Drug Interactions between Lypqozet and st. john's wort

MONITOR: Coadministration with St. John's wort may decrease the plasma concentrations of certain HMG-CoA reductase inhibitors and/or their metabolites. The interaction has been reported specifically with simvastatin and its pharmacologically active acid metabolite. The mechanism is enhanced first-pass metabolism of simvastatin due to induction of hepatic and intestinal CYP450 3A4 activity by constituents of St. John's wort. Reduced absorption of simvastatin secondary to induction of intestinal P-glycoprotein drug efflux pumps may also play a role. In 8 healthy male volunteers, St. John's wort (300 mg orally three times a day for 14 days) decreased the mean area under the plasma concentration-time curve of simvastatin hydroxy acid (from a 10 mg single oral dose of simvastatin) by 62% compared to placebo. The peak plasma concentration (Cmax) of simvastatin and metabolite as well as AUC of simvastatin also decreased but the differences were not statistically significant. In contrast, St. John's wort had no effect on the pharmacokinetics of pravastatin.

MANAGEMENT: While clinical data are lacking, the possibility of a diminished therapeutic response to simvastatin should be considered in patients simultaneously treated with St. John's wort. Other HMG-CoA reductase inhibitors that are substrates of CYP450 3A4 and P-glycoprotein such as lovastatin and atorvastatin are also expected to interact similarly with St. John's wort. Fluvastatin, pravastatin, and rosuvastatin are not expected to participate in this interaction and may be suitable alternatives in patients using St. John's wort.

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.