EZETIMIBE/SIMVASTATIN-WGR

What it is

EZETIMIBE/SIMVASTATIN-WGR is available for oral use as tablets containing combinations of ezetimibe and simvastatin: 10 mg of ezetimibe with 10 mg, 20 mg, 40 mg, or 80 mg of simvastatin.

Approved indications

— Prevention of cardiovascular disease in patients with coronary heart disease and a history of acute coronary syndrome taking their maximum tolerated dose of simvastatin and in need of additional lowering of LDL-C. — Primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed hyperlipidaemia in patients not appropriately controlled with a statin or ezetimibe alone, or patients already treated with a statin and ezetimibe. — Homozygous familial hypercholesterolaemia. — Heterozygous familial hypercholesterolaemia in adolescent patients aged 10–17 years in whom use of a combination product is appropriate, including those not appropriately controlled with a statin or ezetimibe alone or already treated with both agents. — Homozygous familial hypercholesterolaemia in adolescent patients aged 10–17 years.

Dosing overview

For primary hypercholesterolaemia or mixed hyperlipidaemia, EZETIMIBE/SIMVASTATIN-WGR can be administered within the range of 10/10 mg per day to 10/80 mg per day, with a usual starting dose of 10/10 mg per day to 10/40 mg per day. The 10/80 mg dose should only be used in patients at high risk for cardiovascular complications who have not achieved their treatment goals on lower doses and when the benefits are expected to outweigh the potential risks. For patients with coronary heart disease and a history of acute coronary syndrome, the starting dose in the IMPROVE-IT trial was 10/40 mg once daily in the evening. For patients with homozygous familial hypercholesterolaemia, the recommended dosage is 10/40 mg per day or 10/80 mg per day in the evening. For patients with chronic kidney disease and estimated glomerular filtration rate less than 60 mL/min/1.73 m², the dose is 10/20 mg once daily in the evening. For adolescent patients aged 10–17 years, the recommended usual starting dose is 10/10 mg once daily in the evening, with a dosing range from 10/10 mg to a maximum of 10/40 mg per day.

Key safety warnings

Simvastatin occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase above 10 times the upper limit of normal. Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and rare fatalities have occurred. Predisposing factors for myopathy include advanced age (65 years or older), female gender, uncontrolled hypothyroidism, and renal impairment. All patients starting therapy with EZETIMIBE/SIMVASTATIN-WGR or whose dose is being increased should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness. In a large clinical trial, myopathy was reported in 6% of patients receiving simvastatin 80 mg and amiodarone, and a significant interaction at lower simvastatin doses cannot be excluded; therefore the dose of EZETIMIBE/SIMVASTATIN-WGR should not exceed 10/20 mg daily in patients receiving concurrent amiodarone. Co-administration of verapamil increased the incidence of myopathy to 0.7% (with simvastatin 40 mg) or 1% (with simvastatin 80 mg), and co-administration of diltiazem with simvastatin 80 mg was associated with about 1% incidence of myopathy; the dose of EZETIMIBE/SIMVASTATIN-WGR should not exceed 10/20 mg daily in patients receiving verapamil or diltiazem.

Contraindications

EZETIMIBE/SIMVASTATIN-WGR is contraindicated in patients with hypersensitivity to the active substances or excipients, active liver disease or unexplained persistent elevations of serum transaminases, or in pregnancy and lactation. Myopathy secondary to other lipid lowering agents is a contraindication. Concomitant administration of potent CYP3A4 inhibitors (including itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors, boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, nefazodone, and drugs containing cobicistat) is contraindicated. Concomitant administration of gemfibrozil, ciclosporin, danazol, or fusidic acid is contraindicated.

PBS listing

The Pharmaceutical Benefits Scheme listing information for EZETIMIBE/SIMVASTATIN-WGR is not provided in the available source documents.

Regulatory history

EZETIMIBE/SIMVASTATIN-WGR was first registered on the ARTG on 15 October 2019 with four variants listed: 10/10 mg, 10/20 mg, 10/40 mg, and 10/80 mg tablet formulations, all registered under licence category RE (Registered).