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Clinical testing has been conducted over the dose range ezetimibe 10 mg/simvastatin 10 mg to ezetimibe 10 mg/simvastatin 80 mg.
Myopathy/Rhabdomyolysis: Simvastatin, like other inhibitors of HMG-CoA reductase, occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase (CK) >10 times the upper limit of normal (ULN). Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and rare fatalities have occurred. The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma.
Because Vytorin contains simvastatin, the risk of myopathy/rhabdomyolysis is increased by concomitant use of Vytorin with the following: Potent inhibitors of CYP3A4 eg, itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone or large quantities of grapefruit juice (>1 L daily), particularly with higher doses of Vytorin (see Interactions); other drugs: Gemfibrozil and other fibrates or niacin ≥1 g/day, particularly with higher doses of Vytorin (see Interactions); cyclosporine or danazol particularly with higher doses of Vytorin (see Interactions); amiodarone or verapamil with higher doses of Vytorin (see Interactions). In an on-going clinical trial, myopathy has been reported in 6% of patients receiving simvastatin 80 mg and amiodarone; diltiazem: Patients on diltiazem treated concomitantly with ezetemibe 10 mg/simvastatin 80 mg have a slightly increased risk of myopathy. In clinical studies, the risk of myopathy in patients taking simvastatin 40 mg with diltiazem was similar to that in patients taking simvastatin 40 mg without diltiazem (see Interactions).
As with other HMG-CoA reductase inhibitor, the risk of myopathy/rhabdomyolysis is dose-related for simvastatin. In a clinical trial database in which 41,050 patients were treated with simvastatin, with 24,747 (approximately 60%) treated for at least 4 years, the incidence of myopathy was approximately 0.02%, 0.08% and 0.53% at 20, 40 and 80 mg/day, respectively. In these trials, patients were carefully monitored and some interacting medicinal products were excluded.
Consequently: Use of Vytorin concomitantly with potent CYP3A4 inhibitors [eg, itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors or nefazodone or large quantities of grapefruit juice (>1 L daily)] should be avoided. If treatment with itraconazole, ketoconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with Vytorin should be suspended during the course of treatment. Concomitant use with other medicines labeled as having a potent inhibitory effect on CYP3A4 at therapeutic doses should be avoided unless the benefits of combined therapy outweigh the increased risk.
There is an increased risk of myopathy when simvastatin is used concomitantly with gemfibrozil or other fibrates; the safety and effectiveness of ezetimibe administered with fibrates have not been established. Therefore, the concomitant use of Vytorin and fibrates should be avoided (see Interactions).
The dose of Vytorin should not exceed 10/10 mg daily in patients receiving concomitant medication with cyclosporine, danazol or niacin ≥1 g/day. The benefits of the use of Vytorin in patients receiving, cyclosporine, danazol or niacin should be carefully weighed against the risks of these drug combinations and caution should be exercised when initiating Vytorin in the setting of cyclosporine (see Interactions).
The dose of Vytorin should not exceed 10/20 mg daily in patients receiving concomitant medication with amiodarone or verapamil. The combined use of Vytorin at doses >10/20 mg daily with amiodarone or verapamil should be avoided unless the clinical benefit is likely to outweigh the increased risk of myopathy.
All patients starting therapy with Vytorin, or whose dose of Vytorin is being increased, should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness. Vytorin therapy should be discontinued immediately if myopathy is diagnosed or suspected. The presence of these symptoms and/or a CK level >10 times the upper limit of normal indicates myopathy. In most cases, when patients were promptly discontinued from simvastatin treatment, muscle symptoms and CK increases resolved. Periodic CK determinations may be considered in patients starting therapy with Vytorin or whose dose is being increased, but there is no assurance that such monitoring will prevent myopathy.
Many of the patients who have developed rhabdomyolysis on therapy with simvastatin have had complicated medical histories, including renal insufficiency usually as a consequence of long-standing diabetes mellitus. Such patients taking Vytorin merit closer monitoring. Therapy with Vytorin should be temporarily stopped a few days prior to elective major surgery and when any major medical or surgical condition supervenes.
Liver Enzymes: In controlled co-administration trials in patients receiving ezetimibe with simvastatin, consecutive transaminase elevations (≥3 times ULN) have been observed (see Adverse Reactions).
It is recommended that liver function tests (LFTs) be performed before treatment with Vytorin begins and thereafter when clinically indicated. Special attention should be paid to patients who develop elevated serum transaminase levels and in these patients, measurements should be repeated promptly and then performed more frequently. If the transaminase levels show evidence of progression, particularly if they rise to 3 times ULN and are persistent, Vytorin should be discontinued.
Vytorin should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease. Active liver diseases or unexplained persistent transaminase elevations are contraindications to the use of Vytorin.
Information for Patients: Patients should be advised about substances that should not be taken concomitantly with Vytorin and be advised to report promptly unexplained muscle pain, tenderness or weakness.
Hepatic Insufficiency: Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate or severe hepatic insufficiency, Vytorin is not recommended in these patients (see Actions).
Fibrates: The safety and efficacy of ezetimibe administered with fibrates have not been established; therefore, co-administration of Vytorin and fibrates is not recommended (see Interactions).
Cyclosporine: Caution should be exercised when initiating Vytorin in the setting of cyclosporine. Cyclosporine concentrations should be monitored in patients receiving Vytorin and cyclosporine (see Interactions).
Warfarin: If Vytorin is added to warfarin or another coumarin anticoagulant, the International Normalized Ratio (INR) should be appropriately monitored (see Interactions).
Effects on the Ability to Drive or Operate Machinery: No studies on the effects on the ability to drive and use of machines have been performed. However, when driving vehicles or operating machines, it should be taken into account that dizziness has been reported.
Use in children: There are insufficient data for the safe and effective use of Vytorin in pediatric patients (see Ezetimibe and Simvastatin as follows).
Ezetimibe: The pharmacokinetics of ezetimibe in adolescent (10-18 years) have been shown to be similar to that in adults. Treatment experience with ezetimibe in pediatric population is limited to 4 patients (9-17 years) with homozygous sitosterolemia and 5 patients (11-17 years) with HoFH. Treatment with ezetimibe in children (<10 years) is not recommended.
Simvastatin: Safety and effectiveness of simvastatin in patients 10-17 years with heterozygous familial hypercholesterolemia have been evaluated in a controlled clinical trial in adolescent boys and girls who were at least 1 year post-menarche. Patients treated with simvastatin had an adverse experience profile generally similar to that of patients treated with placebo. Doses >40 mg have not been studied in this population. In this limited controlled study, there was no detectable effect on growth or sexual maturation in the adolescent boys or girls, or any effect on menstrual cycle length in girls. Adolescent females should be counseled on appropriate contraceptive methods while on therapy with simvastatin (see Use in pregnancy under Contraindications). Simvastatin has not been studied in patients <10 years, nor in pre-menarchal girls.
