Drug Interactions between ezetimibe / rosuvastatin and gemfibrozil

GENERALLY AVOID: Coadministration with gemfibrozil may significantly increase the plasma concentrations of rosuvastatin. The proposed mechanism is gemfibrozil inhibition of the hepatic uptake of rosuvastatin via organic anion transporting polypeptide 2 (OATP-2). In 20 healthy volunteers, gemfibrozil (600 mg twice a day for 7 days) increased the peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of rosuvastatin (80 mg single oral dose) by 120% and 90%, respectively, compared to placebo. High levels of HMG-CoA reductase inhibitory activity in plasma is associated with an increased risk of musculoskeletal toxicity. Myopathy manifested as muscle pain and/or weakness associated with grossly elevated creatine kinase exceeding ten times the upper limit of normal has been reported occasionally. Rhabdomyolysis has also occurred rarely, which may be accompanied by acute renal failure secondary to myoglobinuria and may result in death. Although there was no evidence of increased skeletal muscle effects when rosuvastatin was used with fibric acid derivatives including gemfibrozil in clinical trials, an increase in the incidence of myositis and myopathy has been observed in patients receiving other HMG-CoA reductase inhibitors with fibric acid derivatives.

MANAGEMENT: Concurrent use of rosuvastatin and gemfibrozil should generally be avoided unless the benefit of further alterations in lipid levels is anticipated to outweigh the potential risks. Addition of fibrates to HMG-CoA reductase inhibitor therapy typically provides little additional reduction in LDL cholesterol, but further reductions of triglycerides and increases in HDL cholesterol may be attained. The daily dosage of rosuvastatin should not exceed 10 mg when used in combination with gemfibrozil. Patients should be advised to promptly report any unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. Therapy should be discontinued if creatine kinase is markedly elevated in the absence of strenuous exercise or if myopathy is otherwise suspected or diagnosed.

GENERALLY AVOID: The safety and efficacy of ezetimibe coadministered with fibrates other than fenofibrate have not been studied. Fibrates can increase cholesterol excretion into the bile and cause cholelithiasis. In dogs, administration of ezetimibe for one month increased the concentration of cholesterol in gallbladder bile by 2- to 4-fold, although administration for one year did not result in gallstone formation or any other adverse hepatobiliary effects. In pharmacokinetic studies, coadministration with fenofibrate (200 mg once daily) and gemfibrozil (600 mg twice daily) increased total ezetimibe concentrations 1.5-fold and 1.7-fold, respectively, in healthy adults. These increases are not considered clinically relevant. Ezetimibe (10 mg once daily) did not significantly affect the pharmacokinetics of fenofibrate or gemfibrozil.

MANAGEMENT: Due to the lack of safety and efficacy data, coadministration of ezetimibe with fibrates other than fenofibrate is not recommended. If cholelithiasis is suspected in a patient receiving such a combination, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered.

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.