Ezetimibe and Simvastatin (Page 2 of 11)

4 CONTRAINDICATIONS

Ezetimibe and simvastatin tablets are contraindicated in the following conditions:

  • Concomitant administration of strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors, boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, nefazodone, and cobicistat-containing products) [ see Warnings and Precautions ( 5.1) ].
  • Concomitant administration of gemfibrozil, cyclosporine, or danazol [ see Warnings and Precautions ( 5.1) ].
  • Hypersensitivity to any component of this medication [ see Adverse Reactions ( 6.2) ].
  • Active liver disease or unexplained persistent elevations in hepatic transaminase levels [ see Warnings and Precautions ( 5.2) ].
  • Women who are pregnant or may become pregnant. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Because HMG-CoA reductase inhibitors (statins), such as simvastatin, decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, ezetimibe and simvastatin tablets may cause fetal harm when administered to a pregnant woman. Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia. There are no adequate and well-controlled studies of ezetimibe and simvastatin tablet use during pregnancy; however, in rare reports congenital anomalies were observed following intrauterine exposure to statins. In rat and rabbit animal reproduction studies, simvastatin revealed no evidence of teratogenicity. Ezetimibe and simvastatin tablets should be administered to women of childbearing age only when such patients are highly unlikely to conceive. If the patient becomes pregnant while taking this drug, ezetimibe and simvastatin tablets should be discontinued immediately and the patient should be apprised of the potential hazard to the fetus [ see Use in Specific Populations ( 8.1) ].
  • Nursing mothers. It is not known whether simvastatin is excreted into human milk; however, a small amount of another drug in this class does pass into breast milk. Because statins have the potential for serious adverse reactions in nursing infants, women who require ezetimibe and simvastatin tablet treatment should not breastfeed their infants [ see Use in Specific Populations ( 8.3) ].

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 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 mg/80 mg dose of ezetimibe and simvastatin tablets should be used only in patients who have been taking ezetimibe and simvastatin tablets 10 mg/80 mg chronically (e.g., for 12 months or more) without evidence of muscle toxicity [ see Dosage and Administration, Restricted Dosing for 10 mg/80 mg ( 2.2) ]. If, however, a patient who is currently tolerating the 10 mg/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), 9,270 patients with chronic kidney disease were allocated to receive ezetimibe and simvastatin tablets 10 mg/20 mg daily (n = 4,650) or placebo (n = 4,620). 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 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 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.

There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents.

All patients starting therapy with ezetimibe and simvastatin tablets or whose dose of ezetimibe and simvastatin tablets is 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 tablet 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 tablet therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. Ezetimibe and simvastatin tablet 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 is 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, ≥ 1 g/day of niacin, 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.: Contraindicated with ezetimibe and simvastatin tablets
Itraconazole
Ketoconazole
Posaconazole
Voriconazole
Erythromycin
Clarithromycin
Telithromycin
HIV protease inhibitors
Boceprevir
Telaprevir
Nefazodone Cobicistat-containing products
Gemfibrozil
CyclosporineDanazol
Niacin (≥1 g/day) For Chinese patients, not recommended with ezetimibe and simvastatin tablets
Verapamil Do not exceed ezetimibe and simvastatin tablets, 10 mg/10 mg daily
Diltiazem
Dronedarone
Amiodarone Do not exceed ezetimibe and simvastatin tablets, 10 mg/20 mg daily
Amlodipine
Ranolazine
Lomitapide For patients with HoFH, do not exceed ezetimibe and simvastatin tablets, 10 mg/20 mg daily1
Daptomycin Temporarlly Suspend ezetimibe and simvastatin tablets
Grapefruit juice Avoid grapefruit juice

1 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 ezetimibe and simvastatin tablets, 10 mg/40 mg daily when taking lomitapide.

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