Drug Interactions between dolutegravir and oxcarbazepine

GENERALLY AVOID: Coadministration with potent inducers of UGT1A1 and CYP450 3A4 isoenzymes may significantly decrease the plasma concentrations of dolutegravir, which is primarily metabolized by UGT1A1 with some contribution from CYP450 3A4. Dolutegravir is also a substrate of UGT1A3, UGT1A9, and P-glycoprotein in vitro. In 16 study subjects, administration of dolutegravir 50 mg once daily with the potent CYP450 3A4 inducer carbamazepine at a dose of 300 mg twice daily decreased dolutegravir peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (Cmin; 24 hours post-dose) by 33%, 49%, and 73%, respectively, compared to administration without carbamazepine. Data are not available for other potent CYP450 3A4 inducers phenytoin, phenobarbital (phenobarbitone), and St. John's wort.

MANAGEMENT: In patients with HIV-1 without integrase inhibitor (INI) resistance, some authorities recommend a dolutegravir dose of 50 mg twice daily for both adults and pediatric patients 12 years of age and older who weigh at least 40 kg when coadministered with potent UGT1A1 and CYP450 3A4 inducers including carbamazepine, phenytoin, phenobarbital, and St. John's Wort. However, other authorities advise that coadministration of dolutegravir with these inducers should be avoided. The safety and efficacy of dosages above 50 mg twice daily have not been evaluated. Alternative treatment combinations that do not include metabolic inducers should be considered whenever possible for INI-experienced patients with certain INI-associated resistance substitutions or clinically suspected INI resistance. In addition, concomitant use of potent UGT1A1 and CYP450 3A4 inducers with fixed-dose combination products containing dolutegravir is not recommended; however, when used in combination with carbamazepine, some authorities advise administration of an additional 50 mg daily dose of dolutegravir approximately 12 hours from the combination product. Local antiretroviral treatment experts should be consulted for current practice.