Ezetimibe / Simvastatin

Pronunciation: e-ZET-i-mibe/SIM-va-STAT-in
Class: Antihyperlipidemic combination

Trade Names

Vytorin 10/10
- Tablets, oral ezetimibe 10 mg/simvastatin 10 mg

Vytorin 10/20
- Tablets, oral ezetimibe 10 mg/simvastatin 20 mg

Vytorin 10/40
- Tablets, oral ezetimibe 10 mg/simvastatin 40 mg

Vytorin 10/80
- Tablets, oral ezetimibe 10 mg/simvastatin 80 mg

Pharmacology

Ezetimibe

Inhibits the absorption of cholesterol by the small intestine.

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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.

Contraindications

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 Administration

Primary Hypercholesterolemia
Adults

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
Adults

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
Diltiazem, verapamil

Do not exceed ezetimibe 10 mg/simvastatin 10 mg daily.

Amiodarone, amlodipine, ranolazine

Do not exceed ezetimibe 10 mg/simvastatin 20 mg daily.

General Advice

  • 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.

Storage/Stability

Store between 68° and 77°F.

Drug Interactions

Amiodarone, 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.

Adverse Reactions

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.

CNS

Headache (6%); depression, dizziness, memory impairment, paresthesia, peripheral neuropathy (postmarketing).

Dermatologic

Alopecia, erythema multiforme, pruritus, skin changes (eg, changes to hair/nails, discoloration, dryness, nodules) (postmarketing).

GI

Diarrhea (3%); cholecystitis, cholelithiasis, nausea, pancreatitis, vomiting (postmarketing).

Hematologic

Anemia, thrombocytopenia (postmarketing).

Hepatic

Increased ALT (4%); elevated CPK, elevated liver transaminases, hepatic failure, hepatitis/jaundice (postmarketing).

Hypersensitivity

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).

Musculoskeletal

Myalgia (4%); pain in extremity (2%); arthralgia, muscle cramps, myopathy/rhabdomyolysis (postmarketing).

Pulmonary

Upper respiratory tract infection (4%); interstitial lung disease (postmarketing).

Miscellaneous

Influenza (2%); erectile dysfunction (postmarketing).

Precautions

Monitor

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.


Pregnancy

Category X . May cause fetal harm. Advise women of childbearing potential who require ezetimibe/simvastatin therapy to use effective contraception.

Lactation

Undetermined.

Children

There are insufficient data for the safe and effective use in children.

Elderly

Use with caution; incidence of myopathy, including rhabdomyolysis, may be increased.

Renal Function

Use with caution in patients with severe renal impairment.

Hepatic Function

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.

Endocrine effects

Increases in HbA 1c and fasting serum glucose levels have been reported.

Hepatotoxicity

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.

Myopathy/Rhabdomyolysis

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.

Overdosage

Symptoms

Limited data are available.

Patient Information

  • 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.

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