Drug Interactions between Atripla and st. john's wort

GENERALLY AVOID: Coadministration with St. John's wort may significantly reduce the plasma concentrations of certain antiretroviral agents such as nonnucleoside reverse transcriptase inhibitors (NNRTIs), and CCR5 coreceptor antagonists. The mechanism is induction of CYP450 3A4 metabolism by constituents of St. John's wort. In eight healthy volunteers, St. John's wort (300 mg, standardized to 0.3% hypericin, three times a day for 14 days) decreased the 8-hour area under the plasma concentration-time curve (AUC) and extrapolated 8-hour trough of indinavir (800 mg every 8 hours for 4 doses) by a mean of 57% and 81%, respectively, compared to administration of indinavir alone. All participants showed a reduction in the indinavir 8-hour postdose concentration ranging from 49% to 99%. The interaction was also suspected as the cause of low nevirapine plasma levels in five HIV patients who used St. John's wort while being treated with nevirapine and two nucleoside reverse transcriptase inhibitors.

MANAGEMENT: Given the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiretroviral drug levels, patients treated with antiretroviral agents should avoid using St. John's wort. Patients should be advised to consult with their caregivers before using any herbal or alternative medicines.

GENERALLY AVOID: Coadministration with inducers of P-glycoprotein (P-gp) 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: Given the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiviral drug levels, concomitant use of tenofovir alafenamide fumarate with P-gp inducers is not recommended. Whether this also applies to tenofovir disoproxil fumarate has not been established.

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.