Cabotegravir

7 DRUG INTERACTIONS • Refer to the full prescribing information for important drug interactions with APRETUDE. ( 4 , 5.7 , 7 ) • Drugs that induce uridine diphosphate glucuronosyltransferase (UGT)1A1 may significantly decrease plasma concentrations of cabotegravir. ( 4 , 7.2 , 7.3 )

7.1 Use of Other Antiretroviral Drugs after Discontinuation of APRETUDE Residual concentrations of cabotegravir may remain in the systemic circulation of individuals for prolonged periods (up to 12 months or longer). These residual concentrations are not expected to affect the exposures of antiretroviral drugs that are initiated after discontinuation of APRETUDE [see Warnings and Precautions ( 5.3 ), Drug Interactions ( 7.4 ), Clinical Pharmacology ( 12.3 )] .

7.2 Potential for Other Drugs to Affect APRETUDE Cabotegravir is primarily metabolized by UGT1A1 with some contribution from UGT1A9. Drugs that are strong inducers of UGT1A1 or 1A9 are expected to decrease cabotegravir plasma concentrations; therefore, coadministration of APRETUDE with these drugs is contraindicated [see Contraindications ( 4 )] .

7.3 Established and Other Potentially Significant Drug Interactions Information regarding potential drug interactions with cabotegravir is provided in Table 8 . These recommendations are based on either drug interaction trials following oral administration of cabotegravir or predicted interactions due to the expected magnitude of the interaction [see Contraindications ( 4 ), Warnings and Precautions ( 5.7 ), Clinical Pharmacology ( 12.3 )] . Table 8 includes potentially significant interactions but is not all inclusive. Table 8. Drug Interactions with APRETUDE ↑ = Increase, ↓ = Decrease, ↔ = No change.

Concomitant Drug Class: Drug Name Effect on Concentration Clinical Comment Anticonvulsants: Carbamazepine Oxcarbazepine Phenobarbital Phenytoin ↓Cabotegravir Coadministration is contraindicated with APRETUDE due to potential for significant decreases in plasma concentration of APRETUDE. Antimycobacterials: Rifampin Rifapentine ↓Cabotegravir Antimycobacterial: Rifabutin ↓Cabotegravir When rifabutin is started before or concomitantly with the first initiation injection of APRETUDE, the recommended dosing of APRETUDE is one 600-mg (3-mL) injection, followed 2 weeks later by a second 600‑mg (3-mL) initiation injection and monthly thereafter while on rifabutin.

When rifabutin is started at the time of the second initiation injection or later, the recommended dosing schedule of APRETUDE is 600‑mg (3 mL) monthly while on rifabutin. After stopping rifabutin, the recommended dosing schedule of APRETUDE is 600-mg (3 mL) every 2 months.

7.4 Drugs without Clinically Significant Interactions with Cabotegravir Based on drug interaction study results, the following drugs can be coadministered with cabotegravir (non-antiretrovirals) or given after discontinuation of cabotegravir (antiretrovirals and non-antiretrovirals) without a dose adjustment: etravirine, midazolam, oral contraceptives containing levonorgestrel and ethinyl estradiol, and rilpivirine [see Clinical Pharmacology ( 12.3 )] .

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to APRETUDE during pregnancy. Healthcare providers are encouraged to register individuals by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary There are insufficient human data on the use of APRETUDE during pregnancy to adequately assess a drug-associated risk of birth defects and miscarriage. Discuss the benefit-risk of using APRETUDE with individuals of childbearing potential or during pregnancy. Cabotegravir use in pregnant individuals has not been evaluated.

APRETUDE should be used during pregnancy only if the expected benefit justifies the potential risk to the fetus. The APR has been established to monitor for birth defects following prenatal exposure to antiretrovirals. The rate of miscarriage is not reported in the APR. The background rate for major birth defects in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) is 2.7%. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%. The APR uses the MACDP as the U.S. reference population for birth defects in the general population.

The MACDP evaluates mothers and infants from a limited geographic area and does not include outcomes for births that occurred at <20 weeks’ gestation. In animal reproduction studies with oral cabotegravir, a delay in the onset of parturition and increased stillbirths and neonatal deaths were observed in a rat pre- and postnatal development study at >28 times the exposure at the recommended human dose (RHD). No evidence of adverse developmental outcomes was observed with oral cabotegravir in rats or rabbits (>28 times or similar to the exposure at the RHD, respectively) given during organogenesis (see Data) .

Clinical Considerations Cabotegravir is detected in systemic circulation for up to 12 months or longer after discontinuing injections of APRETUDE; therefore, consideration should be given to the potential for fetal exposure during pregnancy [see Warnings and Precautions ( 5.3 )] . Data Animal Data: Cabotegravir was administered orally to pregnant rats at 0, 0.5, 5, or 1,000 mg/kg/day from 15 days before cohabitation, during cohabitation, and from Gestation Days 0 to 17. There were no effects on fetal viability when fetuses were delivered by caesarean, although a minor decrease in fetal body weight was observed at 1,000 mg/kg/day (>28 times the exposure in humans at the RHD). No…