Drug Interactions between colestipol and Lypqozet

ADJUST DOSING INTERVAL: Bile acid sequestrants may reduce the systemic exposure and therapeutic effects of ezetimibe. The exact mechanism has not been thoroughly described in the literature, but may involve a reduction in absorption and/or interference with enterohepatic recirculation of ezetimibe by the bile acid sequestrant. In a study of adult subjects with low-density lipoprotein cholesterol (LDL-C) levels of greater than or equal to 130 mg/dL, concomitant administration of cholestyramine (4 g twice daily) with ezetimibe (10 mg) reduced the systemic exposure (AUC) of total ezetimibe (ezetimibe plus its pharmacologically active metabolite) by approximately 55%. In contrast, some clinical trials involving colesevelam with ezetimibe have indicated that the pair may be able to be administered simultaneously without affecting ezetimibe's efficacy. Specific data on the effects of other bile acid sequestrants on the AUC of ezetimibe are not available.

MANAGEMENT: Ezetimibe's labeling indicates that use with a bile acid sequestrant may decrease ezetimibe's efficacy and recommends administration at least 2 hours before or 4 hours after the bile acid sequestrant. However, the labeling for some colesevelam products indicate that this pair can be separated as described in ezetimibe's product information or administered together.

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.

Colestipol has been shown to decrease plasma concentrations of atorvastatin by approximately 25% when coadministered. However, there was a synergistic effect in LDL-C reduction. The mechanism of the interaction has not been described. No action appears necessary.