Drug Interactions between Alagesic LQ and Liptruzet

MONITOR: Barbiturates may increase the hepatotoxic potential of acetaminophen and decrease its therapeutic effects. The mechanism may be related to accelerated CYP450 metabolism of acetaminophen with consequent increase in hepatotoxic metabolites. This interaction is of greatest concern in cases of acetaminophen overdose.

MANAGEMENT: Monitoring for altered efficacy and safety is recommended. Prolonged use or high doses of acetaminophen should be avoided by patients on barbiturate therapy.

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MONITOR: Coadministration with inducers of CYP450 3A4 may decrease the plasma concentrations of atorvastatin and its active metabolites, all of which are substrates of the isoenzyme. When atorvastatin (40 mg/day) was coadministered for 28 days with the potent CYP450 3A4 inducer phenytoin (4 mg/kg/day) in healthy volunteers (n=44), atorvastatin peak plasma concentration (Cmax) and systemic exposure (AUC) decreased by an average of 24% and 54%, respectively. The Cmax of two active metabolites, 2-hydroxy- and 4-hydroxyatorvastatin, also decreased by an average of 22% and 52%, respectively, while AUC decreased by an average of 53% and 44%, respectively. Consistent with the observed pharmacokinetic interaction, there have been isolated reports of reduced efficacy of atorvastatin in the presence of phenytoin, followed by improved cholesterol levels after discontinuation of phenytoin. In another study, coadministration of the mixed CYP450 3A4 inducer/inhibitor efavirenz (600 mg once daily for 15 days) with atorvastatin (10 mg daily during the last 4 days of efavirenz) in 14 healthy volunteers resulted in median decreases of 43% in atorvastatin AUC and 34% in total active atorvastatin (parent drug + active metabolites) AUC. However, the median LDL decrease was not significantly different during coadministration with efavirenz compared to atorvastatin administered alone (-29 versus -22, respectively). Atorvastatin did not affect the AUC of efavirenz. In a study of patients with non-small cell lung cancer receiving the CYP450 3A4 inducer bexarotene (400 mg/m2 orally once a day) plus either paclitaxel/carboplatin or cisplatin/vinorelbine chemotherapy, treatment with atorvastatin or fenofibrate was given to manage bexarotene-induced hyperlipidemia. Investigators reported that bexarotene decreased mean atorvastatin systemic exposure (dose-corrected AUC) by approximately 50%, whereas atorvastatin had no significant effect on bexarotene plasma concentrations. In 16 study subjects administered etravirine with atorvastatin 40 mg once a day, atorvastatin AUC decreased by 37%, while Cmax and AUC of 2-hydroxy-atorvastatin increased by 76% and 27%, respectively. Atorvastatin did not significantly affect the pharmacokinetics of etravirine.

MANAGEMENT: The potential for diminished pharmacologic effects of atorvastatin should be considered during coadministration with CYP450 3A4 inducers. Alternative agents with no or minimal CYP450 3A4 induction potential are recommended whenever possible. Otherwise, pharmacologic response to atorvastatin should be closely monitored, and the dosage adjusted as necessary. A statin that is not metabolized by CYP450 3A4 such as fluvastatin, pitavastatin, pravastatin, or rosuvastatin may also be substituted for atorvastatin when used with certain enzyme inducers.

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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. 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.

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