Ezetimibe and Simvastatin (Page 2 of 11)

5 WARNINGS AND PRECAUTIONS

5.1 Myopathy/Rhabdomyolysis

Simvastatin occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase above ten 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 elevated plasma levels of simvastatin and simvastatin acid. Predisposing factors for myopathy include advanced age (≥65 years), female gender, uncontrolled hypothyroidism, and renal impairment. Chinese patients may be at increased risk for myopathy [see Use in Specific Populations (8.8)].

The risk of myopathy, including rhabdomyolysis, is dose related. In a clinical trial database in which 41,413 patients were treated with simvastatin, 24,747 (approximately 60%) of whom were enrolled in studies with a median follow-up of at least 4 years, the incidence of myopathy was approximately 0.03% and 0.08% at 20 and 40 mg/day, respectively. The incidence of myopathy with 80 mg (0.61%) was disproportionately higher than that observed at the lower doses. In these trials, patients were carefully monitored and some interacting medicinal products were excluded.

In a clinical trial in which 12,064 patients with a history of myocardial infarction were treated with simvastatin (mean follow-up 6.7 years), the incidence of myopathy (defined as unexplained muscle weakness or pain with a serum creatine kinase [CK] >10 times upper limit of normal [ULN]) in patients on 80 mg/day was approximately 0.9% compared with 0.02% for patients on 20 mg/day. The incidence of rhabdomyolysis (defined as myopathy with a CK >40 times ULN) in patients on 80 mg/day was approximately 0.4% compared with 0% for patients on 20 mg/day. The incidence of myopathy, including rhabdomyolysis, was highest during the first year and then notably decreased during the subsequent years of treatment. In this trial, patients were carefully monitored and some interacting medicinal products were excluded.

The risk of myopathy, including rhabdomyolysis, is greater in patients on simvastatin 80 mg compared with other statin therapies with similar or greater LDL-C-lowering efficacy and compared with lower doses of simvastatin. Therefore, the 10/80-mg dose of Ezetimibe and Simvastatin Tablets should be used only in patients who have been taking Ezetimibe and Simvastatin Tablets 10/80 mg chronically (e.g., for 12 months or more) without evidence of muscle toxicity [see Dosage and Administration, Restricted Dosing for 10/80 mg (2.2)]. If, however, a patient who is currently tolerating the 10/80-mg dose of Ezetimibe and Simvastatin Tablets needs to be initiated on an interacting drug that is contraindicated or is associated with a dose cap for simvastatin, that patient should be switched to an alternative statin or statin-based regimen with less potential for the drug-drug interaction. Patients should be advised of the increased risk of myopathy, including rhabdomyolysis, and to report promptly any unexplained muscle pain, tenderness or weakness. If symptoms occur, treatment should be discontinued immediately [see Warnings and Precautions (5.2)].

In the Study of Heart and Renal Protection (SHARP), 9270 patients with chronic kidney disease were allocated to receive Ezetimibe and Simvastatin Tablets 10/20 mg daily (n=4650) or placebo (n=4620). During a median follow-up period of 4.9 years, the incidence of myopathy (defined as unexplained muscle weakness or pain with a serum creatine kinase [CK] >10 times upper limit of normal [ULN]) was 0.2% for Ezetimibe and Simvastatin Tablets and 0.1% for placebo: the incidence of rhabdomyolysis (defined as myopathy with a CK > 40 times ULN) was 0.09% for Ezetimibe and Simvastatin Tablets and 0.02% for placebo.

In postmarketing experience with ezetimibe, cases of myopathy and rhabdomyolysis have been reported. Most patients who developed rhabdomyolysis were taking a statin prior to initiating ezetimibe. However, rhabdomyolysis has been reported with ezetimibe monotherapy and with the addition of ezetimibe to agents known to be associated with increased risk of rhabdomyolysis, such as fibric acid derivatives. Ezetimibe and Simvastatin Tablets and a fenofibrate, if taking concomitantly, should both be immediately discontinued if myopathy is diagnosed or suspected.

All patients starting therapy with Ezetimibe and Simvastatin Tablets or whose dose of Ezetimibe and Simvastatin Tablets are being increased should be advised of the risk of myopathy, including rhabdomyolysis, and told to report promptly any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing Ezetimibe and Simvastatin Tablets. Ezetimibe and Simvastatin Tablets therapy should be discontinued immediately if myopathy is diagnosed or suspected. In most cases, muscle symptoms and CK increases resolved when simvastatin treatment was promptly discontinued. Periodic CK determinations may be considered in patients starting therapy with Ezetimibe and Simvastatin Tablets 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 Ezetimibe and Simvastatin Tablets merit closer monitoring.

Ezetimibe and Simvastatin Tablets therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. Ezetimibe and Simvastatin Tablets therapy should also be temporarily withheld in any patient experiencing an acute or serious condition predisposing to the development of renal failure secondary to rhabdomyolysis, e.g., sepsis; hypotension; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy.

Drug Interactions

The risk of myopathy and rhabdomyolysis is increased by elevated plasma levels of simvastatin and simvastatin acid.Simvastatin is metabolized by the cytochrome P450 isoform 3A4. Certain drugs that inhibit this metabolic pathway can raise the plasma levels of simvastatin and may increase the risk of myopathy. These include itraconazole, ketoconazole, posaconazole, and voriconazole, the macrolide antibiotics erythromycin and clarithromycin, and the ketolide antibiotic telithromycin, HIV protease inhibitors, boceprevir, telaprevir, the antidepressant nefazodone, cobicistat-containing products, or grapefruit juice. [See Clinical Pharmacology (12.3).] Combination of these drugs with Ezetimibe and Simvastatin Tablets are contraindicated. If short-term treatment with strong CYP3A4 inhibitors is unavoidable, therapy with Ezetimibe and Simvastatin Tablets must be suspended during the course of treatment. [see Contraindications (4) and Drug Interactions (7).]

The combined use of Ezetimibe and Simvastatin Tablets with gemfibrozil, cyclosporine, or danazol is contraindicated [see Contraindications (4) and Drug Interactions (7.1 and 7.2)].

Caution should be used when prescribing fenofibrates with Ezetimibe and Simvastatin Tablets, as these agents can cause myopathy when given alone and the risk is increased when they are coadministered [see Drug Interactions (7.2, 7.7)].

Cases of myopathy, including rhabdomyolysis, have been reported with simvastatin coadministered with colchicine, and caution should be exercised when prescribing Ezetimibe and Simvastatin Tablets with colchicine [see Drug Interactions (7.9)].

The benefits of the combined use of Ezetimibe and Simvastatin Tablets with the following drugs should be carefully weighed against the potential risks of combinations: other lipid-lowering drugs (fenofibrates, or, for patients with HoFH, lomitapide), amiodarone, dronedarone, verapamil, diltiazem, amlodipine, or ranolazine [see Dosage and Administration (2.4),Drug Interactions (7.3)]

Cases of myopathy, including rhabdomyolysis, have been observed with simvastatin coadministered with lipid-modifying doses (≥1 g/day niacin) of niacin-containing products [see Drug Interactions (7.4)].

Cases of rhabdomyolysis have been reported with Ezetimibe and Simvastatin Tablets administered with daptomycin. Temporarily suspend Ezetimibe and Simvastatin Tablets in patients taking daptomycin [see Drug Interactions (7.10)]

Prescribing recommendations for interacting agents are summarized in Table 1 [see also Dosage and Administration (2.3, 2.4), Drug Interactions (7), and Clinical Pharmacology (12.3)].

Table 1: Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis

Interacting Agents	Prescribing Recommendations
Strong CYP3A4 Inhibitors, e.g.: Itraconazole Ketoconazole Posaconazole Voriconazole Erythromycin Clarithromycin Telithromycin HIV protease inhibitors Boceprevir TelaprevirNefazodone Cobicistat-containing products Gemfibrozil Cyclosporine Danazol	Contraindicated with Ezetimibe and Simvastatin Tablets
Niacin (≥ 1g/day)	For Chinese patients, not recommended with Ezetimibe and Simvastatin Tablets
VerapamilDiltiazemDronedarone	Do not exceed 10/10 mg Ezetimibe and Simvastatin Tablets daily
Amiodarone AmlodipineRanolazine	Do not exceed 10/20 mg Ezetimibe and Simvastatin Tablets daily
Lomitapide	For patients with HoFH, do not exceed 10/20 mg Ezetimibe and Simvastatin Tablets daily*
Daptomycin	Temporarily suspend ezetimibe and simvastatin tablets
Grapefruit juice	Avoid grapefruit juice

^* For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 10/40 mg Ezetimibe and Simvastatin Tablets when taking lomitapide.