Drug Interactions between atorvastatin / ezetimibe and fosamprenavir

ADJUST DOSE: Protease inhibitors (PIs), particularly ritonavir, may significantly increase the plasma concentrations of atorvastatin. The mechanism is PI inhibition of CYP450 3A4 metabolism. In 14 healthy volunteers, ritonavir (400 mg twice a day) and saquinavir (soft gelatin capsule 400 mg twice a day) given for 14 days increased the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of atorvastatin plus atorvastatin acid (given as atorvastatin 40 mg once a day for 4 days) by 148% and 73%, respectively. In 16 study subjects, amprenavir (given as fosamprenavir 1400 mg twice a day for 2 weeks) increased Cmax and AUC of atorvastatin (10 mg once a day) by 304% and 130%, respectively. These values were increased 184% and 153%, respectively, with ritonavir-fosamprenavir (700 mg-100 mg twice a day). High levels of HMG-CoA reductase inhibitory activity in plasma is associated with an increased risk of musculoskeletal toxicity. Myopathy manifested as muscle pain and/or weakness associated with grossly elevated creatine kinase exceeding ten times the upper limit of normal has been reported occasionally. Rhabdomyolysis has also occurred rarely, which may be accompanied by acute renal failure secondary to myoglobinuria and may result in death.

MANAGEMENT: The benefits of using atorvastatin in combination with protease inhibitors should be carefully weighed against the potentially increased risk of myopathy including rhabdomyolysis. A lower dosage of atorvastatin should be considered if concomitant use is required. Atorvastatin labeling recommends that the dosage not exceed 20 mg/day when used in combination with fosamprenavir or with dual protease inhibitor therapy consisting of ritonavir plus darunavir, saquinavir, or fosamprenavir. Use of atorvastatin with the fixed combination of atazanavir-cobicistat is not recommended. The dosage should not exceed 40 mg/day when used with nelfinavir. Nirmatrelvir-ritonavir product labeling advises temporary discontinuation of atorvastatin be considered during treatment with nirmatrelvir-ritonavir. Fluvastatin, pitavastatin, and pravastatin may be safer alternatives, since they are not metabolized by CYP450 3A4. All patients receiving statin therapy should be advised to promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by fever, malaise and/or dark colored urine. Therapy should be discontinued if creatine kinase is markedly elevated in the absence of strenuous exercise or if myopathy is otherwise suspected or diagnosed.

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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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