Cobicistat

This product is a compound preparation, each tablet contains 150 mg of elvitegravir, 150 mg of cobicistat, 200 mg of emtricitabine and 10 mg of tenofovir alafenamide.

Avitegravir tablets should not be used in combination with other antiretroviral products. Therefore, no information is provided on drug interactions with other antiretroviral products, including P-type and non-nucleoside reverse transcriptase inhibitors [NNRTIs] (see [Precautions]). Interaction studies have been conducted only in adults. Avitegravir tablets should not be used in combination with products containing tenofovir alafenamide, tenofovir disoproxil, lamivudine, or adefovir disoproxil used to treat HBV infection. Avitegravir is primarily metabolized by CYP3A, and products that induce or inhibit CYP3A may affect elvitegravir exposure. Co-administration of Avitegravir tablets with products that induce CYP3A may result in decreased plasma concentrations of elvitegravir and decreased efficacy of Avitegravir tablets (see [Contraindications]). Avitegravir may have the potential to induce CYP2C9 and/or induce uridine diphosphate glucuronosyltransferase (UGT); therefore, plasma concentrations of substrates for these enzymes may be reduced. Cobicistat Cobicistat is a strong mechanism inhibitor of CYP3A and a substrate of CYP3A. Cobicistat is also a weak inhibitor of CYP2D6 and is metabolized by CYP2D6 to a lesser extent. Drugs that inhibit CYP3A may reduce the clearance of cobicistat, resulting in increased plasma concentrations of cobicistat. Drugs that are highly dependent on CYP3A metabolism and have high first-pass metabolism are most sensitive to the significant increase in exposure caused by co-administration of cobicistat (see "Contraindications" and [Contraindications]). Cobicistat is an inhibitor of the following transporters: P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1, and OATP1B3. Co-administration of drugs that are substrates of P-gp, BCRP, OATP1B1, or OATP1B3 may result in increased plasma concentrations of the drug. In vitro studies of emtricitabine and clinical pharmacokinetic and drug-drug interaction studies have shown that emtricitabine has a low potential for CYP-mediated interactions with other drugs. Coadministration of emtricitabine with medicinal products that are eliminated by active tubular secretion may increase concentrations of emtricitabine and/or the coadministered medicinal product. Medications that cause decreased renal function may increase emtricitabine concentrations. Tenofovir Alafenamide Tenofovir Alafenamide is transported by P-gp and BCRP. Medications that have a strong effect on the activity of P-gp and BCRP may result in altered absorption of tenofovir alafenamide. However, when coadministered with cobicistat during treatment with ICONNAMAL, cobicistat produces a near-maximal inhibitory effect on P-gp, thereby increasing the availability of tenofovir alafenamide to exposures comparable to those observed with 25 mg of tenofovir alafenamide administered alone. Therefore, when coadministered with another P-gp and/or BCRP inhibitor, such as ketoconazole, it is not expected that tenofovir alafenamide exposure will be further increased following administration of ICONNAMAL. It is unknown whether coadministration of ICONNAMAL with xanthine oxidase inhibitors, such as febuxostat, will increase systemic exposure of tenofovir. In vitro studies and clinical pharmacokinetic and drug-drug interaction studies have shown that CYP-mediated drug interactions between tenofovir alafenamide and other drugs are less likely. Tenofovir alafenamide is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or CYP2D6. In vivo, tenofovir alafenamide is not an inhibitor of CYP3A4. In vitro, tenofovir alafenamide is a substrate for OATP. Inhibitors of OATP and BCRP include cyclosporine. Concomitant use of icarnoplastin with certain drugs that are primarily metabolized by CYP3A may result in increased plasma concentrations of such drugs, which may cause the following serious or life-threatening adverse reactions: peripheral vasospasm or ischemia (such as dihydroergotamine, ergotamine, ergonovine), myopathy including rhabdomyolysis (such as simvastatin, lovastatin), prolonged or increased sedation, or respiratory depression (such as oral midazolam or diazolom). Coadministration of icosabine with other medicinal products that are primarily metabolized by CYP3A (e.g., amiodarone, quinidine, cisapride, pimozide, alfuzosin, and sildenafil for the treatment of pulmonary hypertension) is contraindicated (see Contraindications). Coadministration of icosabine with certain medicinal products that induce CYP3A (e.g., St. John's wort (Hypericumperforatum), rifampin, carbamazepine, phenobarbital, and phenytoin) may result in a significant decrease in plasma concentrations of cobicistat and elvitegravir, which may lead to loss of efficacy and development of resistance (see Contraindications). Other interactions In vitro, cobicistat and tenofovir alafenamide are not inhibitors of human UGT1A. It is not known whether cobicistat, emtricitabine, or tenofovir alafenamide are inhibitors of other UGT enzymes. Table 2 lists interactions between the components of icosabine and possible coadministered medicinal products (in indicates an increase, "↓" indicates a decrease, and "e" indicates no change). Interaction studies were conducted with Equinoxaline or the components of Equinoxaline (elvitegravir, cobimetin, emtricitabine, and tenofovir alafenamide) as individual agents and/or in combination, or potential drug-drug interactions that may occur with Equinoxaline administration. Studies with Other Medicinal Products Based on drug-drug interaction studies conducted with Equinoxaline or the components of Equinoxaline, no clinically significant drug-drug interactions were observed and are not expected to occur between the components of Equinoxaline and the following medicinal products: entecavir, famciclovir, ribavirin, famotidine, and omeprazole.