Elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil

7 DRUG INTERACTIONS STRIBILD is a complete regimen for the treatment of HIV-1 infection; therefore, STRIBILD should not be administered with other antiretroviral medications for treatment of HIV-1 infection. ( 7.1 ) STRIBILD 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 STRIBILD. Consult the full prescribing information prior to and during treatment for potential drug-drug interactions. ( 4 , 7.2 , 7.3 , 12.3 )

7.1 Not Recommended with Other Antiretroviral Medications STRIBILD is a complete regimen for the treatment of HIV-1 infection; therefore, STRIBILD should not be administered with other antiretroviral medications for treatment of HIV-1 infection. Complete information regarding potential drug-drug interactions with other antiretroviral medications is not provided [see Contraindications (4) , Warnings and Precautions (5.4) and Clinical Pharmacology (12.3) ] .

7.2 Potential for STRIBILD to Affect Other Drugs Cobicistat, a component of STRIBILD, 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 STRIBILD 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 STRIBILD with drugs that have active metabolite(s) formed by CYP3A may result in reduced plasma concentration of these active metabolite(s) (Table 5).

Elvitegravir is a modest inducer of CYP2C9 and may decrease the plasma concentrations of CYP2C9 substrates.

7.3 Potential for Other Drugs to Affect One or More Components of STRIBILD Elvitegravir and cobicistat, components of STRIBILD, 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 and elvitegravir, which may lead to loss of therapeutic effect of STRIBILD and development of resistance (Table 5). Coadministration of STRIBILD with other drugs that inhibit CYP3A may decrease the clearance and increase the plasma concentration of cobicistat (Table 5).

7.4 Drugs Affecting Renal Function Because emtricitabine and tenofovir, components of STRIBILD, are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion, coadministration of STRIBILD 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 (5.2) ] .

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 STRIBILD or the components of STRIBILD (elvitegravir, cobicistat, emtricitabine, and TDF) as individual agents and/or in combination, or are predicted drug interactions that may occur with STRIBILD [for magnitude of interaction see Clinical Pharmacology (12.3) ]. The table includes potentially significant interactions but is not all inclusive [see Contraindications (4) and Clinical Pharmacology (12.3) ].

Table 5 Established and Other Potentially Significant This 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 Clinical Comment 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., amiodarone bepridil digoxin Indicates that a drug-drug interaction trial was conducted.

disopyramide flecainide systemic lidocaine mexiletine propafenone quinidine ↑ antiarrhythmics ↑ digoxin Therapeutic concentration monitoring, if available, is recommended for antiarrhythmics when coadministered with STRIBILD. Antibacterials: clarithromycin ↑ clarithromycin ↑ cobicistat Patients with CLcr greater than or equal to 60 mL/minute: No dose adjustment of clarithromycin is required. Patients with CLcr between 50 mL/minute and 60 mL/minute: The dose of clarithromycin should be reduced by 50%.

Anticoagulants: Direct Oral Anticoagulants (DOACs) apixaban rivaroxaban betrixaban dabigatran edoxaban ↑ apixaban Due to potentially increased bleeding risk, dosing recommendations for coadministration with STRIBILD depends on the apixaban dose. Refer to apixaban dosing instructions for coadministration with strong CYP3A and P-gp inhibitors in apixaban prescribing information. ↑ rivaroxaban Coadministration of rivaroxaban with STRIBILD is not recommended because it may lead to an increased bleeding risk.

↑ betrixaban ↑ dabigatran ↑ edoxaban Due to potentially increased bleeding risk, dosing recommendations for coadministration of betrixaban, dabigatran, or edoxaban with a P-gp inhibitor such as STRIBILD 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 international normalized ratio (INR) upon coadministration of warfarin with STRIBILD.

Anticonvulsants: carbamazepine phenobarbital phenytoin ↓ elvitegravir ↓ cobicistat Coadministration with carbamazepine, phenobarbital, or phenytoin is contraindicated due to potential for loss of elvitegravir therapeutic effect and development of resistance. oxcarbazepine Alternative anticonvulsants should be considered when STRIBILD is coadministered with oxcarbazepine. clonazepam ethosuximide ↑ clonazepam ↑ ethosuximide Clinical monitoring is recommended upon coadministration of clonazepam or ethosuximide with STRIBILD.

Antidepressants: Selective Serotonin Reuptake Inhibitors (SSRIs) e.g., paroxetine ↑ SSRIs (except sertraline) ↑ TCAs ↑ trazodone Careful dose titration of the antidepressant and monitoring for antidepressant response are recommended when coadministered with STRIBILD. Tricyclic Antidepressants (TCAs) e.g., amitriptyline desipramine imipramine nortriptyline bupropion trazodone Antifungals: itraconazole ketoconazole voriconazole ↑ elvitegravir ↑ cobicistat ↑ itraconazole ↑ ketoconazole ↑ voriconazole When coadministered with STRIBILD, the maximum daily dose 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 STRIBILD. Anti-gout: colchicine ↑ colchicine STRIBILD 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 STRIBILD: 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 STRIBILD: 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 STRIBILD: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). Antimycobacterial: rifampin ↓ elvitegravir ↓ cobicistat Coadministration with rifampin is contraindicated due to potential for loss of elvitegravir therapeutic effect and development of resistance . rifabutin rifapentine Coadministration of STRIBILD with rifabutin or rifapentine is not recommended.

Antiplatelets: ticagrelor clopidogrel ↑ ticagrelor ↓ clopidogrel active metabolite Coadministration with ticagrelor is not recommended. Coadministration with clopidogrel is not recommended due to potential 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 STRIBILD in patients taking quetiapine: Consider alternative antiretroviral therapy to avoid increases in quetiapine exposure. If…

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to STRIBILD during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary STRIBILD is not recommended during pregnancy [see Dosage and Administration (2.5) ] . A literature report evaluating the pharmacokinetics (PK) of antiretrovirals during pregnancy demonstrated substantially lower exposures of elvitegravir and cobicistat in the second and third trimesters (see Data ) .

Prospective pregnancy data from the APR are not sufficient to adequately assess the risk of birth defects or miscarriage. However, elvitegravir, cobicistat, emtricitabine, and TDF use during pregnancy have been evaluated in a limited number of individuals as reported to the APR. Available data from the APR show no significant difference in the overall risk of major birth defects for elvitegravir, cobicistat, emtricitabine, or TDF 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) (see Data ) . The rate of miscarriage is not reported in the APR. In the U.S.

general population, the estimated background risk of miscarriage in clinically recognized pregnancies is 15–20%. In animal studies, no adverse developmental effects were observed when the components of STRIBILD were administered separately during the period of organogenesis at exposures up to 23 and 0.2 times (rats and rabbits, respectively, elvitegravir), 1.8 and 4.3 times (rats and rabbits, respectively, cobicistat), and 60 and 120 times (mice and rabbits, respectively, emtricitabine) the exposure at the recommended daily dose of these components in STRIBILD, and at 14 and 19 times (rats and rabbits, respectively, TDF) the human dose based on body surface area comparisons [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 exposure at the recommended daily therapeutic dose, and when emtricitabine was administered to mice through lactation at exposures up to approximately 60 times the exposure at the recommended daily therapeutic dose. No adverse effects were observed in the offspring of rats when TDF was administered through lactation at tenofovir exposures of approximately 2.7 times the exposure at the recommended daily dosage of STRIBILD. Data…