GENVOYA ® (elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide)

GENVOYA ® (elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide)

GENVOYA ® (elvitegravir, cobicistat, emtricitabine, and tenofoviralafenamide)

GENVOYA (elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide) is a fixed-dose combination tablet containing elvitegravir (EVG), cobicistat (COBI), emtricitabine (FTC), and tenofovir alafenamide (TAF) for oral administration.

  • EVG is an HIV-1 integrase strand transfer inhibitor.
  • COBI is a mechanism-based inhibitor of cytochrome P450 (CYP) enzymes of the CYP3A family.
  • FTC, a synthetic nucleoside analog of cytidine, is an HIV nucleoside analog reverse transcriptase inhibitor (HIV NRTI).
  • TAF, an HIV NRTI, is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5′-monophosphate.

Each tablet contains 150 mg of EVG, 150 mg of COBI, 200 mg of FTC, and 10 mg of TAF (equivalent to 11.2 mg of tenofovir alafenamide fumarate).

The tablets include the following inactive ingredients: croscarmellose sodium, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, silicon dioxide, and sodium lauryl sulfate. The tablets are film-coated with a coating material containing FD&C Blue No. 2/indigo carmine aluminum lake, iron oxide yellow, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide.

Elvitegravir: The chemical name of elvitegravir is 6-(3-chloro-2-fluorobenzyl)-1-[(2S)-1­hydroxy-3-methylbutan-2-yl]-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid. It has a molecular formula of C23H23ClFNO5 and a molecular weight of 447.88.

Cobicistat: The chemical name for cobicistat is 2,7,10,12-tetraazatridecanoic acid, 12­methyl-13-[2-(1-methylethyl)-4-thiazolyl]-9-[2-(4-morpholinyl)ethyl]-8,11-dioxo-3,6­bis(phenylmethyl)-, 5-thiazolylmethyl ester, (3R,6R,9S)-. It has a molecular formula of C40H53N7O5S2 and a molecular weight of 776.02.

Emtricitabine: The chemical name of emtricitabine is 4-amino-5-fluoro-1-(2R­ hydroxymethyl-1,3-oxathiolan-5S-yl)-(1H)-pyrimidin-2-one. Emtricitabine is the (-)-enantiomer of a thio analog of cytidine, which differs from other cytidine analogs in that it has a fluorine in the 5 position. It has a molecular formula of C8H10FN3O3S and a molecular weight of 247.24.

Tenofovir alafenamide (TAF): The chemical name of tenofovir alafenamide fumarate drug substance is L -alanine, N-[(S)-[[(1R)-2-(6-amino-9H-purin-9-yl)-1­methylethoxy]methyl]phenoxyphosphinyl]-, 1-methylethyl ester, (2E)-2-butenedioate (2:1). It has an empirical formula of C21H29O5N6P•1⁄2(C4H4O4) and a formula weight of 534.5.

INDICATIONS AND USAGE

GENVOYA is indicated as a complete regimen for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 25 kg 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.

Mechanism of Action

Elvitegravir: Elvitegravir inhibits the strand transfer activity of HIV-1 integrase (integrase strand transfer inhibitor; INSTI), an HIV-1 encoded enzyme that is required for viral replication. Inhibition of integrase prevents the integration of HIV-1 DNA into host genomic DNA, blocking the formation of the HIV-1 provirus and propagation of the viral infection. Elvitegravir does not inhibit human topoisomerases I or II.

Cobicistat: Cobicistat is a selective, mechanism-based inhibitor of cytochromes P450 of the CYP3A subfamily. Inhibition of CYP3A-mediated metabolism by cobicistat enhances the systemic exposure of CYP3A substrates, such as elvitegravir, where bioavailability is limited and half-life is shortened by CYP3A-dependent metabolism.

Emtricitabine: Emtricitabine, a synthetic nucleoside analog of cytidine, is phosphorylated by cellular enzymes to form emtricitabine 5′-triphosphate. Emtricitabine 5′-triphosphate inhibits the activity of the HIV-1 reverse transcriptase by competing with the natural substrate deoxycytidine 5′-triphosphate and by being incorporated into nascent viral DNA which results in chain termination. Emtricitabine 5′-triphosphate is a weak inhibitor of mammalian DNA polymerases α, β, Ɛ, and mitochondrial DNA polymerase γ.

Tenofovir Alafenamide (TAF): TAF is a phosphonamidate prodrug of tenofovir (2’­deoxyadenosine monophosphate analog). Plasma exposure to TAF allows for permeation into cells and then TAF is intracellularly converted to tenofovir through hydrolysis by cathepsin A. Tenofovir is subsequently phosphorylated by cellular kinases to the active metabolite tenofovir diphosphate. Tenofovir diphosphate inhibits HIV-1 replication through incorporation into viral DNA by the HIV reverse transcriptase, which results in DNA chain-termination.

Tenofovir has activity that is specific to human immunodeficiency virus and hepatitis B virus. Cell culture studies have shown that both emtricitabine and tenofovir can be fully phosphorylated when combined in cells. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases that include mitochondrial DNA polymerase γ and there is no evidence of mitochondrial toxicity in cell culture based on several assays including mitochondrial DNA analyses.

DOSAGE AND ADMINISTRATION

Prior to or when initiating GENVOYA, test patients for hepatitis B virus infection.

Prior to or when initiating GENVOYA, and during treatment with GENVOYA on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus.

Recommended Dosage in Adults and Pediatric Patients Weighing at Least 25 kg.

GENVOYA is a four-drug fixed dose combination product containing elvitegravir (EVG), cobicistat (COBI), emtricitabine (FTC), and tenofovir alafenamide (TAF). The recommended dosage of GENVOYA is one tablet containing 150 mg EVG,150 mg COBI, 200 mg FTC, and 10 mg TAF taken orally once daily with food in:

  • adults and pediatric patients with body weight at least 25 kg and creatinine clearance greater than or equal to 30 mL per minute; or
  • adults with creatinine clearance below 15 mL per minute who are receiving chronic hemodialysis. On days of hemodialysis, administer GENVOYA after completion of hemodialysis treatment

Not Recommended in Patients with Severe Renal Impairment

GENVOYA is not recommended in patients with:

  • severe renal impairment (estimated creatinine clearance of 15 to below 30 mL per minute); or
  • end stage renal disease (ESRD; estimated creatinine clearance below 15 mL per minute) who are not receiving chronic hemodialysis

Not Recommended in Patients with Severe Hepatic Impairment

GENVOYA is not recommended in patients with severe hepatic impairment (Child-Pugh Class C)

Not Recommended During Pregnancy

GENVOYA is not recommended for use during pregnancy because of substantially lower exposures of cobicistat and elvitegravir during the second and third trimesters.

GENVOYA should not be initiated in pregnant individuals. An alternative regimen is recommended for individuals who become pregnant during therapy with GENVOYA

CONTRAINDICATIONS

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. These drugs and other contraindicated drugs (which may lead to reduced efficacy of GENVOYA and possible resistance) are listed below

  • Alpha 1-adrenoreceptor antagonist: alfuzosin
  • Anticonvulsants: carbamazepine, phenobarbital, phenytoin
  • Antimycobacterial: rifampin
  • Antipsychotics: lurasidone, pimozide
  • Ergot Derivatives: dihydroergotamine, ergotamine, methylergonovine
  • Herbal Products: St. John’s wort (Hypericum perforatum)
  • Lipid-modifying Agents: lomitapide, lovastatin, simvastatin
  • Phosphodiesterase-5 (PDE-5) Inhibitor: sildenafil when administered as REVATIO® for the treatment of pulmonary arterial hypertension
  • Sedative/hypnotics: triazolam, orally administered midazolam

WARNINGS AND PRECAUTIONS

Severe Acute Exacerbation of Hepatitis B in Patients Coinfected with HIV-1 and HBV: Patients with HIV-1 should be tested for the presence of hepatitis B virus (HBV) before or when initiating antiretroviral therapy.

Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions: The concomitant use of GENVOYA and other drugs may result in known or potentially significant drug interactions, some of which may lead to

  • Loss of of therapeutic effect of GENVOYA and possible development of resistance
  • Clinically significant adverse reactions, potentially leading to severe, life-threatening, or fatal events, from greater exposures of concomitant drugs metabolized by CYP3A.
  • Loss of therapeutic effect of concomitant drugs that utilize CYP3A to form active metabolites.

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including emtricitabine, a component of GENVOYA. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections [such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), or tuberculosis], which may necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves’ disease, polymyositis, Guillain-Barré syndrome, and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment.

New Onset or Worsening Renal Impairment:

Postmarketing cases of renal impairment, including acute renal failure, proximal renal tubulopathy (PRT), and Fanconi syndrome have been reported with TAF-containing products; while most of these cases were characterized by potential confounders that may have contributed to the reported renal events, it is also possible these factors may have predisposed patients to tenofovir-related adverse events

GENVOYA is not recommended in patients with estimated creatinine clearance of 15 to below 30 mL per minute, or in patients with estimated creatinine clearance below 15 mL per minute who are not receiving chronic hemodialysis.

Patients taking tenofovir prodrugs who have impaired renal function and those taking nephrotoxic agents including non-steroidal anti-inflammatory drugs are at increased risk of developing renal-related adverse reactions.

Lactic Acidosis/Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including emtricitabine, a component of GENVOYA, and tenofovir DF, another prodrug of tenofovir, alone or in combination with other antiretrovirals. Treatment with GENVOYA should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

DRUG INTERACTIONS

Not Recommended with Other Antiretroviral Medications

GENVOYA is a complete regimen for the treatment of HIV-1 infection; therefore, coadministration of GENVOYA with other antiretroviral medications for treatment of HIV­1 infection should be avoided. Complete information regarding potential drug-drug interactions with other antiretroviral medications is not provided

USE IN SPECIFIC POPULATIONS

Pregnancy: GENVOYA is not recommended during pregnancy. A literature report evaluating the pharmacokinetics of antiretrovirals during pregnancy demonstrated substantially lower exposures of elvitegravir and cobicistat in the second and third trimesters.

Lactation: The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV.

Based on published data, 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. It is unknown if TAF is present in animal milk.

It is not known if GENVOYA affects milk production or has effects on the breastfed child. Because of the potential for 1) HIV transmission (in HIV-negative infants); 2) developing viral resistance (in HIV-positive infants); and 3) adverse reactions in a breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are receiving GENVOYA.

Pediatric Use

The safety and effectiveness of GENVOYA for the treatment of HIV-1 infection was established in pediatric patients with body weight greater than or equal to 25 kg

Geriatric Use

Clinical trials of GENVOYA included 97 subjects (80 receiving GENVOYA) aged 65 years and over. No differences in safety or efficacy have been observed between elderly subjects and adults between 18 and less than 65 years of age.

Hepatic Impairment

No dosage adjustment of GENVOYA is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. GENVOYA has not been studied in patients with severe hepatic impairment (Child-Pugh Class C). Therefore, GENVOYA is not recommended for use in patients with severe hepatic impairment

OVERDOSAGE

No data are available on overdose of GENVOYA in patients. If overdose occurs, monitor the patient for evidence of toxicity. Treatment of overdose with GENVOYA consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient.

Elvitegravir: Limited clinical experience is available at doses higher than the recommended dose of elvitegravir in GENVOYA. In one study, elvitegravir (administered with the CYP3A inhibitor cobicistat) equivalent to 2 times the therapeutic dose of 150 mg once daily for 10 days was administered to 42 healthy subjects. No severe adverse reactions were reported. The effects of higher doses are not known. As elvitegravir is highly bound to plasma proteins, it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis.

Cobicistat: Limited clinical experience is available at doses higher than the recommended dose of cobicistat in GENVOYA. In two studies, a single dose of cobicistat 400 mg (2.7 times the dose in GENVOYA) was administered to a total of 60 healthy subjects. No severe adverse reactions were reported. The effects of higher doses are not known. As cobicistat is highly bound to plasma proteins, it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis.

Emtricitabine: Limited clinical experience is available at doses higher than the recommended dose of emtricitabine in GENVOYA. In one clinical pharmacology study, single doses of emtricitabine 1200 mg (6 times the dose in GENVOYA) were administered to 11 subjects. No severe adverse reactions were reported. The effects of higher doses are not known.

Hemodialysis treatment removes approximately 30% of the emtricitabine dose over a 3­hour dialysis period starting within 1.5 hours of emtricitabine dosing (blood flow rate of 400 mL per minute and a dialysate flow rate of 600 mL per minute). It is not known whether emtricitabine can be removed by peritoneal dialysis.

Tenofovir alafenamide (TAF): Limited clinical experience is available at doses higher than the recommended dose of TAF in GENVOYA. A single dose of 125 mg TAF (12.5 times the dose in GENVOYA) was administered to 48 healthy subjects; no serious adverse reactions were reported. The effects of higher doses are unknown. Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%.

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