Drug Interactions between atazanavir and ezetimibe / rosuvastatin

ADJUST DOSE: Coadministration with protease inhibitors may significantly increase the plasma concentrations of rosuvastatin. The mechanism may involve inhibition of OATP1B1-mediated hepatic uptake and/or BCRP-mediated intestinal and hepatobiliary efflux. In 15 healthy volunteers, administration of rosuvastatin 20 mg once a day with lopinavir-ritonavir 400 mg-100 mg twice a day for 7 days was associated with an approximately 5-fold increase in rosuvastatin steady-state peak plasma concentration (Cmax) and a 2-fold increase in systemic exposure (AUC) compared to administration of rosuvastatin alone. One subject had asymptomatic creatine phosphokinase elevation 17 times the upper limit of normal (ULN) and another had liver function test elevation between 1.1 and 2.5 times ULN. In a study with 11 subjects, administration of rosuvastatin 5 mg once daily in combination with once daily morning doses of ombitasvir/paritaprevir/ritonavir (25 mg/150 mg/100 mg) plus twice daily doses of dasabuvir resulted in increases of rosuvastatin Cmax and AUC by approximately 7.1- and 2.6-fold, respectively. Likewise, atazanavir/ritonavir 300 mg/100 mg given once daily for 8 days increased the Cmax and AUC of a single 10 mg dose of rosuvastatin by 7.0- and 3.1-fold, respectively. 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 rosuvastatin with protease inhibitors should be carefully weighed against the potentially increased risk of myopathy including rhabdomyolysis. If coadministration is required, rosuvastatin should be initiated at the lowest effective dosage and not exceed 10 mg per day when prescribed with lopinavir-ritonavir, atazanavir-ritonavir, atazanavir-cobicistat, or ombitasvir/paritaprevir/ritonavir plus dasabuvir. The dosage of rosuvastatin should be limited to 20 mg once a day when used with darunavir-cobicistat. Nirmatrelvir-ritonavir product labeling advises temporary discontinuation of rosuvastatin be considered during treatment with nirmatrelvir-ritonavir. Alternatively, a different HMG-CoA reductase inhibitor such as fluvastatin may be considered. 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.

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 inhibitors of the organic anion transporting polypeptides (OATP) 1B1 and/or 1B3 may increase the plasma concentrations and effects of ezetimibe, which is a substrate of these hepatic uptake transporters. When a single dose of ezetimibe was taken with steady state bempedoic acid, a weak inhibitor of OATP1B1 and 1B3, the systemic exposure (AUC) and maximum plasma concentration (Cmax) of total ezetimibe (ezetimibe and its glucuronide form) increased by 1.6- and 1.8-fold, respectively. These increases were not considered clinically significant. When coadministered in patients on cyclosporine, a stronger OATP1B1 and 1B3 inhibitor, the AUC and Cmax of total ezetimibe increased by approximately 3.4- and 3.9-fold, respectively, compared to the exposure observed in a historical healthy control population. In another study, a renal transplant patient with severe renal dysfunction who was receiving multiple medications, including cyclosporine, demonstrated a 12-fold greater exposure to total ezetimibe compared to healthy subjects. The exact mechanism of the interaction with cyclosporine is unknown, but its ability to inhibit OATP1B1 and 1B3 may play a role. Data are not available for all inhibitors of OATP1B1 and/or 1B3 with ezetimibe.

MANAGEMENT: Caution and additional monitoring may be advisable if ezetimibe is used concurrently with OATP1B1 and/or 1B3 inhibitors. Additional monitoring of liver enzymes and creatine kinase (CK) may be necessary. Patients should also be advised to promptly report unexplained muscle pain, tenderness, or weakness to their healthcare provider.