Darunavir and cobicistat

Co-administration of PREZCOBIX or PREZCOBIX PED with other drugs can alter the concentration of other drugs and other drugs may alter the concentrations of darunavir or cobicistat. Consult the full prescribing information prior to and during treatment for potential drug interactions. ( 4 , 5.6 , 7 , 12.3 )

7.1 Potential for PREZCOBIX or PREZCOBIX PED 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 PREZCOBIX or PREZCOBIX PED 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 PREZCOBIX or PREZCOBIX PED 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 2 ).

7.2 Potential for Other Drugs to Affect PREZCOBIX or PREZCOBIX PED Darunavir is metabolized by CYP3A. Cobicistat is metabolized by CYP3A, and to a minor extent, by CYP2D6. Co-administration of PREZCOBIX or PREZCOBIX PED and drugs that induce CYP3A activity are expected to increase the clearance of darunavir and cobicistat, resulting in lowered plasma concentrations of darunavir and cobicistat which may lead to loss of therapeutic effect and development of resistance. Co-administration of PREZCOBIX or PREZCOBIX PED and other drugs that inhibit CYP3A may result in increased plasma concentrations of darunavir and cobicistat (see Table 2 ).

7.3 Established and Other Potentially Significant Drug Interactions Table 2 provides dosing recommendations for expected clinically relevant interactions with PREZCOBIX or PREZCOBIX PED (this table is not all inclusive). These recommendations are based on either drug interaction trials or predicted interactions due to the expected magnitude of interaction and potential for serious adverse events or loss of therapeutic effect.

The table includes examples of potentially significant interactions but is not all inclusive , and therefore the label of each drug that is co-administered with PREZCOBIX or PREZCOBIX PED 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. For the list of examples of contraindicated drugs, [see Contraindications (4) ] .

Table 2: Established and Other Potentially Significant this table is not all inclusive Drug Interactions: Alterations in Dose or Regimen May Be Recommended Concomitant Drug Class: Drug Name Examples Effect on Concentration of Darunavir, Cobicistat, or Concomitant Drug Clinical Comment HIV-1 antiviral agents: Nucleoside Reverse Transcriptase Inhibitors (NRTIs) didanosine ↔ darunavir ↔ cobicistat ↔ didanosine Didanosine should be administered one hour before or two hours after PREZCOBIX or PREZCOBIX PED (administered with food).

HIV-1 antiviral agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) efavirenz ↓ cobicistat ↓ darunavir Co-administration with efavirenz is not recommended because it may result in loss of therapeutic effect and development of resistance to darunavir. etravirine ↓ cobicistat darunavir: effect unknown Co-administration with etravirine is not recommended because it may result in loss of therapeutic effect and development of resistance to darunavir. nevirapine ↓ cobicistat darunavir: effect unknown Co-administration with nevirapine is not recommended because it may result in loss of therapeutic effect and development of resistance to darunavir.

HIV-1 antiviral agents: CCR5 co-receptor antagonists maraviroc ↑ maraviroc Maraviroc is a substrate of CYP3A. When co-administered with PREZCOBIX or PREZCOBIX PED, patients should receive maraviroc 150 mg twice daily. Other agents 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 PREZCOBIX or PREZCOBIX PED.

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 PREZCOBIX or PREZCOBIX PED. 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 PREZCOBIX or PREZCOBIX PED 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 PREZCOBIX or PREZCOBIX PED 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 PREZCOBIX or PREZCOBIX PED 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 PREZCOBIX or PREZCOBIX PED. Other Anticoagulants: warfarin warfarin: effect unknown Monitor the international normalized ratio (INR) when co-administering with warfarin.

Anticonvulsants: carbamazepine, phenobarbital, phenytoin ↓ darunavir ↓ cobicistat Co-administration is contraindicated due to potential for reduced plasma concentrations of darunavir, which may result in loss of therapeutic effect and development of resistance. Anticonvulsants with CYP3A induction effects that are NOT contraindicated: e.g. eslicarbazepine, oxcarbazepine ↓ cobicistat 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 ↑ ketoconazole ↑ isavuconazole ↔ posaconazole 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 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…

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to PREZCOBIX or PREZCOBIX PED during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) 1-800-258-4263. Risk Summary PREZCOBIX or PREZCOBIX PED is not recommended during pregnancy because of substantially lower exposures of darunavir and cobicistat during the second and third trimesters [see Dosage and Administration (2.7) ] .

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 and cobicistat 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 PREZCOBIX were administered separately at darunavir exposures less than 1 (mice and rabbits) and 3-times (rats), and at cobicistat exposures 1.6 (rats) and 3.8 (rabbits) times human exposures at the recommended daily dose of these components in PREZCOBIX (see Data ) . No adverse developmental effects were seen when cobicistat was administered to rats through lactation at cobicistat exposures up to 1.2 times the human exposure at the recommended therapeutic dose.

Clinical Considerations Not Recommended During Pregnancy PREZCOBIX or PREZCOBIX PED 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) ] . PREZCOBIX or PREZCOBIX PED should not be initiated in pregnant individuals. An alternative regimen is recommended for individuals who become pregnant during therapy with PREZCOBIX or PREZCOBIX PED. Data Human Data PREZCOBIX in…