The originating document has been archived. We cannot confirm the completeness, accuracy and currency of the content.
Ezetimibe / Simvastatin
Class: Antihyperlipidemic combination
- Tablets, oral ezetimibe 10 mg/simvastatin 10 mg
- Tablets, oral ezetimibe 10 mg/simvastatin 20 mg
- Tablets, oral ezetimibe 10 mg/simvastatin 40 mg
- Tablets, oral ezetimibe 10 mg/simvastatin 80 mg
Inhibits the absorption of cholesterol by the small intestine.Simvastatin
Inhibits the conversion of HMG-CoA to mevalonate, an early step in the biosynthetic pathway for cholesterol.
Indications and Usage
Adjunctive treatment to diet for reduction of elevated total cholesterol, LDL cholesterol (LDL-C), triglycerides, non-HDL cholesterol (HDL-C), and apolipoprotein B (apo B), and to increase HDL-C in patients with primary hyperlipidemia or mixed hyperlipidemia; as an adjunct to other lipid-lowering treatments (eg, LDL apheresis) for the reduction of total cholesterol and LDL-C in patients with homozygous familial hypercholesterolemia.
Coadministration with strong CYP3A4 inhibitors (eg, clarithromycin, erythromycin, HIV protease inhibitors, itraconazole, ketoconazole, nefazodone, posaconazole, telithromycin), cyclosporine, danazol, or gemfibrozil; active liver disease or unexplained persistent elevations in serum transaminases; women who are or may become pregnant; breast-feeding women; hypersensitivity to any component of the product.
Dosage and AdministrationPrimary Hypercholesterolemia
PO Start with ezetimibe 10 mg/simvastatin 10 mg or ezetimibe 10 mg/simvastatin 20 mg once daily in the evening. Lipid levels may be analyzed after 2 or more wk and dosage adjusted. For patients requiring a large (more than 55%) reduction in LDL-C, therapy may be started at ezetimibe 10 mg/simvastatin 40 mg once daily in the evening. Patients unable to achieve their LDL-C goal utilizing the ezetimibe 10 mg/simvastatin 40 mg dose should not be titrated to ezetimibe 10 mg/simvastatin 80 mg, but should be placed on alternative LDL-C–lowering treatment.Homozygous Familial Hypercholesterolemia
PO Ezetimibe 10 mg/simvastatin 40 mg once daily in the evening. Use as an adjunct to other lipid-lowering treatments.Renal function impairment
In patients with severe renal impairment, do not start ezetimibe/simvastatin unless the patient has already tolerated treatment with simvastatin at a dose of 5 mg or higher.Chinese patients
Use caution when treating Chinese patients with doses exceeding ezetimibe 10 mg/simvastatin 20 mg per day coadministered with lipid-modifying doses of niacin-containing products (niacin 1 g/day or more). These patients should not receive ezetimibe 10 mg/simvastatin 80 mg coadministered with lipid-modifying dosages of niacin-containing products.Concomitant therapy
Do not exceed ezetimibe 10 mg/simvastatin 10 mg daily.Amiodarone, amlodipine, ranolazine
Do not exceed ezetimibe 10 mg/simvastatin 20 mg daily.
- Administer in the evening without regard to meals.
- Administer ezetimibe/simvastatin at least 2 h before or 4 h after administration of a bile acid sequestrant (eg, cholestyramine).
- Use of ezetimibe 10 mg/simvastatin 80 mg should be restricted to patients who have been taking this dose long term (eg, for 12 mo or longer) without evidence of muscle toxicity. Patients currently tolerating ezetimibe 10 mg/simvastatin 80 mg who need to be initiated on an interacting drug that is contraindicated or is associated with a dose limit for simvastatin should be switched to an alternative regimen with less potential for the drug-drug interaction.
Store between 68° and 77°F.
Drug InteractionsAmiodarone, calcium channel blockers (eg, amlodipine, diltiazem, verapamil), dronedarone, imatinib, quinupristin/dalfopristin, ranolazine
Coadministration may result in elevated plasma levels, increasing the risk of toxicity (eg, myositis, rhabdomyolysis). With coadministration of amiodarone, amlodipine, or ranolazine, the dosage of ezetimibe/simvastatin should not exceed 10/20 mg/day. With coadministration of diltiazem or verapamil, the dosage of ezetimibe/simvastatin should not exceed 10/10 mg/day.Antacids
Aluminum and magnesium antacids decreased the C max of ezetimibe by 30%. Use with caution.Azole antifungal agents (eg, itraconazole, ketoconazole, posaconazole), cyclosporine, danazol, gemfibrozil, hepatitis C virus protease inhibitors (eg, boceprevir, telaprevir), macrolide antibiotics (eg, clarithromycin, erythromycin, telithromycin), nefazodone, protease inhibitors (eg, nelfinavir, ritonavir)
May increase the risk of myopathy and rhabdomyolysis. Coadministration is contraindicated. If treatment with these azole antifungal agents or macrolide antibiotics is unavoidable, temporarily discontinue simvastatin therapy.Bosentan, carbamazepine, hydantoins (eg, phenytoin), rifamycins (eg, rifampin)
Simvastatin metabolism may be increased, resulting in a decrease in plasma concentrations and efficacy. If coadministration cannot be avoided, closely monitor the clinical response of the patient and adjust the simvastatin dose as needed.Cholestyramine
Coadministration decreased the mean AUC of total ezetimibe. Simvastatin may adsorb to cholestyramine, reducing GI absorption. The incremental LDL-C reduction caused by adding ezetimibe/simvastatin to cholestyramine may be reduced. Administer ezetimibe/simvastatin at least 2 h before or 4 h or more after cholestyramine administration.Cimetidine
Ezetimibe plasma concentrations may be increased slightly. The change is not likely to be clinically important.Cisapride
Cisapride plasma concentrations may be elevated, increasing the risk of toxicity. Plasma concentrations of simvastatin may be reduced, decreasing the therapeutic effect. Monitor patients for a decrease in the cholesterol-lowering effect of simvastatin and for possible cisapride toxicity.Colchicine
Myopathy and rhabdomyolysis have been reported. Coadminister with caution.Conivaptan
Simvastatin plasma concentrations may be elevated, increasing the risk of myopathy. Suspend concomitant use and restart ezetimibe/simvastatin therapy at least 1 wk after conivaptan therapy is completed.Daptomycin
The risk of myopathy/rhabdomyolysis is increased. Consider a temporary suspension of ezetimibe/simvastatin in patients receiving daptomycin.Digoxin
Digoxin plasma concentrations may be slightly elevated. Clinical and laboratory monitoring is warranted. Adjust the digoxin dose as needed.Fenofibrate
Ezetimibe and simvastatin concentrations may be increased. Use with caution.Fluconazole
The risk of myopathy may be increased. Closely monitor for myopathy. If adverse reactions occur, discontinue 1 or both drugs.Food Grapefruit juice
Coadministration with large quantities of grapefruit juice (at least 1 quart daily) may result in increased plasma levels of simvastatin, increasing the risk of myopathy. Avoid concurrent use.Oat bran/pectin
The pharmacologic effects of simvastatin may be decreased because of decreased GI absorption when coadministered with pectin or oat bran. Taking oat bran or pectin and simvastatin at the same time should be avoided; separate simvastatin administration by as much time as possible.Peppermint oil
Simvastatin levels may be elevated, increasing the pharmacologic and adverse reactions. Coadminister with caution.Glipizide
Plasma concentrations of glipizide and ezetimibe may be decreased slightly. The magnitude of the changes is not likely to be clinically important.Mibefradil
Coadministration will elevate simvastatin plasma concentrations, increasing the risk of rhabdomyolysis and myositis. Coadministration is not recommended.Niacin
Risk of myopathy may be increased, especially with dosages of niacin 1 g/day or more with simvastatin. Coadminister with caution. Because of an increased risk for myopathy in Chinese patients, Chinese patients should not receive ezetimibe/simvastatin 10/80 mg with lipid-modifying doses of niacin-containing products.NNRTIs (eg, delavirdine, efavirenz, nevirapine)
Severe myopathy may occur because of increased simvastatin levels. Monitor for signs of myopathy or renal dysfunction. Efavirenz and nevirapine may reduce simvastatin levels. Monitor LDL concentrations after starting or stopping efavirenz.Sirolimus, tacrolimus, voriconazole
Simvastatin plasma concentrations may be elevated, increasing the risk of myopathy. If coadministration cannot be avoided, advise patients to report any unexplained muscle pain, tenderness, or weakness. An HMG-CoA reductase inhibitor, which is not metabolized by CYP3A4 (eg, fluvastatin, pravastatin), may be less likely to interact and may be a safer alternative.St. John's wort
Coadministration may result in decreased simvastatin levels. Avoid concurrent use.Warfarin
The anticoagulant effect, as measured by the INR, may be modestly potentiated. Carefully monitor anticoagulant parameters and adjust the warfarin dose as needed.
The incidences stated for the following adverse reactions were reported with ezetimibe/simvastatin administration. Adverse reactions occurring with administration of either ezetimibe or simvastatin can be found in their respective monographs.
Headache (6%); depression, dizziness, memory impairment, paresthesia, peripheral neuropathy (postmarketing).
Alopecia, erythema multiforme, pruritus, skin changes (eg, changes to hair/nails, discoloration, dryness, nodules) (postmarketing).
Diarrhea (3%); cholecystitis, cholelithiasis, nausea, pancreatitis, vomiting (postmarketing).
Anemia, thrombocytopenia (postmarketing).
Increased ALT (4%); elevated CPK, elevated liver transaminases, hepatic failure, hepatitis/jaundice (postmarketing).
Hypersensitivity reactions (including anaphylaxis, angioedema, rash, and urticaria), hypersensitivity syndrome (including 1 or more of the following: anaphylaxis, angioedema, arthralgia, arthritis, asthenia, chills, dermatomyositis, dyspnea, eosinophilia, erythema multiforme, erythrocyte sedimentation rate increase, fever, flushing, hemolytic anemia, leukopenia, lupus erythematous syndrome, malaise, photosensitivity, polymyalgia rheumatica, positive antinuclear antibody, purpura, Stevens-Johnson syndrome, TEN, thrombocytopenia, urticaria, vasculitis) (postmarketing).
Myalgia (4%); pain in extremity (2%); arthralgia, muscle cramps, myopathy/rhabdomyolysis (postmarketing).
Upper respiratory tract infection (4%); interstitial lung disease (postmarketing).
Influenza (2%); erectile dysfunction (postmarketing).
Ensure that lipid levels are measured before therapy is started, at least 2 wk after starting therapy or changing the dose, and then periodically thereafter. Monitor LFTs before the initiation of treatment and thereafter when clinically indicated. Periodic creatine kinase determinations may be considered in patients starting therapy or whose dose is being increased.
Category X . May cause fetal harm. Advise women of childbearing potential who require ezetimibe/simvastatin therapy to use effective contraception.
There are insufficient data for the safe and effective use in children.
Use with caution; incidence of myopathy, including rhabdomyolysis, may be increased.
Use with caution in patients with severe renal impairment.
Contraindicated in patients with active liver disease or unexplained, persistent elevations of hepatic transaminases. Use is not recommended in patients with moderate or severe hepatic impairment. Use with caution in patients who consume substantial quantities of alcohol or who have history of liver disease.
Increases in HbA 1c and fasting serum glucose levels have been reported.
Elevations in serum transaminases have been reported. Fatal and nonfatal hepatic failure has been reported rarely in patients taking HMG-CoA reductase inhibitors. Interrupt therapy if serious liver injury with clinical symptoms occurs and do not restart therapy if no alternative etiology is found.
Simvastatin administration has been associated with dose-related myopathy/rhabdomyolysis. Cases of myopathy and rhabdomyolysis have been reported with ezetimibe in postmarketing experiences. Discontinue therapy immediately if markedly elevated CPK levels occur or if myopathy occurs or is suspected.
Limited data are available.
- Advise patients that other substances (eg, grapefruit juice) and medications (eg, fibrates, potent CYP3A4 inhibitors) should not be taken with this medication. Advise patients to inform other health care providers prescribing new medications or increasing the dose of an existing medication that they are taking ezetimibe/simvastatin.
- Advise patients to take prescribed dose once daily in the evening without regard to meals, but to take with food if stomach upset occurs.
- Advise patients who are also taking a bile acid sequestrant (eg, cholestyramine) to take ezetimibe/simvastatin at least 2 h before or 4 h after the sequestrant.
- Advise patients of the risk of myopathy, including rhabdomyolysis, and to report promptly any unexplained muscle pain, tenderness, or weakness. Inform patients using the ezetimibe 10 mg/simvastatin 80 mg dose that the risk of myopathy, including rhabdomyolysis, is increased; the risk may also be increased when taking certain types of medications or consuming large amounts of grapefruit juice.
- Advise patients to promptly report any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice.
- Emphasize to patients the importance of the following other modalities on cholesterol control: dietary changes (eg, reduce saturated fat intake, increase soluble fiber intake), weight control, regular exercise, and smoking cessation.
- Advise women of childbearing potential to use effective contraception during treatment with ezetimibe/simvastatin.
- Advise women who are breast-feeding not to use ezetimibe/simvastatin.
Copyright © 2009 Wolters Kluwer Health.