Drug Interactions between efavirenz / lamivudine / tenofovir disoproxil and rifampin

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 rifampin with agents known to induce hepatotoxicity may potentiate the risk of liver injury. There are various possible mechanisms related to rifampin-associated hepatotoxicity described in product labeling and medical literature, however no consensus has been made. These include increased mitochondrial oxidative stress, apoptotic liver cell injury (in rodent studies), the development of cholestasis, hepatic lipid accumulation, and elevated toxic metabolites caused by rifampin-mediated induction of cytochrome P450 enzymes. Cases of drug-induced liver injury (including fatal cases) have been reported within the first few days to months following rifampin treatment initiation. Additional data suggests that 1-2% of patients receiving rifampin monotherapy for tuberculosis prophylaxis experience hepatotoxicity. The severity of hepatotoxicity from rifampin ranges from asymptomatic elevations in liver enzymes, jaundice and/or hyperbilirubinemia, and symptomatic self-limiting hepatitis to fulminant liver failure and death. In most cases, liver function recovers upon on discontinuation of rifampin treatment, however, progression to acute liver failure requiring liver transplantation is possible. Known risk factors that may predispose the patient to rifampin related hepatotoxicity include: coadministration with other hepatotoxic agents, alcoholism, existing liver disease, malnutrition, extensive liver tuberculosis, liver adenocarcinoma and biliary tract neoplasm. Clinical data have been reported with concurrent use of rifampin with other antituberculosis agents (e.g. isoniazid, pyrazinamide), acetaminophen, antiretroviral agents (e.g., saquinavir/ritonavir) and halothane. Data with other hepatotoxic agents are limited.

MANAGEMENT: Caution and close clinical monitoring should be considered if rifampin is coadministered with other hepatotoxic medications. In addition, the manufacturer recommends patients with impaired liver function only be given rifampin in cases of necessity and then under strict medical supervision. Some authorities consider rifampin treatment in patients with existing liver injury contraindicated (Canada). In cases where coadministration of rifampin with hepatotoxic agents is required, careful monitoring of liver function, especially ALT and AST, should be done prior to therapy and then every 2 to 4 weeks during therapy. If hepatic damage is suspected, rifampin should be immediately discontinued. Furthermore, if hepatitis is attributed to rifampin in patients with tuberculosis, alternative agents should be considered. Patients should be instructed to contact their physician immediately if they experience symptoms such as itching, weakness, loss of appetite, nausea, vomiting, abdominal pain, yellowing of the eyes or skin or dark urine.

ADJUST DOSE: Coadministration with rifampin may decrease the plasma concentrations of efavirenz. The mechanism is rifampin induction of efavirenz metabolism via CYP450 3A4. In 8 HIV-infected subjects, administration of antiretroviral treatment including efavirenz (600 mg once daily) in combination with an antituberculosis regimen containing rifampin (480 to 720 mg/day based on body weight) for 7 days resulted in decreased mean efavirenz peak plasma concentration (Cmax), systemic exposure (AUC) and trough concentration (Cmin) by 24%, and 22% and 25%, respectively, compared to administration with nonrifampin antituberculosis agents. These differences were not statistically significant, and given the large interpatient variability in the pharmacokinetics of efavirenz observed in the study, the clinical relevance of these modest changes is unknown. Differences in bodyweight appeared to cause further variations in exposure to efavirenz. Plasma concentrations of efavirenz in patients weighing less than 50 kg were similar to those previously described in HIV-infected patients without concomitant tuberculosis, whereas plasma concentrations in patients weighing 50 kg or more were almost halved compared to those observed in the lighter patients. In the same study, it was demonstrated in another eight subjects that plasma concentrations of efavirenz 800 mg/day in the presence of rifampin were similar to those of efavirenz 600 mg/day without rifampin. Efavirenz had no significant effect on the pharmacokinetics of rifampin. Likewise, the manufacturer reports that when efavirenz 600 mg/day was coadministered with rifampin 600 mg/day for seven days in 12 subjects, efavirenz Cmax, AUC and Cmin decreased by 20%, 26% and 32%, respectively. In another study consisting of 84 HIV-infected Thai patients (mean body weight approximately 50 kg) receiving at least one month of rifampin for active tuberculosis, the median plasma concentration of efavirenz was similar in patients treated with efavirenz 600 mg/day compared to patients treated with efavirenz 800 mg/day as part of their antiretroviral regimen. There was no significant difference in the time to virologic success (HIV RNA below 50 copies/mL). A follow-up study at 48 weeks also found no significant difference in the virological and immunological outcomes between the two groups. Whether these results are applicable to other ethnic populations with greater body weights is unknown. Interestingly, one group of investigators found an increased incidence of toxicity in patients receiving efavirenz 800 mg/day in combination with antituberculous therapy containing rifampin. In this population, 7 of 9 patients developed clinical toxicity (e.g., anxiety, depression, hepatitis) in association with significantly elevated efavirenz trough levels beyond the therapeutic range. Six of the seven patients who developed toxicity were of African descent.

MONITOR: Coadministration of efavirenz with other agents known to induce hepatotoxicity such as rifampin 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: Some authorities (US manufacturer of Rifadin) recommend avoiding concomitant use of rifampin and efavirenz. If concomitant use is unavoidable, clinicians should be aware that the optimal dosage of efavirenz in combination with rifampin is unknown. Limited data suggest that the usual dosage of 600 mg once daily may be adequate and appropriate in settings of limited resources or where cost is otherwise a concern. Some experts, as well as the efavirenz manufacturer, recommend increasing the dosage of efavirenz to 800 mg once daily when it is coadministered with rifampin in patients weighing 50 kg or more. Because toxicity may be increased with the higher dosage, therapeutic drug monitoring is also recommended. Rifampin can be used with efavirenz without dosage modification. However, interactions with other antiretroviral agents in the regimen (e.g., protease inhibitors) may preclude the use of rifampin or necessitate modification of the existing antiretroviral regimen. In general, treatment of tuberculosis (TB) in the context of antiretroviral therapy is complex and requires an individualized approach. Experts in the treatment of HIV-related TB should be consulted, and TB and HIV care providers should work in close coordination throughout treatment. Due to the potential for additive risk of hepatic injury, patients receiving both efavirenz and rifampin 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, right upper quadrant pain, dark urine, light-colored 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.

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.