GENVOYA (elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide) is a fixed-dose combination tablet containing elvitegravir (EVG), cobicistat (COBI), emtricitabine (FTC), and tenofovir alafenamide (TAF) for oral administration.
- EVG is an HIV-1 integrase strand transfer inhibitor.
- COBI is a mechanism-based inhibitor of cytochrome P450 (CYP) enzymes of the CYP3A family.
- FTC, a synthetic nucleoside analog of cytidine, is an HIV nucleoside analog reverse transcriptase inhibitor (HIV NRTI).
- TAF, an HIV NRTI, is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5′-monophosphate.
Each tablet contains 150 mg of EVG, 150 mg of COBI, 200 mg of FTC, and 10 mg of TAF (equivalent to 11.2 mg of tenofovir alafenamide fumarate). The tablets include the following inactive ingredients: croscarmellose sodium, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, silicon dioxide, and sodium lauryl sulfate. The tablets are film-coated with a coating material containing FD&C Blue No. 2/indigo carmine aluminum lake, iron oxide yellow, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide.
Elvitegravir: The chemical name of elvitegravir is 6-(3-chloro-2-fluorobenzyl)-1-[(2S)-1-hydroxy-3-methylbutan-2-yl]-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid.
It has a molecular formula of C23 H23 ClFNO5 and a molecular weight of 447.88. It has the following structural formula:
Elvitegravir is a white to pale yellow powder with a solubility of less than 0.3 micrograms per mL in water at 20 °C.
Cobicistat: The chemical name for cobicistat is 2,7,10,12-tetraazatridecanoic acid, 12-methyl-13-[2-(1-methylethyl)-4-thiazolyl]-9-[2-(4-morpholinyl)ethyl]-8,11-dioxo-3,6-bis(phenylmethyl)-, 5-thiazolylmethyl ester, (3R ,6R ,9S)-.
It has a molecular formula of C40 H53 N7 O5 S2 and a molecular weight of 776.02. It has the following structural formula:
Cobicistat is adsorbed onto silicon dioxide. Cobicistat on silicon dioxide drug substance is a white to pale yellow powder with a solubility of 0.1 mg per mL in water at 20 °C.
Emtricitabine: The chemical name of emtricitabine is 4-amino-5-fluoro-1-(2R -hydroxymethyl-1,3-oxathiolan-5S -yl)-(1H)-pyrimidin-2-one. Emtricitabine is the (-)-enantiomer of a thio analog of cytidine, which differs from other cytidine analogs in that it has a fluorine in the 5 position.
It has a molecular formula of C8 H10 FN3 O3 S and a molecular weight of 247.24. It has the following structural formula:
Emtricitabine is a white to off-white powder with a solubility of approximately 112 mg per mL in water at 25 °C.
Tenofovir alafenamide (TAF): The chemical name of tenofovir alafenamide fumarate drug substance is L-alanine, N -[(S)-[[(1R)-2-(6-amino-9H -purin-9-yl)-1-methylethoxy]methyl]phenoxyphosphinyl]-, 1-methylethyl ester, (2E)-2-butenedioate (2:1).
It has an empirical formula of C21 H29 O5 N6 P∙½(C4 H4 O4 ) and a formula weight of 534.5. It has the following structural formula:
Tenofovir alafenamide fumarate is a white to off-white or tan powder with a solubility of 4.7 mg per mL in water at 20 °C.
GENVOYA is a fixed-dose combination of antiretroviral drugs elvitegravir (plus the CYP3A inhibitor cobicistat), emtricitabine, and tenofovir alafenamide [see Microbiology (12.4)].
Thorough QT studies have been conducted for elvitegravir, cobicistat, and TAF. The effect of emtricitabine or the combination regimen GENVOYA on the QT interval is not known.
Elvitegravir: In a thorough QT/QTc study in 126 healthy subjects, elvitegravir (coadministered with 100 mg ritonavir) 125 mg and 250 mg (0.83 and 1.67 times the dose in GENVOYA) did not affect the QT/QTc interval and did not prolong the PR interval.
Cobicistat: In a thorough QT/QTc study in 48 healthy subjects, a single dose of cobicistat 250 mg and 400 mg (1.67 and 2.67 times the dose in GENVOYA) did not affect the QT/QTc interval. Prolongation of the PR interval was noted in subjects receiving cobicistat. The maximum mean (95% upper confidence bound) difference in PR from placebo after baseline-correction was 9.5 (12.1) msec for the 250 mg cobicistat dose and 20.2 (22.8) for the 400 mg cobicistat dose. Because the 150 mg cobicistat dose used in the GENVOYA fixed-dose combination tablet is lower than the lowest dose studied in the thorough QT study, it is unlikely that treatment with GENVOYA will result in clinically relevant PR prolongation.
Tenofovir Alafenamide (TAF): In a thorough QT/QTc study in 48 healthy subjects, TAF at the therapeutic dose or at a supratherapeutic dose approximately 5 times the recommended therapeutic dose did not affect the QT/QTc interval and did not prolong the PR interval.
Effects on Serum Creatinine
The effect of cobicistat on serum creatinine was investigated in a Phase 1 study in subjects with an estimated creatinine clearance of at least 80 mL per minute (N=18) and with an estimated creatinine clearance of 50 to 79 mL per minute (N=12). A statistically significant change of estimated creatinine clearance from baseline was observed after 7 days of treatment with cobicistat 150 mg among subjects with an estimated creatinine clearance of at least 80 mL per minute (−9.9 ± 13.1 mL/min) and subjects with an estimated creatinine clearance between 50 and 79 mL per minute (−11.9 ± 7.0 mL per minute). These decreases in estimated creatinine clearance were reversible after cobicistat was discontinued. The actual glomerular filtration rate, as determined by the clearance of probe drug iohexol, was not altered from baseline following treatment of cobicistat among subjects with an estimated creatinine clearance of at least 50 mL per minute, indicating cobicistat inhibits tubular secretion of creatinine, reflected as a reduction in estimated creatinine clearance without affecting the actual glomerular filtration rate.
Absorption, Distribution, Metabolism, and Excretion
The pharmacokinetic (PK) properties of the components of GENVOYA are provided in Table 6. The multiple dose PK parameters of elvitegravir, cobicistat, emtricitabine, TAF and its metabolite tenofovir are provided in Table 7.
|PBMCs = peripheral blood mononuclear cells; CES1 = carboxylesterase 1.|
|Effect of light meal (relative to fasting): AUC Ratio *||1.34(1.19, 1.51)||1.03(0.90, 1.17)||0.95(0.91, 1.00)||1.15(1.07, 1.24)|
|Effect of high fat meal (relative to fasting): AUC Ratio *||1.87(1.66, 2.10)||0.83(0.73, 0.95)||0.96(0.92, 1.00)||1.18(1.09, 1.26)|
|% Bound to human plasma proteins||~99||~98||<4||~80|
|Source of protein binding data||Ex vivo||In vitro||In vitro||Ex vivo|
|Metabolism||CYP3A (major)UGT1A1/3 (minor)||CYP3A (major)CYP2D6 (minor)||Not significantly metabolized||Cathepsin A † (PBMCs)CES1 (hepatocytes)CYP3A (minimal)|
|Major route of elimination||Metabolism||Metabolism||Glomerular filtration and active tubular secretion||Metabolism (>80% of oral dose)|
|% Of dose excreted in urine §||6.7||8.2||70||<1%|
|% Of dose excreted in feces §||94.8||86.2||13.7||31.7|
|ParameterMean (CV%)||Elvitegravir *||Cobicistat *||Emtricitabine *||TAF †||Tenofovir ‡|
|CV = Coefficient of Variation; NA = Not Applicable|
|Cmax (microgram per mL)||2.1 (33.7)||1.5 (28.4)||2.1 (20.2)||0.16 (51.1)||0.02 (26.1)|
|AUCtau (microgram∙hour per mL)||22.8 (34.7)||9.5 (33.9)||11.7 (16.6)||0.21 (71.8)||0.29 (27.4)|
|Ctrough (microgram per mL)||0.29 (61.7)||0.02 (85.2)||0.10 (46.7)||NA||0.01 (28.5)|
Pharmacokinetics of elvitegravir, cobicistat, emtricitabine and tenofovir have not been fully evaluated in the elderly (65 years of age and older). Age does not have a clinically relevant effect on exposures of TAF up to 75 years of age [see Use in Specific Populations (8.5)].
Mean exposures of elvitegravir, cobicistat, and TAF achieved in 24 pediatric subjects aged 12 to less than 18 years who received thedose of GENVOYA containing 150 mg EVG, 150 mg COBI, 200 mg FTC, and 10 mg TAF in Study 106 were decreased compared to exposures achieved in treatment-naïve adults receiving the same dose of GENVOYA, but were overall deemed acceptable based on exposure-response relationships; emtricitabine exposure in adolescents was similar to that in treatment-naïve adults (Table 8).
|CV = Coefficient of Variation; NA = Not Applicable|
|Cmax (microgram per mL)||2.2 (19.2)||1.2 (35.0)||2.3 (22.5)||0.17 (64.4)||0.02 (23.7)|
|AUCtau (microgram∙hour per mL)||23.8 (25.5)||8.2†(36.1)||14.4 (23.9)||0.20†(50.0)||0.29†(18.8)|
|Ctrough (microgram per mL)||0.30 (81.0)||0.03‡(180.0)||0.10†(38.9)||NA||0.01 (21.4)|
Exposures of the components of GENVOYA achieved in 23 pediatric subjects between the ages of 6 to less than 12 years who received the dose of GENVOYA containing 150 mg EVG, 150 mg COBI, 200 mg FTC, and 10 mg TAF in Study 106 were higher (20 to 80% for AUC) than exposures achieved in adults receiving the same dose of GENVOYA; the increase was not considered clinically significant as the safety profiles were similar in adult and pediatric patients (Table 9) [see Use in Specific Populations (8.4)].
|CV = Coefficient of Variation; NA = Not Applicable|
|Cmax (microgram per mL)||3.1 (38.7)||2.1 (46.7)||3.4 (27.0)||0.31 (61.2)||0.03 (20.8)|
|AUCtau (microgram∙hour per mL)||33.8†(57.8)||15.9‡(51.7)||20.6†(18.9)||0.33 (44.8)||0.44 (20.9)|
|Ctrough (microgram per mL)||0.37 (118.5)||0.1 (168.7)||0.11 (24.1)||NA||0.02 (24.9)|
No clinically significant differences in pharmacokinetics of GENVOYA have been identified based on race or gender.
Patients with Renal Impairment
The pharmacokinetics of GENVOYA in HIV-1 infected subjects with mild or moderate renal impairment (estimated creatinine clearance between 30 and 69 mL per minute by Cockcroft-Gault method), and in HIV-1 infected subjects with ESRD (estimated creatinine clearance of less than 15 mL per minute by Cockcroft-Gault method) receiving chronic hemodialysis were evaluated in subsets of virologically suppressed subjects in respective open-label trials, Study 112 and Study 1825. The pharmacokinetics of elvitegravir, cobicistat, and tenofovir alafenamide were similar among healthy subjects, subjects with mild or moderate renal impairment, and subjects with ESRD receiving chronic hemodialysis; increases in emtricitabine and tenofovir exposures in subjects with renal impairment were not considered clinically relevant (Table 10).
|AUCtau (microgram∙hour per mL)Mean (CV%)|
|Estimated Creatinine Clearance *||≥90 mL per minute (N=18)†||60–89 mL per minute (N=11)‡||30–59 mL per minute (N=18)§||<15 mL per minute (N=12)¶|
|Emtricitabine||11.4 (11.9)||17.6 (18.2)||23.0 (23.6)||62.9 (48.0)#|
|Tenofovir||0.32 (14.9)||0.46 (31.5)||0.61 (28.4)||8.72 (39.4)Þ|
Patients with Hepatic Impairment
Elvitegravir and Cobicistat: A study of the pharmacokinetics of elvitegravir (administered with the CYP3A inhibitor cobicistat) was performed in healthy subjects and subjects with moderate hepatic impairment (Child-Pugh Class B). No clinically relevant differences in elvitegravir or cobicistat pharmacokinetics were observed between subjects with moderate hepatic impairment and healthy subjects [see Use in Specific Populations (8.7)].
Emtricitabine: The pharmacokinetics of emtricitabine has not been studied in subjects with hepatic impairment; however, emtricitabine is not significantly metabolized by liver enzymes, so the impact of liver impairment should be limited.
Tenofovir Alafenamide (TAF): Clinically relevant changes in TAF and tenofovir pharmacokinetics were not observed in subjects with mild to moderate (Child-Pugh Class A and B) hepatic impairment [see Use in Specific Populations (8.7)].
Hepatitis B and/or Hepatitis C Virus Co-infection
Elvitegravir: Limited data from population pharmacokinetic analysis (N=24) indicated that hepatitis B and/or C virus infection had no clinically relevant effect on the exposure of elvitegravir (administered with the CYP3A inhibitor cobicistat).
Cobicistat: There were insufficient pharmacokinetic data in the clinical trials to determine the effect of hepatitis B and/or C virus infection on the pharmacokinetics of cobicistat.
Emtricitabine and Tenofovir Alafenamide (TAF): Pharmacokinetics of emtricitabine and TAF have not been fully evaluated in subjects coinfected with hepatitis B and/or C virus.
Drug Interaction Studies
The drug-drug interaction studies described in Tables 11–14 were conducted with GENVOYA, elvitegravir (coadministered with cobicistat or ritonavir), cobicistat administered alone, or TAF (administered alone or coadministered with emtricitabine).
As GENVOYA should not be administered with other antiretroviral medications, information regarding drug-drug interactions with other antiretrovirals agents is not provided.
The effects of coadministered drugs on the exposure of elvitegravir, emtricitabine, and TAF are shown in Table 11, Table 12, and Table 13 respectively. The effects of GENVOYA or its components on the exposure of coadministered drugs are shown in Table 14. For information regarding clinical recommendations, see Drug Interactions (7).
|Coadministered Drug||Dose of Coadministered Drug (mg)||Elvitegravir Dose (mg)||CYP3A Inhibitor Cobicistat or Ritonavir Dose (mg)||N||Mean Ratio of Elvitegravir PharmacokineticParameters (90% CI); No effect = 1.00|
|Maximum strength antacid †||20 mL single dose given 4 hours before elvitegravir||50 single dose||Ritonavir100 single dose||8||0.95(0.84,1.07)||0.96(0.88,1.04)||1.04(0.93,1.17)|
|20 mL single dose given 4 hours after elvitegravir||10||0.98(0.88,1.10)||0.98(0.91,1.06)||1.00(0.90,1.11)|
|20 mL single dose given 2 hours before elvitegravir||11||0.82(0.74,0.91)||0.85(0.79,0.91)||0.90(0.82,0.99)|
|20 mL single dose given 2 hours after elvitegravir||10||0.79(0.71,0.88)||0.80(0.75,0.86)||0.80(0.73,0.89)|
|Atorvastatin||10 single dose||150 once daily ‡||Cobicistat 150 once daily ‡||16||0.91(0.85,0.98)||0.92(0.87,0.98)||0.88(0.81,0.96)|
|Carbamazepine||200 twice daily||150 once daily||Cobicistat150 once daily||12||0.55(0.49,0.61)||0.31(0.28,0.33)||0.03(0.02,0.40)|
|Famotidine||40 once daily given 12 hours after elvitegravir||150 once daily||Cobicistat150 once daily||10||1.02(0.89,1.17)||1.03(0.95,1.13)||1.18(1.05,1.32)|
|40 once daily given simultaneously with elvitegravir||16||1.00(0.92,1.10)||1.03(0.98,1.08)||1.07(0.98,1.17)|
|Ketoconazole||200 twice daily||150 once daily||Ritonavir100 once daily||18||1.17(1.04,1.33)||1.48(1.36,1.62)||1.67(1.48,1.88)|
|Ledipasvir/ Sofosbuvir||90/400 once daily||150 once daily ‡||Cobicistat150 once daily ‡||30||0.98(0.90,1.07)||1.11(1.02,1.20)||1.46(1.28,1.66)|
|Omeprazole||40 once daily given 2 hours before elvitegravir||50 once daily||Ritonavir100 once daily||9||0.93(0.83,1.04)||0.99(0.91,1.07)||0.94(0.85,1.04)|
|20 once daily given 2 hours before elvitegravir||150 once daily||Cobicistat150 once daily||11||1.16(1.04,1.30)||1.10(1.02,1.19)||1.13(0.96,1.34)|
|20 once daily given 12 hours after elvitegravir||11||1.03(0.92,1.15)||1.05(0.93,1.18)||1.10(0.92,1.32)|
|Rifabutin||150 once every other day||150 once daily||Cobicistat150 once daily||12||0.91(0.84,0.99)||0.79(0.74,0.85)||0.33(0.27,0.40)|
|Rosuvastatin||10 single dose||150 once daily||Cobicistat150 once daily||10||0.94(0.83,1.07)||1.02(0.91,1.14)||0.98(0.83,1.16)|
|Sertraline||50 single dose||150 once daily ‡||Cobicistat 150 once daily ‡||19||0.88(0.82,0.93)||0.94(0.89,0.98)||0.99(0.93,1.05)|
|Sofosbuvir/ Velpatasvir||400/100 once daily||150 once daily ‡||Cobicistat150 once daily ‡||24||0.87(0.80,0.94)||0.94(0.88,1.00)||1.08(0.97,1.20)|
|Sofosbuvir/ Velpatasvir/ Voxilaprevir||400/100/100 + 100 Voxilaprevir § once daily||150 once daily ‡||Cobicistat150 once daily ‡||29||0.79(0.75,0.85)||0.94(0.88,1.00)||1.32(1.17,1.49)|
|Coadministered Drug||Dose of Coadministered Drug (mg)||Emtricitabine Dose (mg)||N||Mean Ratio of Emtricitabine Pharmacokinetic Parameters (90% CI); No effect = 1.00|
|Famciclovir||500 single dose||200 single dose||12||0.90 (0.80,1.01)||0.93 (0.87,0.99)||NC|
|Coadministered Drug||Dose of Coadministered Drug (mg)||TAF Dose (mg)||N||Mean Ratio of TAF PharmacokineticParameters (90% CI); No effect = 1.00|
|NC = Not Calculated|
|Cobicistat||150 once daily||8 once daily||12||2.83(2.20,3.65)||2.65(2.29,3.07)||NC|
|Ledipasvir/ Sofosbuvir||90/400 once daily||10 once daily †||30||0.90(0.73,1.11)||0.86(0.78,0.95)||NC|
|Sertraline||50 single dose||10 once daily †||19||1.00(0.86,1.16)||0.96(0.89,1.03)||NC|
|Sofosbuvir/ Velpatasvir||400/100 once daily||10 once daily †||24||0.80(0.68,0.94)||0.87(0.81,0.94)||NC|
|Sofosbuvir/ Velpatasvir/ Voxilaprevir||400/100/100 + 100 Voxilaprevir ‡ once daily||10 once daily †||29||0.79(0.68,0.92)||0.93(0.85,1.01)||NC|
|Coadministered Drug||Dose of CoadministeredDrug (mg)||Elvitegravir Dose (mg)||CYP3A Inhibitor Cobicistat Dose (mg)||FTC Dose (mg)||TAF Dose (mg)||N||Mean Ratio of Coadministered Drug Pharmacokinetic Parameters (90% CI);No effect = 1.00|
|FTC = emtricitabine; TAF = tenofovir alafenamide|
|N/A = Not Applicable; NC = Not Calculated|
|Atorvastatin||10 single dose||150 once daily †||150 once daily †||200 once daily †||10 once daily †||16||2.32(1.91,2.82)||2.60(2.31,2.93)||NC|
|Buprenorphine||16 – 24 once daily||150 once daily||150 once daily||N/A||N/A||17||1.12(0.98,1.27)||1.35(1.18,1.55)||1.66(1.43,1.93)|
|Carbamazepine||200 twice daily||150 once daily||150 once daily||N/A||N/A||12||1.40(1.32,1.49)||1.43(1.36,1.52)||1.51(1.41,1.62)|
|Desipramine||50 single dose||N/A||150 once daily||N/A||N/A||8||1.24(1.08,1.44)||1.65(1.36,2.02)||NC|
|Digoxin||0.5 single dose||N/A||150 once daily||N/A||N/A||22||1.41 (1.29,1.55)||1.08(1.00,1.17)||NC|
|Famciclovir||500 single dose||N/A||N/A||200 single dose||N/A||12||0.93 (0.78,1.11)||0.91 (0.84,0.99)||N/A|
|Ledipasvir||90 once daily||150 once daily †||150 once daily †||200 once daily †||10 once daily †||30||1.65(1.53,1.78)||1.79(1.64,1.96)||1.93(1.74,2.15)|
|Sofosbuvir||400 once daily||1.28(1.13,1.47)||1.47(1.35,1.59)||N/A|
|Naloxone||4–6 once daily||150 once daily||150 once daily||N/A||N/A||17||0.72(0.61,0.85)||0.72(0.59,0.87)||N/A|
|Norgestimate/ ethinyl estradiol §||0.180/0.215/ 0.250 norgestimate once daily||150 once daily §||150 once daily §||200 once daily §||N/A||13||2.08(2.00,2.17)||2.26(2.15,2.37)||2.67(2.43,2.92)|
|0.025 ethinyl estradiol once daily||0.94(0.86,1.04)||0.75(0.69,0.81)||0.56(0.52,0.61)|
|Norgestromin||0.180/0.215/ 0.250 norgestimate once daily / 0.025 ethinyl estradiol once daily||N/A||N/A||200 once daily ¶||25 once daily ¶||15||1.17(1.07,1.26)||1.12(1.07,1.17)||1.16(1.08,1.24)|
|R-Methadone||80–120 daily||150 once daily||150 once daily||N/A||N/A||11||1.01(0.91,1.13)||1.07(0.96,1.19)||1.10(0.95,1.28)|
|Sertraline||50 single dose||150 once daily †||150 once daily †||200 once daily †||10 once daily †||19||1.14(0.94,1.38)||0.93(0.77,1.13)||N/A|
|Rifabutin||150 once every other day||150 once daily||150 once daily||N/A||N/A||12||1.09(0.98,1.20)#||0.92(0.83,1.03)#||0.94(0.85,1.04)#|
|Rosuvastatin||10 single dose||150 once daily||150 once daily||N/A||N/A||10||1.89(1.48,2.42)||1.38(1.14,1.67)||NC|
|Sofosbuvir||400 once daily||150 once daily †||150 once daily †||200 once daily †||10 once daily †||24||1.23(1.07,1.42)||1.37(1.24,1.52)||N/A|
|Velpatasvir||100 once daily||1.30 (1.17,1.45)||1.50 (1.35,1.66)||1.60 (1.44,1.78)|
|Sofosbuvir||400 once daily||150 once daily †||150 once daily †||200 once daily †||10 once daily †||29||1.27(1.09,1.48)||1.22(1.12,1.32)||NC|
|Velpatasvir||100 once daily||0.96(0.89,1.04)||1.16(1.06,1.27)||1.46(1.30,1.64)|
|Voxilaprevir||100 + 100Þ once daily||1.92(1.63,2.26)||2.71(2.30,3.19)||4.50(3.68,5.50)|
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