Drug Interactions between ezetimibe / rosuvastatin and lorlatinib

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: Coadministration with lorlatinib may decrease the plasma concentrations of drugs that are substrates of the CYP450 2C9 isoenzyme. The proposed mechanism involves increased metabolic clearance due to induction of CYP450 2C9 by lorlatinib. When a single 100 mg oral dose of tolbutamide, a sensitive CYP450 2C9 substrate, was administered with lorlatinib (100 mg orally once daily for 15 days), tolbutamide peak plasma concentration (Cmax) and systemic exposure (AUC) decreased by 15% and 43%, respectively.

MANAGEMENT: Caution is advised when lorlatinib is used concurrently with drugs that are known CYP450 2C9 substrates, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever lorlatinib is added to or withdrawn from therapy.