Cobicistat

7 DRUG INTERACTIONS TYBOST, in combination with atazanavir or darunavir, can alter the concentration of drugs metabolized by CYP3A or CYP2D6. Drugs that induce CYP3A can alter the concentrations of TYBOST, atazanavir and darunavir. Consult the full prescribing information prior to and during treatment for potential drug interactions. ( 4 , 5.3 , 7 , 12.3 )

7.1 Potential Effect of Cobicistat (Coadministered with Atazanavir or Darunavir) on the Pharmacokinetics of Concomitant Drugs Cobicistat is an inhibitor of CYP3A and CYP2D6. The transporters that cobicistat inhibits include p-glycoprotein (P-gp), BCRP, OATP1B1, and OATP1B3. The plasma concentration of drugs that are primarily metabolized by CYP3A or CYP2D6, or are substrates of P-gp, BCRP, OATP1B1, or OATP1B3 may be increased if those drugs are coadministered with TYBOST. Based on in vitro data, cobicistat is not expected to induce CYP1A2 or CYP2B6 and based on in vivo data, cobicistat is not expected to induce MDR1 or, in general, CYP3A to a clinically significant extent.

The induction effect of cobicistat on CYP2C9, CYP2C19, or UGT1A1 is unknown, but is expected to be low based on CYP3A in vitro induction data. Coadministration of TYBOST with atazanavir or darunavir with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated. Coadministration with drugs that have active metabolite(s) formed by CYP3A may result in reduced plasma concentrations of these active metabolite(s). Coadministration with other CYP3A substrates may require a dose adjustment or additional monitoring as shown in Table 7 .

7.2 Potential Effect of Concomitant Drugs on the Pharmacokinetics of Cobicistat (Coadministered with Atazanavir or Darunavir) Cobicistat is metabolized by CYP3A, and to a minor extent, by CYP2D6. Atazanavir and darunavir are also metabolized by CYP3A. Coadministration of TYBOST with atazanavir or darunavir in combination with drugs that induce CYP3A activity have the potential to decrease plasma concentrations of cobicistat, atazanavir, and darunavir, which may lead to loss of therapeutic effect and development of resistance (see Table 7 ).

Coadministration of TYBOST with atazanavir or darunavir in combination with other drugs that inhibit CYP3A may further increase the plasma concentrations of cobicistat, atazanavir, and darunavir (see Table 7 ).

7.3 Established and Other Potentially Significant Interactions Coadministration of TYBOST with fosamprenavir, saquinavir, or tipranavir is not recommended because pharmacokinetic data are not available to provide appropriate dosing recommendations. Use of TYBOST with lopinavir is not recommended because lopinavir is co-formulated with ritonavir. Table 7 provides dosing recommendations as a result of drug interactions with TYBOST coadministered with atazanavir or darunavir.

These recommendations are based on either drug interaction trials or predicted interactions due to the expected magnitude of the interaction and potential for serious adverse events or loss of therapeutic effect [see Contraindications (4) , Warnings and Precautions (5.3 , 5.4) , and Clinical Pharmacology (12.3) ]. In Table 7 , if not specifically stated, the drug interaction information applies to both coadministered agents: TYBOST coadministered with atazanavir or darunavir [see Clinical Pharmacology (12.3) ] .

In addition to the drug interactions noted in Table 7 , TYBOST is not recommended for use in combination with fixed-dose combination tablets that contain cobicistat, lopinavir/ritonavir or regimens containing ritonavir, or in combination with more than one antiretroviral agent that requires pharmacokinetic enhancement [see Warnings and Precautions (5.4) ].

Evaluate whether dosing adjustments of concomitant medications or coadministered antiretroviral drugs are necessary in: Patients on a stable concomitant medication who initiate or switch to a TYBOST-containing regimen Patients on a TYBOST-containing regimen who initiate a new concomitant medication Patients initiating a TYBOST-containing regimen and a new concomitant medication simultaneously Under these circumstances, also monitor for adverse events and/or monitor concentrations of concomitant medications if appropriate. No dose adjustment is required when TDF or rilpivirine are coadministered with TYBOST and atazanavir or darunavir.

Table 7 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 Potential Effect ↑ = Increase, ↓ = Decrease, ↔ = No change Clinical Comment Antiretroviral Agents: Nucleotide Reverse Transcriptase Inhibitor (NRTI) tenofovir alafenamide ↔tenofovir alafenamide ↑tenofovir alafenamide TYBOST coadministered with darunavir in pediatric patients weighing at least 15 kg: No dose adjustment.

TYBOST coadministered with atazanavir in pediatric patients weighing 14 to less than 35 kg: Coadministration is not recommended [see Use in Specific Populations (8.4) ]. Antiretroviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) efavirenz ↓ cobicistat ↓ darunavir ↓ atazanavir TYBOST coadministered with darunavir: Coadministration of darunavir and TYBOST with efavirenz is not recommended because it may result in the loss of therapeutic effect and development of resistance to darunavir.

TYBOST coadministered with atazanavir: In treatment-naïve adult patients: Atazanavir 400 mg with TYBOST 150 mg should be coadministered once daily as a single dose with food, and efavirenz 600 mg should be administered once daily on an empty stomach, preferably at bedtime. In treatment-experienced adult patients: Coadministration of atazanavir and TYBOST with efavirenz in treatment-experienced patients is not recommended because it may result in the loss of therapeutic effect and development of resistance to atazanavir.

etravirine ↓ cobicistat darunavir: effect unknown ↓ atazanavir Coadministration with etravirine is not recommended because it may result in the loss of therapeutic effect and development of resistance to atazanavir or darunavir. nevirapine ↓ atazanavir ↑ nevirapine ↓ cobicistat darunavir: effect unknown Contraindicated with TYBOST coadministered with atazanavir only: Coadministration of atazanavir with nevirapine is contraindicated due to potential for loss of atazanavir therapeutic effect and development of resistance, and potential for nevirapine-associated adverse reactions.

TYBOST coadministered with darunavir: TYBOST coadministration with nevirapine and darunavir is not recommended because it may result in the loss of therapeutic effect and development of resistance to darunavir. Antiretroviral Agents: CCR5 Antagonists maraviroc ↑ maraviroc Maraviroc is a substrate of CYP3A. When coadministering with maraviroc, adult patients should receive maraviroc 150 mg twice daily. Antiretroviral Agents: Protease Inhibitors indinavir Contraindicated with TYBOST coadministered with atazanavir only: Both atazanavir and indinavir are associated with indirect (unconjugated) hyperbilirubinemia.

Other Agents: Alpha 1- adrenoreceptor antagonist: alfuzosin ↑ alfuzosin Coadministration with alfuzosin is contraindicated due to potential for serious and/or life-threatening reactions such as hypotension. Antianginal ranolazine ↑ ranolazine Coadministration with ranolazine is contraindicated due to potential for serious and/or life-threatening reactions. Antacids: e.g., aluminum and magnesium hydroxide (please also see H2-Receptor Antagonists and Proton Pump Inhibitors below) ↓ atazanavir TYBOST coadministered with atazanavir: With concomitant use, administer a minimum of 2 hours apart.

Antiarrhythmics: dronedarone ↑ dronedarone Coadministration with dronedarone is contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias. digoxin ↑ digoxin When coadministering with digoxin, titrate the digoxin dose and monitor digoxin concentrations. Other antiarrhythmics: e.g., amiodarone disopyramide flecainide mexiletine propafenone quinidine ↑ antiarrhythmics Clinical monitoring is recommended upon coadministration with antiarrhythmics.

Antibacterials (macrolide or ketolide antibiotics): clarithromycin erythromycin telithromycin ↑ clarithromycin ↑ erythromycin ↑ telithromycin ↑ cobicistat ↑ atazanavir ↑ darunavir Consider alternative antibiotics with concomitant use of TYBOST coadministered with atazanavir or darunavir. Anticancer Agents: irinotecan ↑ irinotecan Contraindicated with TYBOST coadministered with atazanavir only: Coadministration of atazanavir with irinotecan is contraindicated due to potential for increased irinotecan toxicity. dasatinib nilotinib vinblastine vincristine ↑ anticancer agents A decrease in the dosage or an adjustment of the dosing interval of dasatinib…

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors fetal outcomes in individuals exposed to TYBOST during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) 1-800-258-4263. Risk Summary TYBOST coadministered with darunavir or atazanavir is not recommended during pregnancy [see Dosage and Administration (2.5) ] . In a clinical trial of individuals taking cobicistat coadministered with darunavir, exposures of cobicistat and darunavir were substantially lower during the second and third trimesters of pregnancy [see Data and Clinical Pharmacology (12.3) ] .

TYBOST use during pregnancy has been evaluated in a limited number of individuals as reported by the APR, and available data show no significant difference in the rate of overall birth defects for cobicistat compared with the background rate for major 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%.

In animal reproduction studies in rats and rabbits, no evidence of fetal harm was observed with oral administration of cobicistat during organogenesis at doses that produced exposures up to 1.4 and 3.3 times, respectively, the maximal recommended human dose (MRHD) of 150 mg (see Data ). Because TYBOST is coadministered with atazanavir or darunavir and other antiretroviral drugs, also refer to the prescribing information of each drug for information about pregnancy.

Data Human Data Cobicistat coadministered with darunavir as a fixed dose combination, in combination with a background regimen, was evaluated in a clinical trial of 7 pregnant individuals taking darunavir/cobicistat prior to enrollment and who were willing to remain on darunavir/cobicistat throughout the study. The study period included the second and third trimesters, and through 12 weeks postpartum. Six pregnant individuals completed the trial. Exposure to darunavir and cobicistat as part of an antiretroviral regimen was substantially lower during the second and third trimesters of pregnancy compared with postpartum [see Clinical Pharmacology (12.3) ] .

One out of 6 individuals who completed the study experienced virologic failure with HIV-1 RNA >1,000 copies/mL from the third trimester visit through the postpartum period. Five individuals had sustained virologic response (HIV-1 RNA <50…