Dosing and uses of Genvoya (elvitegravir/cobicistat/emtricitabine/tenofovir AF)
Adult dosage forms and strengths
elvitegravir/cobicistat/emtricitabine/tenofovir AF (tenofovir alafenamide)
tablet
- 150mg/150mg/200mg/10mg
HIV Infection
Description and indications
- Four-drug antiretroviral (ART) combination of elvitegravir (integrase strand transfer inhibitor [INSTI]), cobicistat (CYP3A inhibitor), and emtricitabine and tenofovir alafenamide (TAF), both nucleoside analog reverse transcriptase inhibitors (NRTIs)
- It is indicated as a complete treatment regimen for HIV-1 infection in adults and children aged ≥12 yr who are ART-naïve or to replace the current ART regimen in those who are virologically suppressed (HIV-1 RNA <50 copies/mL) on a stable ART regimen for at least 6 months with no history of treatment failure and no known substitutions associated with resistance to the individual components
Dosage
- 1 tablet PO qDay with food
- Prior to initiation, test patients for hepatitis B infection
Dosage modifications
Renal impairment
- Mild-to-moderate (eCrCl ≥30 mL/min): No dosage adjustment required
- Severe or ESRD (eCrCl <30 mL/min): Not recommended; data are insufficient in this population
Hepatic impairment
- Mild-to-moderate (Child-Pugh A or B): No dosage adjustment required
- Severe (Child-Pugh C): Not recommended; data are insufficient in this population
Dosing Considerations
Tenofovir alafenamide (TAF) is a prodrug of tenofovir that has high antiviral efficacy similar to and at a dose less than one-tenth that of the original formulation of tenofovir prodrug (ie, tenofovir disoproxil fumarate [TDF])
TAF provides lower levels of drug in the bloodstream, but higher intracellular compared with TDF
TAF appears to be associated with less kidney toxicity and decreases in bone density than previously approved tenofovir-containing regimens; although not recommended for patients with severe renal impairment, those with moderate renal impairment can take TAF
In clinical trials, patients receiving Genvoya showed greater increases in serum lipids (total cholesterol and low-density lipoprotein) than those receiving other ART regimens
Pediatric dosage forms and strengths
elvitegravir/cobicistat/emtricitabine/tenofovir AF (tenofovir alafenamide)
tablet
- 150mg/150mg/200mg/10mg
HIV Infection
Description and indications
- Four-drug antiretroviral (ART) combination of elvitegravir (integrase strand transfer inhibitor [INSTI]), cobicistat (CYP3A inhibitor), and emtricitabine and tenofovir alafenamide (TAF), both nucleoside analog reverse transcriptase inhibitors (NRTIs)
- It is indicated as a complete treatment regimen for HIV-1 infection in adults and children aged ≥12 yr who are ART-naïve or to replace the current ART regimen in those who are virologically suppressed (HIV-1 RNA <50 copies/mL) on a stable ART regimen for at least 6 months with no history of treatment failure and no known substitutions associated with resistance to the individual components
Dosage
- <12 years: Safety and efficacy not established
- ≥12 years and weight ≥35 kg: 1 tablet PO qDay with food
- Prior to initiation, test patients for hepatitis B infection
Dosage modifications
Renal impairment
- Mild-to-moderate (eCrCl ≥30 mL/min): No dosage adjustment required
- Severe or ESRD (eCrCl <30 mL/min): Not recommended; data are insufficient in this population
Hepatic impairment
- Mild-to-moderate (Child-Pugh A or B): No dosage adjustment required
- Severe (Child-Pugh C): Not recommended; data are insufficient in this population
Dosing Considerations
Tenofovir alafenamide (TAF) is a prodrug of tenofovir that has high antiviral efficacy similar to and at a dose less than one-tenth that of the original formulation of tenofovir prodrug (ie, tenofovir disoproxil fumarate [TDF])
TAF provides lower levels of drug in the bloodstream, but higher intracellular compared with TDF
TAF appears to be associated with less kidney toxicity and decreases in bone density than previously approved tenofovir-containing regimens; although not recommended for patients with severe renal impairment, those with moderate renal impairment can take TAF
In clinical trials, patients receiving Genvoya showed greater increases in serum lipids (total cholesterol and low-density lipoprotein) than those receiving other ART regimens
Genvoya (elvitegravir/cobicistat/emtricitabine/tenofovir AF) adverse (side) effects
1-10%
Nausea (10%)
BMD decline >5% (10%)
Diarrhea (7%)
Creatine kinase ≥10 x ULN (7%)
Headache (6%)
Fatigue (5%)
LDL-C >190 mg/dL (5%)
Total cholesterol >300 mg/dL (2%)
Warnings
Black box warnings
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs (tenofovir), a component of Genvoya, in combination with other antiretrovirals
Not approved for chronic hepatitis B virus (HBV) infection and the safety and efficacy have not been established in patients coinfected with HBV and HIV-1; severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued emtricitabine or tenofovir, which are components of Genvoya
Monitor hepatic function with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue Genvoya; if appropriate, initiation of anti-hepatitis B therapy may be warranted
Contraindications
Drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events; cobicistat is a CYP3A4 inhibitor and increases serum levels of CYP3A4 substrates
Strong CYP3A inducers (may lead to a loss of virologic response and possible resistance)
Use with the following drugs is contraindicated: alfuzosin, rifampin, dihydroergotamine, ergotamine, methylergonovine, cisapride, lovastatin, simvastatin, lurasidone, pimozide, sildenafil for pulmonary arterial hypertension, triazolam, oral midazolam, carbamazepine, phenobarbital, phenytoin, and St. John’s wort
Cautions
Lactic acidosis and severe hepatomegaly with steatosis reported (see Black box warnings)
Patients with HIV-1 infection should be tested for the presence of chronic hepatitis B virus (HBV) before initiating antiretroviral therapy (ART); not approved for the treatment of chronic HBV infection (see Black box warnings)
Should not be coadministered with antiretroviral agents containing any of the same active components, with products containing lamivudine, with adefovir dipivoxil, or with products containing ritonavir
Concomitant use with other drugs may result in known or potentially significant drug interactions, some of which may lead to loss of therapeutic effects and possible development of resistance
Decreases in bone mineral density (BMD) and cases of osteomalacia associated with proximal renal tubulopathy reported with tenofovir; consider monitoring BMD with a history of pathologic fracture or if risk factors for bone loss exist
Fat redistribution and accumulation observed with ART therapy
Immune reconstitution syndrome reported, including the occurrence of autoimmune disorders (eg, Graves disease, polymyositis, Guillain-Barre syndrome) with variable time to onset
New-onset or worsening renal impairment
- Estimate CrCl in all patients before initiating and avoid concurrent or recent use of nephrotoxic drugs
- Cases of acute renal failure and Fanconi syndrome reported with the use of tenofovir and Genvoya; monitor estimated CrCl, urine glucose, and urine protein in all patients prior to initiating and during therapy; additionally monitor serum phosphorus in patients with or at risk for renal impairment
- Discontinue drug if clinically significant decreases in renal function or evidence of Fanconi syndrome develop
- Cobicistat may cause modest increases in serum creatinine and modest declines in CrCl without affecting renal glomerular function; serum creatinine >0.4 mg/dL from baseline should be closely monitored for renal safety
- Do not initiate with CrCl <30 mL/min
Pregnancy
Pregnancy
Pregnancy category: B
An ART pregnancy registry has been established (1-800-258-4263)
Lactation
Emtricitabine and tenofovir have been detected in human milk
Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Genvoya (elvitegravir/cobicistat/emtricitabine/tenofovir AF)
Mechanism of action
Elvitegravir: Integrase inhibitor; inhibits catalytic activity (ie, strand transfer) of HIV-1 integrase, an HIV encoded enzyme required for viral replication; CYP3A4 substrate
Cobicistat: CYP3A4 inhibitor; mechanism-based pharmaco-enhancer, first product to be developed and submitted solely as pharmacokinetic booster for elvitegravir; enhances the systemic exposure of CYP3A substrates, such as elvitegravir, where bioavailability is limited and half-life is shortened by CYP3A-dependent metabolism
Emtricitabine: Synthetic nucleoside analog of cytidine and is phosphorylated by cellular enzymes to form emtricitabine 5'-triphosphate (active); inhibits the activity of the HIV-1 RT by competing with the natural substrate deoxycytidine 5'-triphosphate and by being incorporated into nascent viral DNA, which results in chain termination
Tenofovir alafenamide (AF): Prodrug of tenofovir; compared with tenofovir disoproxil fumarate (tenofovir DF, Viread), tenofovir AF is a more targeted form of tenofovir that has demonstrated high antiviral efficacy at a dose that is 10 times lower than tenofovir DF, as well as an improved renal and bone safety profile; inhibits HIV-1 RT by competing with the natural substrate deoxyadenosine 5′-triphosphate and, after incorporation into DNA, by DNA chain termination
Absorption
Food increases mean systemic exposure of elvitegravir by 34%
A high fat meal (~800 kcal, 50% fat) increases mean systemic exposure of elvitegravir by 87%
Elvitegravir
- Peak plasma time: 4 hr
- Peak plasma concentration: 1.7 mcg/mL
- Trough plasma concentration: 0.45 mcg/mL
- AUC: 23 mcg•hr/mL
Cobicistat
- Peak plasma time: 3 hr
- Peak plasma concentration: 1.1 mcg/mL
- Trough plasma concentration: 0.05 mcg/mL
- AUC: 8.3 mcg•hr/mL
Emtricitabine
- Peak plasma time: 3 hr
- Peak plasma concentration: 1.9 mcg/mL
- Trough plasma concentration: 0.14 mcg/mL
- AUC: 12.7 mcg•hr/mL
Tenofovir
- Peak plasma time: 1 hr
- Peak plasma concentration: 0.16 mcg/mL
- AUC: 0.21 mcg•hr/mL
Distribution
Elvitegravir
- Protein Bound: 98-99%
Cobicistat
- Protein Bound: 97-98%
Emtricitabine
- Protein Bound: <4%
Tenofovir
- Protein Bound: 80%
- Vd: 1.2-1.3 L/kg
Metabolism
Elvitegravir
- Metabolized by CY3A4 (major)
- Also undergoes glucuronidation via UGT1A1/3 enzymes
Cobicistat
- Metabolized by CYP3A4 (major) and CYP2D6 (minor)
- Strong CYP3A4 inhibitor
Emtricitabine
- Not significantly metabolized
- Metabolized by oxidation
Tenofovir
- Tenofovir AF (TAF) is hydrolyzed within cells to form tenofovir (major metabolite), which is phosphorylated to the active metabolite, tenofovir diphosphate
- In vitro studies have shown that TAF is metabolized to tenofovir by cathepsin A in PBMCs and macrophages; and by CES1 in hepatocytes
- Upon coadministration with the moderate CYP3A inducer probe efavirenz, TAF exposure was unaffected
Elimination
Elvitegravir
- Half-life: 12.9 hr
- Excretion: 94.8% feces; 6.7% urine
Cobicistat
- Half-life: 3.5 hr
- Excretion: 86.2% feces; 8.2% urine
Emtricitabine
- Half-life: 10 hr
- Dialyzable: 30% removed by hemodialysis
- Excretion: 70% urine; 14% feces
Tenofovir
- Half-life: 0.51 hr
- Excretion: 31.7% feces; <1% urine
Administration
Instructions
For oral use only
Swallow 1 capsule once daily with food
Storage
Store below 30°C (86°F)
Keep container tightly closed
Dispense only in original container
Do not use if seal over bottle opening is broken or missing
