Darunavir, cobicistat, emtricitabine, and tenofovir alafenamide

7. DRUG INTERACTIONS Co-administration of SYMTUZA with other drugs can alter the concentration of other drugs and other drugs may alter the concentrations of SYMTUZA components. Consult the full prescribing information prior to and during treatment for potential drug interactions. ( 4 , 5.4 , 7 , 12.3 )

7.1 Not Recommended With Other Antiretroviral Medications SYMTUZA is a complete regimen for HIV-1 infection and co-administration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended. For this reason, information regarding potential drug-drug interactions with other antiretroviral medications is not provided.

7.2 Potential for SYMTUZA to Affect Other Drugs Darunavir co-administered with cobicistat is an inhibitor of CYP3A and CYP2D6. Cobicistat inhibits the following transporters: P-glycoprotein (P-gp), BCRP, MATE1, OATP1B1 and OATP1B3. Therefore, co-administration of SYMTUZA with drugs that are primarily metabolized by CYP3A and/or CYP2D6, or are substrates of P-gp, BCRP, MATE1, OATP1B1 or OATP1B3 may result in increased plasma concentrations of such drugs, which could increase or prolong their therapeutic effect and can be associated with adverse events.

Co-administration of SYMTUZA with drugs that have active metabolite(s) formed by CYP3A may result in reduced plasma concentrations of these active metabolite(s), potentially leading to loss of their therapeutic effect (see Table 4 ).

7.3 Potential for Other Drugs to Affect SYMTUZA Darunavir is metabolized by CYP3A. Cobicistat is metabolized by CYP3A and, to a minor extent, by CYP2D6. Co-administration of drugs that induce CYP3A activity are expected to increase the clearance of darunavir and cobicistat, resulting in lowered plasma concentrations which may lead to loss of therapeutic effect and development of resistance. Co-administration of SYMTUZA with other drugs that inhibit CYP3A may result in increased plasma concentrations of darunavir and cobicistat (see Table 4 ). Tenofovir alafenamide (TAF) is a substrate of P-gp, BCRP, OATP1B1, and OATP1B3.

Drugs that strongly affect P-gp activity may lead to changes in TAF absorption. Drugs that induce P-gp activity are expected to decrease the absorption of TAF, resulting in decreased plasma concentrations of TAF, which may lead to loss of therapeutic effect of SYMTUZA and development of resistance. Co-administration of SYMTUZA with other drugs that inhibit P-gp may increase the absorption and plasma concentrations of TAF (see Table 4 ).

7.4 Drugs Affecting Renal Function Because emtricitabine and tenofovir are primarily excreted by the kidneys through glomerular filtration and active tubular secretion, co-administration of SYMTUZA 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 Significant Drug Interactions Table 4 provides examples of established or potentially clinically significant drug interactions with SYMTUZA and recommended steps to prevent or manage these interactions. These recommendations are based on drug interaction trials conducted with the components of SYMTUZA, as individual agents or in combination, or are predicted interactions. No drug interaction trials have been performed with SYMTUZA or with all the components administered together. Drug interaction trials have been conducted with darunavir co-administered with ritonavir or cobicistat or with emtricitabine and tenofovir prodrugs.

The table includes potentially significant interactions but is not all inclusive , and therefore the label of each drug that is co- administered with SYMTUZA should be consulted for information related to the route of metabolism, interaction pathways, potential risks, and specific actions to be taken with regard to co- administration.

Table 4: Significant Drug Interactions Concomitant Drug Class: Drug Name Examples Effect on Concentration Clinical Comment This table is not all inclusive ↑ = increase, ↓ = decrease, ↔ = no effect Alpha 1-adrenoreceptor antagonist: alfuzosin ↑ alfuzosin Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as hypotension. Antibacterials: clarithromycin, erythromycin, telithromycin ↑ darunavir ↑ cobicistat ↑ antibacterial Consider alternative antibiotics with concomitant use of SYMTUZA.

Anticancer agents: dasatinib, nilotinib ↑ anticancer agent A decrease in the dosage or an adjustment of the dosing interval of dasatinib or nilotinib may be necessary when co-administered with SYMTUZA. Consult the dasatinib and nilotinib prescribing information for dosing instructions. vinblastine, vincristine For vincristine and vinblastine, consider temporarily withholding the cobicistat-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when SYMTUZA is administered concurrently with vincristine or vinblastine.

If the antiretroviral regimen must be withheld for a prolonged period, consider initiating a revised regimen that does not include a CYP3A or P-gp inhibitor. Anticoagulants: Direct Oral Anticoagulants (DOACs) apixaban ↑ apixaban Due to potentially increased bleeding risk, dosing recommendations for co-administration of apixaban with SYMTUZA depend on the apixaban dose. Refer to apixaban dosing instructions for co-administration with P-gp and strong CYP3A inhibitors in apixaban prescribing information. rivaroxaban ↑ rivaroxaban Co-administration of rivaroxaban with SYMTUZA is not recommended because it may lead to an increased bleeding risk.

dabigatran etexilate edoxaban ↑ dabigatran ↑ edoxaban Refer to the dabigatran etexilate or edoxaban prescribing information for recommendations regarding co-administration. The specific recommendations are based on indication, renal function, and effect of the co-administered P-gp inhibitors on the concentration of dabigatran or edoxaban. Clinical monitoring is recommended when a DOAC not affected by CYP3A4 but transported by P-gp, including dabigatran etexilate and edoxaban, is co-administered with SYMTUZA. Other Anticoagulants warfarin warfarin: effect unknown Monitor international normalized ratio (INR) upon co-administration of SYMTUZA with warfarin.

Anticonvulsants: carbamazepine, phenobarbital, phenytoin ↓ cobicistat ↓ darunavir ↓ tenofovir alafenamide Co-administration is contraindicated due to potential for loss of therapeutic effect and development of resistance. Anticonvulsants with CYP3A induction effects that are NOT contraindicated: e.g., eslicarbazepine, oxcarbazepine ↓ cobicistat ↓ tenofovir alafenamide darunavir: effect unknown Consider alternative anticonvulsant or antiretroviral therapy to avoid potential changes in exposures. If co-administration is necessary, monitor for lack or loss of virologic response.

Anticonvulsants that are metabolized by CYP3A: e.g., clonazepam ↑ clonazepam Clinical monitoring of anticonvulsants is recommended. Antidepressants: Selective Serotonin Reuptake Inhibitors (SSRIs): e.g., paroxetine, sertraline SSRIs: effects unknown When co-administering with SSRIs, TCAs, or trazodone, careful dose titration of the antidepressant to the desired effect, including using the lowest feasible initial or maintenance dose, and monitoring for antidepressant response are recommended.

Tricyclic Antidepressants (TCAs): e.g., amitriptyline, desipramine, imipramine, nortriptyline ↑ TCAs Other antidepressants: trazodone ↑ trazodone Antifungals: itraconazole, isavuconazole, ketoconazole, posaconazole ↑ darunavir ↑ cobicistat Monitor for increased darunavir or cobicistat and/or antifungal adverse reactions. ↑ itraconazole ↑ isavuconazole ↑ ketoconazole ↔ posaconazole (not studied) Specific dosing recommendations are not available for co-administration with these antifungals. Monitor for increased itraconazole or ketoconazole adverse reactions.

voriconazole voriconazole: effects unknown Co-administration with voriconazole is not recommended unless benefit/risk assessment justifies the use of voriconazole. Anti-gout: colchicine ↑ colchicine Co-administration is contraindicated in patients with renal and/or hepatic impairment due to potential for serious and/or life-threatening reactions. For patients without renal or hepatic impairment: Treatment of gout flares – co-administration of colchicine: 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 – co-administration of colchicine: If the original regimen was 0.6 mg twice a day, the regimen should be…

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to SYMTUZA during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary SYMTUZA is not recommended during pregnancy because of substantially lower exposures of darunavir and cobicistat during the second and third trimesters [see Dosage and Administration (2.5) ] .

A study evaluating the pharmacokinetics of antiretrovirals during pregnancy demonstrated substantially lower exposures of darunavir and cobicistat in the second and third trimesters compared to the post-partum period (see Data ) and [see Clinical Pharmacology (12.3) ]. Prospective pregnancy data from the APR are not sufficient to adequately assess the risk of birth defects or miscarriage. However, available data from the APR show no statistically significant difference in the overall risk of major birth defects for darunavir, cobicistat, emtricitabine, or tenofovir alafenamide (TAF) 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. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15–20%. The background risk of major birth defects and miscarriage for the indicated population is unknown.

In animal reproduction studies, no adverse developmental effects were observed when the components of SYMTUZA were administered separately at darunavir exposures less than 1- (mice and rabbits) and 2.6-times (rats) higher, at cobicistat exposures 1.7- and 4.1-times higher (rats and rabbits respectively), at emtricitabine exposures 88- and 7.3- times higher (mice and rabbits, respectively), and tenofovir alafenamide exposures equal to or 85- times higher (rats and rabbits, respectively) than human exposures at the recommended daily dose of these components in SYMTUZA (see Data ) .

No adverse developmental effects were seen when cobicistat was administered to rats through lactation at cobicistat exposures up to 1.1 times the human exposure at the recommended therapeutic dose. Clinical Considerations Not Recommended During Pregnancy SYMTUZA is not recommended for use during pregnancy because of substantially lower exposures of darunavir and cobicistat during pregnancy (see Data ) and [see Clinical Pharmacology (12.3) ] . SYMTUZA should not be…