GENVOYA
Clinical safety rating: caution
Comprehensive clinical and safety monograph for GENVOYA (GENVOYA).
Genvoya is a fixed-dose combination of elvitegravir (integrase strand transfer inhibitor), cobicistat (CYP3A inhibitor), emtricitabine (nucleoside reverse transcriptase inhibitor), and tenofovir alafenamide (nucleotide reverse transcriptase inhibitor). Elvitegravir inhibits HIV integrase, blocking viral DNA integration. Emtricitabine and tenofovir alafenamide inhibit HIV reverse transcriptase. Cobicistat boosts elvitegravir levels by inhibiting CYP3A.
| Metabolism | Elvitegravir is primarily metabolized by CYP3A; cobicistat is a mechanism-based CYP3A inhibitor; emtricitabine is not significantly metabolized; tenofovir alafenamide is hydrolyzed to tenofovir (by cathepsin A in PBMCs or by CES1 in hepatocytes) and then phosphorylated; tenofovir undergoes renal excretion. |
| Excretion | Elvitegravir: 94.8% fecal, 6.7% renal; Cobicistat: 86.2% fecal, 8.2% renal; Emtricitabine: 70% renal (active tubular secretion); Tenofovir alafenamide: <1% renal, >80% fecal as tenofovir |
| Half-life | Elvitegravir: 12.9 h; Cobicistat: 3.5 h; Emtricitabine: 10 h (prolonged in renal impairment); Tenofovir alafenamide: 0.5 h (but intracellular tenofovir-diphosphate half-life >60 h). Effective dosing interval: 24 h |
| Protein binding | Elvitegravir: 98-99% to albumin; Cobicistat: 97-98% to albumin; Emtricitabine: <4% (minimal); Tenofovir alafenamide: ~80% to albumin |
| Volume of Distribution | Elvitegravir: 0.65 L/kg; Cobicistat: 0.72 L/kg; Emtricitabine: 1.4 L/kg (total body water); Tenofovir alafenamide: 0.2 L/kg (extensive tissue distribution). Clinical meaning: high distribution indicates extravascular penetration |
| Bioavailability | 100% oral bioavailability for the fixed-dose combination tablet (compared to individual components); food effect: increased absorption with moderate-fat meal |
| Onset of Action | Virologic suppression typically observed within 4-8 weeks of continuous once-daily oral dosing |
| Duration of Action | Sustained virologic suppression for 24 h with once-daily dosing; missed doses should be taken as soon as remembered if within 12 h of next dose |
One tablet (150 mg elvitegravir, 150 mg cobicistat, 200 mg emtricitabine, 300 mg tenofovir alafenamide) orally once daily with food.
| Dosage form | TABLET |
| Renal impairment | Not recommended for patients with CrCl <30 mL/min. No dose adjustment required for CrCl >=30 mL/min. |
| Liver impairment | No dose adjustment required for mild to moderate hepatic impairment (Child-Pugh A or B). Not recommended for severe hepatic impairment (Child-Pugh C). |
| Pediatric use | Approved for pediatric patients weighing >=25 kg: one tablet orally once daily with food. Not recommended for <25 kg. |
| Geriatric use | No specific dose adjustment recommended; monitor renal function closely due to age-related decline in CrCl. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for GENVOYA (GENVOYA).
| Breastfeeding | Breastfeeding is not recommended for HIV-infected women to avoid postnatal transmission of HIV. Elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide are excreted into rat milk; human data are lacking. The M/P ratio is unknown. Emtricitabine and tenofovir have been detected in human breast milk in small amounts. Given the potential for HIV transmission and unknown effects on the infant, advise mothers not to breastfeed. |
| Teratogenic Risk | Genvoya (elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide) is classified as FDA Pregnancy Category B for the individual components. No adequate and well-controlled studies in pregnant women exist. In animal studies, no evidence of teratogenicity or fetal harm was observed at exposures up to those achieved with the recommended human dose. However, because animal reproduction studies are not always predictive of human response, Genvoya should be used during pregnancy only if clearly needed. There are no known specific fetal risks by trimester; however, tenofovir disoproxil fumarate (TDF) has been associated with reduced bone mineral density in infants exposed in utero. TAF, a prodrug of tenofovir, may have lower bone effects but data are limited. Emtricitabine and tenofovir are known to cross the placenta. Hypotheses for potential risks include mitochondrial toxicity from NRTIs, but not established. |
■ FDA Black Box Warning
WARNING: POST-TREATMENT ACUTE EXACERBATION OF HEPATITIS B. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing emtricitabine and/or tenofovir disoproxil fumarate. Hepatic function should be monitored closely in these patients.
| Serious Effects |
["Coadministration with drugs highly dependent on CYP3A for clearance (e.g., alfuzosin, amiodarone, sildenafil for PAH, ergot derivatives, lovastatin, simvastatin, oral midazolam, triazolam, pimozide, ranolazine, St. John's wort)","Coadministration with rifampin","Coadministration with adefovir dipivoxil","Hypersensitivity to any component (e.g., severe rash)"]
| Precautions | ["Risk of post-treatment acute exacerbation of hepatitis B in HIV/HBV coinfected patients","New onset or worsening renal impairment (monitor serum creatinine, estimated creatinine clearance, urine glucose and urine protein)","Lactic acidosis and severe hepatomegaly with steatosis","Immune reconstitution syndrome","Decreases in bone mineral density (more pronounced with TAF than TDF?)","Drug interactions (especially with CYP3A substrates and drugs affecting renal function)"] |
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| Fetal Monitoring | Monitor HIV viral load and CD4+ cell count every 1-2 months during pregnancy. Assess for adverse effects such as hepatotoxicity, renal impairment (serum creatinine, eGFR, urine protein), and bone mineral density changes. Perform fetal ultrasound for growth and anatomy as per standard obstetric care. Consider monitoring for gestational diabetes due to potential effects from cobicistat boosting of corticosteroids. Monitor liver function tests closely in patients with hepatitis B coinfection, as discontinuation may lead to severe exacerbations. |
| Fertility Effects | No significant effects on fertility have been reported in animal studies for Genvoya components. In humans, no evidence suggests impairment of male or female fertility. However, HIV infection itself can reduce fertility, and antiretroviral therapy may improve fertility by improving overall health. No specific contraceptive advice beyond standard barrier methods to prevent HIV transmission and pregnancy. |