Drug Interactions between efavirenz / lamivudine / tenofovir disoproxil and etranacogene dezaparvovec

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 with other hepatotoxic agents may increase the risk of liver injury and decrease the therapeutic efficacy of fidanacogene elaparvovec and etranacogene dezaparvovec, liver-directed adeno-associated virus (AAV) vectors designed to help replace missing coagulation factor IX. Increased transaminase levels, particularly those observed in the first 3 to 4 months after administration of these agents, have been attributed to immune-mediated injury of transduced hepatocytes, which may decrease its therapeutic efficacy. In a prospective, open-label, single-arm, multinational clinical study of adult male patients with moderately severe to severe hemophilia B (n=45) receiving a single dose of fidanacogene elaparvovec (5 x 10[11] vector genomes [vg]/kg), 29 patients experienced increased transaminase levels greater than or equal to 1.5 times baseline. Of these patients, 28 received treatment with corticosteroids due to increased transaminases and/or a decline in factor IX activity, with a mean initiation time to corticosteroid therapy reported at 45 days. However, no serious adverse reactions were reported. Likewise, clinical studies with etranacogene dezaparvovec have also reported asymptomatic and mostly mild elevations in transaminases. The majority of elevated ALT levels returned to baseline; however, there were cases where they remained between 48 IU/L to 193 IU/L at two years post-administration of etranacogene dezaparvovec.

MANAGEMENT: As part of monitoring post-administration of fidanacogene elaparvovec, the manufacturer generally recommends monitoring of ALT and factor IX activity levels (e.g., one to two times a week for at least 4 months). The manufacturer of etranacogene dezaparvovec advises weekly transaminase level monitoring at weekly intervals for 3 months after its administration and, in patients with elevated levels, until those enzymes return to baseline. Initiation of corticosteroid therapy and monitoring of Factor IX activity should be considered in cases where ALT levels rise above the upper limit of normal or double baseline levels. The risk of additive hepatotoxicity and decreased therapeutic efficacy of fidanacogene elaparvovec should be considered after coadministration with other hepatotoxic agents. Alternative treatment may be required if an interaction is suspected. The manufacturer of etranacogene dezaparvovec does not provide specific recommendations concerning coadministration with other hepatotoxic agents. Local protocols and/or the product labeling of the concomitant drug(s) should be consulted for additional guidance.

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 with other hepatotoxic agents may increase the risk of liver injury and decrease the therapeutic efficacy of fidanacogene elaparvovec and etranacogene dezaparvovec, liver-directed adeno-associated virus (AAV) vectors designed to help replace missing coagulation factor IX. Increased transaminase levels, particularly those observed in the first 3 to 4 months after administration of these agents, have been attributed to immune-mediated injury of transduced hepatocytes, which may decrease its therapeutic efficacy. In a prospective, open-label, single-arm, multinational clinical study of adult male patients with moderately severe to severe hemophilia B (n=45) receiving a single dose of fidanacogene elaparvovec (5 x 10[11] vector genomes [vg]/kg), 29 patients experienced increased transaminase levels greater than or equal to 1.5 times baseline. Of these patients, 28 received treatment with corticosteroids due to increased transaminases and/or a decline in factor IX activity, with a mean initiation time to corticosteroid therapy reported at 45 days. However, no serious adverse reactions were reported. Likewise, clinical studies with etranacogene dezaparvovec have also reported asymptomatic and mostly mild elevations in transaminases. The majority of elevated ALT levels returned to baseline; however, there were cases where they remained between 48 IU/L to 193 IU/L at two years post-administration of etranacogene dezaparvovec.

MANAGEMENT: As part of monitoring post-administration of fidanacogene elaparvovec, the manufacturer generally recommends monitoring of ALT and factor IX activity levels (e.g., one to two times a week for at least 4 months). The manufacturer of etranacogene dezaparvovec advises weekly transaminase level monitoring at weekly intervals for 3 months after its administration and, in patients with elevated levels, until those enzymes return to baseline. Initiation of corticosteroid therapy and monitoring of Factor IX activity should be considered in cases where ALT levels rise above the upper limit of normal or double baseline levels. The risk of additive hepatotoxicity and decreased therapeutic efficacy of fidanacogene elaparvovec should be considered after coadministration with other hepatotoxic agents. Alternative treatment may be required if an interaction is suspected. The manufacturer of etranacogene dezaparvovec does not provide specific recommendations concerning coadministration with other hepatotoxic agents. Local protocols and/or the product labeling of the concomitant drug(s) should be consulted for additional guidance.

MONITOR: Coadministration with other hepatotoxic agents may increase the risk of liver injury and decrease the therapeutic efficacy of fidanacogene elaparvovec and etranacogene dezaparvovec, liver-directed adeno-associated virus (AAV) vectors designed to help replace missing coagulation factor IX. Increased transaminase levels, particularly those observed in the first 3 to 4 months after administration of these agents, have been attributed to immune-mediated injury of transduced hepatocytes, which may decrease its therapeutic efficacy. In a prospective, open-label, single-arm, multinational clinical study of adult male patients with moderately severe to severe hemophilia B (n=45) receiving a single dose of fidanacogene elaparvovec (5 x 10[11] vector genomes [vg]/kg), 29 patients experienced increased transaminase levels greater than or equal to 1.5 times baseline. Of these patients, 28 received treatment with corticosteroids due to increased transaminases and/or a decline in factor IX activity, with a mean initiation time to corticosteroid therapy reported at 45 days. However, no serious adverse reactions were reported. Likewise, clinical studies with etranacogene dezaparvovec have also reported asymptomatic and mostly mild elevations in transaminases. The majority of elevated ALT levels returned to baseline; however, there were cases where they remained between 48 IU/L to 193 IU/L at two years post-administration of etranacogene dezaparvovec.

MANAGEMENT: As part of monitoring post-administration of fidanacogene elaparvovec, the manufacturer generally recommends monitoring of ALT and factor IX activity levels (e.g., one to two times a week for at least 4 months). The manufacturer of etranacogene dezaparvovec advises weekly transaminase level monitoring at weekly intervals for 3 months after its administration and, in patients with elevated levels, until those enzymes return to baseline. Initiation of corticosteroid therapy and monitoring of Factor IX activity should be considered in cases where ALT levels rise above the upper limit of normal or double baseline levels. The risk of additive hepatotoxicity and decreased therapeutic efficacy of fidanacogene elaparvovec should be considered after coadministration with other hepatotoxic agents. Alternative treatment may be required if an interaction is suspected. The manufacturer of etranacogene dezaparvovec does not provide specific recommendations concerning coadministration with other hepatotoxic agents. Local protocols and/or the product labeling of the concomitant drug(s) should be consulted for additional guidance.