Drug Interaction Report

ADJUST DOSE: Coadministration with bempedoic acid may increase the plasma concentrations of simvastatin and pravastatin and risk of statin-related myopathy. The mechanism of the interaction has not been reported. In one study, coadministration of bempedoic acid at steady-state with simvastatin resulted in approximately 2-fold and 1.5-fold increases in simvastatin systemic exposure (AUC) and peak plasma concentrations (Cmax), respectively. In another study, coadministration of bempedoic acid at steady-state with pravastatin resulted in 99% and 104% (2-fold each) increases in pravastatin AUC and Cmax, respectively.

MANAGEMENT: When coadministered with bempedoic acid the simvastatin dosage should not exceed 20 mg daily and the pravastatin dosage should not exceed 40 mg daily. Patients should be monitored for the development of statin-related myopathy. Some authorities consider concomitant use with simvastatin at doses greater than 40 mg daily to be contraindicated (UK). In addition, these same authorities consider coadministration of bempedoic acid with a statin contraindicated in patients with active liver disease or unexplained persistent elevations in serum transaminases.

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: Concomitant use of statin medication with substantial quantities of alcohol may increase the risk of hepatic injury. Transient increases in serum transaminases have been reported with statin use and while these increases generally resolve or improve with continued therapy or a brief interruption in therapy, there have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins. Patients who consume substantial quantities of alcohol and/or have a history of liver disease may be at increased risk for hepatic injury. Active liver disease or unexplained transaminase elevations are contraindications to statin use.

MANAGEMENT: Patients should be counseled to avoid substantial quantities of alcohol in combination with statin medications and clinicians should be aware of the increased risk for hepatotoxicity in these patients.