Drug Interaction Report

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.

Coadministration with epigallocatechin-3-gallate (EGCG), the most abundant and biologically active catechin in green tea, has been shown to modestly decrease the oral bioavailability of rosuvastatin. The mechanism of interaction has not been established, but may involve inhibition of organic anion transporting polypeptide (OATP) 1A2- and/or 2B1-mediated uptake of rosuvastatin in the intestine by EGCG. In a study with 13 healthy volunteers, administration of a single 20 mg dose of rosuvastatin in combination with 300 mg of EGCG (estimated in the study to be at least twice the amount contained in one cup of green tea) decreased rosuvastatin peak plasma concentration (Cmax) and systemic exposure (AUC) by 15% and 19%, respectively, compared to administration of rosuvastatin alone. By contrast, administration of the same dose of rosuvastatin following 10 days of pretreatment with 300 mg EGCG had no significant effect on the pharmacokinetics of rosuvastatin. It was suggested by the investigators of the study that chronic administration of EGCG may inhibit both the absorption (via intestinal OATP 1A2 and/or 2B1) and elimination (via hepatic OATP 1B1 and/or 2B1) of rosuvastatin, resulting in no net changes in plasma concentrations of rosuvastatin. Presumably, low bioavailability of EGCG and its accumulation with multiple-dose administration may be responsible for the difference in pharmacokinetics of rosuvastatin between single dosing and chronic dosing of EGCG, with plasma concentrations of EGCG after single dosing not being sufficient to inhibit hepatic uptake of rosuvastatin. It is not known whether an interaction may occur with green tea extracts or infusions, which contain additional catechins that may contribute to further inhibition of transporters.