Genvoya 150 MG / 150 MG / 200 MG / 10 MG Oral Tablet
DRUG INTERACTIONS
7 GENVOYA should not be administered with other antiretroviral medications for treatment of HIV-1 infection.
(7.1) GENVOYA can alter the concentration of drugs metabolized by CYP3A or CYP2D6.
Drugs that induce CYP3A can alter the concentrations of one or more components of GENVOYA.
Consult the full prescribing information prior to and during treatment for potential drug-drug interactions.
(4, 7.2, 7.3, 12.3) 7.1 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 HIV-1 infection should be avoided.
Complete information regarding potential drug-drug interactions with other antiretroviral medications is not provided [see Contraindications, Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)].
7.2 Potential for GENVOYA to Affect Other Drugs Cobicistat, a component of GENVOYA, is an inhibitor of CYP3A and CYP2D6 and an inhibitor of the following transporters: p-glycoprotein (P-gp), BCRP, OATP1B1 and OATP1B3.
Thus, coadministration of GENVOYA with drugs that are primarily metabolized by CYP3A or CYP2D6, or are substrates of P-gp, BCRP, OATP1B1 or OATP1B3 may result in increased plasma concentrations of such drugs (see Table 5).
Elvitegravir is a modest inducer of CYP2C9 and may decrease the plasma concentrations of CYP2C9 substrates.
TAF is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or UGT1A1.
TAF is a weak inhibitor of CYP3A in vitro.
TAF is not an inhibitor or inducer of CYP3A in vivo.
7.3 Potential for Other Drugs to Affect One or More Components of GENVOYA Elvitegravir and cobicistat, components of GENVOYA, are metabolized by CYP3A.
Cobicistat is also metabolized, to a minor extent, by CYP2D6.
Drugs that induce CYP3A activity are expected to increase the clearance of elvitegravir and cobicistat, resulting in decreased plasma concentration of cobicistat, elvitegravir, and TAF, which may lead to loss of therapeutic effect of GENVOYA and development of resistance (see Table 5).
Coadministration of GENVOYA with other drugs that inhibit CYP3A may decrease the clearance and increase the plasma concentration of cobicistat (see Table 5).
TAF, a component of GENVOYA, is a substrate of P-gp, BCRP, OATP1B1 and OATP1B3.
Drugs that inhibit P-gp and/or BCRP, such as cobicistat, may increase the absorption of TAF (see Table 10).
However, when TAF is administered as a component of GENVOYA, its availability is increased by cobicistat and a further increase of TAF concentrations is not expected upon coadministration of an additional P-gp and/or BCRP inhibitor.
Drugs that induce P-gp activity are expected to decrease the absorption of TAF, resulting in decreased plasma concentration of TAF.
7.4 Drugs Affecting Renal Function Because emtricitabine and tenofovir are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion, coadministration of GENVOYA with drugs that reduce renal function or compete for active tubular secretion may increase concentrations of emtricitabine, tenofovir, and other renally eliminated drugs and this may increase the risk of adverse reactions.
Some examples of drugs that are eliminated by active tubular secretion include, but are not limited to, acyclovir, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs [see Warnings and Precautions (5.6)].
7.5 Established and Other Potentially Significant Interactions Table 5 provides a listing of established or potentially clinically significant drug interactions.
The drug interactions described are based on studies conducted with either GENVOYA, the components of GENVOYA (elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide) as individual agents and/or in combination, or are predicted drug interactions that may occur with GENVOYA [for magnitude of interaction, see Clinical Pharmacology (12.3)].
The table includes potentially significant interactions but is not all inclusive.
Table 5 Established and Other Potentially SignificantThis table is not all inclusive.
Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction Concomitant Drug Class: Drug Name Effect on Concentration↑ = Increase, ↓ = Decrease, ↔ = No Effect Clinical Comment Acid Reducing Agents: antacidsIndicates that a drug-drug interaction trial was conducted.
e.g., aluminum and magnesium hydroxide ↓ elvitegravir Separate GENVOYA and antacid administration by at least 2 hours.
Antiarrhythmics: e.g., amiodarone bepridil digoxin disopyramide flecainide systemic lidocaine mexiletine propafenone quinidine ↑ antiarrhythmics ↑ digoxin Caution is warranted and therapeutic concentration monitoring, if available, is recommended for antiarrhythmics when coadministered with GENVOYA.
Antibacterials: clarithromycin telithromycin ↑ clarithromycin ↑ telithromycin ↑ cobicistat Patients with CLcr greater than or equal to 60 mL/minute: No dosage adjustment of clarithromycin is required.
Patients with CLcr between 50 mL/minute and 60 mL/minute: The dosage of clarithromycin should be reduced by 50%.
Anticoagulants: warfarin Effect on warfarin unknown Monitor the international normalized ratio (INR) upon coadministration with GENVOYA.
Anticonvulsants: ethosuximide oxcarbazepine ↑ ethosuximide ↓ elvitegravir ↓ cobicistat ↓ TAF Contraindicated anticonvulsants [see Contraindications (4)] Alternative anticonvulsants should be considered when GENVOYA is administered with oxcarbazepine.
Clinical monitoring is recommended upon coadministration of ethosuximide with GENVOYA.
Antidepressants: Selective Serotonin Reuptake Inhibitors (SSRIs) e.g., paroxetine Tricyclic Antidepressants (TCAs) e.g., amitriptyline desipramine imipramine nortriptyline bupropion trazodone ↑ SSRIs (except sertraline) ↑ TCAs ↑ trazodone Careful dosage titration of the antidepressant and monitoring for antidepressant response are recommended when coadministered with GENVOYA.
Antifungals: itraconazole ketoconazole voriconazole ↑ elvitegravir ↑ cobicistat ↑ itraconazole ↑ ketoconazole ↑ voriconazole When administering with GENVOYA, the maximum daily dosage of ketoconazole or itraconazole should not exceed 200 mg per day.
An assessment of benefit/risk ratio is recommended to justify use of voriconazole with GENVOYA.
Anti-gout: colchicine ↑ colchicine GENVOYA is not recommended to be coadministered with colchicine to patients with renal or hepatic impairment.
Treatment of gout-flares – coadministration of colchicine in patients receiving GENVOYA: 0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later.
Treatment course to be repeated no earlier than 3 days.
Prophylaxis of gout-flares – coadministration of colchicine in patients receiving GENVOYA: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.
If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.
Treatment of familial Mediterranean fever – coadministration of colchicine in patients receiving GENVOYA: Maximum daily dosage of 0.6 mg (may be given as 0.3 mg twice a day).
Antimycobacterial: rifabutin rifapentine ↓ elvitegravir ↓ cobicistat ↓ TAF Contraindicated antimycobacterials [see Contraindications (4)] Coadministration of GENVOYA with rifabutin or rifapentine is not recommended.
Antipsychotics: e.g., perphenazine risperidone thioridazine quetiapine ↑ antipsychotic ↑ quetiapine Contraindicated antipsychotics [see Contraindications (4)] A decrease in dose of the antipsychotics that are metabolized by CYP3A or CYP2D6 may be needed when co-administered with GENVOYA.
Initiation of GENVOYA in patients taking quetiapine: Consider alternative antiretroviral therapy to avoid increases in quetiapine exposure.
If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions.
Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring.
Initiation of quetiapine in patients taking GENVOYA: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.
Benzodiazepines: e.g., Parenterally administered midazolam clorazepate diazepam estazolam flurazepam lorazepam ↑ diazepam ↔ lorazepam ↑ midazolam Coadministration of GENVOYA with diazepam or parenterally administered midazolam should be done in a setting that ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation.
Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered.
Based on non-CYP-mediated elimination pathways for lorazepam, no effect on plasma concentrations is expected upon coadministration with GENVOYA.
Beta-Blockers: e.g., metoprolol timolol ↑ beta-blockers Clinical monitoring is recommended and a dosage decrease of the beta blocker may be necessary when these agents are coadministered with GENVOYA.
Calcium Channel Blockers: e.g., amlodipine diltiazem felodipine nicardipine nifedipine verapamil ↑ calcium channel blockers Caution is warranted and clinical monitoring is recommended upon coadministration of calcium channel blockers with GENVOYA.
Corticosteroid: Systemic: dexamethasone ↓ elvitegravir ↓ cobicistat An alternative corticosteroid should be considered for coadministration with GENVOYA.
Corticosteroid: Inhaled/Nasal: fluticasone ↑ fluticasone Alternative corticosteroids should be considered, particularly for long term use.
Endothelin Receptor Antagonists: bosentan ↑ bosentan Coadministration of bosentan in patients on GENVOYA: In patients who have been receiving GENVOYA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
Coadministration of GENVOYA in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of GENVOYA.
After at least 10 days following the initiation of GENVOYA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
HMG-CoA Reductase Inhibitors: atorvastatin ↑ atorvastatin Contraindicated HMG-CoA reductase inhibitors [see Contraindications (4)] Initiate with the lowest starting dose of atorvastatin and titrate carefully while monitoring for safety.
Hormonal Contraceptives: norgestimate/ethinyl estradiol ↑ norgestimate ↓ ethinyl estradiol The effects of increases in the concentration of the progestational component norgestimate are not fully known and can include increased risk of insulin resistance, dyslipidemia, acne, and venous thrombosis.
The potential risks and benefits associated with coadministration of norgestimate/ethinyl estradiol with GENVOYA should be considered, particularly in women who have risk factors for these events.
The effect of GENVOYA on other hormonal contraceptives (e.g., contraceptive patch, contraceptive vaginal ring, or injectable contraceptives) or oral contraceptives containing progestogens other than norgestimate is not known; therefore, alternative (non-hormonal) methods of contraception can be considered.
Immuno-suppressants: e.g., cyclosporine (CsA) sirolimus tacrolimus ↑ immuno-suppressants ↑ elvitegravir (with CsA) ↑ cobicistat (with CsA) Therapeutic monitoring of the immunosuppressive agents is recommended upon coadministration with GENVOYA.
Monitor for adverse events associated with GENVOYA when coadministered with cyclosporine.
Narcotic Analgesics: buprenorphine/ naloxone ↑ buprenorphine ↑ norbuprenorphine ↓ naloxone No dosage adjustment of buprenorphine/naloxone is required upon coadministration with GENVOYA.
Patients should be closely monitored for sedation and cognitive effects.
Inhaled Beta Agonist: salmeterol ↑ salmeterol Coadministration of salmeterol and GENVOYA is not recommended.
Coadministration of salmeterol with GENVOYA may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.
Phosphodiesterase-5 (PDE5) Inhibitors: sildenafil tadalafil vardenafil ↑ PDE5 inhibitors Contraindicated PDE-5 inhibitors [see Contraindications (4)] Coadministration with GENVOYA may result in an increase in PDE-5 inhibitor associated adverse reactions, including hypotension, syncope, visual disturbances, and priapism.
Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH): Use of sildenafil is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH).
The following dose adjustments are recommended for the use of tadalafil with GENVOYA: Coadministration of tadalafil in patients on GENVOYA: In patients receiving GENVOYA for at least 1 week, start tadalafil at 20 mg once daily.
Increase tadalafil dose to 40 mg once daily based upon individual tolerability.
Coadministration of GENVOYA in patients on tadalafil: Avoid use of tadalafil during the initiation of GENVOYA.
Stop tadalafil at least 24 hours prior to starting GENVOYA.
After at least one week following initiation of GENVOYA, resume tadalafil at 20 mg once daily.
Increase tadalafil dose to 40 mg once daily based upon individual tolerability.
Use of PDE-5 inhibitors for erectile dysfunction: Sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg in 72 hours, or tadalafil at a single dose not exceeding 10 mg in 72 hours can be used with increased monitoring for PDE-5 inhibitor associated with adverse events.
Sedative/hypnotics: buspirone zolpidem ↑ sedatives/hypnotics Contraindicated sedative/hypnotics [see Contraindications (4)] With sedative/hypnotics, dose reduction may be necessary and clinical monitoring is recommended.
7.6 Drugs without Clinically Significant Interactions with GENVOYA Based on drug interaction studies conducted with the components of GENVOYA, no clinically significant drug interactions have been either observed or are expected when GENVOYA is combined with the following drugs: entecavir, famciclovir, H2 receptor antagonists, ledipasvir, lorazepam, methadone, proton pump inhibitors, ribavirin, sertraline, sofosbuvir, and velpatasvir.
OVERDOSAGE
10 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, boosted elvitegravir 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 3-hour 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%.
DESCRIPTION
11 GENVOYA (elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide) is a fixed-dose combination tablet containing elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide for oral administration.
Elvitegravir is an HIV-1 integrase strand transfer inhibitor.
Cobicistat is a mechanism-based inhibitor of cytochrome P450 (CYP) enzymes of the CYP3A family.
Emtricitabine, a synthetic nucleoside analog of cytidine, is an HIV nucleoside analog reverse transcriptase inhibitor (HIV NRTI).
Tenofovir alafenamide, 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 elvitegravir, 150 mg of cobicistat, 200 mg of emtricitabine, and 10 mg of tenofovir alafenamide (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)-1-hydroxy-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.
It has the following structural formula: Elvitegravir is a white to pale yellow powder with a solubility of less than 0.3 micrograms per mL in water at 20 °C.
Chemical Structure Cobicistat: The chemical name for cobicistat is 2,7,10,12-tetraazatridecanoic acid, 12-methyl-13-[2-(1-methylethyl)-4-thiazolyl]-9-[2-(4-morpholinyl)ethyl]-8,11-dioxo-3,6-bis(phenylmethyl)-, 5-thiazolylmethyl ester, (3R,6R,9S)-.
It has a molecular formula of C40H53N7O5S2 and a molecular weight of 776.02.
It has the following structural formula: Cobicistat is adsorbed onto silicon dioxide.
Cobicistat on silicon dioxide drug substance is a white to pale yellow powder with a solubility of 0.1 mg per mL in water at 20 °C.
Chemical Structure 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.
It has the following structural formula: Emtricitabine is a white to off-white powder with a solubility of approximately 112 mg per mL in water at 25 °C.
Chemical Structure 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)-1-methylethoxy]methyl]phenoxyphosphinyl]-, 1-methylethyl ester, (2E)-2-butenedioate (2:1).
It has an empirical formula of C21H29O5N6P∙½(C4H4O4) and a formula weight of 534.5.
It has the following structural formula: Tenofovir alafenamide fumarate is a white to off-white or tan powder with a solubility of 4.7 mg per mL in water at 20 °C.
Chemical Structure
CLINICAL STUDIES
14 14.1 Description of Clinical Trials The efficacy and safety of GENVOYA were evaluated in the studies summarized in Table 12.
Table 12 Trials Conducted with GENVOYA in Subjects with HIV-1 Infection Trial Population Study Arms (N) Timepoint (Week) Study 104Randomized, double blind, active controlled trial.
Study 111 Treatment-naïve adults GENVOYA (866) STRIBILD (867) 96 Study 109Randomized, open label, active controlled trial.
Virologically-suppressedHIV-1 RNA less than 50 copies per mL.
adults GENVOYA (799) ATRIPLA® or TRUVADA®+atazanavir+cobicistat or ritonavir or STRIBILD (397) 48 Study 112Open label trial.
Virologically-suppressed adults with renal impairmenteGFR of 30 to 69 mL per minute by Cockcroft-Gault method.
GENVOYA (242) 24 Study 106 Treatment-naïve adolescents between the ages of 12 to less than 18 years GENVOYA (23) 24 14.2 Clinical Trial Results in HIV-1 Treatment-Naïve Subjects In both Study 104 and Study 111, subjects were randomized in a 1:1 ratio to receive either GENVOYA (N=866) once daily or STRIBILD (elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, TDF 300 mg) (N=867) once daily.
The mean age was 36 years (range 18–76), 85% were male, 57% were White, 25% were Black, and 10% were Asian.
Nineteen percent of subjects identified as Hispanic/Latino.
The mean baseline plasma HIV-1 RNA was 4.5 log10 copies per mL (range 1.3–7.0) and 23% of subjects had baseline viral loads greater than 100,000 copies per mL.
The mean baseline CD4+ cell count was 427 cells per mm3 (range 0–1360) and 13% had CD4+ cell counts less than 200 cells per mm3.
Pooled treatment outcomes of Studies 104 and 111 through Week 96 are presented in Table 13.
Table 13 Pooled Virologic Outcomes of Randomized Treatment in Studies 104 and 111 at Week 96Week 96 window was between Day 630 and 713 (inclusive).
in Treatment-Naïve Subjects GENVOYA (N=866) STRIBILD (N=867) HIV-1 RNA < 50 copies/mL 87% 85% Treatment Difference 1.5% (95% CI: –1.7% to 4.8%) HIV-1 RNA ≥ 50 copies/mL Included subjects who had ≥50 copies/mL in the Week 96 window; subjects who discontinued early due to lack or loss of efficacy; subjects who discontinued for reasons other than an adverse event (AE), death or lack or loss of efficacy and at the time of discontinuation had a viral value of ≥ 50 copies/mL.
5% 4% No Virologic Data at Week 96 Window 9% 11% Discontinued Study Drug Due to AE or DeathIncludes subjects who discontinued due to AE or death at any time point from Day 1 through the time window if this resulted in no virologic data on treatment during the specified window.
1% 2% Discontinued Study Drug Due to Other Reasons and Last Available HIV-1 RNA < 50 copies/mLIncludes subjects who discontinued for reasons other than an AE, death or lack or loss of efficacy; e.g., withdrew consent, loss to follow-up, etc.
6% 7% Missing Data During Window but on Study Drug 2% 1% Treatment outcomes were similar across subgroups by age, sex, race, baseline viral load, and baseline CD4+ cell count.
In Studies 104 and 111, the mean increase from baseline in CD4+ cell count at Week 96 was 280 cells per mm3 in GENVOYA-treated subjects and 266 cells per mm3 in STRIBILD-treated subjects.
14.3 Clinical Trial Results in HIV-1 Virologically-Suppressed Subjects Who Switched to GENVOYA In Study 109, the efficacy and safety of switching from either ATRIPLA, TRUVADA plus atazanavir (given with either cobicistat or ritonavir), or STRIBILD to GENVOYA once daily were evaluated in a randomized, open-label trial of virologically-suppressed (HIV-1 RNA less than 50 copies per mL) HIV-1 infected adults (1196 of 1436 enrolled and treated were evaluable for efficacy).
Subjects must have been suppressed (HIV-1 RNA less than 50 copies per mL) on their baseline regimen for at least 6 months and had no known resistance-associated substitutions to any of the components of GENVOYA prior to study entry.
Subjects were randomized in a 2:1 ratio to either switch to GENVOYA at baseline (N=799), or stay on their baseline antiretroviral regimen (N=397).
Subjects had a mean age of 41 years (range 21–72), 90% were male, 67% were White, and 21% were Black.
The mean baseline CD4+ cell count was 705 cells per mm3 (range 79–1951).
Subjects were stratified by prior treatment regimen.
At screening, 42% of subjects were receiving TRUVADA plus atazanavir (given with either cobicistat or ritonavir), 32% were receiving STRIBILD, and 26% were receiving ATRIPLA.
Treatment outcomes of Study 109 through 48 weeks are presented in Table 14.
Table 14 Virologic Outcomes of Study 109 at Week 48Week 48 window was between Day 294 and 377 (inclusive).
in Virologically-Suppressed Subjects who Switched to GENVOYA GENVOYA (N=799) ATRIPLA or TRUVADA+atazanavir +cobicistat or ritonavir or STRIBILD (N=397) HIV-1 RNA < 50 copies/mL 96% 93% HIV-1 RNA ≥ 50 copies/mLIncluded subjects who had ≥50 copies/mL in the Week 48 window; subjects who discontinued early due to lack or loss of efficacy; subjects who discontinued for reasons other than an adverse event (AE), death or lack or loss of efficacy and at the time of discontinuation had a viral value of ≥50 copies/mL.
1% 1% No Virologic Data at Week 48 Window 3% 6% Discontinued Study Drug Due to AE or DeathIncludes subjects who discontinued due to AE or death at any time point from Day 1 through the time window if this resulted in no virologic data on treatment during the specified window.
1% 1% Discontinued Study Drug Due to Other Reasons and Last Available HIV-1 RNA < 50 copies/mLIncludes subjects who discontinued for reasons other than an AE, death or lack or loss of efficacy; e.g., withdrew consent, loss to follow-up, etc.
1% 4% Missing Data During Window but on Study Drug 2% 1% Treatment outcomes were similar across subgroups receiving ATRIPLA, TRUVADA plus atazanavir (given with either cobicistat or ritonavir), or STRIBILD prior to randomization.
In Study 109, the mean increase from baseline in CD4+ cell count at Week 48 was 33 cells per mm3 in GENVOYA-treated subjects and 27 cells per mm3 in subjects who stayed on their baseline regimen.
14.4 Clinical Trial Results in HIV-1 Infected Subjects with Renal Impairment In Study 112, the efficacy and safety of GENVOYA once daily were evaluated in an open-label clinical trial of 248 HIV-1 infected subjects with renal impairment (eGFR of 30 to 69 mL per minute by Cockcroft-Gault method).
Of the 248 enrolled, 6 were treatment naïve and 242 were virologically suppressed (HIV-1 RNA less than 50 copies per mL) for at least 6 months before switching to GENVOYA [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].
The mean age was 58 years (range 24–82), with 63 subjects (26%) who were 65 years of age or older.
Seventy-nine percent were male, 63% were White, 18% were Black, and 14% were Asian.
Thirteen percent of subjects identified as Hispanic/Latino.
The mean baseline CD4+ cell count was 664 cells per mm3 (range 126–1813).
At Week 24, 95% (230/242 virologically suppressed subjects) maintained HIV-1 RNA less than 50 copies per mL after switching to GENVOYA.
Three subjects had virologic failure at Week 24.
14.5 Clinical Trial Results in HIV-1 Treatment-Naïve Adolescent Subjects Aged 12 to Less than 18 In Study 106, the efficacy, safety, and pharmacokinetics of GENVOYA were evaluated in an open-label trial in HIV-1 infected treatment-naïve adolescents aged 12 to less than 18 years.
Twenty-three subjects treated with GENVOYA once daily for 24 weeks had a mean age of 14 years; 52% were male, 17% were Asian, and 83% were black.
At baseline, mean plasma HIV-1 RNA was 4.8 log10 copies per mL (35% had baseline plasma HIV-1 RNA greater than 100,000 copies per mL), median CD4+ cell count was 456 cells per mm3 (range: 104 to 748), and median CD4+ percentage was 23% (range: 7% to 41%).
At 24 weeks, the virologic response rate to GENVOYA in treatment-naïve HIV-1 infected adolescents was similar to response rates in trials of treatment-naïve HIV-1 infected adults; 91% achieved HIV-1 RNA less than 50 copies per mL.
The mean increase from baseline in CD4+ cell count at Week 24 was 212 cells per mm3.
Two subjects had virologic failure at Week 24; neither subject had evidence of resistance to GENVOYA.
HOW SUPPLIED
Product: 50090-2279 NDC: 50090-2279-0 30 TABLET in a BOTTLE, PLASTIC
RECENT MAJOR CHANGES
Contraindications (4) 09/2016
GERIATRIC USE
8.5 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 those between 12 and less than 65 years of age.
DOSAGE FORMS AND STRENGTHS
3 Each GENVOYA tablet contains 150 mg of elvitegravir, 150 mg of cobicistat, 200 mg of emtricitabine, and 10 mg of tenofovir alafenamide (TAF) (equivalent to 11.2 mg of tenofovir alafenamide fumarate).
The tablets are green, capsule-shaped, film-coated tablets, debossed with “GSI” on one side of the tablet and the number “510” on the other side of the tablet.
Tablets: 150 mg of elvitegravir, 150 mg of cobicistat, 200 mg of emtricitabine, and 10 mg of tenofovir alafenamide.
(3)
MECHANISM OF ACTION
12.1 Mechanism of Action GENVOYA is a fixed-dose combination of antiretroviral drugs elvitegravir (boosted by the CYP3A inhibitor cobicistat), emtricitabine, and tenofovir alafenamide [see Microbiology (12.4)].
INDICATIONS AND USAGE
1 GENVOYA is indicated as a complete regimen for the treatment of HIV-1 infection in adults and pediatric patients 12 years of age and older 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 [see Clinical Studies (14)].
GENVOYA is a four-drug combination of elvitegravir, an HIV-1 integrase strand transfer inhibitor (INSTI), cobicistat, a CYP3A inhibitor, and emtricitabine and tenofovir alafenamide (TAF), both HIV-1 nucleoside analog reverse transcriptase inhibitors (NRTIs) and is indicated as a complete regimen for the treatment of HIV-1 infection in adults and pediatric patients 12 years of age and older 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.
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PEDIATRIC USE
8.4 Pediatric Use The efficacy and safety of GENVOYA for the treatment of HIV-1 infection was established in pediatric patents aged 12 years and older with body weight greater than or equal to 35 kg [see Dosage and Administration (2.2)].
Use of GENVOYA in this age group is supported by studies in adults and by a 24-week open-label trial of 23 antiretroviral treatment-naïve HIV-1 infected pediatric subjects 12 to less than 18 years old treated with GENVOYA (Study 106).
The safety and efficacy of GENVOYA in these subjects was similar to that in antiretroviral treatment-naïve adults [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.5)].
Safety and effectiveness of GENVOYA in pediatric patients less than 12 years of age or less than 35 kg have not been established.
PREGNANCY
8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to GENVOYA during pregnancy.
Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.
Risk Summary There are insufficient human data on the use of GENVOYA during pregnancy to inform a drug-associated risk of birth defects and miscarriage.
TAF use in women during pregnancy has not been evaluated; however, elvitegravir, cobicistat, and emtricitabine use during pregnancy has been evaluated in a limited number of women as reported to the APR.
Available data from the APR show no birth defects reported for elvitegravir or cobicistat, and no difference in the risk of overall major birth defects for emtricitabine (2.4%) compared with the background rate for major birth defects of 2.7% in a U.S.
reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP).
The rate of miscarriage is not reported in the APR.
The estimated background rate of miscarriage in the clinically recognized pregnancies in the U.S.
general population is 15–20%.
In animal studies, no adverse developmental effects were observed when the components of GENVOYA were administered separately during the period of organogenesis at exposures up to 23 and 0.2 times (rat and rabbits, respectively: elvitegravir), 1.6 and 3.8 times (rats and rabbits, respectively: cobicistat), 60 and 108 times (mice and rabbits, respectively; emtricitabine) and equal to and 53 times (rats and rabbits, respectively; TAF) the exposure at the recommended daily dosage of these components in GENVOYA [see Data].
Likewise, no adverse developmental effects were seen when elvitegravir or cobicistat was administered to rats through lactation at exposures up to 18 times or 1.2 times, respectively, the human exposure at the recommended therapeutic dose, and when emtricitabine was administered to mice through lactation at exposures up to approximately 60 times the exposure at the recommended daily dose.
No adverse effects were observed in the offspring when TDF was administered through lactation at tenofovir exposures of approximately 14 times the exposure at the recommended daily dosage of GENVOYA.
Data Human Data Elvitegravir: Based on prospective reports from the APR through July 2015 of 49 exposures to elvitegravir-containing regimens during pregnancy resulting in live births (including 31 exposed in the first trimester), there have been no birth defects reported.
Cobicistat: Based on prospective reports from the APR through July 2015 of 50 exposures to cobicistat-containing regimens during pregnancy resulting in live births (including 32 exposed in the first trimester), there have been no birth defects reported.
Emtricitabine: Based on prospective reports to the APR through July 2015 of 2933 exposures to emtricitabine-containing regimens during pregnancy resulting in live births (including 1984 exposed in the first trimester and 949 exposed in the second/third trimester), there was no difference between FTC and overall birth defects compared with the background birth defect rate of 2.7% in the U.S.
reference population of the MACDP.
The prevalence of birth defects in live births was 2.4% (95% CI: 1.7% to 3.1%) with first trimester exposure to FTC-containing regimens and 2.1% (95% CI: 1.3% to 3.2%) with the second/third trimester exposure to emtricitabine-containing regimens.
Animal Data Elvitegravir: Elvitegravir was administered orally to pregnant rats (0, 300, 1000, and 2000 mg/kg/day) and rabbits (0, 50, 150, and 450 mg/kg/day) through organogenesis (on gestation days 7 through 17 and days 7 through 19, respectively).
No significant toxicological effects were observed in embryo-fetal toxicity studies performed with elvitegravir in rats at exposures (AUC) approximately 23 times higher and in rabbits at approximately 0.2 times higher than human exposures at the recommended daily dose.
In a pre/postnatal developmental study, elvitegravir was administered orally to rats at doses of 0, 300, 1000, and 2000 mg/kg from gestation day 7 to day 20 of lactation.
At doses of 2000 mg/kg/day of elvitegravir, neither maternal nor developmental toxicity was noted.
Systemic exposures (AUC) at this dose were 18 times the human exposures at the recommended daily dose.
Cobicistat: Cobicistat was administered orally to pregnant rats at doses of 0, 25, 50, 125 mg/kg/day on gestation day 6 to 17.
Increases in postimplantation loss and decreased fetal weights were observed at a maternal toxic dose of 125 mg/kg/day.
No malformations were noted at doses up to 125 mg/kg/day.
Systemic exposures (AUC) at 50 mg/kg/day in pregnant females was 1.6 times higher than human exposures at the recommended daily dose.
In pregnant rabbits, cobicistat was administered orally at doses of 0, 20, 50, and 100 mg/kg/day during gestation days 7 to 20.
No maternal or embryo/fetal effects were noted at the highest dose of 100 mg/kg/day.
Systemic exposures (AUC) at 100 mg/kg/day were 3.8 times higher than human exposures at the recommended daily dose.
In a pre/postnatal developmental study in rats, cobicistat was administered orally at doses of 0, 10, 30, and 75 mg/kg from gestation day 6 to postnatal day 20, 21, or 22.
At doses of 75 mg/kg/day of cobicistat, neither maternal nor developmental toxicity was noted.
Systemic exposures (AUC) at this dose were 1.2 times the human exposures at the recommended daily dose.
Emtricitabine: Emtricitabine was administered orally to pregnant mice (250, 500, or 1000 mg/kg/day) and rabbits (100, 300, or 1000 mg/kg/day) through organogenesis (on gestation days 6 through 15, and 7 through 19, respectively).
No significant toxicological effects were observed in embryo-fetal toxicity studies performed with emtricitabine in mice at exposures (AUC) approximately 60 times higher and in rabbits at approximately 108 times higher than human exposures at the recommended daily dose.
In a pre/postnatal development study with emtricitabine, mice were administered doses up to 1000 mg/kg/day; no significant adverse effects directly related to drug were observed in the offspring exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 60 times higher than human exposures at the recommended daily dose.
Tenofovir Alafenamide (TAF): TAF was administered orally to pregnant rats (25, 100, or 250 mg/kg/day) and rabbits (10, 30, or 100 mg/kg/day) through organogenesis (on gestation days 6 through 17, and 7 through 20, respectively).
No adverse embryo-fetal effects were observed in rats and rabbits at TAF exposures similar to (rats) and approximately 53 (rabbits) times higher than the exposure in humans at the recommended daily dose of GENVOYA.
TAF is rapidly converted to tenofovir; the observed tenofovir exposure in rats and rabbits were 59 (rats) and 93 (rabbits) times higher than human tenofovir exposures at the recommended daily doses.
Since TAF is rapidly converted to tenofovir and a lower tenofovir exposure in rats and mice was observed after TAF administration compared to TDF administration, a pre/postnatal development study in rats was conducted only with TDF.
Doses up to 600 mg/kg/day were administered through lactation; no adverse effects were observed in the offspring on gestation day 7 [and lactation day 20] at tenofovir exposures of approximately 14 [21] times higher than the exposures in humans at the recommended daily dose of GENVOYA.
BOXED WARNING
WARNING: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs in combination with other antiretrovirals [see Warnings and Precautions (5.1)].
GENVOYA is not approved for the treatment of chronic hepatitis B virus (HBV) infection and the safety and efficacy of GENVOYA have not been established in patients coinfected with human immunodeficiency virus-1 (HIV-1) and HBV.
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 (TDF), and may occur with discontinuation of GENVOYA.
Hepatic function should be monitored closely 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 [see Warnings and Precautions (5.2)].
WARNING: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B See full prescribing information for complete boxed warning.
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs.
(5.1) GENVOYA is not approved for the treatment of chronic hepatitis B virus (HBV) infection.
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 (TDF), and may occur with discontinuation of GENVOYA.
Hepatic function should be monitored closely in these patients.
If appropriate, initiation of anti-hepatitis B therapy may be warranted.
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WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS 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 therapeutic effect of GENVOYA and possible development of resistance; and possible clinically significant adverse reactions from greater exposures of concomitant drugs.
(5.3) Redistribution/accumulation of body fat: Observed in patients receiving antiretroviral therapy.
(5.4) Immune reconstitution syndrome: May necessitate further evaluation and treatment.
(5.5) New onset or worsening renal impairment: Assess creatinine clearance, urine glucose, and urine protein in all patients before initiating GENVOYA therapy and monitor during therapy.
Monitor serum phosphorus in patients with chronic kidney disease.
(5.6) Bone loss and mineralization defects: Consider monitoring BMD in patients with a history of pathologic fracture or other risk factors of osteoporosis or bone loss.
(5.7) 5.1 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 in combination with other antiretrovirals.
A majority of these cases have been in women.
Obesity and prolonged nucleoside exposure may be risk factors.
Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors.
Since TAF and emtricitabine are nucleos(t)ide analogs, 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).
5.2 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 initiating antiretroviral therapy [see Dosage and Administration (2.1)].
GENVOYA is not approved for the treatment of chronic HBV infection and the safety and efficacy of GENVOYA have not been established in patients coinfected with HIV-1 and HBV.
Severe acute exacerbations of hepatitis B (e.g., liver decompensation and liver failure) have been 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 of GENVOYA.
Patients coinfected with HIV-1 and HBV who discontinue GENVOYA should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment.
If appropriate, initiation of anti-hepatitis B therapy may be warranted, especially in patients with advanced liver disease or cirrhosis, since post-treatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure.
5.3 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 [see Contraindications (4) and Drug Interactions (7.5)]: Loss of therapeutic effect of GENVOYA and possible development of resistance.
Possible clinically significant adverse reactions from greater exposures of concomitant drugs.
See Table 5 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations.
Consider the potential for drug interactions prior to and during GENVOYA therapy; review concomitant medications during GENVOYA therapy; and monitor for the adverse reactions associated with the concomitant drugs.
5.4 Fat Redistribution Redistribution or accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy.
The mechanism and long-term consequences of these events are currently unknown.
A causal relationship has not been established.
5.5 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, and Guillain-Barré syndrome) 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.
5.6 New Onset or Worsening Renal Impairment Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of tenofovir prodrugs in both animal toxicology studies and human trials.
In clinical trials of GENVOYA, there have been no cases of Fanconi syndrome or Proximal Renal Tubulopathy (PRT).
In clinical trials of GENVOYA in treatment naïve subjects and in virologically suppressed subjects switched to GENVOYA with eGFRs greater than 50 mL per minute, renal serious adverse events or discontinuations due to renal adverse reactions were encountered in less than 1% of participants treated with GENVOYA.
In a study of virologically suppressed subjects with baseline eGFRs between 30 and 69 mL per minute treated with GENVOYA for a median duration of 43 weeks, GENVOYA was permanently discontinued due to worsening renal function in two of 80 (3%) subjects with a baseline eGFR between 30 and 50 mL per minute [see Adverse Reactions (6.1)].
GENVOYA is not recommended in patients with estimated creatinine clearance below 30 mL per minute because data in this population are insufficient.
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.
Estimated creatinine clearance, urine glucose and urine protein should be assessed before initiating GENVOYA therapy and should be monitored during therapy in all patients.
Serum phosphorus should be monitored in patients with chronic kidney disease because these patients are at greater risk of developing Fanconi syndrome on tenofovir prodrugs.
Discontinue GENVOYA in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome.
Cobicistat, a component of GENVOYA, produces elevations of serum creatinine due to inhibition of tubular secretion of creatinine without affecting glomerular filtration [see Adverse Reactions (6.1)].
The elevation is typically seen within 2 weeks of starting therapy and is reversible after discontinuation.
Patients who experience a confirmed increase in serum creatinine of greater than 0.4 mg per dL from baseline should be closely monitored for renal safety.
5.7 Bone Loss and Mineralization Defects Bone Mineral Density (BMD): In animal toxicology studies and human clinical trials, TAF and tenofovir have been associated with decreases in bone mineral density and increases in biochemical markers of bone metabolism suggestive of increased bone turnover.
In clinical trials in HIV-1 infected treatment-naïve adults, a significant decline in bone mineral density was observed in 15% of subjects treated with GENVOYA [see Adverse Reactions (6.1)].
The long-term clinical significance of these changes has not been established.
Assessment of BMD should be considered for adults and pediatric patients treated with GENVOYA who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss.
Calcium and vitamin D supplementation may be beneficial for all patients.
If bone abnormalities are suspected then appropriate consultation should be obtained.
Mineralization Defects: Cases of osteomalacia associated with proximal renal tubulopathy, manifested as bone pain or pain in extremities and which may contribute to fractures, have been reported in association with the use of TDF-containing products.
Hypophosphatemia and osteomalacia secondary to proximal renal tubulopathy have occurred in patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms while receiving products containing TDF [see Warnings and Precautions (5.6)].
While not observed in clinical studies of GENVOYA, the risk of osteomalacia with GENVOYA is not known.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information).
Drug Interactions GENVOYA may interact with many drugs; therefore, advise patients to report to their healthcare provider the use of any other prescription or non-prescription medication or herbal products including St.
John’s wort [see Contraindications (4) and Drug Interactions (7)].
Lactic Acidosis Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with use of drugs similar to GENVOYA.
Advise patients that they should stop GENVOYA if they develop clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity [see Warnings and Precautions (5.1)].
Post-treatment Acute Exacerbation of Hepatitis B in Patients with HBV Co-Infection Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued products containing emtricitabine and/or TDF, and may likewise occur with discontinuation of GENVOYA [see Warnings and Precautions (5.2)].
Advise the patient to not discontinue GENVOYA without first informing their healthcare provider.
Fat Redistribution Inform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known [see Warnings and Precautions (5.4)].
Immune Reconstitution Syndrome Advise patients to inform their healthcare provider immediately of any symptoms of infection, as in some patients with advanced HIV infection (AIDS), signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started [see Warnings and Precautions (5.5)].
Renal Impairment Advise patients to avoid taking GENVOYA with concurrent or recent use of nephrotoxic agents.
Renal impairment including cases of acute renal failure has been reported in association with the use of tenofovir prodrugs [see Warnings and Precautions (5.6)].
Decrease in Bone Mineral Density Advise patients that decreases in bone mineral density have been observed with the use of GENVOYA.
Assessment of bone mineral density (BMD) should be considered in patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss [see Warnings and Precautions (5.7)].
Missed Dosage Inform patients that it is important to take GENVOYA on a regular dosing schedule with food and to avoid missing doses as it can result in development of resistance [see Dosage and Administration (2.2)].
Pregnancy Registry Inform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes of pregnant women exposed to GENVOYA [see Use in Specific Populations (8.1)].
Lactation Instruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in breast milk [see Use in Specific Populations (8.2)].
DOSAGE AND ADMINISTRATION
2 Testing: Prior to initiation of GENVOYA, patients should be tested for hepatitis B virus infection.
(2.1) Recommended dosage: One tablet taken orally once daily with food in patients 12 years old and older with body weight at least 35 kg and a creatinine clearance greater than or equal to 30 mL per minute.
(2.2) Renal impairment: GENVOYA is not recommended in patients with estimated creatinine clearance below 30 mL per minute.
(2.3) Hepatic impairment: GENVOYA is not recommended in patients with severe hepatic impairment.
(2.4) 2.1 Testing Prior to Initiation of GENVOYA Prior to initiation of GENVOYA, patients should be tested for hepatitis B virus infection [see Warnings and Precautions (5.2)].
2.2 Recommended Dosage GENVOYA is a four-drug fixed dose combination product containing 150 mg of elvitegravir, 150 mg of cobicistat, 200 mg of emtricitabine, and 10 mg of tenofovir alafenamide (TAF).
The recommended dosage of GENVOYA is one tablet taken orally once daily with food in adults and pediatric patients 12 years of age and older with body weight at least 35 kg and creatinine clearance greater than or equal to 30 mL per minute [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].
2.3 Not Recommended in Patients with Severe Renal Impairment GENVOYA is not recommended in patients with estimated creatinine clearance below 30 mL per minute [see Use in Specific Populations (8.6)].
2.4 Not Recommended in Patients with Severe Hepatic Impairment GENVOYA is not recommended in patients with severe hepatic impairment (Child-Pugh Class C) [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].