Genvoya (Page 3 of 11)

6.2 Postmarketing Experience

The following events have been identified during post approval use of products containing TAF, including GENVOYA. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Skin and Subcutaneous Tissue Disorders

Angioedema, urticaria, and rash

Renal and Urinary Disorders

Acute renal failure, acute tubular necrosis, proximal renal tubulopathy, and Fanconi syndrome

7 DRUG INTERACTIONS

7.1 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 HIV-1 infection should be avoided. Complete information regarding potential drug-drug interactions with other antiretroviral medications is not provided [see Contraindications (4), Warnings and Precautions (5.2) 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 . Coadministration of GENVOYA with drugs that have active metabolite(s) formed by CYP3A may result in reduced plasma concentration of these active metabolite(s) (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 13). 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 (5.4)].

7.5 Established and Other Potentially Significant Interactions

Table 5 provides a listing of established or potentially clinically significant drug interactions [see Contraindications (4)]. 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 Significant * 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 †	Clinical Comment
* This table is not all inclusive. † ↑ = Increase, ↓ = Decrease ‡ Indicates that a drug-drug interaction trial was conducted.
Alpha 1-adrenoreceptor antagonist: alfuzosin	↑ alfuzosin	Coadministration with alfuzosin is contraindicated due to potential for serious and/or life-threatening reactions such as hypotension.
Antiarrhythmics: e.g.,amiodaronebepridildigoxin ‡disopyramideflecainidesystemic lidocaine mexiletinepropafenonequinidine	↑ antiarrhythmics↑ digoxin	Caution is warranted and therapeutic concentration monitoring, if available, is recommended for antiarrhythmics when coadministered with GENVOYA.
Antibacterials: clarithromycintelithromycin	↑ 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: Direct Oral Anticoagulants (DOACs)apixabanrivaroxabanbetrixabandabigatranedoxaban	↑ apixaban	Due to potentially increased bleeding risk, dosing recommendations for coadministration with GENVOYA depends on the apixaban dose. Refer to apixaban dosing instructions for coadministration with strong CYP3A and P-gp inhibitors in apixaban prescribing information.
	↑ rivaroxaban↑ betrixaban↑ dabigatran↑ edoxaban	Coadministration of rivaroxaban with GENVOYA is not recommended because it may lead to an increased bleeding risk.Due to potentially increased bleeding risk, dosing recommendations for coadministration of betrixaban, dabigatran, or edoxaban with a P-gp inhibitor such as GENVOYA depends on DOAC indication and renal function. Refer to DOAC dosing instructions for coadministration with P-gp inhibitors in DOAC prescribing information.
warfarin	Effect on warfarin unknown	Monitor the international normalized ratio (INR) upon coadministration of warfarin with GENVOYA.
Anticonvulsants: carbamazepine ‡phenobarbitalphenytoin	↓ elvitegravir↓ cobicistat↓ TAF	Coadministration with carbamazepine, phenobarbital, or phenytoin is contraindicated due to potential for loss of therapeutic effect and development of resistance.
oxcarbazepine		Alternative anticonvulsants should be considered when GENVOYA is administered with oxcarbazepine.
ethosuximide	↑ ethosuximide	Clinical monitoring is recommended upon coadministration of ethosuximide with GENVOYA.
Antidepressants: Selective Serotonin Reuptake Inhibitors (SSRIs)e.g.,paroxetineTricyclicAntidepressants (TCAs)e.g.,amitriptylinedesipramine ‡imipraminenortriptylinebupropiontrazodone	↑ SSRIs (except sertraline)↑ TCAs↑ trazodone	Careful dosage titration of the antidepressant and monitoring for antidepressant response are recommended when coadministered with GENVOYA.
Antifungals: itraconazoleketoconazole ‡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: rifampin	↓ elvitegravir↓ cobicistat↓ TAF	Coadministration with rifampin is contraindicated due to potential for loss of therapeutic effect and development of resistance.
rifabutin ‡rifapentine		Coadministration of GENVOYA with rifabutin or rifapentine is not recommended.
Antiplatelets:
ticagrelor	↑ ticagrelor	Coadminstration with ticagrelor is not recommended.
clopidogrel	↓ clopidogrel active metabolite	Coadministration with clopidogrel is not recommended due to protential reduction of the antiplatelet activity of clopidogrel.
Antipsychotics:
lurasidone	↑ lurasidone	Coadministration with lurasidone is contraindicated due to potential for serious and/or life-threatening reactions.
pimozide	↑ pimozide	Coadministration with pimozide is contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
quetiapine	↑ quetiapine	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.
Other antipsychoticse.g.,perphenazinerisperidonethioridazine	↑ antipsychotic	A decrease in dose of the antipsychotics that are metabolized by CYP3A or CYP2D6 may be needed when coadministered with GENVOYA.
Beta-Blockers: e.g.,metoprololtimolol	↑ 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.,amlodipinediltiazemfelodipinenicardipinenifedipineverapamil	↑ calcium channel blockers	Caution is warranted and clinical monitoring is recommended upon coadministration of calcium channel blockers with GENVOYA.
Corticosteroids: e.g.,betamethasonebudesonideciclesonidedexamethasonefluticasonemethylprednisolonemometasoneprednisonetriamcinolone	↓ elvitegravir↓ cobicistat↑ corticosteroids	Coadministration with oral dexamethasone or other systemic corticosteroids that induce CYP3A may result in loss of therapeutic effect and development of resistance to elvitegravir. Consider alternative corticosteroids.Coadministration with corticosteroids (all routes of administration) whose exposures are significantly increased by strong CYP3A inhibitors can increase the risk for Cushing’s syndrome and adrenal suppression.Alternative corticosteroids including beclomethasone and prednisolone (whose PK and/or PD are less affected by strong CYP3A inhibitors relative to other studied steroids) 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.
Ergot Derivatives: dihydroergotamineergotaminemethylergonovine	↑ ergot derivatives	Coadministration is contraindicated due to potential for serious and/or life-threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues [see Contraindications (4)].
Herbal Products: St. John’s wort (Hypericum perforatum)	↓ elvitegravir↓ cobicistat↓ TAF	Coadministration is contraindicated due to potential for loss of therapeutic effect and development of resistance.
Hormonal Contraceptives: drospirenone/ethinyl estradiol ‡levonorgestrel norgestimate/ethinyl estradiol	↑ drospirenone ↑ norgestimate↑ levonorgestrel↓ ethinyl estradiol	Additional or alternative non-hormonal forms of contraception should be considered when estrogen based contraceptives are coadministered with GENVOYA. Plasma concentrations of drospirenone may be increased when coadministered with cobicistat-containing products. Clinical monitoring is recommended due to the potential for hyperkalemia.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 patients 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 drospirenone, levonorgestrel, or norgestimate has not been studied; therefore, alternative (non-hormonal) methods of contraception can be considered.
Immuno-suppressants: e.g.,cyclosporine (CsA)sirolimustacrolimus	↑ 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.
Lipid-modifying Agents:
HMG-CoA Reductase Inhibitors: lovastatin simvastatin	↑ lovastatin ↑ simvastatin	Coadministration with lovastatin or simvastatin is contraindicated due to potential for serious reactions such as myopathy including rhabdomyolysis.
atorvastatin	↑ atorvastatin	Initiate atorvastatin with the lowest starting dose of atorvastatin and titrate carefully while monitoring for safety (e.g., myopathy). Do not exceed a dosage of atorvastatin 20 mg daily.
Other Lipid-modifying Agents: lomitapide	↑ lomitapide	Coadministration with lomitapide is contraindicated due to potential for markedly increased transaminases.
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.
fentanyl	↑ fentanyl	Careful monitoring of therapeutic and adverse effects of fentanyl (including potentially fatal respiratory depression) is recommended with coadministration.
tramadol	↑ tramadol	A dose decrease may be needed for tramadol with concomitant use.
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.
Medications or Oral Supplements Containing Polyvalent Cations (e.g., Mg, Al, Ca, Fe, Zn): calcium or iron supplements, including multivitaminscation-containing antacids ‡ or laxativessucralfatebuffered medications	↓ elvitegravir	Separate GENVOYA and administration of medications, antacids, or oral supplements containing polyvalent cations by at least 2 hours.
Phosphodiesterase-5 (PDE5) Inhibitors: sildenafiltadalafilvardenafil	↑ PDE5 inhibitors	Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH):Coadministration of sildenafil with GENVOYA is contraindicated when used for treatment of PAH, due to potential for PDE-5 inhibitor associated adverse reactions, including hypotension, syncope, visual disturbances, and priapism.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 ofGENVOYA. 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/hypnotic: midazolam (oral)triazolam	↑ midazolam↑ triazolam	Coadministration with triazolam or orally administered midazolam is contraindicated due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression.
Other benzodiazepines: e.g., parenterally administered midazolam clorazepate diazepam estazolam flurazepam	↑ sedatives/hypnotics	Triazolam and orally administered midazolam are extensively metabolized by CYP3A. Coadministration of triazolam or orally administered midazolam with GENVOYA may cause large increases in the concentrations of these benzodiazepines. Coadministration of parenteral midazolam with GENVOYA 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.
buspironezolpidem		With other sedative/hypnotics, dose reduction may be necessary and clinical monitoring is recommended.