Drug Interactions between Symfi Lo and telaprevir

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.

GENERALLY AVOID: Coadministration with efavirenz may decrease the plasma concentrations of telaprevir. The mechanism is efavirenz induction of CYP450 3A4, the isoenzyme responsible for the metabolic clearance of telaprevir. When telaprevir (750 mg every 8 hours for 10 days) was given in combination with efavirenz (600 mg once daily for 20 days) to 21 study subjects, telaprevir peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (Cmin) decreased by 9%, 26% and 47%, respectively. Efavirenz Cmax also decreased by 16% and AUC decreased by 7% in the presence of telaprevir, although these changes were not considered significant. When telaprevir (1125 mg every 8 hours) was given in combination with both efavirenz (600 mg once daily) and tenofovir disoproxil fumarate (300 mg once daily) for 7 days to fifteen study subjects, the Cmax, AUC and Cmin of telaprevir decreased by an average of 14%, 18% and 25%, respectively, compared to telaprevir administered alone at 750 mg every 8 hours. When telaprevir was given at a dosage of 1500 mg every 12 hours with the same dosages of efavirenz and tenofovir DF for 7 days, the Cmax, AUC and Cmin of telaprevir was reduced by an average of 3%, 20% and 48%, respectively, compared to telaprevir administered alone at 750 mg every 8 hours. The substantial reduction in trough concentrations of telaprevir during coadministration of efavirenz may lead to virologic failure.

MANAGEMENT: Given the risk of reduced viral susceptibility and resistance development associated with subtherapeutic drug levels, concomitant use of telaprevir with efavirenz should generally be avoided.

MONITOR: Coadministration of tenofovir disoproxil fumarate with telaprevir may increase the plasma concentrations of tenofovir. The mechanism of interaction has not been described. In 16 study subjects, administration of tenofovir DF (300 mg once daily) in combination with telaprevir (750 mg every 8 hours) for 7 days increased the tenofovir peak plasma concentration (Cmax) and systemic exposure (AUC) by an average of 30% and the trough plasma concentration (Cmin) by 41% compared to administration alone. The Cmax, AUC and Cmin of telaprevir did not change significantly. When the same dosage of tenofovir DF was given in combination with both efavirenz (600 mg once daily) and telaprevir (1125 mg every 8 hours) for 7 days to fifteen study subjects, tenofovir Cmax, AUC and Cmin increased by an average of just 22%, 10% and 17%, respectively. Similar results were observed when the telaprevir dosage was changed to 1500 mg every 12 hours and administered with tenofovir DF and efavirenz.

MANAGEMENT: Increased clinical and laboratory monitoring are warranted when tenofovir DF is coadministered with telaprevir. Treatment with tenofovir DF should be discontinued in patients who develop tenofovir-related toxicities such as renal impairment or lactic acidosis and severe hepatomegaly with steatosis.