Elvitegravir + Cobicistat + Emtricitabine +Tenofovir alafenamide

Indications

Elvitegravir + Cobicistat + Emtricitabine +Tenofovir alafenamide is used for: HIV Infection

Adult Dose

HIV Infection Indicated as a complete treatment regimen for HIV-1 infection in adults and children weighing ?25 kg who are ART-naïve or to replace current ART regimen in those who are virologically suppressed (HIV-1 RNA <50 copies/mL) on a stable ART regimen for ?6 months with no history of treatment failure and no known substitutions associated with resistance to the individual components 1 tablet PO qDay with food 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

Child Dose

HIV Infection Weight <25 kg: Safety and efficacy not established Weight >25 kg: 1 tablet PO qDay with food

Renal Dose

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

Administration

Take with food

Contra Indications

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

Precautions

Lactic acidosis and severe hepatomegaly with steatosis reported 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 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 Lactation The Centers for Disease Control and Prevention do not recommend HIV-infected mothers breastfeed their infants due to potential risk for postnatal transmission of HIV Emtricitabine has been shown to be present in human breast milk; it is unknown if elvitegravir, cobicistat, and TAF are present in human breast milk Elvitegravir and cobicistat are present in rat milk, and tenofovir has been shown to be present in the milk of lactating rats and rhesus monkeys after administration of TDF Owing to the potential for HIV transmission (in HIV-negative infants); developing viral resistance (in HIV-positive infants); and adverse reactions in a breastfed infant similar to those seen in adults, instruct mothers not to breastfeed

Pregnancy-Lactation

Pregnancy Not recommended for use during pregnancy because of substantially lower exposures of cobicistat and elvitegravir during second and third trimesters Avoid use in pregnant individuals; an alternative regimen is recommended for individuals who become pregnant during therapy Lactation The Centers for Disease Control and Prevention do not recommend HIV-infected mothers breastfeed their infants due to potential risk for postnatal transmission of HIV Emtricitabine has been shown to be present in human breast milk; it is unknown if elvitegravir, cobicistat, and TAF are present in human breast milk Elvitegravir and cobicistat are present in rat milk, and tenofovir has been shown to be present in the milk of lactating rats and rhesus monkeys after administration of TDF Owing to the potential for HIV transmission (in HIV-negative infants); developing viral resistance (in HIV-positive infants); and adverse reactions in a breastfed infant similar to those seen in adults, instruct mothers not to breastfeed

Interactions

Should not be coadministered with antiretroviral agents containing any of the same active components, with products containing lamivudine, emtricitabine, tenofovir, 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 Cobicistat an inhibitor of CYP3A and CYP2D6 and an inhibitor of the following transporters: P-glycoprotein (P-gp), BCRP, OATP1B1 and OATP1B3; coadministration with drugs that are primarily metabolized by CYP3A or CYP2D6, or P-gp, BCRP, OATP1B1 or OATP1B3 substrates may result in increased plasma concentrations of such drugs Elvitegravir is a modest CYP2C9 inducer and may decrease plasma concentrations of CYP2C9 substrates TAF is a weak CYP3A inhibitor Emtricitabine and tenofovir are primarily excreted by the kidneys; coadministration of Genvoya with drugs that reduce renal function or compete for active tubular secretion may increase concentrations and effects of emtricitabine, tenofovir, and other renally eliminated drugs

Adverse Effects

Side effects of Elvitegravir + Cobicistat + Emtricitabine +Tenofovir alafenamide : 1-10% Nausea (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%)

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