elvitegravir/cobicistat/emtricitabine/tenofovir AF (Rx)

Brand and Other Names:Genvoya
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

elvitegravir/cobicistat/emtricitabine/tenofovir AF

tablet

  • 150mg/150mg/200mg/10mg

HIV Infection

Indicated in adults 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 individual components

1 tablet PO qDay with food

See also Administration

Dosage Modifications

Renal impairment

  • Mild-to-moderate (eCrCl ≥30 mL/min): No dosage adjustment required
  • Severe or ESRD (eCrCl <30 mL/min): Not recommended; safety has not been established

Hepatic impairment

  • Mild-to-moderate (Child Pugh A or B): No dosage adjustment required
  • Severe (Child Pugh C): Not recommended; not studied

Dosing Considerations

Testing prior and during treatment

  • Prior to initiation, test patients for hepatitis B infection
  • Assess serum creatinine, serum phosphorous, estimated CrCl, urine glucose, and urine protein before initiating and during therapy in all patients as clinically appropriate; in patients with chronic kidney disease, also assess serum phosphorus

Dosage Forms & Strengths

elvitegravir/cobicistat/emtricitabine/tenofovir AF (tenofovir alafenamide)

tablet

  • 150mg/150mg/200mg/10mg

HIV Infection

Indicated in adults 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 individual components

Dosage

  • Weight <25 kg: Safety and efficacy not established
  • Weight ≥25 kg: 1 tablet PO qDay with food

Dosage Modifications

Renal impairment

  • Mild-to-moderate (eCrCl ≥30 mL/min): No dosage adjustment required
  • Severe or ESRD (eCrCl <30 mL/min): Not recommended; safety has not been established

Hepatic impairment

  • Mild-to-moderate (Child-Pugh A or B): No dosage adjustment required
  • Severe (Child Pugh C): Not recommended; not studied

Dosing Considerations

Testing prior and during treatment

  • Prior to initiation, test patients for hepatitis B infection
  • Assess serum creatinine, serum phosphorous, estimated CrCl, urine glucose, and urine protein before initiating and during therapy in all patients as clinically appropriate; in patients with chronic kidney disease, also assess serum phosphorus
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Interactions

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            Adverse Effects

            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%)

            Postmarketing Reports

            Suicidal ideation, suicidal behavior, and suicide attempt

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            Warnings

            Black Box Warnings

            Post treatment acute exacerbation of hepatitis B

            • Severe acute exacerbations of hepatitis B reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing emtricitabine and/or tenofovir disoproxil fumarate (TDF), and may occur with discontinuation treatment
            • Closely 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 treatment
            • If appropriate, antihepatitis B therapy may be warranted

            Contraindications

            Coadministration with drugs highly dependent on CYP3A for clearance

            • Alfuzosin
            • Carbamazepine, phenobarbital, phenytoin
            • Rifampin
            • Lurasidone, pimozide
            • Dihydroergotamine, ergotamine, methylergonovine
            • Cisapride
            • St. John’s wort (Hypericum perforatum)
            • Lomitapide, lovastatin, simvastatin
            • Phosphodiesterase-5 (PDE-5) inhibitor: Sildenafil when administered for treatment of pulmonary arterial hypertension
            • Midazolam, triazolam

            Cautions

            Lactic acidosis and severe hepatomegaly with steatosis reported

            Test patients with HIV-1 infection 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)

            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

            • Measure serum creatinine, serum phosphorous, estimated CrCl, urine glucose, and urine protein before initiating drug and during therapy in all patients as clinically appropriate
            • 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

            Drug interactions overview

            • Avoid coadministration of Genvoya and other antiretroviral medications for HIV-1 since Genvoya is a complete HIV infection
            • 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
            • 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
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            Pregnancy

            Pregnancy

            An ART pregnancy registry has been established (1-800-258-4263); prospective pregnancy data from the Antiviral Pregnancy Registry (APR) not sufficient to adequately assess risk of birth defects or miscarriage

            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

            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.

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            Pharmacology

            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
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            Administration

            Oral Administration

            For oral use only

            Take 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

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            Formulary

            FormularyPatient Discounts

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            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.