Drug Interactions between fenofibric acid and Lypqozet

MONITOR CLOSELY: Data from observational studies suggest that the risk of severe myopathy and rhabdomyolysis is increased when fibric acid derivatives are coadministered with an HMG-CoA reductase inhibitor (i.e., statin), even in the absence of a marked pharmacokinetic interaction. Additive pharmacodynamic effects may be involved, since these agents individually have been associated with the development of myopathy. Although gemfibrozil has been implicated most often, presumably due to a pharmacokinetic interaction with statins that significantly increases their concentrations in plasma, other fibrates have also been involved. In clinical trials for delayed-release fenofibric acid, myalgia was reported in 3.3% of patients receiving monotherapy and 3.1% to 3.5% of patients receiving concomitant statin therapy, compared to 4.7% to 6.1% of patients receiving statin monotherapy. Increases in creatine phosphokinase (CPK) to greater than 5 times upper limit of normal occurred in no patients receiving fenofibric acid monotherapy and 0.2% to 1.2% of patients receiving concomitant statin therapy, compared to 0.4% to 1.3% of patients receiving statin monotherapy. Addition of a fibrate 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.

MANAGEMENT: Caution is advised if delayed-release fenofibric acid is coadministered with a statin. A lower dosage of the statin may be appropriate, particularly if the patient is already receiving the maximum dosage. Coadministration with the maximum dosage of a statin has not been evaluated in clinical studies and should be avoided unless the benefits are expected to outweigh the risks. All patients treated with HMG-CoA reductase inhibitors and/or fibrates 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. In addition, patients should be closely monitored for hepatotoxicity.

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 ezetimibe may potentiate the risk of cholelithiasis associated with fenofibrate and other fibrates. Fibrates can increase cholesterol excretion into the bile and cause cholelithiasis. A study comparing fenofibrate monotherapy (n=188) to ezetimibe combined with fenofibrate (n=183) found incidence rates for cholecystectomy were numerically higher in the combination group (0.6% vs 1.7%). In a study of 32 adult subjects with low-density lipoprotein cholesterol (LDL-C) levels of greater than or equal to 130 mg/dL, coadministration with fenofibrate (200 mg once daily) increased the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of total ezetimibe by approximately 64% and 48%, respectively. Fenofibrate's Cmax and AUC were increased by 7% and 11%, respectively. The increases in total ezetimibe and fenofibrate are not considered clinically relevant. Similarly, when fenofibric acid delayed-release capsules (135 mg once daily) were coadministered with ezetimibe (10 mg once daily) for 10 days, the AUC of fenofibric acid was also not significantly increased and the AUC of total ezetimibe increased by only 27%.

MANAGEMENT: Caution and increased monitoring are advised during coadministration of ezetimibe and fenofibrate. This recommendation may also apply if ezetimibe is administered with fenofibric acid. If cholelithiasis is suspected, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered. Some authorities consider concomitant use of ezetimibe and fenofibrate to be contraindicated in patients with preexisting gallbladder disease.