot sinergistiese effekte is waargeneem in studies van kombinasie middels met emtrisitabien en nukleosied omgekeerde transkriptase inhibeerders (abakavir, lamivudien, stavudien, salsitabien, sidovudien), nie-nukleosied omgekeerde transkriptase inhibeerders (delavirdien, efavirens, nevirapien) en protease inhibeerders (amprenavir, nelfinavir, ritonavir, sakwinavir). Die meerderheid van hierdie middel kombinasies is nie in mense bestudeer nie. Emtrisitabien het antivirale aktiwiteit in vitro teen MIV-1 klades A, B, C, D, E, F en G (IK50-waardes met ‘n reikwydte van 0,007 – 0,075 μM) en het stam-spesifieke aktiwiteit teen MIV-2 (IK50-waardes met ‘n reikwydte van 0,007 – 1,5 μM) getoon.Tenofovir disoproksielfumaraat: Tenofovir se in vitro antivirale aktiwiteit teen laboratorium en kliniese isolate van MIV-1 was in limfoblastoïede sellyne, primêre monosiet/makrofaag selle en perifere bloed limfosiete geëvalueer. Die IK50-waardes vir tenofovir het ‘n reikwydte van 0,04 tot 8,5 μM getoon. Additiewe tot sinergistiese effekte is waargeneem tydens middel kombinasie studies van tenofovir met nukleosied omgekeerde transkriptase inhibeerders (abakavir, didanosien, lamivudien, stavudien, salsitabien, sidovudien), nie-nukleosied omgekeerde transkriptase inhibeerders (delavirdien, efavirens, nevirapien) en protease inhibeerders (amprenavir, indinavir, nelfinavir, ritonavir, sakwinavir). Tenofovir toon in vitro antivirale aktiwiteit teen MIV-1 klades A, B, C, D, E, F, G en O (IK50-waardes het ‘n reikwydte van 0,5 – 2,2 μM). Die IK50-waardes van tenofovir teen MIV-2 het ‘n reikwydte van 1,6 μM tot 4,9 μM.Efavirens:Die kliniese belang van in vitro vatbaarheid van MIV-1 vir efavirens is nog nie vasgestel nie. Limfoblastoïede sellyne, perifere bloed mononukleêre selle (PBMS) en makrofaag/monosiet kulture verryk met PBMS is gebruik om die in vitro antivirale aktiwiteit van efavirens te beoordeel. Die 90 tot 95  % inhibitoriese konsentrasie (IK90-95) vir wilde tipe, laboratoriumaangepaste stamme en kliniese isolate het tussen 1,7 en 25 nM gewissel. Sinergistiese aktiwiteit is in selkulture getoon wanneer efavirens met die nukleosied analoog omgekeerde transkriptase inhibeerders (NRTIs), sidovudien (ZDV) of didanosien (ddI), of die protease inhibeerder, indinavir (IDV), gekombineer is.Middelweerstand:Emtrisitabien en tenofovir disoproksielfumaraat: MIV-1 isolate wat verminderde vatbaarheid vir die emtrisitabien en tenofovir kombinasie getoon het, is in vitrogeselekteer. Na genotipiese analise is die M184V/I en/of K65R aminosuur substitusies in die virale omgekeerde transkriptase geïdentifiseer.Emtrisitabien: MIV isolate weerstandig teen emtrisitabien is in vitro geselekteer. Genotipiese analise van hierdie isolate het getoon dat verminderde vatbaarheid vir emtrisitabien met ‘n mutasie in die MIV omgekeerde transkriptase geen by kodon 184 geassosieer word. Hierdie mutasie het ‘n aminosuur substitusie van metionien met valien of isoleusien (M184V/I) tot gevolg.MIV isolate weerstandig teen emtrisitabien is ook geïdentifiseer in sommige pasiënte wie behandeling met emtrisitabien alleen of in kombinasie met ander antiretrovirale middels ontvang het. Genotipiese analise van hierdie isolate het getoon dat die weerstand deur M184V/I mutasies in die MIV omgekeerde transkriptase geen veroorsaak is. Tenofovir disoproksielfumaraat: Isolate van MIV-1 wat verminderde vatbaarheid vir tenofovir getoon het, is in vitro geselekteer. Hierdie virusse toon ‘n K65R mutasie in omgekeerde transkriptase en toon ‘n verminderde vatbaarheid vir tenofovir van tussen 2- tot 4-voudig.Tenofovir-weerstandbiedende MIV-1 stamme is ook geïsoleer vanaf sommige pasiënte wie tenofovir in kombinasie met sekere antiretrovirale middels ontvang het. Genotipiese analise van die weerstandige isolate het ‘n mutasie in die MIV-1 omgekeerde transkriptase geen getoon wat tot die K65R aminosuur substitusie lei.Efavirens:MIV-1 isolate met verminderde vatbaarheid vir efavirens (> 380-voudige toename in IK90) in vergelyking met basislyn is in vitro geïdentifiseer. Fenotipiese veranderinge is in evalueerbare MIV-1 isolate en genotipiese veranderinge is in plasmavirus afkomstig van geselekteerde pasiënte wie met efavirens in kombinasie met IDV of met ZDV plus lamivudien behandel is, gemonitor. Een of meer RT mutasies is by verskeie aminosuur posisies (100, 101, 103, 108, 190 en 225) in al 62 pasiënte met ‘n frekwensie van ten minste 10 % vergeleke met basislyn waargeneem. Die mutasie by RT aminosuur posisie 103 (lisien tot asparagien) is mees dikwels (groter of gelyk aan 90  %) waargeneem. Ses-en-twintig kliniese isolate het ‘n 47-voudige gemiddelde verlies in vatbaarheid (IK90) vir efavirens getoon. Vyf kliniese isolate is vir beide genotipiese en fenotipiese veranderinge vanaf basislyn beoordeel. Verlies in vatbaarheid vir efavirens (reikwydte van 9- tot groter as 312-voudige toename in IK90) in vergelyking met basislyn is in vitro in hierdie isolate waargeneem. Al 5 isolate het oor ten minste een van die efavirens-geassosieerde omgekeerde transkriptase mutasies beskik. Die kliniese belang van hierdie fenotipiese en genotipiese veranderinge geassosieer met efavirens behandeling is nog nie vasgestel nie.Kruisweerstandigheid:Emtrisitabien en tenofovir disoproksielfumaraat: Dit is bekend dat kruisweerstandigheid tussen sekere nukleosied omgekeerde transkriptase inhibeerders (NRTIs) mag ontwikkel. Die M184V/I en/of K65R substitusies wat in vitro deur die kombinasie van emtrisitabien en tenofovir geselekteer word, word ook gesien in sommige MIV-1 stamme geïsoleer van individue wie behandeling met tenofovir in kombinasie met óf lamivudien óf emtrisitabien en óf abakavir óf didanosien gefaal het. Kruisweerstandigheid tussen hierdie middels mag derhalwe ontwikkel in pasiënte wie se virus een of beide van hierdie aminosuur substitusies berg.Emtrisitabien: Alhoewel emtrisitabien-weerstandbiedende isolate (M184V/I) ook kruisweerstandigheid teen lamivudien en salsitabien getoon het, het hierdie isolate in vitro vatbaarheid vir didanosien, stavudien, tenofovir, sidovudien en NNRTIs (delavirdien, efavirens en nevirapien) behou. MIV stamme, geïsoleer van pasiënte met baie behandelingsondervinding, wat beskik oor die M184V/l aminosuur substitusie in die konteks van ander NRTI substitusies geassosieer met weerstand mag vatbaar vir tenofovir bly. MIV isolate met die K65R substitusie, in vivo geselekteer deur abakavir, didanosien, tenofovir en salsitabien, toon verminderde vatbaarheid vir inhibisie deur emtrisitabien. Virusse wat mutasies bevat wat hulle minder vatbaar maak vir stavudien en sidovudien (M41L, D67N, K70R, L210W, T215Y/F, K219Q/E) of didanosien (L74V) bly sensitief vir emtrisitabien. MIV-1 virale isolate met die K103N substitusie wat geassosieer word met weerstand teen NNRTIs was vatbaar vir emtrisitabien.Tenofovir disoproksielfumaraat: MIV-1 isolate van individue wie se MIV-1 ‘n gemiddelde van 3 sidovudien-geassosieerde aminosuur substitusies in omgekeerde transkriptase (M41L, D67N, K70R, L210W, T215Y/F of K219Q/E/N) uitgedruk het, het verminderde vatbaarheid vir tenofovir getoon. MIV-1 met multinukleosied weerstand met ‘n T69S dubbelinvoeging mutasie in omgekeerde transkriptase toon verminderde vatbaarheid vir tenofovir.Efavirens:MIV-1 stamme met kruisweerstand teen nie-nukleosied omgekeerde transkriptase inhibeerders tree spoedig in vitro na vore. Kliniese isolate voorheen as efavirensweerstandig gekarakteriseer, is in vitro ook fenotipies vir nevirapien en delavirdien weerstandig in vergelyking met basislyn. ZDV-weerstandige MIV-1 stamme wat klinies verkry is en in vitro geïsoleer en getoets is, het vatbaarheid vir efavirens behou. Aangesien verskillende ensiemteikens betrokke is, is dit onwaarskynlik dat kruisweerstandigheid tussen efavirens en MIV protease inhibeerders sal ontwikkel.Farmakokinetika:Volwassenes:Emtrisitabien: Na mondelingse toediening van emtrisitabien (200 mg), word emtrisitabien vinnig geabsorbeer. Piek plasmakonsentrasies word binne 1 – 2 uur na dosering bereik. Binding van emtrisitabien aan menslike plasmaproteïene in vitro is minder as 4 %. Hierdie is nie afhanklik van konsentrasie oor die reikwydte van 0,02 – 200 µg/ml nie. Mediane (reikwydte) orale biobeskikbaarheid van emtrisitabien onder vastende toestande is 92 % (83,1 – 106,4 %). By ewewigsvlak is gemiddelde (± SD) Cmaks (maksimum plasma konsentrasie) van emtrisitabien 1,8 ± 0,72 μg/ml, terwyl gemiddelde (± SD) AOK by ewewigsvlak 10,0 ± 3,12 μg.hr/ml is.Nagenoeg 86  % van radiogemerkte emtrisitabien word in die uriene herwin en 13  % word as metaboliete herwin. Emtrisitabien metaboliete sluit 3'-sulfoksied diastereomere en hulle glukuroonsuur konjugaat in. Eliminasie van emtrisitabien is via ‘n kombinasie van glomerulêre filtrasie en aktiewe tubulêre sekresie. Emtrisitabien se plasma halflewe is ongeveer 10 uur na toediening van ‘n enkele orale dosis (200 mg).Tenofovir disoproksielfumaraat: Na die orale toediening van tenofovir neem dit 1,0 ± 0,4 uur om maksimum tenofovir serumkonsentrasies te bereik. Binding van tenofovir aan menslike plasmaproteïene in vitro is minder as 0,7 %. Dit is nie afhanklik van konsentrasie oor die reikwydte van 0,01 – 25 µg/ml nie. Mediane (reikwydte) orale biobeskikbaarheid van tenofovir onder vastende toestande is 25 % (Nie bereken [NB] – 45 %). Tenofovir het ‘n gemiddelde (± SD) Cmaks van 0,30 ± 0,09 μg/ml en gemiddelde (± SD) AOK van 2,29 ± 0,69 μg.hr/mlNa intraveneuse toediening van tenofovir word ongeveer 70 – 80 % van die dosis onveranderd in die uriene herwin. Eliminasie van tenofovir is via ‘n kombinasie van glomerulêre filtrasie en aktiewe tubulêre sekresie. Tenofovir het ‘n terminale eliminasie halflewe van ongeveer 17 uur na ‘n enkele orale dosis.Effek van voedsel op orale absorpsie:Die kombinasie tablet kan met of sonder voedsel geneem word. Die tyd tot tenofovir Cmaks word met nagenoeg 0,75 uur vertraag na toediening van die kombinasie tablet met ‘n hoë-vet maaltyd of ‘n ligte maaltyd. Vergeleke met toediening onder vastende toestande het toediening met ‘n hoë-vet of ligte maaltyd tot gemiddelde toenames in tenofovir AOK en Cmaks van onderskeidelik ongeveer 35 % en 15 % gelei. In vorige veiligheids- en effektiwiteitstudies is tenofovir onder gevoede toestande toegedien. Emtrisitabien sistemiese blootstellings (AOK en Cmaks) het onveranderd gebly wanneer die kombinasie tablet met óf ‘n hoë-vet óf ligte maaltyd geneem is.Efavirens:Absorpsie: Piek efavirens plasmakonsentrasies van 1,6 – 9,1 μM word teen 5 uur na toediening van enkel orale dosisse van 100 mg tot 1600 mg aan ongeïnfekteerde individue bereik. Alhoewel dosisverwante toenames in Cmaks en AOK gesien word vir dosisse tot 1600 mg, is hierdie toenames minder as proporsioneel, wat aandui dat absorpsie met hoër dosisse minder is. Ewewigsplasmakonsentrasies word binne 6 – 7 dae bereik.Verspreiding: Efavirens is hoogs aan plasmaproteïene gebonde (ongeveer 99,5 – 99,75 %) –hoofsaaklik aan albumien. Serebrospinale vogkonsentrasies wissel vanaf 0,26 tot 1,19 % (gemiddeld 0,69 %) van die ooreenstemmende plasmakonsentrasies in MIV-1 geïnfekteerde individue wie 200 tot 600 mg efavirens een maal daagliks vir ten minste een maand ontvang het. Hierdie vlakke is ongeveer drie maal hoër as die nie-proteïengebonde (vrye) fraksie van efavirens in plasma. Metabolisme: Efavirens word hoofsaaklik deur die sitochroom P450 sisteem tot gehidroksileerde metaboliete gemetaboliseer. Hierdie gehidroksileerde metaboliete ondergaan hierna glukuronidasie. Die metaboliete is nie aktief teen MIV-1 nie. CYP3A4 en CYP2B6 is die hoof iso-ensieme betrokke by efavirens metabolisme. Efavirens, deur induksie van P450 ensieme, induseer sy eie metabolisme.Eliminasie: Efavirens het ‘n lang terminale halflewe van onderskeidelik 52 – 76 en 40 – 55 uur na enkel- en veelvuldige dosisse. Na toediening van ‘n radiogemerkte dosis, word 14 – 34 % van efavirens in die uriene herwin en 16 – 61 % in die feses, hoofsaaklik in die vorm van metaboliete. Spesiale bevolkings:Geslag:

Emtrisitabien en tenofovir farmakokinetiese eienskappe is soortgelyk in manlike en vroulike pasiënte. Farmakokinetiese eienskappe van efavirens in pasiënte blyk om soortgelyk in mans en vrouens te wees.Pediatriese en geriatriese pasiënte: Emtrisitabien en tenofovir disoproksielfumaraat:Emtrisitabien en tenofovir farmakokinetika is nie in kinders < 18 jaar of in bejaardes (> 65 jaar) bestudeer nie (sien "Spesiale Voorsorgmaatreëls").Efavirens:Farmakokinetika van efavirens is nie bestudeer in individue 65 jaar en ouer om vas te stel of hulle verskillend reageer nie. Die farmakokinetiese eienskappe van efavirens in pediatriese pasiënte is soortgelyk aan dié in volwassenes.Pasiënte met ingekorte nierfunksie: Emtrisitabien en tenofovir disoproksielfumaraat:Die farmakokinetiese eienskappe van emtrisitabien en tenofovir is gewysig in pasiënte met ingekorte nierfunksie (sien "WAARSKUWINGS"). Die Cmaks en AOK0-∞ van emtrisitabien en tenofovir is vermeerder in pasiënte met kreatinienopruiming van < 50 ml/min. Die dosisinterval vir die kombinasie moet aangepas word in pasiënte met kreatinienopruiming van 30 – 49 ml/min. Aangesien dit nie met ‘n vaste dosis kombinasie moontlik is nie, moet so ‘n kombinasie nie aan pasiënte met kreatinienopruiming < 50 ml/min en aan pasiënte met eindstadium niersiekte wat dialise benodig, toegedien word nie (sien "KONTRA-INDIKASIES", "WAARSKUWINGS" en "DOSIS EN GEBRUIKSAANWYSINGS").Efavirens:Die farmakokinetiese eienskappe van efavirens is nie in pasiënte met nierontoereikendheid bestudeer nie. Aangesien minder as 1  % van efavirens egter onveranderd in die uriene uitgeskei word, behoort die impak van ingekorte nierfunksie op eliminasie van efavirens minimaal te wees.Pasiënte met lewerinkorting: Emtrisitabien en tenofovir disoproksielfumaraat:Die farmakokinetiese eienskappe van tenofovir na ‘n 300 mg dosis tenofovir disoproksielfumaraat is geëvalueer in nie-MIV geïnfekteerde individue met matige tot erge inkorting van lewerfunksie. Tenofovir farmakokinetika is nie wesenlik anders in pasiënte met lewerinkorting in vergelyking met normale pasiënte nie. Farmakokinetiese eienskappe van die kombinasie tablet of emtrisitabien is nie geëvalueer in pasiënte met ingekorte lewerfunksie nie. Aangesien emtrisitabien nie tot ‘n betekenisvolle mate deur lewerensieme gemetaboliseer word nie, behoort die impak van lewerinkorting beperk te wees.Efavirens:Die farmakokinetika van efavirens is nog nie voldoende in pasiënte met lewerinkorting bestudeer nie.INDIKASIES:TRENVIR is aangedui vir die behandeling van MIV-1 infeksie in volwassenes.KONTRA-INDIKASIES:TRENVIR is teenaangedui in pasiënte:

• Wie vantevore hipersensitiwiteit vir emtrisitabien, tenofovir, efavirens of enige van die ander komponente van die produk getoon het.

• Met matige tot erge inkorting van nierfunksie (kreatinienopruiming < 50 ml/min) (sien "WAARSKUWINGS" en "DOSIS EN GEBRUIKSAANWYSINGS").

• Wie swanger is of borsvoed (sien "SWANGERSKAP EN LAKTASIE").• Wie gesamentlik behandeling met astemisool, sisapried, midasolam, triasolam of ergotderivate ontvang,

aangesien kompetisie vir CYP3A4 deur die efavirens in TRENVIR tot inhibisie van die metabolisme van hierdie middels mag lei en dit mag potensieel ernstige en/of lewensdreigende newe-effekte tot gevolg hê (bv. kardiale disritmieë, verlengde sedasie of respiratoriese onderdrukking).

• Jonger as 18 jaar vanweë gebrek aan data oor veiligheid en effektiwiteit.• Met erge lewerinkorting.• Wie gesamentlik vorikonasool neem, aangesien efavirens vorikonasool plasmakonsentrasies betekenisvol

verminder, terwyl vorikonasool efavirens plasmakonsentrasies betekenisvol vermeerder. Aangesien TRENVIR ‘n vaste dosis kombinasie produk is, kan die dosis van efavirens nie verander word nie; dus moet vorikonasool en TRENVIR nie gesamentlik toegedien word nie.

• Wie gesamentlik enige ander medisinale produkte neem wat enige van die komponente (efavirens, emtrisitabien of tenofovir) bevat of wie gesamentlik ander sitidien analoë, soos lamivudien, en adefovir dipivoksiel neem.

WAARSKUWINGS:LET WEL: Vind uit oor middels wat NIE saam met TRENVIR geneem moet word nie (sien "KONTRA-INDIKASIES", "INTERAKSIES" en "NEWE-EFFEKTE EN SPESIALE VOORSORGMAATREËLS").Ernstige senusisteem en psigiatriese simptome is met efavirens, een van die aktiewe bestanddele in TRENVIR, gemeld.Melksuurasidose / Erge hepatomegalie met steatose:Melksuurasidose en erge hepatomegalie met steatose, wat in sommige gevalle noodlottig was, is met die toediening van nukleosied analoë, soos bevat in TRENVIR, alleen of in kombinasie met ander antiretrovirale middels gemeld. Meeste van hierdie gevalle het in vroue voorgekom. Moontlike risikofaktore sluit obesiteit en verlengde nukleosied blootstelling in. Uiterse omsigtigheid is nodig wanneer TRENVIR toegedien word aan enige pasiënt met bekende risikofaktore vir lewersiekte; tog is sodanige komplikasies ook gemeld in pasiënte sonder enige bekende risikofaktore. Staak behandeling met TRENVIR in enige pasiënt wie kliniese of laboratorium bevindings aanduidend van melksuurasidose of uitgesproke hepatotoksisiteit ontwikkel (wat vergroting van die lewer en steatose selfs in die afwesigheid van opvallende verhogings in transaminases) mag insluit.Pasiënte met hepatitis B en MIV gesamentlike infeksie:Dit word aanbeveel dat alle MIV-positiewe pasiënte getoets word vir die teenwoordigheid van hepatitis B virus (HBV) voor die aanvang van behandeling met antiretrovirale middels. TRENVIR is nie aangedui vir die behandeling van chroniese HBV infeksie nie. Die veiligheid en effektiwiteit van TRENVIR is nog nie bevestig in pasiënte met HBV en MIV gesamentlike infeksie nie. Na staking van behandeling met emtrisitabien (200 mg) en tenofovir disoproksielfumaraat was daar melding gemaak van erge akute opflikkerings van hepatitis B. Pasiënte met HBV en MIV gesamentlike infeksie wie behandeling met TRENVIR staak, benodig noukeurige monitering van hulle lewerfunksie vir ten minste verskeie maande; dit behoort beide kliniese en laboratorium opvolg in te sluit. Toepaslike inisiëring van anti-hepatitis B terapie mag nodig wees.Renale inkorting:Eliminasie van emtrisitabien en tenofovir, twee van die aktiewe substanse in TRENVIR, is hoofsaaklik via die niere. In alle pasiënte met kreatinienopruiming van 30 – 49 ml/min moet die doseringsinterval aangepas word. Aangesien dit nie met ‘n vaste dosis kombinasie moontlik is nie, moet TRENVIR nie aan pasiënte met kreatinienopruiming < 50 ml/min of pasiënte wie hemodialise benodig, toegedien word nie (sien "DOSIS EN GEBRUIKSAANWYSINGS").Inkorting van nierfunksie, insluitende gevalle van akute nierversaking en Fanconi se sindroom (renale tubulêre skade met erge hipofosfatemie) is in assosiasie met die gebruik van tenofovir gemeld (sien "Newe-Effekte"). Meeste van hierdie gevalle het in pasiënte met onderliggende sistemiese of niersiekte ontwikkel, of in pasiënte wie nefrotoksiese middels ontvang het. Sommige van hierdie komplikasies het egter ontwikkel in pasiënte sonder enige identifiseerbare risikofaktore.Die gebruik van TRENVIR moet vermy word in pasiënte wie gesamentlik ‘n nefrotoksiese middel neem of onlangs geneem het. Versigtige monitering vir veranderinge in serumkreatinien en -fosfor is nodig in pasiënte met ‘n risiko vir, of met ‘n geskiedenis van, nierdisfunksie asook in pasiënte wie gepaardgaande nefrotoksiese middels ontvang.INTERAKSIES:Algemene interaksies:Geen interaksiestudies is met TRENVIR tablette uitgevoer nie. Aangesien TRENVIR efavirens, emtrisitabien en tenofovir bevat, mag enige interaksies wat met hierdie middels individueel geïdentifiseer is, met TRENVIR voorkom. Interaksiestudies met hierdie middels is slegs in volwassenes gedoen.As ‘n vaste kombinasie moet TRENVIR nie saam met ander medisinale produkte wat enige van die bestanddele (efavirens, emtrisitabien of tenofovir) bevat, toegedien word nie en ook nie saam met ander sitidien analoë, soos lamivudien, en adefovir dipivoksiel nie (sien "KONTRA-INDIKASIES").TRENVIR moenie saam met terfenadien, astemisool, sisapried, midasolam, triasolam, pimosied, bepridil, of ergotderivate toegedien word nie, aangesien inhibisie van hierdie middels se metabolisme erge, lewensdreigende gevolge mag hê (sien "KONTRA-INDIKASIES").Die farmakokinetiese eienskappe van emtrisitabien en tenofovir by ewewigsvlak het onveranderd gebly toe emtrisitabien en tenofovir disoproksielfumaraat gesamentlik toegedien is versus elke middel afsonderlik gegee. Geen klinies betekenisvolle interaksies is tussen emtrisitabien en tenofovir waargeneem nie.Gesamentlike toediening van tenofovir disoproksielfumaraat 300 mg een maal per dag vir 7 dae met emtrisitabien 200 mg een maal daagliks vir 7 dae het geen veranderinge in die Cmaks of AOK van emtrisitabien tot gevolg gehad nie. Daarteenoor het die Cmin van emtrisitabien met 20 % [90 % vertrouensinterval (VI) +12 % tot +29 %] vermeerder. Die Cmaks, AOK en Cmin van tenofovir was onveranderd.In vitro en kliniese farmakokinetiese middelinteraksiestudies het gevind dat die potensiaal vir CYP450 bemiddelde interaksies tussen emtrisitabien en tenofovir, twee van die aktiewe komponente van TRENVIR, met ander middels gering is.Die niere is primêr verantwoordelik vir die uitskeiding van emtrisitabien en tenofovir deur ‘n kombinasie van glomerulêre filtrasie en aktiewe tubulêre sekresie. Alhoewel geen middelinteraksies vanweë kompetisie vir renale uitskeiding waargeneem is nie, is dit moontlik dat wanneer TRENVIR saam met middels toegedien word wat deur aktiewe tubulêre sekresie geëlimineer word, die konsentrasies van emtrisitabien, tenofovir en/of die gepaardgaande middel mag toeneem.Middels wat nierfunksie belemmer, mag emtrisitabien en/of tenofovir konsentrasies verhoog.Die efavirens in TRENVIR induseer CYP3A4. Ander samestellings wat substrate van CYP3A4 is, mag verlaagde plasmakonsentrasies toon wanneer dit saam met TRENVIR toegedien word.Geen klinies beduidende middelinteraksies is vir tenofovir disoproksielfumaraat en efavirens getoon nie. Gesamentlike toediening van efavirens 600 mg een maal per dag vir 14 dae met tenofovir 300 mg een maal per dag het nie enige veranderinge in die Cmaks, Cmin of AOK van óf efavirens óf tenofovir veroorsaak nie.Abakavir:Geen klinies beduidende middelinteraksies is tussen tenofovir disoproksielfumaraat, een van die aktiewe komponente van TRENVIR, en abakavir waargeneem nie. Gesamentlike toediening van ‘n enkel dosis abakavir 300  mg met tenofovir 300 mg het geen veranderinge in die Cmaks of AOK van tenofovir veroorsaak nie. Die Cmaks van abakavir het egter met 12 % (90 % VI -1 % tot +26 %) toegeneem terwyl die AOK onveranderd gebly het.Adefovir dipivoksiel:Geen klinies beduidende middelinteraksies is tussen tenofovir disoproksielfumaraat, een van die aktiewe komponente van TRENVIR, en adefovir dipivoksiel waargeneem nie. Gepaardgaande toediening van ‘n enkel dosis van adefovir dipivoksiel 10 mg met tenofovir 300 mg het nie tot enige veranderinge in die Cmaks, Cmin of AOK van tenofovir of in die Cmaks of AOK van adefovir dipivoksiel gelei nie.TRENVIR moet egter vanweë die verhoogde risiko vir nefrotoksisiteit nie saam met adefovir dipivoksiel toegedien word nie.Amprenavir:Gepaardgaande toediening van amprenavir/ritonavir en TRENVIR word nie aanbeveel nie, aangesien efavirens die Cmaks, Cmin en AOK van amprenavir met 40 % verminder.Atasanavir:Gesamentlike toediening van atasanavir 400 mg een maal daagliks vir 14 dae met tenofovir 300 mg een maal per dag het tot ‘n toename van 14 % (90 % VI +8 % tot +20 %) in tenofovir Cmaks, van 24 % (+21 % tot +28 %) in tenofovir AOK en van 22 % (+15 % tot +30 %) in tenofovir Cmin gelei. Ooreenstemmende parameters vir atasanavir het ‘n afname van 21 % (-27 % tot -14 %) in Cmaks, van 25 % (-30 % tot -19 %) in AOK en van 40 % (-48 % tot -32 %) in Cmin getoon. In MIV-geïnfekteerde pasiënte het toevoeging van tenofovir disoproksielfumaraat tot atasanavir 300 mg plus ritonavir 100 mg tot AOK-en Cmin-waardes van atasanavir gelei wat 2,3- tot 4-voudig hoër was as die onderskeie waardes waargeneem vir atasanavir 400 mg wanneer alleen toegedien.Gesamentlike toediening van atasanavir/ritonavir met tenofovir het tot verhoogde blootstelling aan tenofovir gelei. Hoër tenofovir konsentrasies kan tenofovir-geassosieerde newe-effekte, insluitende renale afwykings, vererger.Gesamentlike toediening van efavirens met atasanavir in kombinasie met lae-dosis ritonavir het tot beduidende afnames in atasanavir blootstelling gelei vanweë CYP3A4 induksie. Dit het dosisaanpassing van atasanavir genoodsaak. Gesamentlike toediening van efavirens en atasanavir in kombinasie met ritonavir mag tot verhoogde efavirens blootstelling lei wat die verdraagsaamheidsprofiel van efavirens mag verswak.Data om ’n dosisaanbeveling vir atasanavir/ritonavir in kombinasie met TRENVIR te maak is nie voldoende nie. Derhalwe kan gesamentlike toediening van atasanavir/ritonavir en TRENVIR nie aanbeveel word nie.Kalsiumkanaalblokkers:Wanneer efavirens saam met ’n kalsiumkanaalblokker wat ’n substraat van die CYP3A4 ensiem is gegee word, is daar ’n moontlikheid dat die plasmakonsentrasie van die kalsiumkanaalblokker verminder mag word. Dosisaanpassings van diltiasem en ander kalsiumkanaalblokkers (soos verapamil, felodipien, nifedipien en nikardipien) wanneer saam met TRENVIR toegedien, moet deur kliniese respons gelei word.Kannabinoïede toetsinteraksie: Efavirens bind nie aan kannabinoïede reseptore nie. Vals-positiewe uriene kannabinoïede toetsresultate is verkry in ongeïnfekteerde vrywilligers wie efavirens geneem het en is dus moontlik met TRENVIR toediening. Vals-positiewe toetsresultate te wyte aan efavirens is slegs met die CEDIA DAU Multi-Level THC ontleding, wat vir sifting gebruik word, waargeneem en nie met ander getoetsde kannabinoïed ontledings nie – dit sluit toetse vir bevestiging van positiewe resultate in.Karbamasepien:Gesamentlike toediening van karbamasepien met efavirens het die AOK, Cmaks en Cmin van karbamasepien met onderskeidelik 27 % (90 % VI -20 % tot -33 %), 20 % (-15 % tot -24 %), en 35 % (-24 % tot -44 %) laat afneem vanweë CYP3A4 induksie. Ooreenstemmende afnames in efavirens AOK, Cmaks en Cmin (vanweë CYP3A4 en CYP2B6 induksie) was onderskeidelik 36 % (-32 % tot -40 %), 21 % (-15 % tot -26 %), en 47 % (-41 % tot -53 %). Geen dosisaanbeveling kan vir die gebruik van TRENVIR saam met karbamasepien gemaak word nie. ’n Alternatiewe antikonvulsant moet oorweeg word. Karbamasepien vlakke moet periodiek gemonitor word.Klaritromisien: Gesamentlike toediening van 400 mg efavirens een maal daagliks met klaritromisien toegedien as 500 mg elke 12 uur vir sewe dae het getoon dat efavirens die farmakokinetika van klaritromisien betekenisvol verander. Die AOK en Cmaks van klaritromisien het met onderskeidelik 39 % en 26 % verminder, terwyl die AOK en Cmaks van die aktiewe klaritromisien hidroksimetaboliet met onderskeidelik 34 % en 49 % vermeerder het tydens gesamentlike toediening met efavirens. Die kliniese belang van hierdie veranderinge in klaritromisien plasmavlakke is nie bekend nie. Ses-en-veertig (46) persent van ongeïnfekteerde vrywilligers wie efavirens en klaritromisien geneem het, het ’n uitslag ontwikkel. Geen dosisaanpassing word vir efavirens aanbeveel wanneer dit saam met klaritromisien gegee word nie; alternatiewe vir klaritromisien moet egter oorweeg word.Ander antibiotika wat aan die makrolied klas behoort, soos eritromisien, is nie in kombinasie met TRENVIR bestudeer nie.Didanosien:Gepaardgaande toediening van ‘n eenmalige dosis van enteriesbedekte didanosien 400 mg met tenofovir 300 mg het nie enige veranderinge in die Cmaks, Cmin of AOK van tenofovir veroorsaak nie. Dieselfde is waar vir die kombinasie van gebufferde didanosien 250 of 400 mg een maal daagliks vir 7 dae met tenofovir 300 mg een maal per dag.

Wanneer toegedien saam met veelvuldige dosisse van tenofovir, het die Cmaks en AOK van didanosien 400 mg betekenisvol toegeneem. Die meganisme vir hierdie interaksie is nog nie geïdentifiseer nie. Gesamentlike toediening van didanosien 250 mg enteriesbedekte kapsules met tenofovir het sistemiese blootstelling soortgelyk aan dié verkry met die 400 mg enteriesbedekte kapsules alleen onder vastende toestande tot gevolg gehad.Vir ‘n volledige opsomming van die veranderinge in farmakokinetiese parameters van didanosien, sien asseblief die onderstaande tabel.Tabel 1: Middelinteraksies: Farmakokinetiese parameters van didanosien in die teenwoordigheid van tenofovir soos bevat in TRENVIR.

Didanosien dosis (mg) / Tenofovir wyse van % Verskil (90 % VI) vs. didanosien 400 mg alleen, Wyse van toediening1 toediening1 N vastend2

Cmaks AOKGebufferde tablette

400 een maal per dag3 Vastend 1 uur voor 14 ↑28 ↑44X 7 dae didanosien (↑11 - ↑48) (↑31 - ↑59)

seluspak etkedebseiretnE 400 eenmalig, Met voedsel, 2 uur na 26 ↑48 ↑48

vastend didanosien (↑25 - ↑76) (↑31 - ↑67)400 eenmalig, met Gelyktydig met 26 ↑64 ↑60

voedsel didanosien (↑41 - ↑89) (↑44 - ↑79)250 eenmalig, Met voedsel, 2 uur na 28 ↓10

vastend didanosien (↓22 - ↑3) ↔

250 eenmalig, Gelyktydig met 28 ↔ ↑14vastend didanosien (0 - ↑31)

250 eenmalig, met Gelyktydig met 28 ↓29 ↓11voedsel didanosien (↓39 - ↓18) (↓23 - ↑2)

.dytlaam etgil n‘ tem saw lesdeov tem gnineideoT .12. ↑ = toename; ↓ = afname; ↔ = geen verskil.

.teh gnavtno gm 052 Idd taw teh geeweg gk 06 < taw ni eudividni 4 tiulS .3Gesamentlike toediening van tenofovir disoproksielfumaraat en didanosien lei tot ’n 40  % tot 60  % toename in sistemiese blootstelling aan didanosien wat die risiko vir didanosien-verwante newe-effekte mag verhoog. Gevalle van pankreatitis en melksuurasidose, soms noodlottig, is gemeld. Gesamentlike toediening van tenofovir disoproksielfumaraat en didanosien teen ’n dosis van 400  mg daagliks is met ’n betekenisvolle afname in CD4 seltellings geassosieer, moontlik weens ’n intrasellulêre interaksie wat gefosforileerde (d.i. aktiewe) didanosien laat toeneem. ’n Verminderde dosis van 250 mg didanosien toegedien saam met tenofovir disoproksielfumaraat is met hoë insidensies van virologiese mislukking binne verskeie getoetsde kombinasies geassosieer. Gesamentlike toediening van TRENVIR en didanosien word nie aanbeveel nie.Famsiklovir:Geen klinies betekenisvolle middelinteraksies is tussen emtrisitabien, een van die aktiewe komponente van TRENVIR, en famsiklovir waargeneem nie. Gesamentlike toediening van ’n enkel dosis van famsiklovir 500 mg met ’n enkel dosis van emtrisitabien 200 mg het nie die Cmaks of AOK van emtrisitabien of famsiklovir verander nie.HMG Ko-A reduktase-inhibeerders:Gesamentlike toediening van efavirens met HMG Ko-A reduktase-inhibeerders, soos atorvastatien en pravastatien, lei tot dalings in die AOK en Cmaks van die HMG Ko-A reduktase-inhibeerders en hulle aktiewe metaboliete. Cholesterolvlakke moet periodiek gemonitor word wanneer atorvastatien, pravastatien of simvastatien saam met TRENVIR gegee word. Aanpassings in die dosis van die statien mag nodig wees.Immuunonderdrukkers:Gesamentlike toediening van takrolimus met emtrisitabien of tenofovir disoproksielfumaraat het nie enige veranderinge in die AOK, Cmaks of Cmin van takrolimus, emtrisitabien of tenofovir disoproksielfumaraat tot gevolg gehad nie. Alhoewel die interaksie tussen efavirens en takrolimus nie bestudeer is nie, kan verminderde blootstelling aan takrolimus verwag word vanweë induksie van CYP3A4. Dit word nie verwag dat takrolimus blootstelling aan efavirens sal beïnvloed nie. Takrolimus dosisaanpassings mag nodig wees. Sorgvuldige monitering van takrolimus konsentrasies word vir ten minste twee weke (totdat stabiele konsentrasies bereik word) aanbeveel wanneer behandeling met TRENVIR begin of gestaak word.Indinavir:Geen klinies betekenisvolle middelinteraksies is tussen die emtrisitabien in TRENVIR en indinavir waargeneem nie. Gesamentlike toediening van ‘n enkel dosis van indinavir 800 mg met ’n enkel dosis van emtrisitabien 200 mg het nie die Cmaks of AOK van emtrisitabien of indinavir verander nie.Soortgelyk is daar geen klinies betekenisvolle middelinteraksies tussen tenofovir disoproksielfumaraat, een van die aktiewe komponente van TRENVIR, en indinavir waargeneem nie. Daar was ’n 14 % toename (90 % VI -3 % tot +33 %) in die Cmaks van tenofovir toe indinavir 800 mg drie keer per dag vir 7 dae saam met tenofovir 300 mg een maal per dag toegedien is. Die Cmin en AOK van tenofovir het onveranderd gebly en so ook die Cmin en AOK van indinavir. Indinavir Cmaks het met 11 % (-30 % tot +12 %) afgeneem.Wanneer indinavir (800 mg elke 8 uur) saam met efavirens (200 mg elke 24 uur) toegedien is, het indinavir se AOK en Ctrog met onderskeidelik ongeveer 31 % en 16 % vanweë ensieminduksie afgeneem.Daar is nie voldoende data om ’n doseringsaanbeveling vir indinavir te maak wanneer dit saam met TRENVIR gedoseer word nie. Alhoewel die kliniese belang van verlaagde indinavir konsentrasies nie vasgestel is nie, moet die omvang van die waargeneemde farmakokinetiese interaksie in ag geneem word wanneer ’n behandelingsregimen gekies word wat beide efavirens, ’n komponent van TRENVIR, en indinavir bevat.Itrakonasool:Gesamentlike toediening van itrakonasool en efavirens het tot verlaagde itrakonasool AOK, Cmaks en Cmin gelei vanweë CYP3A4 induksie. Geen dosisaanbevelings kan vir die gebruik van TRENVIR in kombinasie met itrakonasool gemaak word nie. ’n Alternatiewe antiswammiddel moet oorweeg word.Interaksiestudies met TRENVIR en ketokonasool is nie gedoen nie. Efavirens het die potensiaal om plasmakonsentrasies van ketokonasool te verminder.Lamivudien:Geen klinies betekenisvolle middelinteraksies is tussen die tenofovir disoproksielfumaraat in TRENVIR en lamivudien waargeneem nie. Gepaardgaande toediening van lamivudien 150 mg twee maal per dag vir 7 dae met tenofovir 300 mg een maal per dag het nie enige veranderinge in die Cmaks, Cmin of AOK van tenofovir tot gevolg gehad nie. Terwyl die Cmin en AOK van lamivudien onveranderd gebly het, het die Cmaks met 24 % (90 % VI -34 % tot -12 %) afgeneem.Vanweë ooreenkomste met emtrisitabien, moet TRENVIR egter nie saam met ander sitidien analoë, soos lamivudien, toegedien word nie.Lopinavir/Ritonavir:Geen klinies betekenisvolle middelinteraksies is tussen tenofovir disoproksielfumaraat, een van die aktiewe komponente van TRENVIR, en lopinavir/ritonavir waargeneem nie. Gesamentlike toediening van ‘n kombinasie van lopinavir 400 mg en ritonavir 100 mg twee maal per dag vir 14 dae met tenofovir 300 mg een maal per dag het gelei tot ‘n toename van 32 % (90 % VI +26 % tot + 38%) in tenofovir AOK en van 29 % (+23 % tot +66 %) in tenofovir Cmin, terwyl tenofovir Cmaks onveranderd gebly het. Daar was geen veranderinge in die Cmaks, Cmin of AOK van lopinavir en ritonavir nie. Hoër tenofovir konsentrasies kan tenofovir-geassosieerde newe-effekte, veral renale afwykings, vererger.Toe efavirens 600 mg (toegedien een maal daagliks met slapenstyd) en ritonavir 500 mg (toegedien elke 12 uur) in ongeïnfekteerde vrywilligers bestudeer is, het hulle die kombinasie nie goed verdra nie. Hierdie kombinasie was met ’n hoër frekwensie van nadelige kliniese gevolge (byvoorbeeld duiseligheid, naarheid, parestesie en verhoogde lewerensieme) geassosieer. Lewerensieme moet gemonitor word wanneer efavirens in kombinasie met ritonavir gebruik word.Gepaardgaande toediening van lopinavir/ritonavir met efavirens het ’n beduidende afname in lopinavir blootstelling tot gevolg wat ‘n dosisaanpassing van lopinavir/ritonavir noodsaak.Onvoldoende data is beskikbaar om ’n doseringsaanbeveling vir lopinavir/ritonavir in kombinasie met TRENVIR te maak. Gesamentlike toediening van lopinavir/ritonavir met TRENVIR word nie aanbeveel nie.Metadoon:Geen klinies betekenisvolle middelinteraksies is tussen die tenofovir disoproksielfumaraat in TRENVIR en metadoon geïdentifiseer nie. Tenofovir farmakokinetiese eienskappe by ewewigsvlak was soortgelyk na veelvuldige dosering aan MIV-negatiewe individue wie chroniese metadoon instandhoudingsterapie ontvang het as aan dié vantevore waargeneem. Dit dui op ’n gebrek aan klinies betekenisvolle middelinteraksies tussen metadoon en die tenofovir in TRENVIR.Spesifiek, wanneer metadoon 40 – 110 mg een maal per dag vir 14 dae saam met tenofovir 300 mg een maal per dag toegedien is, was R-(aktiewe), S- en totale metadoon blootstelling dieselfde hetsy alleen of saam met tenofovir toegedien. Individuele pasiënte was instandgehou op hulle stabiele metadoon dosis. Daar was geen melding van farmakodinamiese veranderinge, soos opiaattoksisiteit of onttrekkingstekens of –simptome, nie.Daarteenoor het gesamentlike toediening van efavirens en metadoon in MIV-geïnfekteerde IV dwelmgebruikers tot verlaagde plasmakonsentrasies van metadoon en tekens van opiaatonttrekking gelei. Onttrekkingsimptome is verlig deur die metadoon dosis met ‘n gemiddelde van 22 % te verhoog. Pasiënte moet vir onttrekkingstekens gemonitor word en hulle metadoon dosis moet verhoog word soos benodig om onttrekkingsimptome te verlig.Orale voorbehoedmiddels:Geen klinies betekenisvolle middelinteraksies is tussen die tenofovir disoproksielfumaraat in TRENVIR en orale voorbehoedmiddels waargeneem nie.Tenofovir farmakokinetiese eienskappe by ewewigsvlak was soortgelyk na veelvuldige dosering aan MIV-negatiewe individue wie orale voorbehoedmiddels ontvang het as aan dié vantevore waargeneem. Dit dui op ’n gebrek aan klinies betekenisvolle middelinteraksies tussen hierdie middels en die tenofovir in TRENVIR.In terme van moontlike interaksies met efavirens, is slegs die etinielestradiol komponent van orale voorbehoedmiddels bestudeer. Na veelvuldige dosering met efavirens, was die AOK van etinielestradiol na ’n enkele dosis verhoog (37 %). Die Cmaks van etinielestradiol was nie betekenisvol anders nie. Die kliniese belang van hierdie veranderinge is nie duidelik nie. ‘n Enkele dosis etinielestradiol blyk om geen effek op efavirens Cmaks of AOK te hê nie. Aangesien die potensiële interaksie tussen TRENVIR en orale voorbehoedmiddels nog nie volledig gekarakteriseer is nie, moet pasiënte van ‘n betroubare skansmetode van geboortebeperking addisioneel tot orale voorbehoedmiddels gebruik maak.Fenitoïen, fenobarbitaal en ander antikonvulsante:Efavirens mag potensieel die plasmavlakke van fenitoïen, fenobarbitaal en ander antikonvulsante wat substrate van CYP450 iso-ensieme is, verminder of vermeerder. Wanneer TRENVIR gesamentlik met ’n antikonvulsant wat ‘n substraat van CYP450 iso-ensieme is toegedien word, moet die konsentrasies van die antikonvulsant periodiek gemonitor word.TRENVIR en vigabatrien of gabapentien kan gesamentlik sonder dosisaanpassings gegee word. Klinies betekenisvolle interaksies word nie verwag nie, aangesien vigabatrien en gabapentien eksklusief onveranderd in die uriene uitgeskei word en derhalwe waarskynlik nie met efavirens vir dieselfde metaboliese ensieme en eliminasie roetes sal kompeteer nie.Ribavirien:Geen klinies betekenisvolle middelinteraksies is tussen die tenofovir disoproksielfumaraat in TRENVIR en ribavirien aangetoon nie. Tenofovir farmakokinetiese eienskappe by ewewigsvlak was soortgelyk na veelvuldige dosering aan MIV-negatiewe individue wie enkele dosisse van ribavirien ontvang het as aan dié vantevore waargeneem. Dit dui op ’n gebrek aan klinies betekenisvolle middelinteraksies tussen ribavirien en die tenofovir in TRENVIR.Rifamisiene: Met gepaardgaande toediening aan ongeïnfekteerde vrywilligers verminder rifampisien efavirens AOK met 26 % en Cmaks met 20 %. Die efavirens dosis moet tot 800 mg/dag vermeerder word wanneer dit in kombinasie met rifampisien gebruik word. Derhalwe word ‘n bykomende 200 mg efavirens per dag benodig wanneer rifampisien saam met TRENVIR gedoseer word. Geen dosisaanpassing van rifampisien word aanbeveel wanneer dit saam met TRENVIR gegee word nie.Gesamentlike toediening van enkel dosisse van rifabutien 300 mg en efavirens 600 mg lei tot afnames van 38 % (90 % VI -28 % tot -36 %) in AOK, 32 % (-15 % tot -46 %) in Cmaks en 45 % (-31 % tot -56 %) in Cmin van rifabutien. Die AOK en Cmaks van efavirens het onveranderd gebly; daarteenoor het die Cmin met 12 % (-24 % tot -1 %) verminder. Die daaglikse dosis van rifabutien moet met 50 % vermeerder word wanneer dit saam met TRENVIR gegee word. Skenk oorweging aan verdubbeling van die rifabutien dosis in regimens waar rifabutien 2 tot 3 keer per week in kombinasie met TRENVIR gebruik word.Ritonavir:Efavirens word nie goed verdra wanneer dit saam met ritonavir 500 mg of 600 mg twee keer per dag gegee word nie (bv. duiseligheid, naarheid, parestesie en stygings in lewerensieme mag voorkom). Efavirens se AOK, Cmaks en Cmin het onderskeidelik met 21 % (+10 % tot +34 %), 14 % (+4 % tot +26 %) en 25 % (+7 % tot +46 %) toegeneem. Data rakende die toleransie vir efavirens saam met lae-dosis ritonavir (100 mg een of twee keer daagliks) is nie voldoende nie. Gepaardgaande toediening van ritonavir teen dosisse van 600  mg saam met TRENVIR word nie aanbeveel nie. Wanneer TRENVIR gebruik word in ‘n regimen wat lae-dosis ritonavir insluit, moet die moontlikheid dat die insidensie van efavirens-geassosieerde newe-effekte mag toeneem vanweë ‘n moontlike farmakodinamiese interaksie in gedagte gehou word.Sakwinavir: Wanneer sakwinavir (1200 mg toegedien 3 maal per dag, sagte gel kapsule formule) saam met efavirens toegedien is, was die sakwinavir AOK en Cmaks met onderskeidelik 62 % en 50 % verminder, terwyl efavirens se AOK, Cmaks en Cmin met onderskeidelik 12 %, 13 % en 14 % verminder was. Toediening van TRENVIR saam met sakwinavir as die enigste protease inhibeerder word nie aanbeveel nie.Data rakende die potensiële interaksies tussen efavirens en die kombinasie van sakwinavir en ritonavir is nie beskikbaar nie. Vanweë gebrekkige data is dit nie moontlik om ‘n dosisaanbeveling vir sakwinavir/ritonavir te maak wanneer dit saam met TRENVIR gedoseer word nie. Gesamentlike gebruik van sakwinavir/ritonavir en TRENVIR word derhalwe nie aanbeveel nie.Selektiewe serotonien heropname-inhibeerders (SSRIs):Wanneer sertralien in kombinasie met TRENVIR voorgeskryf word, moet dosisverhogings van sertralien deur kliniese respons gelei word, aangesien gepaardgaande toediening van sertralien 50 mg met efavirens 600 mg tot gemiddelde afnames in sertralien se AOK, Cmaks en Cmin van onderskeidelik 39 %, 29 % en 46 % gelei het.Gepaardgaande toediening van TRENVIR en paroksetien benodig nie dosisaanpassings nie. Gesamentlike toediening van efavirens en paroksetien het nie tot enige veranderinge in die AOK, Cmaks of Cmin van óf paroksetien óf efavirens gelei nie.Omdat fluoksetien ‘n soortgelyke metaboliese profiel as paroksetien het, dit is sterk CYP2D6 inhibitoriese effek, is dosisaanpassings nie nodig wanneer fluoksetien en TRENVIR gesamentlik gegee word nie. Vanweë die soortgelyke metaboliese profiel word ‘n soortgelyke gebrek aan interaksie met fluoksetien verwag.Stavudien:Geen klinies betekenisvolle middelinteraksies is tussen die emtrisitabien in TRENVIR en stavudien waargeneem nie. Gepaardgaande toediening van ‘n enkele dosis van stavudien 40 mg met ‘n enkele dosis van emtrisitabien 200 mg het nie die Cmaks of AOK van emtrisitabien of stavudien verander nie. St. John's wort (Hypericum perforatum): Pasiënte wie TRENVIR neem, moenie daarmee saam produkte gebruik wat St. John's wort (Hypericum perforatum)

bevat nie, aangesien dit na verwagting plasmavlakke van efavirens sal verminder. Dit geskied as gevolg van induksie van CYP3A4 en mag tot verlies van terapeutiese effek en die ontwikkeling van weerstandigheid lei.Vorikonasool:Gesamentlike toediening van standaard dosisse van efavirens en vorikonasool is teenaangedui vanweë betekenisvolle toenames in die AOK en Cmaks van efavirens en betekenisvolle dalings in die AOK en Cmaks van vorikonasool. Aangesien TRENVIR ’n vaste dosis kombinasie produk is, kan die dosis van efavirens nie verander word nie; gevolglik moet vorikonasool en TRENVIR nie gesamentlik gegee word nie (sien "KONTRA-INDIKASIES" en "WAARSKUWINGS").SWANGERSKAP EN LAKTASIE:Die gebruik van TRENVIR gedurende swangerskap word nie aanbeveel nie aangesien veiligheid en effektiwiteit nog nie vasgestel is nie (sien "KONTRA-INDIKASIES").Skansmetodes van voorbehoeding moet altyd in kombinasie met ander geboortebeperkingsmaatreëls (bv. orale of ander hormonale voorbehoeding) gebruik word.Vrouens in hulle reproduktiewe jare moet swangerskapstoetse ondergaan voor behandeling met TRENVIR begin word (sien "KONTRA-INDIKASIES").Borsvoedende moeders: MIV-geïnfekteerde moeders moenie hulle babas borsvoed nie. Dit is nie bekend of efavirens, emtrisitabien of tenofovir in menslike melk uitgeskei word nie. Vanweë die moontlike oordraging van MIV en die potensiaal vir ernstige ongewenste reaksies in suigelinge, moet moeders instruksies ontvang om nie te borsvoed as hulle TRENVIR gebruik nie.DOSIS EN GEBRUIKSAANWYSINGS:Behandeling moet deur ‘n geneesheer met ondervinding in die behandeling van MIV infeksie geïnisieer word.Volwassenes: Die aanbevole dosis van TRENVIR is een tablet oraal toegedien een maal per dag.Dit word aanbeveel dat TRENVIR heel met water gesluk word.TRENVIR moet op ’n leë maag geneem word, aangesien voedsel blootstelling aan efavirens mag vermeerder en dit ‘n toename in die frekwensie van newe-effekte tot gevolg mag hê. Om die toleransie vir efavirens in terme van senusisteem newe-effekte te verbeter, word dit aanbeveel dat TRENVIR met slapenstyd geneem word.Kinders en adolessente:TRENVIR word nie aanbeveel vir gebruik in kinders onder 18 jaar nie vanweë gebrek aan data rakende veiligheid en effektiwiteit (sien "KONTRA-INDIKASIES").Bejaardes:Die aantal bejaarde pasiënte wie in kliniese proewe met die komponente van TRENVIR bestudeer is, was nie voldoende om te kon bepaal of hulle anders reageer as jonger pasiënte nie. Omsigtigheid is nodig wanneer TRENVIR aan bejaardes voorgeskryf word en dit moet in gedagte gehou word dat bejaarde pasiënte ‘n hoër frekwensie van inkorting van lewer- en nierfunksie het.Nierinkorting:TRENVIR word nie aanbeveel vir pasiënte met matige tot erge inkorting van nierfunksie nie (kreatinienopruiming < 50 ml/min). Pasiënte met matige tot erge nierinkorting benodig dosisinterval aanpassings van emtrisitabien en tenofovir wat nie met TRENVIR verkry kan word nie (sien "KONTRA-INDIKASIES" en "WAARSKUWINGS").Lewerinkorting:Die farmakokinetiese eienskappe van TRENVIR is nie in pasiënte met lewerinkorting bestudeer nie. Pasiënte met geringe tot matige lewersiekte (Child-Pugh-Turcotte Graad A of B) mag die gewone aanbevole dosis van TRENVIR ontvang. Pasiënte benodig sorgvuldige monitering vir ongewenste reaksies as gevolg van efavirens, veral van die senusisteem.Wanneer behandeling met TRENVIR in pasiënte met MIV en HBV gesamentlike infeksie gestaak word, moet hierdie pasiënte sorgvuldig gemonitor word vir bewyse van opflikkering van hepatitis.Dit is belangrik om TRENVIR volgens ‘n gereelde doseringskedule te neem om te voorkom dat dosisse oorgeslaan word. Pasiënte moet ingelig word dat, indien hulle vergeet om TRENVIR te neem, moet hulle die oorgeslane dosis onmiddellik neem, tensy dit minder as 12 ure tot die volgende dag se dosis is. In so geval moet pasiënte ingelig word om die oorgeslane dosis weg te laat en om hulle volgende dosis op die gewone tyd te neem.Waar staking van behandeling met een van die komponente van TRENVIR aangedui is of waar dosisaanpassing benodig word, is afsonderlike preparate van efavirens, emtrisitabien en tenofovir beskikbaar. Verwys asseblief na die individuele voubiljette van hierdie middels.Wanneer behandeling met TRENVIR gestaak word, is dit belangrik om die lang halflewe van efavirens en die lang intrasellulêre halfleeftye van tenofovir en emtrisitabien in gedagte te hou. As gevolg van interpasiënt variansie in hierdie parameters en kommer oor die ontstaan van weerstandigheid, moet MIV behandelingsriglyne geraadpleeg word terwyl die rede vir die staking van behandeling ook in ag geneem moet word.NEWE-EFFEKTE EN SPESIALE VOORSORGMAATREËLS:Newe-Effekte:EMTRISITABIEN:Hematologiese en limfatiese sisteem afwykings:Die volgende newe-effekte is gemeld en die frekwensies daarvan is onbekend: Neutropenie, anemie. Metaboliese en voedingsafwykings:Die volgende newe-effekte is gemeld en die frekwensies daarvan is onbekend: Melksuurasidose, gewoonlik vergesel van erge hepatomegalie en steatose, is

geassosieer met die gebruik van nukleosied omgekeerde transkriptase inhibeerders.Hiperglisemie en hipertrigliseridemie.

Neuropsigiatriese sisteem afwykings: Dikwels: Hoofpyn, astenie. Minder dikwels: Depressiewe steuring, duiseligheid, slaapstoornisse (abnormale drome,

slaaploosheid), neuritis, parestesie en perifere neuropatie.Respiratoriese sisteem afwykings:Dikwels: Vermeerderde hoes, rinitis.Gastro-intestinale sisteem afwykings:Dikwels: Naarheid, diarree. Minder dikwels: Abdominale pyn, dispepsie en braking. Hepatobiliêre sisteem afwykings:Die volgende newe-effekte is gemeld en die frekwensies daarvan is onbekend: Verhoogde konsentrasies van lewerensieme en hiperbilirubinemie. Vel- en subkutane weefselafwykings:Minder dikwels: Uitslag (insluitende pruritus, makulopapulêre uitslag, urtikarieë, vesikobulleuse uitslag,

pustulêre uitslag en allergiese reaksies) en verkleuring van die vel wat manifesteer as hiperpigmentasie op die palms en/of voetsole (gewoonlik gering).

Muskuloskeletale sisteem afwykings:Minder dikwels: Artralgie, mialgie.Renale en urinêre sisteem afwykings:Dikwels: Verhoogde kreatienkinase. TENOFOVIR:Hematologiese en limfatiese sisteem afwykings:Die volgende newe-effekte is gemeld en die frekwensies daarvan is onbekend: Neutropenie, hematurie.Immuunsisteem afwykings:Die volgende newe-effekte is gemeld en die frekwensies daarvan is onbekend: Allergiese reaksies. Metabolisme en voedingsafwykings: Die volgende newe-effekte is gemeld en die frekwensies daarvan is onbekend: Melksuurasidose, gewoonlik vergesel van erge hepatomegalie en steatose; ook

hipertrigliseridemie, hiperglisemie en hipofosfatemie. Neuropsigiatriese sisteem afwykings:Dikwels: .einetsA Minder dikwels: Eetlusverlies.Die volgende newe-effekte is gemeld en die frekwensies daarvan is onbekend: Depressie, hoofpyn, duiseligheid, slaaploosheid, perifere neuropatie en angstigheid.Respiratoriese sisteem afwykings:Die volgende newe-effekte is gemeld en die frekwensies daarvan is onbekend: Borskaspyn, pneumonie, dispnee.Gastro-intestinale sisteem afwykings:Dikwels: Naarheid, braking, diarree. Minder dikwels: Verhoogde serumkonsentrasies van amilase, abdominale pyn en winderigheid.Die volgende newe-effekte is gemeld en die frekwensies daarvan is onbekend: Pankreatitis en dispepsie.Hepatobiliêre sisteem afwykings:Minder dikwels: Hepatotoksisiteit, insluitende melksuurasidose.Die volgende newe-effekte is gemeld en die frekwensies daarvan is onbekend: Verhoogde vlakke van lewerensieme en hepatitis. Vel- en subkutane weefselafwykings:Die volgende newe-effekte is gemeld en die frekwensies daarvan is onbekend: Veluitslae (insluitende pruritus, makulopapulêre uitslag, urtikarieë, vesikobulleuse

uitslag en pustulêre uitslag). Muskuloskeletale sisteem afwykings:Die volgende newe-effekte is gemeld en die frekwensies daarvan is onbekend: Artralgie, rugpyn en mialgie. Renale en urinêre sisteem afwykings:Die volgende newe-effekte is gemeld en die frekwensies daarvan is onbekend: Verhoogde vlakke van kreatienkinase, nefritis, nefrogene diabetes insipidus,

nierinkorting, akute nierversaking en effekte op die renale proksimale tubules, insluitende Fanconi se sindroom en akute tubulêre nekrose.

Algemene afwykings:Die volgende newe-effekte is gemeld en die frekwensies daarvan is onbekend: Koors, sweet en gewigsverlies.EFAVIRENS:Metaboliese en voedingsafwykings:Die volgende newe-effekte is gemeld en die frekwensies daarvan is onbekend: Gewigstoename en gewigsverlies.Neuropsigiatriese sisteem afwykings:Dikwels: Duiseligheid, ingekorte konsentrasie, slaperigheid, slaaploosheid en hoofpyn.Minder dikwels: Abnormale drome, eetlusverlies en hipestesie.Die volgende newe-effekte is gemeld en die frekwensies daarvan is onbekend: Abnormale koördinasie, ataksie, konvulsies, parestesieë, neuropatie, tremore,

verergerende depressie, agitasie, geheueverlies, angs, apatie, verhoogde aptyt, verwardheid, emosionele labiliteit, euforie, hallusinasies, swak koördinasie, impotensie, verminderde libido, verhoogde libido, neuralgie, perifere neuropatie, spraakafwyking en vertigo.

Afwykings van die spesiale sintuie:Die volgende newe-effekte is gemeld en die frekwensies daarvan is onbekend: Abnormale visie, tinnitus en smaakstoornisse.Kardiovaskulêre sisteem afwykings:Die volgende newe-effekte is gemeld en die frekwensies daarvan is onbekend: Blosing, hartkloppings en tagikardie.Respiratories sisteem afwykings:Die volgende newe-effekte is gemeld en die frekwensies daarvan is onbekend: Asma, sinusitis, dispnee en boonste respiratoriese infeksies. Gastro-intestinale sisteem afwykings:Dikwels: Naarheid, braking en diarree. Minder dikwels: Dispepsie en abdominale pyn.Die volgende newe-effekte is gemeld en die frekwensies daarvan is onbekend: Gastritis, gastro-enteritis, gastro-esofageale refluks, hardlywigheid en wanabsorpsie.Hepatobiliêre sisteem afwykings:Die volgende newe-effekte is gemeld en die frekwensies daarvan is onbekend: Hepatitis, stygings in lewerensieme en lewerversaking.Vel- en subkutane weefselafwykings: Dikwels: Uitslag, pruritus en vermeerderde sweet.Die volgende newe-effekte is gemeld en die frekwensies daarvan is onbekend: Aknee, haarverlies, ekseem, follikulitis, seborree, afskilfering van die vel, urtikarieë,

eritema multiforme, naelafwykings, velverkleuring, Stevens-Johnson sindroom.Muskuloskeletale, been- en bindweefselafwykings:Die volgende newe-effekte is gemeld en die frekwensies daarvan is onbekend: Artralgie, mialgie en miopatie.Algemene afwykings:Dikwels: Moegheid en pyn.Die volgende newe-effekte is gemeld en die frekwensies daarvan is onbekend: Alkoholintoleransie, allergiese reaksies, astenie, warmgloede, simptome soos dié van

griep, malaise, pyn, sinkopie en herverspreiding/akkumulasie van liggaamsvet. Laboratoriumafwykings:Stygings in lewerensiemwaardes het voorgekom, veral in pasiënte met virale hepatitis. Verhoogde serumcholesterol en -trigliseried konsentrasies is gemeld.Lewerensieme: Stygings in AST en ALT tot meer as vyf keer die boonste grens van normaal is waargeneem in pasiënte wie met 600 mg efavirens behandel is. Stygings in GGT vlakke in pasiënte wie efavirens neem, mag ‘n weerspieëling van ensieminduksie nie geassosieer met lewertoksisiteit nie wees (sien "Spesiale Voorsorgmaatreëls").Lipiede: Stygings in totale cholesterol van 10 tot 20 % was in sommige ongeïnfekteerde vrywilligers wie efavirens geneem het, gemerk. Stygings in nie-vastende totale cholesterol en HDL vlakke van onderskeidelik ongeveer 20 % en 25 % was gesien in pasiënte wie met efavirens + ZDV + 3TC behandel is en van onderskeidelik ongeveer 40 % en 35 % in pasiënte wie met efavirens + IDV behandel is. Die invloed van efavirens op trigliseried en LDL konsentrasies is nie volledig duidelik nie. Dit is nie bekend of hierdie bevindings van kliniese belang is nie (sien "Spesiale

Voorsorgmaatreëls").Spesiale Voorsorgmaatreëls:Middelinteraksies:LET WEL: Vind uit oor middels wat NIE saam met TRENVIR geneem moet word nie (sien "WAARSKUWINGS" en "INTERAKSIES).Aangesien die niere primêr vir die eliminasie van emtrisitabien en tenofovir verantwoordelik is, mag gesamentlike toediening van TRENVIR met middels wat nierfunksie verminder of kompeteer vir aktiewe tubulêre sekresie lei tot stygings in serumkonsentrasies van emtrisitabien, tenofovir en/of die ander middels wat renaal uitgeskei word. Voorbeelde van sodanige middels sluit onder andere adefovir dipivoksiel, sidofovir, asiklovir, valasiklovir, gansiklovir en valgansiklovir in.TRENVIR moenie saam met emtrisitabien, tenofovir of efavirens gegee word nie. Vanweë ooreenkomste tussen emtrisitabien en lamivudien, moet TRENVIR nie saam met ander middels wat lamivudien bevat, gegee word nie. Dit sluit lamivudien en sidovudien koformulering, lamivudien vir MIV, lamivudien vir HBV, abakavirsulfaat en lamivudien koformulering of abakavirsulfaat, lamivudien en sidovudien koformulering in.Effekte op been:Tenofovir: In ‘n 144-week kliniese studie was afnames vanaf basislyn in beenmineraaldigtheid (BMD) in die lumbale werwels en heup in beide behandelingsbene van die studie waargeneem. Teen week 144 was daar ‘n betekenisvolle groter gemiddelde persentasie afname vanaf basislyn in BMD in die lumbale werwels van deelnemers wie tenofovir + lamivudien + efavirens geneem het in vergelyking met deelnemers wie stavudien + lamivudien + efavirens geneem het. BMD veranderinge in die heup was soortgelyk in die twee behandelingsgroepe. In beide groepe het die grootste gedeelte van die afname in BMD in die eerste 24 tot 48 weke van die studie plaasgevind en hierdie afname is regdeur die studie (144 weke) gehandhaaf. Agt-en-twintig persent van pasiënte wie tenofovir ontvang het teenoor 21 % van stavudien-behandelde pasiënte het ‘n minimum van 5 % van BMD in die werwels of 7 % van BMD in die heup verloor. Frakture van kliniese belang (uitsluitende vingers en tone) is in 4 pasiënte wie tenofovir ontvang het en in 6 pasiënte wie stavudien geneem het, gemeld. Verder was daar betekenisvolle stygings in die vlakke van biochemiese merkers vir beenmetabolisme (serumbeenspesifieke alkaliese fosfatase, serumosteokalsien, serum C-telopeptied en urinêre N-telopeptied) in die tenofovir-groep vergeleke met die stavudien-groep wat verhoogde omset van been suggereer. Serumparatiroïedhormoon vlakke en 1,25 vitamien D vlakke was ook hoër in die groep van pasiënte wie tenofovir ontvang het. Met die uitsondering van beenspesifieke alkaliese fosfatase, het hierdie veranderinge waardes tot gevolg gehad wat binne die normale reikwydte gebly het. Hoe hierdie tenofovir-geassosieerde veranderinge in BMD en biochemiese merkers langtermyn beengesondheid en toekomstige fraktuur risiko gaan beïnvloed is nie bekend nie. MIV geïnfekteerde pasiënte met ‘n geskiedenis van patologiese beenfrakture of wie ‘n risiko vir osteopenie het, moet beenmonitering ondergaan. Alhoewel die invloed van kalsium- en vitamien D-aanvulling nie bestudeer is nie, mag sulke aanvullings alle pasiënte tot voordeel strek. Dit is noodsaaklik om toepaslike konsultasie in te win as beenabnormaliteite vermoed word.Herverspreiding van vet:Daar is melding gemaak van herverspreiding/akkumulasie van liggaamsvet insluitende sentrale obesiteit, dorsoservikale vetvergroting (buffelskof), perifere uittering, uittering van die gesig, borsvergroting en "cushingoïede voorkoms" in pasiënte wie met antiretrovirale middels, soos TRENVIR, behandel is. Die meganisme en langtermyn gevolge van hierdie verskynsels is nie tans bekend nie. Dit is ook nie bekend of antiretrovirale terapie oorsaaklik hiermee verband hou nie.Immuunheraktivering sindroom:Daar is melding gemaak van immuunheraktivering sindroom in pasiënte wie kombinasie antiretrovirale terapie ontvang het. Gedurende die aanvanklike fase van behandeling met kombinasie antiretrovirale middels mag ‘n anti-inflammatoriese respons tot sluimerende of residuele opportunistiese infeksies [soos Mycobacterium avium infeksie, sitomegalovirus, Pneumocystis jirovecii pneumonie (PCP), of tuberkulose] ontwikkel in pasiënte wie se immuunstelsels reageer op behandeling. Sodanige reaksies mag verdere evaluasie en behandeling noodsaak.Pediatriese gebruik:Die veiligheid en effektiwiteit van TRENVIR in kinders is nog nie vasgestel nie.Gebruik in bejaardes:Kliniese studies van vaste dosis kombinasies van emtrisitabien en tenofovir, soos in TRENVIR, het nie ‘n voldoende aantal individue ouer as 65 jaar ingesluit om te kon vasstel of hulle anders reageer as jonger persone nie. Omsigtigheid word oor die algemeen aanbeveel wanneer dosisse vir bejaarde pasiënte gekies word, inaggenome die groter frekwensie van ingekorte lewer-, nier- en kardiale funksie asook gepaardgaande siektetoestande en medisinale behandeling.Veluitslag: Milde-tot-matige uitslag, wat gewoonlik met volgehoue behandeling opklaar, is met die gebruik van efavirens waargeneem. Behandeling met toepaslike antihistamiene en/of kortikosteroïede mag simptome verlig en help om die uitslag vinniger te laat opklaar. Behandeling met TRENVIR moet gestaak word in pasiënte wie ‘n erge uitslag geassosieer met blase, afskilfering, slymvliesaantasting of koors ontwikkel. Profilakse met toepaslike antihistamiene voor aanvang van behandeling met TRENVIR in kinders kan oorweeg word.Senusisteem simptome: Senusisteem simptome is met die gebruik van efavirens gemeld (sien "Newe-Effekte"). Daarmee saam is ook melding gemaak van psigoseagtige reaksies, insluitende delusies en ontoepaslike gedrag (insluitende aggressiewe reaksies). Hierdie reaksies het hoofsaaklik in pasiënte met ‘n geskiedenis van geestesversteurings of middelmisbruik ontwikkel. Daar is ook ongereeld melding gemaak van erge akute depressie (insluitende selfmoordneigings of –pogings) in beide efavirens-behandelde en kontrole pasiënte, oorwegend in pasiënte met ‘n vorige geskiedenis van depressie. Pasiënte moet aangeraai word om hulle geneesheer onmiddellik te kontak as hulle hierdie simptome ontwikkel aangesien staking van behandeling met TRENVIR nodig mag wees.Lewerensieme: Monitering van lewerensieme word aanbeveel in pasiënte met bekende of vermoedelike geskiedenis van hepatitis B of C infeksie asook in pasiënte wie met ander middels geassosieer met lewertoksisiteit behandel word. Die voordeel van volgehoue behandeling met TRENVIR moet teen die onbekende risiko van betekenisvolle lewertoksisiteit opgeweeg word in pasiënte wie volgehoue stygings in serumtransaminases tot meer as 5 maal die boonste grens van die normale reikwydte openbaar (sien "Newe-Effekte").Cholesterol: Monitering van cholesterol en trigliseried vlakke moet in pasiënte wie behandeling met TRENVIR ontvang, oorweeg word (sien "Newe-Effekte").Opportunistiese infeksies:Pasiënte wie TRENVIR of enige ander antiretrovirale behandeling neem, mag voortgaan om opportunistiese infeksies en ander komplikasies van MIV infeksie te ontwikkel. Hulle moet gevolglik onder die waaksame kliniese oog van geneeshere met ondervinding in die behandeling van pasiënte met MIV geassosieerde siekte bly.Oordrag van MIV:Pasiënte moet geadviseer word dat daar geen bewyse is dat antiretrovirale behandeling, insluitende TRENVIR, die risiko vir oordrag van MIV na ander deur seksuele kontak of bloedkontaminasie voorkom nie. Pasiënte moet voortgaan om toepaslike voorkomende maatreëls te tref.Melksuurasidose:Melksuurasidose en erge hepatomegalie met steatose, wat in sommige gevalle noodlottig was, is met die gebruik van nukleosied analoë alleen of in kombinasie met ander antiretrovirale middels gemeld. Die meerderheid van gevalle was in vroue. Vetsug en verlengde nukleosied blootstelling mag risiko faktore wees. Omsigtigheid moet veral uitgeoefen word wanneer nukleosied analoë toegedien word aan enige pasiënt met bekende risikofaktore vir lewersiekte. Gevalle is egter gemeld in pasiënte met geen bekende risiko faktore nie. Behandeling met TRENVIR moet gestaak word in enige pasiënt wie kliniese of laboratorium bevindinge aanduidend van melksuurasidose of erge hepatotoksisiteit (wat hepatomegalie en steatose kan insluit selfs in die afwesigheid van noemenswaardig verhoogde transaminase).Roetiene bepaling van serum laktaatvlakke in asimptomatiese pasiënte op antiretrovirale behandeling word nie aanbeveel nie. Bepaling van serum laktaatvlakke word slegs aanbeveel in pasiënte wie presenteer met kliniese tekens of simptome aanduidend van meksuurasidose.Laktaat 2 – 5 mmol/ℓ: monitor gereeld en wees bedag op kliniese tekens.Laktaat 5 – 10 mmol/ℓ sonder simptome: monitor sorgvuldig.Laktaat 5 – 10 mmol/ℓ met simptome: STAAK alle terapie. Sluit ander oorsake (bv. sepsis, uremie, diabetiese keto-asidose, tirotoksikose, limfoom) uit.Laktaat > 10 mmol/ℓ: STAAK alle terapie (80 % mortaliteit in gevallestudies).

Effekte op die vermoë om te bestuur en masjinerie te gebruik:Die efavirens in TRENVIR mag tot duiseligheid, ingekorte konsentrasie en/of lomerigheid lei. Pasiënte moet ingelig word dat, indien hulle hierdie simptome ontwikkel, moet hulle potensieel gevaarlike take, soos om te bestuur of masjinerie te hanteer, vermy. BEKENDE SIMPTOME VAN OORDOSERING EN BESONDERHEDE VAN DIE BEHANDELING DAARVAN:In die geval van oordosering moet die pasiënt vir bewyse van toksisiteit gemonitor word en moet standaard ondersteunende behandeling soos nodig toegedien word.Emtrisitabien: Daar is beperkte kliniese ondervinding met dosisse groter as die terapeutiese dosis van emtrisitabien (200 mg). Daar was geen melding gemaak van ongewenste reaksies wanneer enkel emtrisitabien dosisse van 1200 mg toegedien is aan pasiënte wie aan kliniese proewe deelgeneem het nie. Hemodialise verwyder ongeveer 30 % van die emtrisitabien dosis oor ‘n 3-uur periode wat binne 1,5 uur na toediening van emtrisitabien geïnisieer is (bloedvloei tempo van 400 ml/min en ‘n dialisaat vloeitempo van 600 ml/min). Dit is nie bekend of peritoneale dialise emtrisitabien sal verwyder nie.Tenofovir disoproksielfumaraat: Daar is beperkte kliniese ondervinding met dosisse groter as die terapeutiese dosis van tenofovir 300 mg. Daar was geen melding gemaak van ernstige ongewenste reaksies toe tenofovir disoproksielfumaraat 600 mg oraal vir pasiënte vir 28 dae gegee is nie. Die effekte van hoër doserings as hierdie is nie bekend nie.Hemodialise verwyder tenofovir effektief met ‘n ekstraksie koëffisiënt van ongeveer 54 %. Ongeveer 10 % van die toegediende tenofovir dosis word verwyder gedurende ‘n 4-uur hemodialise sessie na ‘n enkel 300 mg dosis van tenofovir.Efavirens:‘n Aantal pasiënte wie per abuis 600 mg twee keer per dag geneem het, het verhoogde senusisteem simptome en onwillekeurige spierkontraksies gerapporteer. Behandeling van efavirens oordosering behoort uit algemene ondersteunende maatreëls te bestaan. Hierdie behoort monitering van vitale tekens en waarneming van die pasiënt se kliniese status in te sluit. Toediening van geaktiveerde houtskool kan bydra om ongeabsorbeerde middel te verwyder. Dit is onwaarskynlik dat dialise efavirens betekenisvol uit die bloed sal verwyder, aangesien hierdie middel hoogs proteïengebonde is.IDENTIFIKASIE:Pienkgekleurde, kapsulevormige, bikonvekse, filmbedekte tablette.AANBIEDING:Dertig (30) tablette voorsien in ‘n wit, ondeursigtige, HDPE bottel wat ‘n silika gel sakkie gemaak van nie-geweefde materiaal bevat en wat toegemaak is met ‘n wit ondeursigtige HDPE skroefdoppie. Die dertig tablette is verpak in ‘n karton.BERGINGSINSTRUKSIES:Berg teen of benede 30 °C.Hou die bottel dig toe. Moenie gebruik as die seël bo-op die bottelopening geskeur of weg is nie. HOU BUITE BEREIK VAN KINDERS.REGISTRASIENOMMER:44/20.2.8/0780NAAM EN BESIGHEIDSADRES VAN DIE HOUER VAN DIE SERTIFIKAAT VAN REGISTRASIE:CIPLA LIFE SCIENCES (EDMS) BPKGebou 9, Parc du Cap,Mispel Straat, Bellville, 7530, RSA.Tel. (021) 943 4200.Kliëntediens: 080 222 6662

Bemark en versprei deur: Legacy Pharmaceuticals Manufacturers (Pty) LimitedUnit 6, Building A2, Wild Fig Office Park,Cranberry Road, Laser Park, Honeydew, 2170.

DATUM VAN PUBLIKASIE VAN HIERDIE VOUBILJET:9 Februarie 2012© CIPLA LIFE SCIENCES (EDMS) BPK

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SCHEDULING STATUS: S4PROPRIETARY NAME (AND DOSAGE FORM):

TRENVIR (Tablets)COMPOSITION:Each film-coated tablet contains emtricitabine 200 mg, tenofovir disoproxil fumarate 300 mg and efavirenz 600 mg.Inactive ingredients include croscarmellose sodium, red oxide of iron, microcrystalline cellulose, hypromellose, corn starch, magnesium stearate, sodium lauryl sulphate, hydroxyl propyl cellulose, opadry pink, and opadry brown.WARNING:THERE HAVE BEEN REPORTS OF LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, IN SOME CASES RESULTING IN DEATH, WITH THE USE OF NUCLEOSIDE ANALOGUES ALONE OR IN COMBINATION WITH OTHER ANTIRETROVIRALS (SEE "WARNINGS"). TRENVIR IS NOT INDICATED FOR THE TREATMENT OF CHRONIC INFECTION WITH THE HEPATITIS B VIRUS (HBV). THE SAFETY AND EFFICACY OF TRENVIR HAVE NOT BEEN ESTABLISHED IN PATIENTS WITH HBV AND HIV CO-INFECTION. SEVERE ACUTE EXACERBATIONS OF HEPATITIS B INFECTION HAVE BEEN REPORTED IN INDIVIDUALS WHO HAVE DISCONTINUED EMTRICITABINE (200 mg) OR TENOFOVIR. PATIENTS WITH HIV AND HBV CO-INFECTION WHO DISCONTINUE TRENVIR REQUIRE CLOSE MONITORING OF THEIR HEPATIC FUNCTION FOR AT LEAST SEVERAL MONTHS; THIS SHOULD INCLUDE BOTH CLINICAL AND LABORATORY FOLLOW-UP. APPROPRIATE INITIATION OF ANTI-HEPATITIS B THERAPY MAY BE NECESSARY (SEE "WARNINGS").

PHARMACOLOGICAL CLASSIFICATION:A 20.2.8 Antimicrobial (chemotherapeutic) agents. Antiviral agents.PHARMACOLOGICAL ACTION:Mechanism of action:Emtricitabine: Emtricitabine, a NRTI, is a synthetic nucleoside analogue of cytidine. Cellular enzymes phosphorylate emtricitabine to emtricitabine 5'-triphosphate. Emtricitabine 5'-triphosphate competes with the natural substrate, deoxycytidine 5'-triphosphate, and is incorporated into nascent viral DNA leading to chain termination. Thus the activity of HIV-1 reverse transcriptase (RT) is inhibited. Emtricitabine 5'-triphosphate weakly inhibits mammalian DNA polymerase α, β, ε and mitochondrial DNA polymerase γ.Tenofovir disoproxil fumarate: Tenofovir disoproxil fumarate, a NRTI, also known as tenofovir DF, an acyclic nucleoside phosphonate diester analogue of adenosine monophosphate, requires initial diester hydrolysis for conversion to tenofovir. Cellular enzymes are responsible for subsequent phosphorylations to form tenofovir diphosphate. Tenofovir diphosphate inhibits the activity of HIV-1 RT through competition with the natural substrate deoxyadenosine 5'-triphosphate. After incorporation into DNA, the DNA chain is terminated. Tenofovir diphosphate weakly inhibits mammalian DNA polymerases α, β, and mitochondrial DNA polymerase γ.Efavirenz:Efavirenz, a selective non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1, diffuses into the cell where it binds adjacent to the active site of reverse transcriptase. Thus a conformational change in the enzyme is produced and its function is inhibited. Efavirenz is a non-competitive inhibitor of HIV-1 reverse transcriptase (RT) with respect to template, primer or nucleoside triphosphates, with a small component of competitive inhibition. Efavirenz does not inhibit HIV-2 RT and human cellular DNA polymerases alpha, beta, gamma and delta.Pharmacodynamics:Antiviral activity:Emtricitabine and tenofovir disoproxil fumarate: In combination studies that evaluated the in vitro antiviral activity of emtricitabine and tenofovir collectively, synergistic antiviral effects were observed. Emtricitabine: Lymphoblastoid cell lines, the MAGI-CCR5 cell line, and peripheral blood mononuclear cells were used to assess the in vitro activity of emtricitabine against laboratory and clinical isolates of HIV. The IC50 (50 % inhibitory concentration) values for emtricitabine were in the range of 0,0013 – 0,64 μM (0,0003 – 0,158 μg/ml). Medicine combination studies of emtricitabine with nucleoside reverse transcriptase inhibitors (abacavir, lamivudine, stavudine, zalcitabine, zidovudine), non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, nevirapine), and protease inhibitors (amprenavir, nelfinavir, ritonavir, saquinavir) demonstrated additive to synergistic effects. The majority of these medicine combinations have not been studied in humans. Emtricitabine exhibits antiviral activity in vitro against HIV-1 clades A, B, C, D, E, F and G (IC50 values ranged from 0,007 – 0,075 μM) and demonstrated strain specific activity against HIV-2 (IC50 values ranged from 0,007 – 1,5 μM).Tenofovir disoproxil fumarate: Lymphoblastoid cell lines, primary monocyte/macrophage cells and peripheral blood lymphocytes were used to assess the in vitro antiviral activity of tenofovir against laboratory and clinical isolates of HIV-1. The IC50 values for tenofovir ranged from 0,04 – 8,5 μM. Medicine combination studies of tenofovir with nucleoside reverse transcriptase inhibitors (abacavir, didanosine, lamivudine, stavudine, zalcitabine, zidovudine), non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, nevirapine), and protease inhibitors (amprenavir, indinavir, nelfinavir, ritonavir, saquinavir) demonstrated additive to synergistic effects. Tenofovir exhibits antiviral activity in vitro against HIV-1 clades A, B, C, D, E, F, G and O (IC50 values ranged from 0,5 – 2,2 μM). The IC50 values of tenofovir against HIV-2 were in the range of 1,6 μM to 4,9 μM.Efavirenz:The clinical significance of in vitro susceptibility of HIV-1 to efavirenz has not been established. Lymphoblastoid cell lines, peripheral blood mononuclear cells (PBMCs) and macrophage/monocyte cultures enriched from PBMCs were used to assess the in vitro antiviral activity of efavirenz. The 90 to 95 % inhibitory concentration (IC90-95) of efavirenz for wild type, laboratory adapted strains and clinical isolates were in the range of 1,7 to 25  nM. Efavirenz displayed synergistic activity in cell culture in combination with the nucleoside analogue reverse transcriptase inhibitors (NRTIs), zidovudine (ZDV) or didanosine (ddI), or the protease inhibitor, indinavir (IDV).Drug resistance:Emtricitabine and tenofovir disoproxil fumarate: HIV-1 isolates demonstrating reduced susceptibility to the emtricitabine and tenofovir combination have been selected in vitro. Following genotypic analysis, the M184V/I and/or K65R amino acid substitutions were identified in the viral RT.Emtricitabine: HIV isolates resistant to emtricitabine have been selected in vitro. Genotypic analysis of these isolates demonstrated that reduced emtricitabine susceptibility was associated with a mutation in the HIV RT gene at codon 184. This mutation caused an amino acid substitution of methionine by valine or isoleucine (M184V/I).HIV isolates resistant to emtricitabine have also been recovered from some patients who received therapy with emtricitabine alone or in combination with other antiretroviral medicines. Genotypic analysis of these isolates demonstrated that the resistance was caused by M184V/I mutations in the HIV RT gene. Tenofovir disoproxil fumarate: Isolates of HIV-1 that exhibited reduced susceptibility to tenofovir have been selected in vitro. These viruses expressed a K65R mutation in reverse transcriptase and demonstrated a reduced susceptibility to tenofovir of between 2- and 4-fold.Tenofovir-resistant HIV-1 strains have also been isolated from some patients who received tenofovir in combination with certain antiretroviral medicines. Genotypic analysis of the resistant isolates revealed a mutation in the HIV-1 reverse transcriptase gene that gave rise to the K65R amino acid substitution.Efavirenz:Isolates of HIV-1 that demonstrate reduced susceptibility to efavirenz (greater than 380-fold increase in IC90) compared to baseline can emerge in vitro. Phenotypic changes in evaluable HIV-1 isolates and genotypic changes in plasma virus from selected individuals who received therapy with efavirenz in combination with IDV or with ZDV plus lamivudine were monitored. One or more RT mutations at amino acid positions 100, 101, 103, 108, 190 and 225 were noted in all 62 patients with a frequency of at least 10 % compared to baseline. The most frequently observed mutation (greater or equal to 90 %) was the mutation at RT amino acid position 103 (lysine to asparagine). Twenty-six clinical isolates demonstrated a 47-fold mean loss in susceptibility (IC90) to efavirenz. Five clinical isolates were assessed for both genotypic and phenotypic changes from baseline. Decreases in susceptibility to efavirenz (range from 9- to greater than 312-fold increase in IC90) were seen for these isolates in vitro compared to baseline. All 5 isolates possessed at least one of the efavirenz-associated RT mutations. The clinical relevance of phenotypic and genotypic changes associated with efavirenz treatment has not been established.Cross-resistance:Emtricitabine and tenofovir disoproxil fumarate: It is known that cross-resistance may develop among certain nucleoside reverse transcriptase inhibitors (NRTIs). The M184V/I and/or K65R substitutions selected in vitro by the combination of emtricitabine and tenofovir are also seen in some HIV-1 strains isolated from individuals failing treatment with tenofovir in combination with either lamivudine or emtricitabine, and either abacavir or didanosine. Cross-resistance among these agents may therefore develop in patients whose virus harbours either or both of these amino acid substitutions.Emtricitabine: While emtricitabine-resistant isolates (M184V/I) demonstrated cross-resistance to lamivudine and zalcitabine, these isolates retained susceptibility in vitro to didanosine, stavudine, tenofovir, zidovudine, and NNRTIs (delavirdine, efavirenz, and nevirapine). HIV strains isolated from heavily treatment-experienced patients containing the M184V/l amino acid substitution in the context of other NRTI substitutions associated with resistance may remain susceptible to tenofovir. HIV-1 isolates harbouring the K65R substitution, selected in vivo by abacavir, didanosine, tenofovir, and zalcitabine, showed reduced susceptibility to inhibition by emtricitabine. Viruses containing mutations that made them less susceptible to stavudine and zidovudine (M41L, D67N, K70R, L210W, T215Y/F, K219Q/E) or didanosine (L74V) remained sensitive to emtricitabine. HIV-1 viral isolates harbouring the K103N substitution that is associated with resistance to NNRTIs were susceptible to emtricitabine.Tenofovir disoproxil fumarate: HIV-1 isolates from subjects whose HIV-1 expressed an average of 3 zidovudine-associated amino acid substitutions in reverse transcriptase (M41L, D67N, K70R, L210W, T215Y/F or K219Q/E/N) demonstrated a reduced susceptibility to tenofovir. HIV-1 with multinucleoside resistance with a T69S double insertion mutation in the RT demonstrated reduced susceptibility to tenofovir.Efavirenz:HIV-1 strains that are cross-resistant to non-nucleoside RT inhibitors emerge rapidly in vitro. Clinical isolates formerly characterised as efavirenz-resistant were also phenotypically resistant to nevirapine and delavirdine in vitro in comparison to baseline. Clinically derived ZDV-resistant HIV-1 strains isolated and tested in vitro remained susceptible to efavirenz. Cross-resistance is unlikely to develop between efavirenz and HIV protease inhibitors due to the different enzyme targets involved.Pharmacokinetics:Adults:Emtricitabine: Subsequent to oral administration of emtricitabine (200 mg), emtricitabine is rapidly absorbed. Peak plasma concentrations are reached 1 – 2 hours post-dose. Binding of emtricitabine to human plasma proteins in vitro is less than 4 % and is independent of concentration over the range of 0,02 – 200 µg/ml. Median (range) oral bioavailability of emtricitabine under fasting conditions is 92  % (83,1 – 106,4 %). At steady state mean (± SD) Cmax (maximum plasma concentration) of emtricitabine is 1,8 ± 0,72 μg/ml, while mean (± SD) AUC at steady state is 10,0 ± 3,12 μg.hr/ml.Approximately 86  % of radiolabeled emtricitabine is recovered in the urine and 13  % is recovered as metabolites. Emtricitabine metabolites include 3'-sulphoxide diastereomers and their glucuronic acid conjugate. Elimination of emtricitabine is via a combination of glomerular filtration and active tubular secretion. Emtricitabine displays a plasma half-life of approximately 10 hours following a single oral dose (200 mg).Tenofovir disoproxil fumarate: Subsequent to oral administration of tenofovir, it takes 1,0 ± 0,4 hours to reach maximum tenofovir serum concentrations. Binding of tenofovir to human plasma proteins in vitro is less than 0,7 %. This is not dependent on concentration over the range of 0,01 – 25 µg/ml. Median (range) oral bioavailability of tenofovir under fasting conditions is 25 % (Not calculated [NC] – 45 %). Tenofovir has a mean (± SD) Cmax of 0,30 ± 0,09 μg/ml and mean (± SD) AUC of 2,29 ± 0,69 μg.hr/ml.Following intravenous administration of tenofovir approximately 70 – 80 % of the dose is recovered unchanged in the urine. Elimination of tenofovir is through a combination of glomerular filtration and active tubular secretion. Tenofovir has a terminal elimination half-life of approximately 17 hours following a single oral dose.Effects of food on oral absorption:A fixed dose combination tablet of emtricitabine and tenofovir may be taken with or without food. Time to tenofovir Cmax was delayed by approximately 0,75 hours following administration of the combination tablet with a high fat meal or a light meal. Compared to administration under fasting conditions, administration with a high fat or light meal resulted in mean increases in tenofovir AUC and Cmax of approximately 35 % and 15 %, respectively. In previous safety and efficacy studies, tenofovir was administered under fed conditions. Emtricitabine systemic exposures (AUC and Cmax) remained unchanged when the combination tablet was taken with either a high fat or a light meal.Efavirenz:Absorption: Peak efavirenz plasma concentrations of 1,6 – 9,1 μM are reached by 5 hours following single oral doses of 100 mg to 1600 mg given to uninfected volunteers. Although dose-related increases in Cmax and AUC are seen for doses up to 1600 mg, these increases are less than proportional, indicating diminished absorption at higher doses. Steady state plasma concentrations are reached in 6 to 7 days.Distribution: Efavirenz is very highly plasma protein bound (approximately 99,5 – 99,75  %) and predominantly to albumin. Cerebrospinal fluid concentrations ranged from 0,26 to 1,19 % (mean 0,69 %) of the corresponding plasma concentrations in HIV-1 infected individuals administered 200 to 600 mg efavirenz once daily for at least one month. This is about three times higher than the non-protein-bound (free) fraction of efavirenz in plasma. Metabolism: Efavirenz is principally metabolised by the cytochrome P450 system to hydroxylated metabolites. These hydroxylated metabolites subsequently undergo glucuronidation. The metabolites are not active against HIV-1. CYP3A4 and CYP2B6 are the major isozymes involved in efavirenz metabolism. Efavirenz, through induction of P450 enzymes, induces its own metabolism.Elimination: Efavirenz has a long terminal half-life of 52 – 76 hours and 40 – 55 hours after single and multiple doses, respectively. Subsequent to the administration of a radio-labelled dose, 14 – 34 % of efavirenz is recovered in the urine and 16 – 61 % is recovered in the faeces, mainly in the form of metabolites.Special populations:Gender:Emtricitabine and tenofovir pharmacokinetic properties are similar in male and female patients. Pharmacokinetic characteristics of efavirenz in patients appear to be similar between men and women.

Paediatric and geriatric patients: Emtricitabine and tenofovir disoproxil fumarate:Emtricitabine and tenofovir pharmacokinetics have not been evaluated in children < 18 years or in the elderly (> 65 years) (see "Special Precautions"). Efavirenz:Pharmacokinetics of efavirenz have not been studied in subjects aged 65 and over to determine whether they respond differently. The pharmacokinetic properties of efavirenz in paediatric patients are similar to those in adults.Patients with impaired renal function: Emtricitabine and tenofovir disoproxil fumarate:The pharmacokinetic properties of emtricitabine and tenofovir are altered in patients with impairment of kidney function (see "WARNINGS"). The Cmax and AUC0−∞ of emtricitabine and tenofovir are increased in patients with creatinine clearance < 50 ml/min. The dosing interval for the combination tablet should be modified in patients with creatinine clearance 30 – 49 ml/min. Since this is not possible with a fixed dose combination, such a combination should not be administered to patients with creatinine clearance < 50 ml/min and in patients with end-stage renal disease requiring dialysis (see "CONTRA-INDICATIONS", "WARNINGS" and "DOSAGE AND DIRECTIONS FOR USE"). Efavirenz:The pharmacokinetic properties of efavirenz have not been studied in patients with renal insufficiency. However, since less than 1  % of efavirenz is excreted unchanged in the urine, the impact of impaired renal function on efavirenz elimination should be minimal.Patients with hepatic impairment: Emtricitabine and tenofovir disoproxil fumarate:The pharmacokinetic properties of tenofovir following a 300  mg dose of tenofovir disoproxil fumarate have been evaluated in non-HIV infected individuals with moderate to severe impairment of liver function. Tenofovir pharmacokinetics were not substantially altered in patients with hepatic impairment compared with unimpaired patients. Pharmacokinetic properties of emtricitabine or a fixed dose combination of emtricitabine and tenofovir have not been studied in patients with hepatic impairment. Since emtricitabine is not metabolised by liver enzymes to a significant extent, the impact of liver impairment should be limited.Efavirenz:Efavirenz pharmacokinetics have not been adequately studied in patients with impaired hepatic function.INDICATIONS:TRENVIR is indicated for the treatment of HIV-1 infection in adults. CONTRA-INDICATIONS:TRENVIR is contra-indicated in patients:

• Who previously demonstrated hypersensitivity to emtricitabine, tenofovir or efavirenz or any of the other components of the product.

• With moderate to severe impairment of renal function (creatinine clearance < 50 ml/min) (see "WARNINGS" and "DOSAGE AND DIRECTIONS FOR USE").

• Who are pregnant or breast feeding (see "PREGNANCY AND LACTATION").• Who are concurrently receiving treatment with astemizole, cisapride, midazolam, triazolam or ergot derivatives,

because competition for CYP3A4 by the efavirenz in TRENVIR could result in inhibition of the metabolism of these medicines and create the potential for serious and/or life-threatening adverse events (e.g., cardiac dysrhythmias, prolonged sedation or respiratory depression).

• Younger than 18 years of age due to lack of data on safety and efficacy.• With severe hepatic impairment.• Who are concurrently using voriconazole, since efavirenz significantly decreases voriconazole plasma

concentrations, while voriconazole significantly increases efavirenz plasma concentrations. Since TRENVIR is a fixed-dose combination product, the dose of efavirenz cannot be altered; therefore voriconazole and TRENVIR must not be co-administered.

• Who concomitantly take other medicinal products containing any of the components (efavirenz, emtricitabine or tenofovir) or who concomitantly take other cytidine analogues, such as lamivudine, and adefovir dipivoxil.

WARNINGS:ALERT: Find out about medicines that should NOT be taken with TRENVIR (see "CONTRA-INDICATIONS", "INTERACTIONS" and "SIDE-EFFECTS AND SPECIAL PRECAUTIONS").Serious nervous system and psychiatric symptoms have been reported with efavirenz, one of the active ingredients in TRENVIR.Lactic acidosis / Severe hepatomegaly with steatosis:Lactic acidosis and severe hepatomegaly with steatosis, which were fatal in some instances, have been reported with the administration of nucleoside analogues, such as contained in TRENVIR, alone or in combination with other antiretroviral agents. Most of these cases have been in women. Possible risk factors include obesity and prolonged nucleoside exposure. Particular caution is required when TRENVIR is administered to any patient with known risk factors for hepatic disease; however, such complications have also been reported in patients without known risk factors. Suspend treatment with TRENVIR in any patient who develops clinical or laboratory findings indicative of lactic acidosis or pronounced hepatotoxicity (which may include enlargement of the liver and steatosis even in the absence of marked transaminase elevations). Patients with HIV and hepatitis B virus co-infection:It is recommended that all patients with HIV be tested for the presence of hepatitis B virus (HBV) prior to the initiation of therapy with antiretroviral agents. TRENVIR is not indicated for the treatment of chronic HBV infection. The safety and efficacy of TRENVIR have not been confirmed in patients with HBV and HIV co-infection. Severe acute exacerbations of hepatitis B have occurred in patients following the discontinuation of emtricitabine (200 mg) and tenofovir disoproxil fumarate. Patients with HBV and HIV co-infection who discontinue TRENVIR require close monitoring of their hepatic function for at least several months; this should include both clinical and laboratory follow-up. Appropriate initiation of anti-hepatitis B therapy may be necessary. Renal impairment:Emtricitabine and tenofovir, two of the active ingredients in TRENVIR, are principally eliminated by the kidney. Dosing interval adjustment of emtricitabine and tenofovir is recommended in all patients with creatinine clearance 30 – 49 ml/min. Since this is not possible with a fixed dose combination, TRENVIR should not be administered to patients with creatinine clearance < 50 ml/min or patients requiring haemodialysis (see "DOSAGE AND DIRECTIONS FOR USE"). There have been reports of impairment of renal function which included cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphataemia) in association with the use of tenofovir (see "Side-Effects"). Most of these cases developed in patients with underlying systemic or renal disease, or in patients who received nephrotoxic agents. However, some of these complications occurred in patients without any identifiable risk factors.The use of TRENVIR should be avoided in patients who are concurrently taking or who have recently taken a nephrotoxic agent. Careful monitoring for changes in serum creatinine and phosphorus are necessary in patients at risk for, or with a history of, renal dysfunction as well as in patients receiving concomitant nephrotoxic agents. INTERACTIONS:General interactions:No interaction studies have been conducted using TRENVIR tablets. As TRENVIR contains efavirenz, emtricitabine and tenofovir, any interactions that have been identified with these agents individually may occur with TRENVIR. Interaction studies with these agents have only been performed in adults.As a fixed combination, TRENVIR should not be given concomitantly with other medicinal products containing any of the components, efavirenz, emtricitabine or tenofovir, concomitantly with other cytidine analogues, such as lamivudine, and adefovir dipivoxil (see "CONTRA-INDICATIONS").TRENVIR must not be co-administered with terfenadine, astemizole, cisapride, midazolam, triazolam, pimozide, bepridil, or ergot alkaloids, since inhibition of their metabolism may lead to serious, life-threatening events (see "CONTRA-INDICATIONS").The steady state pharmacokinetic properties of emtricitabine and tenofovir remained unchanged when emtricitabine and tenofovir disoproxil fumarate were administered together versus each agent given alone. No clinically significant interactions have been noted between emtricitabine and tenofovir. Co-administration of tenofovir disoproxil fumarate 300 mg once daily for 7 days with emtricitabine, 200 mg once daily for 7 days, caused no changes in the Cmax or AUC of emtricitabine. However, Cmin of emtricitabine increased by 20 % [90 % confidence interval (CI) +12 % to +29 %]. The Cmax, AUC and Cmin of tenofovir were unchanged.In vitro and clinical pharmacokinetic drug-drug interaction studies have demonstrated the potential for CYP450 mediated interactions involving emtricitabine and tenofovir, two of the active ingredients in TRENVIR, with other medicinal products is low. The kidneys are primarily responsible for the excretion of emtricitabine and tenofovir through a combination of glomerular filtration and active tubular secretion. Although no interactions due to competition for renal excretion have been observed, it is possible that, when TRENVIR is co-administered with medicines that are eliminated by active tubular secretion, the concentrations of emtricitabine, tenofovir and/or the concomitant medicine may increase.Medicines that reduce renal function may increase emtricitabine and/or tenofovir concentrations. The efavirenz in TRENVIR induces CYP3A4. Other compounds that are substrates of CYP3A4 may have decreased plasma concentrations when administered concurrently with TRENVIR.No clinically significant drug interactions were demonstrated for tenofovir disoproxil fumarate and efavirenz. Concomitant administration of efavirenz 600 mg once daily for 14 days with tenofovir 300 mg once daily did not result in any changes in the Cmax, Cmin or AUC of either efavirenz or tenofovir.Abacavir:No clinically significant drug interactions have been observed between tenofovir disoproxil fumarate, one of the active ingredients in TRENVIR, and abacavir. Co-administration of a single dose of abacavir 300 mg with tenofovir 300 mg caused no changes in the Cmax or AUC of tenofovir. However, Cmax of abacavir increased by 12 % (90 % CI -1 % to +26 %), while the AUC remained unchanged.Adefovir dipivoxil:No clinically significant drug interactions have been observed between tenofovir disoproxil fumarate, one of the active ingredients in TRENVIR, and adefovir dipivoxil. Concomitant administration of a single dose of adefovir dipivoxil 10 mg with tenofovir 300 mg did not result in any changes in the Cmax, Cmin or AUC of tenofovir nor in the Cmax or AUC of adefovir dipivoxil.TRENVIR should, however, not be administered concomitantly with adefovir dipivoxil due to the increased risk of renal toxicity.Amprenavir:Co-administration of amprenavir/ritonavir and TRENVIR is not recommended, as efavirenz reduces the Cmax, Cmin and AUC of amprenavir by 40 %.Atazanavir:Co-administration of atazanavir 400 mg once daily for 14 days with tenofovir 300 mg once daily resulted in a 14 % increase (90 % CI +8 % to +20 %) in tenofovir Cmax, 24 % increase (+21 % to +28 %) in tenofovir AUC and 22 % increase (+15 % to +30 %) in tenofovir Cmin. Corresponding parameters for atazanavir showed a 21 % decrease (-27 % to -14 %) in Cmax, 25 % decrease (-30 % to -19 %) in AUC and 40 % decrease (-48 % to -32 %) in Cmin. In HIV-infected patients, addition of tenofovir disoproxil fumarate to atazanavir 300 mg plus ritonavir 100 mg, resulted in AUC and Cmin values of atazanavir that were 2,3- and 4-fold higher than the respective values observed for atazanavir 400 mg when given alone.Co-administration of atazanavir/ritonavir with tenofovir resulted in increased exposure to tenofovir. Higher tenofovir concentrations could potentiate tenofovir-associated adverse events, including renal disorders. Co-administration of efavirenz with atazanavir in combination with low-dose ritonavir resulted in substantial decreases in atazanavir exposure due to CYP3A4 induction, necessitating dosage adjustment of atazanavir. Co-administration of efavirenz and atazanavir in combination with ritonavir may lead to increases in efavirenz exposure which may worsen the tolerability profile of efavirenz. Insufficient data are available to make a dosing recommendation for atazanavir/ritonavir in combination with TRENVIR. Therefore co-administration of atazanavir/ritonavir and TRENVIR is not recommended.Calcium channel blockers:When efavirenz is given concomitantly with a calcium channel blocker that is a substrate of the CYP3A4 enzyme, there is a potential for reduction in the plasma concentration of the calcium channel blocker. Dose adjustments of diltiazem and other calcium channel blockers (such as verapamil, felodipine, nifedipine and nicardipine) when co-administered with TRENVIR should be guided by clinical response.Cannabinoid test interaction: Efavirenz does not occupy cannabinoid receptors. False positive urine cannabinoid test results have been reported in uninfected volunteers who took efavirenz and are therefore possible with TRENVIR administration. False positive test results due to efavirenz have only been seen with the CEDIA DAU Multi-Level THC assay, which is used for screening, and have not been observed with other cannabinoid assays tested – these included tests used for confirmation of positive results.Carbamazepine:Co-administration of carbamazepine with efavirenz decreased carbamazepine AUC, Cmax and Cmin by 27 % (90 % CI -20  % to -33  %), 20  % (-15  % to -24  %), and 35  % (-24  % to -44  %), respectively, due to CYP3A4 induction. Corresponding decreases in efavirenz AUC, Cmax and Cmin (due to CYP3A4 and CYP2B6 induction) were 36 % (-32 % to -40 %), 21 % (-15 % to -26 %), and 47 % (-41 % to -53 %), respectively. No dose recommendation can be made for the use of TRENVIR with carbamazepine. An alternative anticonvulsant should be considered. Carbamazepine plasma levels should be monitored periodically.Clarithromycin: Co-administration of 400 mg of efavirenz once daily with clarithromycin given as 500 mg every 12 hours for seven days resulted in a significant effect of efavirenz on the pharmacokinetics of clarithromycin. The AUC and Cmax of clarithromycin decreased by 39 % and 26 %, respectively, while the AUC and Cmax of the active clarithromycin hydroxymetabolite were increased by 34 % and 49 %, respectively, when used in combination with efavirenz. The clinical significance of these changes in clarithromycin plasma levels is not known. Forty-six (46) percent of uninfected volunteers who took efavirenz and clarithromycin developed a rash. No dose adjustment of efavirenz is recommended when administered with clarithromycin; however, alternatives to clarithromycin should be considered.Other antibiotics belonging to the macrolide class, such as erythromycin, have not been studied in combination with TRENVIR.Didanosine:Concomitant administration of a single dose of enteric-coated didanosine 400 mg with tenofovir 300 mg did not result in any changes in the Cmax, Cmin or AUC of tenofovir. The same holds true for the combination of buffered didanosine 250 or 400 mg once daily for 7 days with tenofovir 300 mg once daily. When administered with multiple doses of tenofovir, the Cmax and AUC of didanosine 400 mg increased significantly. The mechanism of this interaction is unknown. When didanosine 250 mg enteric-coated capsules were administered with tenofovir systemic exposures to didanosine were similar to those seen with the 400 mg enteric-coated capsules alone under fasted conditions.

For a detailed summary of the changes in pharmacokinetic parameters for didanosine, please refer to the table below.Table 1: Drug interactions: Pharmacokinetic parameters for didanosine in the presence of tenofovir as in TRENVIR.

gm 004 enisonadid .sv )IC % 09( ecnereffiD % fo dohtem rivofoneT /)gm( esod enisonadiD noitartsinimda fo dohteM 1 administration1 N alone, fasted2

Cmax AUC Buffered tablets

400 once daily3 Fasted 1 hour after 14 ↑28 ↑44 X 7 days didanosine (↑11 - ↑48) (↑31 - ↑59) Enteric-coated tablets

400 once, fasted With food, 2 hrs after 26 ↑48 ↑48 didanosine (↑25 - ↑76) (↑31 - ↑67) 400 once, with food Simultaneously with 26 ↑64 ↑60

didanosine (↑41 - ↑89) (↑44 - ↑79) 250 once, fasted With food, 2 hrs after 28 ↓10 ↔ didanosine (↓22 - ↑3) 250 once, fasted Simultaneously with 28 ↔ ↑14 didanosine (0 - ↑31) 250 once, with food Simultaneously with 28 ↓29 ↓11 didanosine (↓39 - ↓18) (↓23 - ↑2) 1. Administration with food was with a light meal. 2. ↑ = increase; ↓ = decrease; ↔ = no difference. 3. Includes 4 subjects weighing < 60 kg receiving ddI 250 mg.Co-administration of tenofovir disoproxil fumarate and didanosine results in a 40  % to 60  % increase in systemic exposure to didanosine that may increase the risk for didanosine-related adverse events. Cases of pancreatitis and lactic acidosis, sometimes fatal, have been reported. Co-administration of tenofovir disoproxil fumarate and didanosine at a dose of 400 mg daily has been associated with a significant decrease in CD4 cell count, possibly due to an intracellular interaction increasing phosphorylated (i.e. active) didanosine. A decreased dosage of 250 mg didanosine co-administered with tenofovir disoproxil fumarate therapy has been associated with reports of high rates of virologic failure within several tested combinations. Co-administration of TRENVIR and didanosine is not recommended.Famciclovir:No clinically significant drug interactions have been observed between emtricitabine, one of the active ingredients in TRENVIR, and famciclovir. Co-administration of a single dose of famciclovir 500 mg with a single dose of emtricitabine 200 mg did not alter the Cmax or AUC of emtricitabine or famciclovir.HMG Co-A reductase inhibitors:Co-administration of efavirenz with HMG Co-A reductase inhibitors, such as atorvastatin and pravastatin, led to decreases in the AUC and Cmax of the HMG Co-A reductase inhibitors and their active metabolites. Cholesterol levels should be periodically monitored when atorvastatin, pravastatin, or simvastatin is co-administered with TRENVIR. Dosage adjustments of statins may be required.Immunosuppressants:Co-administration of tacrolimus with emtricitabine or tenofovir disoproxil fumarate did not result in any changes in the AUC, Cmax or Cmin of tacrolimus, emtricitabine or tenofovir disoproxil fumarate. Although the interaction between efavirenz and tacrolimus has not been studied, decreased exposure of tacrolimus may be expected due to CYP3A4 induction. Tacrolimus is not anticipated to impact exposure of efavirenz. Dose adjustments of tacrolimus may be required. Close monitoring of tacrolimus concentrations for at least two weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with TRENVIR.Indinavir:No clinically significant drug interactions have been observed between the emtricitabine in TRENVIR and indinavir. Co-administration of a single dose of indinavir 800 mg with a single dose of emtricitabine 200 mg did not alter the Cmax or AUC of emtricitabine or indinavir.Similarly, no clinically significant drug interactions have been observed between tenofovir disoproxil fumarate, one of the active ingredients in TRENVIR, and indinavir. There was a 14 % increase (90 % CI -3 % to +33 %) in the Cmax of tenofovir when indinavir 800 mg three times daily for 7 days was co-administered with tenofovir 300 mg once daily. The Cmin and AUC of tenofovir remained unchanged as did the Cmin and AUC of indinavir. Indinavir Cmax decreased by 11 % (-30 % to +12 %).When indinavir (800 mg every 8 hours) was administered with efavirenz (200 mg every 24 hours), the indinavir AUC and Ctrough were decreased by approximately 31 % and 16 %, respectively, due to enzyme induction. Insufficient data are available to make a dosing recommendation for indinavir when dosed with TRENVIR. While the clinical significance of decreased indinavir concentrations has not been established, the magnitude of the observed pharmacokinetic interaction should be taken into consideration when choosing a regimen containing both efavirenz, a component of TRENVIR, and indinavir.Itraconazole:Co-administration of itraconazole and efavirenz resulted in decreased itraconazole AUC, Cmax and Cmin due to CYP3A4 induction. No dose recommendations can be made for the use of TRENVIR in combination with itraconazole. An alternative antifungal treatment should be considered.Interaction studies with TRENVIR and ketoconazole have not been conducted. Efavirenz has the potential to decrease plasma concentrations of ketoconazole.Lamivudine:No clinically significant drug interactions have been observed between the tenofovir disoproxil fumarate in TRENVIR and lamivudine. Co-administration of lamivudine 150 mg twice daily for 7 days with tenofovir 300 mg once daily did not result in any changes in the Cmax, Cmin or AUC of tenofovir. While the Cmin and AUC of lamivudine were unchanged, the Cmax decreased by 24 % (-34 % to -12 %).Due to similarities with emtricitabine, TRENVIR should not be administered concomitantly with other cytidine analogues, such as lamivudine.Lopinavir/Ritonavir:No clinically significant drug interactions have been observed between tenofovir disoproxil fumarate, one of the active ingredients in TRENVIR, and lopinavir/ritonavir. Co-administration of a combination of lopinavir 400 mg and ritonavir 100 mg twice daily for 14 days with tenofovir 300 mg once daily resulted in a 32 % increase (90 % CI +26 % to +38 %) in tenofovir AUC and 29 % increase (+23 % to +66 %) in tenofovir Cmin, while tenofovir Cmax remained unchanged. There were no changes in Cmax, Cmin or AUC of lopinavir and ritonavir. Higher tenofovir concentrations could potentiate tenofovir-associated adverse events, including renal disorders.When efavirenz 600 mg (administered once daily at bedtime) and ritonavir 500 mg (administered every 12 hours) were studied in uninfected volunteers, the combination was not well tolerated. The combination was associated with a higher frequency of adverse clinical events (for example dizziness, nausea, paraesthesia, and elevated liver enzymes). Liver enzymes should be monitored when efavirenz is used in combination with ritonavir.Co-administration of lopinavir/ritonavir with efavirenz resulted in a substantial decrease in lopinavir exposure, necessitating dosage adjustment of lopinavir/ritonavir. Insufficient data are available to make a dosing recommendation for lopinavir/ritonavir when dosed with TRENVIR. Co-administration of lopinavir/ritonavir and TRENVIR is not recommended.Methadone:No clinically significant drug interactions have been identified between the tenofovir disoproxil fumarate in TRENVIR and methadone. Following multiple dosing to HIV-negative individuals receiving chronic methadone maintenance therapy, steady state tenofovir pharmacokinetic properties were similar to those observed in previous studies, indicating lack of clinically significant drug interactions between methadone and the tenofovir in TRENVIR.Specifically, when methadone 40 – 110 mg once daily for 14 days was given concomitantly with tenofovir 300 mg once daily, R-(active), S- and total methadone exposures were similar when dosed alone or with tenofovir. Individual patients were maintained on their stable methadone dose. There were no reports of pharmacodynamic alterations, such as opiate toxicity or withdrawal signs or symptoms.However, concomitant administration of efavirenz with methadone, in HIV-infected IV drug users, resulted in decreased plasma concentrations of methadone and signs of opiate withdrawal. Increasing the methadone dose by a mean of 22  % alleviated withdrawal symptoms. Patients require monitoring for signs of withdrawal and their methadone dose should be increased as required to alleviate withdrawal symptoms.Oral contraceptives:No clinically significant drug interactions have been observed between the tenofovir disoproxil fumarate in TRENVIR and oral contraceptives. Following multiple dosing to HIV-negative subjects taking oral contraceptives, steady state tenofovir pharmacokinetics were comparable to those observed in previous studies, indicating lack of clinically significant drug interactions between these agents and the tenofovir in TRENVIR. In terms of possible interactions with efavirenz, only the ethinyloestradiol component of oral contraceptives has been studied. After multiple dosing with efavirenz, the AUC of a single dose ethinyloestradiol was increased (37 %). The Cmax of ethinyloestradiol was not significantly changed. It is not known whether these effects are clinically significant. A single dose of ethinyloestradiol appeared to have no effect on efavirenz Cmax or AUC. Since the potential interaction between TRENVIR and oral contraceptive agents has not been fully characterised, patients should employ a reliable method of barrier contraception in addition to oral contraceptives.Phenytoin, phenobarbital, and other anticonvulsants:Efavirenz may potentially reduce or increase the plasma levels of phenytoin, phenobarbital and other anticonvulsants that are substrates of CYP450 isoenzymes. When TRENVIR is administered concomitantly with an anticonvulsant that is a substrate of CYP450 isoenzymes, periodic monitoring of anticonvulsant concentrations should be performed.TRENVIR and vigabatrin or gabapentin can be given concurrently without dose adjustment. Clinically significant interactions are not expected, because vigabatrin and gabapentin are exclusively eliminated unchanged in the urine and are therefore not likely to compete for the same metabolic enzymes and elimination pathways as efavirenz.Ribavirin:No clinically significant drug interactions have been demonstrated between the tenofovir disoproxil fumarate in TRENVIR and ribavirin. Following multiple dosing to HIV-negative individuals receiving single doses of ribavirin, steady state tenofovir pharmacokinetics were similar to those seen in previous studies, indicating lack of clinically significant drug interactions between ribavirin and the tenofovir in TRENVIR. Rifamycins: With concomitant administration in uninfected volunteers, rifampicin reduced efavirenz AUC by 26 % and Cmax by 20 %. The dose of efavirenz must be increased to 800 mg/day when taken in combination with rifampicin. Therefore, when TRENVIR is co-administered with rifampicin, an additional 200  mg/day of efavirenz is recommended. No dose adjustment of rifampicin is recommended when given with TRENVIR. Concomitant administration of single doses of rifabutin 300 mg and efavirenz 600 mg resulted in decreases of 38 % (90 % CI -28 % to -36 %) in AUC, 32 % (-15 % to -46 %) in Cmax and 45 % (-31 % to -56 %) in Cmin of rifabutin. The AUC and Cmax of efavirenz remained unchanged; however, the Cmin decreased by 12 % (-24 % to -1 %). The daily dose of rifabutin should be increased by 50 % when administered with TRENVIR. Consider doubling the rifabutin dose in regimens where rifabutin is administered 2 to 3 times a week in combination with TRENVIR.Ritonavir:Efavirenz co-administered with ritonavir 500 mg or 600 mg twice daily is not well tolerated (e.g., dizziness, nausea, paraesthesia and elevated liver enzymes may occur). Efavirenz AUC, Cmax and Cmin increased by 21 % (+10 % to +34 %), 14 % (+4 % to +26 %), and 25 % (+7 % to +46 %), respectively. Data on the tolerability of efavirenz with low-dose ritonavir (100 mg, once or twice daily) are not sufficient. Concurrent administration of ritonavir at doses of 600 mg and TRENVIR is not recommended. When using TRENVIR in a regimen including low-dose ritonavir, the possibility of an increase in the incidence of efavirenz-associated adverse events due to a possible pharmacodynamic interaction should be kept in mind.Saquinavir: When saquinavir (1200 mg given 3 times a day, soft gel capsule formulation) was administered with efavirenz, the saquinavir AUC and Cmax were reduced by 62 % and 50 %, respectively, while the efavirenz AUC, Cmax and Cmin were reduced by 12 %, 13 %, and 14 %, respectively. Use of TRENVIR in combination with saquinavir as the sole protease inhibitor is not recommended.Data regarding the potential interactions of efavirenz with the combination of saquinavir and ritonavir are not available. Due to insufficient data it is not possible to make a dosing recommendation for saquinavir/ritonavir when dosed with TRENVIR. Concomitant administration of saquinavir/ritonavir and TRENVIR is therefore not recommended.Selective serotonin reuptake inhibitors (SSRIs):When given in combination with TRENVIR, sertraline dose increases should be guided by clinical response, since concomitant administration of sertraline 50 mg with efavirenz 600 mg resulted in mean decreases in sertraline AUC, Cmax and Cmin of 39 %, 29 %, and 46 %, respectively.Co-administration of TRENVIR and paroxetine does not require dose adjustment. Concomitant administration of efavirenz and paroxetine did not cause any changes in the AUC, Cmax or Cmin of either paroxetine or efavirenz.Co-administration of TRENVIR and fluoxetine does not require dose adjustment, since fluoxetine shares a similar metabolic profile with paroxetine, i.e., strong CYP2D6 inhibitory effect. Therefore, a similar lack of interaction would be expected with fluoxetine.Stavudine:No clinically significant drug interactions have been observed between the emtricitabine in TRENVIR and stavudine. Co-administration of a single dose of stavudine 40 mg with a single dose of emtricitabine 200 mg did not alter the Cmax or AUC of emtricitabine or stavudine.St. John's wort (Hypericum perforatum): Patients taking TRENVIR should not concomitantly use products containing St. John's wort (Hypericum perforatum), since it is expected to reduce plasma levels of efavirenz. This effect occurs because of an induction of CYP3A4 and may lead to loss of therapeutic effect and development of resistance.Voriconazole:Co-administration of standard doses of efavirenz and voriconazole is contra-indicated due to significant increases in the AUC and Cmax of efavirenz and significant decreases in the AUC and Cmax of voriconazole. Since TRENVIR is a fixed-dose combination product, the dose of efavirenz cannot be altered; therefore, voriconazole and TRENVIR must not be co-administered (see "CONTRA-INDICATIONS" and "WARNINGS").PREGNANCY AND LACTATION:The use of TRENVIR during pregnancy is not recommended as safety and efficacy have not been established (see "CONTRA-INDICATIONS").Barrier contraception should always be employed in combination with other contraceptive methods (e.g., oral or other

hormonal contraceptives). Women of childbearing potential should undergo pregnancy testing prior to initiation of treatment with TRENVIR (see "CONTRA-INDICATIONS").Nursing mothers: HIV-infected mothers should not breast feed their infants. It is not known whether efavirenz, emtricitabine or tenofovir are excreted in human milk. Due to the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast feed if they are taking TRENVIR.DOSAGE AND DIRECTIONS FOR USE:Therapy should be initiated by a physician experienced in the management of HIV infection.Adults: The recommended dose of TRENVIR is one tablet taken orally once daily.It is recommended that TRENVIR be swallowed whole with water.TRENVIR should be taken on an empty stomach, since food may increase efavirenz exposure and this may cause an increase in the frequency of adverse reactions. In order to improve the tolerability to efavirenz with respect to undesirable effects on the nervous system, it is recommended that TRENVIR be taken at bedtime.Children and adolescents:TRENVIR is not recommended for use in children below 18 years of age due to lack of data on safety and efficacy (see "CONTRA-INDICATIONS").Elderly:Insufficient numbers of elderly patients have been evaluated in clinical trials of the components of TRENVIR to determine whether they respond differently than younger patients. Caution is required when TRENVIR is prescribed to the elderly, keeping in mind the greater frequency of decreased hepatic or renal function in elderly patients.Renal impairment:TRENVIR is not recommended for patients with moderate to severe impairment of renal function (creatinine clearance < 50 ml/min). Patients with moderate or severe kidney impairment require dose interval adjustments of emtricitabine and tenofovir that cannot be achieved with TRENVIR (see "CONTRA-INDICATIONS" and "WARNINGS").Hepatic impairment:The pharmacokinetic properties of TRENVIR have not been evaluated in patients with hepatic impairment. Patients with mild to moderate liver disease (Child-Pugh-Turcotte Grade A or B) may receive the normal recommended dose of TRENVIR. Patients require careful monitoring for adverse reactions, especially nervous system symptoms related to efavirenz.If treatment with TRENVIR is discontinued in patients with HIV and HBV co-infection, these patients should be closely monitored for evidence of exacerbation of hepatitis.It is important to take TRENVIR according to a regular dosing schedule to avoid missing doses. Patients should be instructed that, if they forget to take TRENVIR, they should take the missed dose immediately, unless it is less than 12 hours until the next day’s dose. In this instance, patients should be instructed to skip the missed dose and to take their next dose at the usual time.Where discontinuation of treatment with one of the components of TRENVIR is indicated or where dose modification is required, separate preparations of efavirenz, emtricitabine and tenofovir are available. Please refer to the individual package inserts of these medicines.If treatment with TRENVIR is discontinued, it is important to consider the long half-life of efavirenz and long intracellular half-lives of tenofovir and emtricitabine. Due to interpatient variability in these parameters and concerns regarding development of resistance, HIV treatment guidelines need to be consulted, also taking into consideration the reason for cessation of treatment.SIDE-EFFECTS AND SPECIAL PRECAUTIONS:Side-Effects:EMTRICITABINE:Blood and lymphatic system disorders:The following side-effects have been reported and frequencies are unknown: Neutropenia, anaemia. Metabolic and nutrition disorders:The following side-effects have been reported and frequencies are unknown: Lactic acidosis, usually accompanied by severe hepatomegaly and steatosis, has

been associated with nucleoside reverse transcriptase inhibitors. Hypertriglyceridaemia and hyperglycaemia.Neuropsychiatric system disorders: Frequent: Headache, asthenia. Less frequent: Depressive disorders, dizziness, sleep disturbances (abnormal dreams, insomnia),

neuritis, paraesthesia, and peripheral neuropathy.Respiratory system disorders:Frequent: Increased cough, rhinitis.Gastrointestinal system disorders:Frequent: Nausea, diarrhoea. Less frequent: Abdominal pain, dyspepsia, and vomiting. Hepatobiliary system disorders:The following side-effects have been reported and frequencies are unknown: Raised liver enzyme concentrations and hyperbilirubinaemia. Skin and subcutaneous tissue disorders:Less frequent: Rash (including pruritus, maculopapular rash, urticaria, vesiculobullous rash, pustular

rash and allergic reactions) and skin discolouration, manifested by hyperpigmentation on the palms and/or soles (generally mild).

Musculoskeletal system disorders:Less frequent: Arthralgia, myalgia.Renal and urinary system disorders:Frequent: Raised creatine kinase. TENOFOVIR:Blood and lymphatic system disorders:The following side-effects have been reported and frequencies are unknown: Neutropenia, haematuria.Immune system disorders:The following side-effects have been reported and frequencies are unknown: Allergic reactions. Metabolism and nutrition disorders:The following side-effects have been reported and frequencies are unknown: Lactic acidosis, usually in combination with severe hepatomegaly and steatosis; also

hypertriglyceridaemia, hyperglycaemia, hypophosphataemia. Neuropsychiatric system disorders:Frequent: Asthenia.Less frequent: Anorexia.The following side-effects have been reported and frequencies are unknown: Depression, headache, dizziness, insomnia, peripheral neuropathy, and anxiety.Respiratory system disorders:The following side-effects have been reported and frequencies are unknown: Chest pain, pneumonia, dyspnoea.Gastrointestinal system disorders:Frequent: Nausea, vomiting, diarrhoea. Less frequent: Raised serum amylase concentrations, abdominal pain, and flatulence.The following side-effects have been reported and frequencies are unknown: Pancreatitis and dyspepsia.Hepatobiliary system disorders:Less frequent: Hepatotoxicity, including lactic acidosis.The following side-effects have been reported and frequencies are unknown: Raised liver enzymes and hepatitis. Skin and subcutaneous tissue disorders:The following side-effects have been reported and frequencies are unknown: Skin rashes (including pruritus, maculopapular rash, urticaria, vesiculobullous rash

and pustular rash). Musculoskeletal system disorders:The following side-effects have been reported and frequencies are unknown: Back pain, myalgia, arthralgia. Renal and urinary system disorders:The following side-effects have been reported and frequencies are unknown: Raised creatine kinase levels, nephritis, nephrogenic diabetes insipidus, renal

impairment, acute renal failure, and effects on the renal proximal tubules, including Fanconi syndrome and acute tubular necrosis.

General disorders:The following side-effects have been reported and frequencies are unknown: Fever, sweating, and weight loss.EFAVIRENZ:Metabolic and nutritional disorders:The following side-effects have been reported and frequencies are unknown: Weight gain and weight loss.Neuropsychiatric system disorders:Frequent: Dizziness, impaired concentration, somnolence, insomnia, and headache.Less frequent: Abnormal dreams, anorexia and hypoaesthesia.The following side-effects have been reported and frequencies are unknown: Abnormal coordination, ataxia, convulsions, paraesthesia, neuropathy, tremors,

aggravated depression, agitation, amnesia, anxiety, apathy, increased appetite, confusion, emotional lability, euphoria, hallucinations, impaired coordination, impotence, decreased libido, increased libido, neuralgia, peripheral neuropathy, speech disorder and vertigo.

Disorders of the special senses:The following side-effects have been reported and frequencies are unknown: Abnormal vision, tinnitus and taste perversion.Cardiovascular system disorders:The following side-effects have been reported and frequencies are unknown: Flushing, palpitations and tachycardia.Respiratory system disorders:The following side-effects have been reported and frequencies are unknown: Asthma, sinusitis, dyspnoea and upper respiratory tract infections. Gastrointestinal system disorders:Frequent: Nausea, vomiting and diarrhoea. Less frequent: Dyspepsia and abdominal pain.The following side-effects have been reported and frequencies are unknown: Gastritis, gastroenteritis, gastro-oesophageal reflux, constipation and malabsorption.Hepatobiliary system disorders:The following side-effects have been reported and frequencies are unknown: Hepatitis, hepatic enzyme increase and hepatic failure.Skin and subcutaneous tissue disorders: Frequent: Rash, pruritus and increased sweating.The following side-effects have been reported and frequencies are unknown: Acne, alopecia, eczema, folliculitis, seborrhoea, skin exfoliation, urticaria, erythema

multiforme, nail disorders, skin discolouration, Stevens-Johnson syndrome.Musculoskeletal system disorders:The following side-effects have been reported and frequencies are unknown: Arthralgia, myalgia and myopathy.General disorders:Frequent: Fatigue and pain.The following side-effects have been reported and frequencies are unknown: Alcohol intolerance, allergic reactions, asthenia, hot flushes, influenza-like symptoms,

malaise, pain, syncope and redistribution/accumulation of body fat. Laboratory abnormalities:Increases in liver enzyme values have occurred, particularly in patients with viral hepatitis. There have been reports of raised serum cholesterol and triglyceride concentrations.Liver enzymes: Elevations of AST and ALT levels to greater than five times the upper limit of the normal range were observed in patients treated with 600 mg of efavirenz. Elevations of GGT levels in patients taking efavirenz may reflect enzyme induction not associated with liver toxicity (see "Special Precautions").Lipids: Increases in total cholesterol of 10 to 20 % were noted in some uninfected volunteers taking efavirenz. Increases in non-fasting total cholesterol and HDL levels of approximately 20 % and 25 %, respectively, were seen in patients treated with efavirenz + ZDV + 3TC and of approximately 40 % and 35 %, in patients treated with efavirenz + IDV. The effects of efavirenz on triglyceride and LDL concentrations were not well characterised. Whether these findings are clinically significant are not known (see "Special Precautions").Special Precautions:Medicine interactions:ALERT: Find out about medicines that should NOT be taken with TRENVIR (see "WARNINGS" and "INTERACTIONS").Since the kidneys are primarily responsible for the elimination of emtricitabine and tenofovir, co-administration of TRENVIR with medicines that reduce renal function or compete for active tubular secretion may cause increases in serum concentrations of emtricitabine, tenofovir, and/or other renally eliminated medicines. Examples of such medicines include, but are not limited to, adefovir dipivoxil, cidofovir, aciclovir, valaciclovir, ganciclovir and

valganciclovir.TRENVIR should not be given concurrently with emtricitabine, tenofovir or efavirenz. Due to similarities between emtricitabine and lamivudine, TRENVIR should not be concomitantly administered with other medicines containing lamivudine, including lamivudine and zidovudine coformulation, lamivudine for HIV, lamivudine for HBV, abacavir sulphate and lamivudine coformulation or abacavir sulphate, lamivudine and zidovudine coformulation.Bone effects:Tenofovir: In a 144-week clinical trial, decreases from baseline in bone mineral density (BMD) were observed at the lumbar spine and hip in both treatment arms of the study. At week 144, there was a significantly greater mean percentage decrease from baseline in BMD at the lumbar spine in subjects who took tenofovir + lamivudine + efavirenz compared to subjects who took stavudine + lamivudine + efavirenz. BMD changes at the hip were similar between the two treatment arms. In both groups, the largest part of the decrease in BMD occurred in the first 24 to 48 weeks of the study and this reduction was sustained throughout the study (144 weeks). Twenty-eight percent of patients who received tenofovir versus 21 % of stavudine-treated patients lost a minimum of 5 % of BMD at the spine or 7 % of BMD at the hip. Clinically relevant fractures (excluding fingers and toes) were reported in 4 patients who received tenofovir and 6 patients who took stavudine. In addition, there were significant increases in the levels of biochemical markers for bone metabolism (serum bone-specific alkaline phosphatase, serum osteocalcin, serum C-telopeptide and urinary N-telopeptide) in the tenofovir-group relative to the stavudine-group, suggesting increased bone turnover. Serum parathyroid hormone levels and 1,25 vitamin D levels were also higher in the group of patients who received tenofovir. With the exception of bone-specific alkaline phosphatase, these changes produced values that remained within the normal range. How these tenofovir-associated changes in BMD and biochemical markers will affect long-term bone health and future fracture risk is unknown.HIV infected patients with a history of pathologic bone fracture or who are at risk for osteopenia should undergo bone monitoring. Although the effect of calcium and vitamin D supplementation has not been studied, such supplementation may benefit all patients. It is necessary to obtain appropriate consultation if bone abnormalities are suspected.Fat redistribution:There have been reports of redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" in patients treated with antiretroviral agents, such as TRENVIR. The mechanism and long-term consequences of these events are not known at this time. Whether antiretroviral therapy is causally related to these events is not known.Immune reconstitution syndrome:There have been reports of immune reconstitution syndrome in patients who received combination antiretroviral therapy. During the initial phase of treatment with combination antiretroviral agents, an inflammatory response to indolent or residual opportunistic infections [such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), or tuberculosis] may develop in patients whose immune system responds. Such reactions may necessitate further evaluation and treatment.Paediatric use:The safety and efficacy of TRENVIR in children have not been established.Geriatric use:Clinical studies of fixed dose combinations of emtricitabine and tenofovir, as in TRENVIR, did not include sufficient numbers of individuals older than 65 years to establish whether they respond differently from younger subjects. Generally, caution is required when doses are selected for elderly patients, bearing in mind the greater frequency of decreased liver, kidney and cardiac function, and of concomitant disease or medicinal therapy.Skin rash: Mild-to-moderate rash, which usually resolves with continued treatment, has been observed with efavirenz use. Treatment with appropriate antihistamines and/or corticosteroids may improve tolerability and hasten resolution of symptoms. Treatment with TRENVIR should be discontinued in patients who experience severe rash associated with blistering, desquamation, mucosal involvement or fever. Prophylaxis with appropriate antihistamines before start of therapy with TRENVIR in children may be considered.Nervous system symptoms: There have been reports of nervous system symptoms with efavirenz use (see "Side-Effects"). In addition, psychosis-like reactions, including delusions and inappropriate behaviour (including aggressive reactions), have also been reported. These reactions occurred predominantly in patients with a history of mental illness or substance abuse. There have been infrequent reports of severe acute depression (including suicidal ideation/attempts) in both efavirenz-treated and control-treated patients, predominantly in patients with a previous history of depression. Patients should be advised to contact their doctor immediately if they experience these symptoms since discontinuation of TRENVIR may be required.Liver enzymes: Monitoring of liver enzyme levels is recommended in patients with known or suspected history of hepatitis B or C infection and in patients treated with other medicines associated with hepatic toxicity. The benefit of continued therapy with TRENVIR has to be weighed against the unknown risks of significant hepatic toxicity in patients who show persistent elevations of serum transaminases to greater than 5 times the upper limit of the normal range (see "Side-Effects").Cholesterol: Monitoring of cholesterol and triglyceride levels should be considered in patients treated with TRENVIR (see "Side-Effects").Opportunistic infections:Patients taking TRENVIR or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV infection. They should therefore remain under close clinical observation by medical practitioners with experience in the treatment of patients with HIV associated disease.Transmission of HIV:Patients must be advised that there is no proof that antiretroviral therapies, including TRENVIR, prevent the risk of transmission of HIV to others through sexual contact or blood contamination. Patients must continue to use appropriate precautions.Lactic acidosis:Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination with other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogues to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with TRENVIR should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).Routine testing of serum lactate levels in asymptomatic patients on antiretroviral treatment is not recommended. Measurement of serum lactate levels is recommended only for patients presenting with clinical signs or symptoms consistent with lactic acidosis.Lactate 2 to 5 mmol/ℓ: monitor regularly and be alert for clinical signs.Lactate 5 to 10 mmol/ℓ without symptoms: monitor closely.Lactate 5 to 10 mmol/ℓ with symptoms: STOP all therapy. Exclude other causes (e.g. sepsis, uraemia, diabetic ketoacidosis, thyrotoxicosis, lymphoma).Lactate greater than or equal to 10 mmol/ℓ: STOP all therapy (80 % mortality in case studies).

Effects on the ability to drive and use machines:The efavirenz in TRENVIR may lead to dizziness, impaired concentration, and/or drowsiness. Patients should be instructed that, if they develop these symptoms, they should keep away from potentially hazardous tasks, such as driving or operating machinery.KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:In the event of overdose, the patient must be monitored for evidence of toxicity, and standard supportive treatment given as necessary.Emtricitabine: There is limited clinical experience with doses in excess of the therapeutic dose of emtricitabine (200 mg). There were no reports of adverse reactions when single emtricitabine doses of 1200 mg were administered to patients in a clinical study. Haemodialysis removes approximately 30 % of the emtricitabine dose over a 3-hour dialysis period initiated within 1,5 hours of emtricitabine administration (blood flow rate of 400 ml/min and a dialysate flow rate of 600 ml/min). Whether peritoneal dialysis will remove emtricitabine is not known.Tenofovir disoproxil fumarate: There is limited clinical experience with doses in excess of the therapeutic dose of tenofovir 300 mg. There were no reports of severe adverse reactions when tenofovir disoproxil fumarate 600 mg was given orally to patients for 28 days. The effects of doses higher than these are not known.Haemodialysis efficiently removes tenofovir with an extraction coefficient of approximately 54 %. Approximately 10 % of the administered tenofovir dose is removed during a four-hour haemodialysis session following a single 300 mg dose of tenofovir.Efavirenz:A number of patients accidentally taking 600 mg twice daily have reported increased nervous system symptoms and involuntary muscle contractions. Treatment of efavirenz overdose should consist of general supportive measures. These should include vital sign monitoring and observation of the patient's clinical status. Activated charcoal may be administered to aid removal of unabsorbed medicine. Dialysis is unlikely to significantly remove efavirenz from the blood, since the medicine is highly protein bound.IDENTIFICATION:Pink-coloured, capsule-shaped, biconvex, film-coated tablets.PRESENTATION:Thirty (30) tablets supplied in a white opaque, HDPE bottle containing a silica gel bag made from non-woven fabric and closed with a white opaque HDPE screw cap. The thirty tablet container is packed in a carton.STORAGE INSTRUCTIONS:Store at or below 30 °C.Keep the bottle tightly closed. Do not use if seal over bottle opening is broken or missing. KEEP OUT OF REACH OF CHILDREN.REGISTRATION NUMBER:44/20.2.8/0780NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION:CIPLA LIFE SCIENCES (PTY) LTDBuilding 9, Parc du Cap,Mispel Street, Bellville, 7530, RSA.Tel. (021) 943 4200.Customer Care: 080 222 6662

Marketed and distributed by: Legacy Pharmaceuticals Manufacturers (Pty) LimitedUnit 6, Building A2, Wild Fig Office Park,Cranberry Road, Laser Park, Honeydew, 2170.

DATE OF PUBLICATION OF THIS PACKAGE INSERT:9 February 2012© CIPLA LIFE SCIENCES (PTY) LTD

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