Drug Interactions between ezetimibe / rosuvastatin and pazopanib

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.

MONITOR: Concomitant use of pazopanib with simvastatin may increase the risk of ALT elevations, possibly due to additive hepatotoxic effects. In clinical trials, potentially severe and life-threatening hepatotoxicity manifested as increases in serum transaminases (ALT, AST) and bilirubin was observed with pazopanib use. Transaminase elevations occurred early in the course of treatment, with 92.5% of all cases of any grade occurring in the first 18 weeks. Across all monotherapy studies with pazopanib (n=977), ALT exceeding 3 times the upper limit of normal (ULN) was reported in 14% of patients who received pazopanib and ALT exceeding 8 times ULN was reported in 4%. Concurrent elevations in ALT greater than 3 times ULN and bilirubin greater than 2 times ULN regardless of alkaline phosphatase levels were detected in 1% of patients. Four of these patients had no other explanation for the elevations. Two of the total 977 patients (0.2%) died with disease progression and hepatic failure. Of the 41 patients who had concomitant use of simvastatin, 11 (27%) developed ALT exceeding 3 times ULN.

MANAGEMENT: Caution is advised if pazopanib is used in combination with simvastatin. Serum liver transaminases and bilirubin should be measured prior to initiation of pazopanib and regularly during treatment as recommended in the product labeling. If ALT elevations occur, simvastatin should be discontinued and guidelines for pazopanib dosage adjustments should be followed, or alternatives to pazopanib considered. Patients should be advised to seek medical attention if they experience potential signs and symptoms of hepatotoxicity such as fever, rash, itching, anorexia, nausea, vomiting, fatigue, malaise, right upper quadrant pain, dark urine, light colored stools, and jaundice. Insufficient data are available to assess the risk of pazopanib administered concomitantly with other HMG-CoA reductase inhibitors.