FDA Approves GENVOYA® (Elvitegravir/Cobicistat/Emtricitabine/Tenofovir alafenamide) for the Treatment of HIV-1

On November 5, 2015, the United States Food and Drug Administration (FDA) approved GENVOYA (Elvitegravir/Cobicistat/Emtricitabine/Tenofovir alafenamide) as a complete regimen for the treatment of HIV-1 infection in adults and pediatric patients 12 years of age and older who have no antiretroviral treatment history or to replace the current antiretroviral regimen in those who are virologically-suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen for at least 6 months with no history of treatment failure and no known substitutions associated with resistance to the individual components of GENVOYA. The approved recommended dosage of GENVOYA tablets is one tablet taken orally once daily with food. Each tablet contains 150 mg of elvitegravir (EVG), 150 mg of cobicistat (COBI), 200 mg of emtricitabine (FTC), and 10 mg of tenofovir alafenamide (TAF). EVG, COBI, and FTC are approved drugs, and TAF is a prodrug of tenofovir (TFV).

Mechanism of Action (MOA), General Pharmacokinetics (PK) and Pharmacodynamics (PD) of GENVOYA

MOA: GENVOYA is a four-drug combination of EVG, an HIV-1 integrase strand transfer inhibitor (INSTI), COBI, a CYP3A inhibitor, and FTC and TAF, both HIV1 nucleoside analog reverse transcriptase inhibitors (NRTIs).

Absorption (Median Tmax): EVG: 4 hours/ COBI: 3 hours/ FTC: 3 hours/ TAF: 1 hour

Food effect: A 34% and 87% increase in EVG AUC was observed when GENVOYA was co-administered with a light meal and high fat meal, respectively. No clinically meaningful food effect on COBI, FTC, TAF was observed.

Plasma protein binding: EVG: ~99% / COBI: ~98% / FTC: <4% / TAF: ~80%

Metabolism:

  • EVG: CYP3A (major) and UGT1A1/3 (minor)
  • COBI: CYP3A (major) and CYP2D6 (minor)
  • FTC: Not significantly metabolized
  • TAF: Cathepsin A (major), carboxylesterase 1 (minor), and CYP3A (minimal)  

Median Terminal half-lives: EVG: 12.9 hours/ COBI: 3.5 hours / FTC: 10 hours/ TAF: 0.51 hours

Excretion:

  • FTC is excreted renally.
  • TFV (the primary metabolite of TAF) is excreted renally.
  • EVG and COBI metabolites are primarily eliminated in feces.

Exposure-Response: No exposure-response relationships for safety or efficacy were identified for any of the components of GENVOYA at the approved recommended dosage.

Drug Interaction Potential

  • GENVOYA can alter the concentration of drugs metabolized by CYP3A or CYP2D6.
  • Coadministration of GENVOYA is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events, and drugs that may lead to reduced efficacy of GENVOYA and possible resistance, such as potent CYP450 inducers.
  • Coadministration of GENVOYA is not recommended with rifabutin, rifapentine, salmeterol, and/or colchicine in patients in patients with renal or hepatic impairment.
  • Consider alternatives to the coadministration of GENVOYA with oxcarbazepine, systemic dexamethasone, and/or inhaled/nasal fluticasone.
  • Consider alternatives to the coadministration of GENVOYA with contraceptive patch, vaginal ring, injectable contraceptives, and oral contraceptives containing progestogens other than norgestimate.
  • Dose reduction may be necessary for sedative/hypnotics, neuroleptics, midazolam, and beta blockers when coadministered with GENVOYA.
  • Specific dosage regimens are required for phosphodiesterase-5 inhibitors, colchicine, and bosentan when coadministered with GENVOYA. See the prescribing information for details.
  • Initiate with the lowest starting dose of atorvastatin when coadministered with GENVOYA and titrate carefully while monitoring for safety.
  • Separate GENVOYA and antacid administration by at least 2 hours.
  • The maximum daily dosage of ketoconazole or itraconazole should not exceed 200 mg per day when coadministered with GENVOYA. Assessment of benefit/risk is recommended to justify use with voriconazole.

Use in Specific Populations

  • No dosage adjustment is recommended based on gender, race, creatinine clearance ≥30 mL/min, mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment, or age ≥12 to ≤75 years.
  • Renal Impairment: GENVOYA is not recommended in patients with estimated creatinine clearance below 30 mL/min.
  • Hepatic Impairment: GENVOYA is not recommended in patients with severe hepatic impairment (Child-Pugh Class C).

Safety and Efficacy

The GENVOYA pivotal studies consisted of two randomized, double blind, active controlled studies in treatment-naïve subjects (n=1733), where efficacy (based on the primary endpoint of HIV-1 RNA <50 copies/mL at week 48 and pooled across the two studies) was 92% in the GENVOYA arm and 90% in the active control (STRIBILD) arm. Additional clinical studies were conducted in virologically suppressed (n=1196), virologically suppressed with mild to moderate renal impairment (n=242), and adolescent (n=23) populations. The most common adverse reaction (incidence greater than or equal to 10%, all grades) with GENVOYA is nausea. 

Full prescribing information is available at http://go.usa.gov/cbhUA.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA's MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

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 This burst was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.