Drug Interactions between carbamazepine and Symfi Lo

ADJUST DOSE: Coadministration with inducers of P-glycoprotein (P-gp), such as carbamazepine, may decrease the oral bioavailability and plasma concentrations of tenofovir alafenamide (TAF), which is a substrate of the efflux transporter. In 26 healthy study subjects, administration of TAF (25 mg once daily) with the P-gp inducer carbamazepine (300 mg twice daily) decreased TAF plasma concentration (Cmax) and systemic exposure (AUC) by an average of 57% and 55%, respectively, compared to TAF administered alone. It is not known if, and to what extent, tenofovir disoproxil fumarate (TDF), another prodrug of tenofovir, may interact with P-gp inducers. The interaction has not been studied with TDF, and no information is found in the labeling of various products containing TDF, although it has been reported to be a P-gp substrate also.

MANAGEMENT: When coadministered with carbamazepine, the dose of tenofovir alafenamide should be increased to 50 mg once daily. Patients should be monitored for subtherapeutic antiviral drug levels and loss of antiviral activity. Some authorities recommend avoiding concomitant administration of tenofovir alafenamide with carbamazepine (UK). Whether this interaction also applies to tenofovir disoproxil fumarate has not been established.

GENERALLY AVOID: The plasma concentrations of both carbamazepine and efavirenz may decrease during concomitant administration, since both drugs are substrates as well as inducers of CYP450 3A4. In a 2-period crossover pharmacokinetic study, 12 healthy volunteers were randomized to receive either efavirenz 600 mg once daily for 14 days or carbamazepine titrated to 400 mg once daily for 21 days, followed with both drugs for another 21 or 14 days. During coadministration, carbamazepine peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (Cmin) decreased by an average of 20%, 27% and 35%, respectively, while efavirenz Cmax, AUC and Cmin decreased by an average of 21%, 36% and 47%, respectively. The pharmacokinetics of the major metabolite of carbamazepine, carbamazepine-10,11-epoxide, were not significantly affected. Convulsions have been observed during efavirenz therapy, generally in patients with a known medical history of seizures. This may be at least partially related to the drug interaction between efavirenz and anticonvulsants including carbamazepine that are primarily metabolized by hepatic CYP450 microsomal isoenzymes.

MANAGEMENT: There are insufficient data to make a dosage recommendation for efavirenz during coadministration with carbamazepine. Given the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiretroviral drug levels, alternative anticonvulsant treatment should be used if efavirenz is required. Otherwise, pharmacologic effects and serum levels of both drugs should be closely monitored during concomitant use.

MONITOR: Coadministration of efavirenz with other agents known to induce hepatotoxicity may potentiate the risk of liver injury. Efavirenz has been associated with hepatotoxicity during postmarketing use. Among reported cases of hepatic failure, a few occurred in patients with no preexisting hepatic disease or other identifiable risk factors.

MANAGEMENT: The risk of hepatic injury should be considered when efavirenz is used in combination with other agents that are potentially hepatotoxic (e.g., acetaminophen; alcohol; androgens and anabolic steroids; antituberculous agents; azole antifungal agents; ACE inhibitors; cyclosporine (high dosages); disulfiram; endothelin receptor antagonists; interferons; ketolide and macrolide antibiotics; kinase inhibitors; minocycline; nonsteroidal anti-inflammatory agents; other HIV reverse transcriptase inhibitors; proteasome inhibitors; retinoids; sulfonamides; tamoxifen; thiazolidinediones; tolvaptan; vincristine; zileuton; anticonvulsants such as carbamazepine, hydantoins, felbamate, and valproic acid; lipid-lowering medications such as fenofibrate, lomitapide, mipomersen, niacin, and statins; herbals and nutritional supplements such as black cohosh, chaparral, comfrey, DHEA, kava, pennyroyal oil, and red yeast rice). Patients should be advised to seek medical attention if they experience potential signs and symptoms of hepatotoxicity such as fever, rash, itching, anorexia, nausea, vomiting, fatigue, malaise, right upper quadrant pain, dark urine, pale stools, and jaundice. Monitoring of liver function tests should occur before and during treatment, especially in patients with underlying hepatic disease (including hepatitis B or C coinfection) or marked transaminase elevations. The benefit of continued therapy with efavirenz should be considered against the unknown risks of significant liver toxicity in patients who develop persistent elevations of serum transaminases greater than five times the upper limit of normal.

MONITOR: Coadministration of efavirenz with other agents known to induce hepatotoxicity may potentiate the risk of liver injury. Efavirenz has been associated with hepatotoxicity during postmarketing use. Among reported cases of hepatic failure, a few occurred in patients with no preexisting hepatic disease or other identifiable risk factors.

MANAGEMENT: The risk of hepatic injury should be considered when efavirenz is used in combination with other agents that are potentially hepatotoxic (e.g., acetaminophen; alcohol; androgens and anabolic steroids; antituberculous agents; azole antifungal agents; ACE inhibitors; cyclosporine (high dosages); disulfiram; endothelin receptor antagonists; interferons; ketolide and macrolide antibiotics; kinase inhibitors; minocycline; nonsteroidal anti-inflammatory agents; other HIV reverse transcriptase inhibitors; proteasome inhibitors; retinoids; sulfonamides; tamoxifen; thiazolidinediones; tolvaptan; vincristine; zileuton; anticonvulsants such as carbamazepine, hydantoins, felbamate, and valproic acid; lipid-lowering medications such as fenofibrate, lomitapide, mipomersen, niacin, and statins; herbals and nutritional supplements such as black cohosh, chaparral, comfrey, DHEA, kava, pennyroyal oil, and red yeast rice). Patients should be advised to seek medical attention if they experience potential signs and symptoms of hepatotoxicity such as fever, rash, itching, anorexia, nausea, vomiting, fatigue, malaise, right upper quadrant pain, dark urine, pale stools, and jaundice. Monitoring of liver function tests should occur before and during treatment, especially in patients with underlying hepatic disease (including hepatitis B or C coinfection) or marked transaminase elevations. The benefit of continued therapy with efavirenz should be considered against the unknown risks of significant liver toxicity in patients who develop persistent elevations of serum transaminases greater than five times the upper limit of normal.