Drug Interactions between etranacogene dezaparvovec and ezetimibe / rosuvastatin

MONITOR: Coadministration with ezetimibe may rarely increase the risk of myopathy and serum transaminase elevations associated with HMG-CoA reductase inhibitors (i.e., statins). The mechanism of interaction is unknown. A case report describes two patients whose serum creatine kinase increased after ezetimibe was added to their statin therapy (atorvastatin and fluvastatin, respectively). One of the patients also developed myalgia and tendinopathy, which resolved promptly after withdrawal of both drugs. Statin therapy was subsequently reintroduced at the previous dosage without incident. In the other patient, serum creatine kinase returned to normal within 4 weeks after discontinuation of ezetimibe while the statin was continued. On the contrary, no cases of myopathy or tendinopathy occurred in a study of 33 hypercholesterolemic patients treated with ezetimibe and atorvastatin or simvastatin. There were also no reports of myopathy or significant increases in serum creatine kinase in a study of 32 subjects treated with ezetimibe and fluvastatin. In controlled clinical studies, the incidence of consecutive elevations (greater than 3 times the upper limit of normal) in serum transaminases was 1.3% for patients treated with ezetimibe in combination with a statin versus 0.4% for patients treated with a statin alone. These elevations were generally asymptomatic, not associated with cholestasis, and returned to baseline after discontinuation of therapy or with continued treatment.

MANAGEMENT: Until further information is available, use of a statin in combination with ezetimibe should be approached with caution. Some authorities consider concomitant use to be contraindicated in patients with active liver disease or unexplained persistent elevations in serum transaminases. Patients should be advised to promptly report to their physician any unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. The drugs should be discontinued if creatine kinase is markedly elevated in the absence of strenuous exercise or if myopathy is otherwise suspected or diagnosed. In addition, liver function tests should be performed at initiation of therapy and according to the recommendations of the HMG-CoA reductase inhibitor.

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.