Class: HMG-CoA reductase inhibitor
- Tablets, oral 5 mg
- Tablets, oral 10 mg
- Tablets, oral 20 mg
- Tablets, oral 40 mg
- Tablets, oral 80 mg
CO Simvastatin (Canada)
Sandoz Simvastatin (Canada)
Increases the rate at which the body removes cholesterol from blood and reduces production of cholesterol by inhibiting the enzyme that catalyzes an early rate-limiting step in cholesterol synthesis.
T max is 4 h. Bioavailability is less than 5%.
Approximately 95% bound to plasma proteins.
Simvastatin undergoes extensive first-pass metabolism in the liver. Rapidly hydrolyzed to the beta-hydroxyacid of simvastatin and its 6′-hydroxy, 6′-hydroxymethyl, and 6′-exomethylene derivatives.
13% is excreted in urine; 60% in feces.
Special PopulationsRenal Function Impairment
Higher systemic exposure may be achieved in patients with severe renal insufficiency.Hepatic Function Impairment
No data available.Elderly
Mean plasma level of HMG-CoA reductase inhibitory activity is increased approximately 45%.
Indications and UsageHeterozygous Familial Hypercholesterolemia in Adolescents
As an adjunct to diet to reduce total cholesterol, LDL-cholesterol, and apolipoprotein B (apo B) levels in adolescent boys and girls 10 to 17 y who are at least 1 y postmenarche with heterozygous familial hypercholesterolemia, if, after an adequate trial of diet therapy, LDL-cholesterol remains at 190 mg/dL or higher, or LDL-cholesterol remains at 160 mg/dL or higher and there is a positive family history of premature CV disease or 2 or more other CV disease risk factors are present.Hyperlipidemia
For the reduction of elevated total cholesterol, LDL-cholesterol, apo B and triglyceride levels, and to increase HDL-cholesterol in patients with primary hyperlipidemia (Fredrickson type IIa, heterozygous familial and nonfamilial) or mixed dyslipidemia (Fredrickson type IIb); to reduce elevated triglyceride levels in patients with hypertriglyceridemia (Fredrickson type IV hyperlipemia); to reduce elevated triglyceride and VLDL-cholesterol in patients with primary dysbetalipoproteinemia (Fredrickson type III hyperlipidemia); to reduce total cholesterol and LDL-cholesterol in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering treatments (eg, LDL apheresis) or if such treatments are unavailable.Prevention of Coronary Events
In patients at high risk of coronary events from existing coronary heart disease (CHD), diabetes, peripheral vessel disease, or history of stroke or other cerebrovascular disease, to reduce the risk of total mortality by reducing CHD deaths, reduce the risk of nonfatal MI and stroke, and reduce the need for coronary and noncoronary revascularization procedures.
Active liver disease or unexplained persistent elevations of hepatic transaminases; pregnancy; lactation; coadministration with strong CYP3A4 inhibitors (eg, clarithromycin, erythromycin, HIV protease inhibitors, itraconazole, ketoconazole, nefazodone, posaconazole, telithromycin), cyclosporine, danazol, or gemfibrozil; hypersensitivity to any component.
Dosage and AdministrationHyperlipidemia/Prevention of Coronary Events
PO Start with 10 to 20 mg once daily in the evening. For patients at high risk for a CHD event caused by existing CHD, diabetes, peripheral vascular disease, history of stroke, or other cerebrovascular disease, start with 40 mg/day. Usual dosage range is 5 to 40 mg daily.Homozygous Familial Hypercholesterolemia
PO 40 mg once daily in the evening as an adjunct to other lipid-lowering treatment (eg, LDL apheresis).Heterozygous Familial Hypercholesterolemia
Children 10 to 17 y
PO Start with 10 mg once daily in the evening. Make dose adjustments at intervals of 4 wk or more. Usual dosage range is 10 to 40 mg daily (max, 40 mg/day).Concurrent Diltiazem or Verapamil
PO Do not exceed 10 mg/day.Concurrent Amiodarone, Amlodipine, or Ranolazine
PO Do not exceed 20 mg/day.Restricted Dosing
Because of the increased risk of myopathy, including rhabdomyolysis, particularly during the first year of treatment, use of simvastatin 80 mg should be restricted to patients who have been taking simvastatin 80 mg long term (eg, for 12 mo or longer) without evidence of muscle toxicity. Patients who are currently taking simvastatin 80 mg who need to be initiated on an interacting drug that is contraindicated or is associated with a dose cap for simvastatin should be switched to an alternative HMG-CoA reductase inhibitor with less potential for the drug-drug interaction. Patients unable to achieve their LDL-cholesterol goal utilizing simvastatin 40 mg should not be titrated to the 80 mg dose, but should be placed on alternative LDL-cholesterol–lowering treatment(s) that provides greater LDL-cholesterol lowering.Chinese Patients
PO Use caution when treating Chinese patients with simvastatin dosages exceeding 20 mg/day coadministered with lipid-modifying doses of niacin-containing products (niacin 1 g/day or more). Do not use simvastatin 80 mg in Chinese patients receiving lipid-modifying doses of niacin-containing products.Renal Function Impairment
PO Start with 5 mg/day in patients with severe renal impairment and monitor closely.
- Administer once daily in the evening.
- Avoid large quantities of grapefruit juice (more than 1 qt daily).
- Individualize the dosage according to the goals of therapy and the patients response.
- Patients should adhere to their National Cholesterol Education Program (NCEP)–recommended diet and a regular exercise program. In patients with CHD or who are at high risk of CHD, simvastatin can be started simultaneously with diet.
Store between 41° and 86°F.
Drug InteractionsAmiodarone, amlodipine, ranolazine
Risk of myopathy or rhabdomyolysis may be increased. With coadministration of these agents, the dosage of simvastatin should not exceed 20 mg daily.Anticoagulants (eg, warfarin)
Anticoagulant effect of warfarin may be increased. Closely monitor anticoagulant activity and adjust the warfarin dose as needed.Azole antifungal agents (eg, itraconazole, ketoconazole, posaconazole), cyclosporine, danazol, gemfibrozil, hepatic C virus protease inhibitors (eg, boceprevir, telaprevir), macrolide antibiotics (eg, clarithromycin, erythromycin, telithromycin), nefazodone, protease inhibitors (eg, nelfinavir, ritonavir)
Risk of myopathy or rhabdomyolysis may be increased. Coadministration is contraindicated. If treatment with these azole antifungal agents or macrolide antibiotics is unavoidable, temporarily discontinue simvastatin therapy.Bile acid sequestrants (eg, cholestyramine, colestipol)
Simvastatin plasma levels may be reduced, decreasing the efficacy. Separate administration times as much as possible (at least 4 h before simvastatin).Bosentan, carbamazepine, efavirenz, hydantoins (eg, phenytoin), rifamycins (eg, rifampin)
Simvastatin metabolism may be increased, resulting in a decrease in simvastatin plasma levels and efficacy. If coadministration cannot be avoided, closely monitor the clinical response of the patient and adjust the simvastatin dose as needed.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 with concurrent use of colchicine with simvastatin. Coadminister with caution.Conivaptan
Simvastatin plasma concentrations may be elevated, increasing the risk of myopathy. Suspend concomitant use and restart simvastatin therapy at least 1 wk after conivaptan therapy is completed.Daptomycin
The risk of myopathy/rhabdomyolysis is increased with coadministration of daptomycin and simvastatin. Consider a temporary suspension of simvastatin in patients receiving daptomycin.Delavirdine, dronedarone, fenofibrate, imatinib, quinupristin/dalfopristin, voriconazole
May increase the risk of myopathy and rhabdomyolysis. Use with caution. Simvastatin dosage adjustments may be needed.Digoxin
Digoxin concentrations may be elevated slightly. Monitor digoxin concentrations and adjust the dose as needed.Diltiazem, verapamil
Risk of myopathy or rhabdomyolysis may be increased. With coadministration of these agents, the dosage of simvastatin should not exceed 10 mg daily.Grapefruit juice
Coadministration of grapefruit juice (more than 1 qt daily) may increase simvastatin serum levels and adverse reactions (eg, rhabdomyolysis). Avoid coadministration.Mibefradil
Coadministration may increase the risk of adverse reactions, including myopathy and rhabdomyolysis. Coadministration is not recommended.Niacin
Lipid-lowering doses (at least 1 g/day) of niacin with simvastatin increases the risk of severe myopathy or rhabdomyolysis. Caution should be used when treating Chinese patients with simvastatin dosages exceeding 20 mg/day when coadministered with lipid-modifying dose of niacin-containing products. Chinese patients should not receive simvastatin 80 mg with lipid-modifying doses of niacin-containing products.Propranolol
Simvastatin peak plasma levels may be decreased. The clinical importance of this interaction has not been determined.Sirolimus, tacrolimus
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. Additionally, concentrations of sirolimus or tacrolimus may be elevated when coadministered with simvastatin. An HMG-CoA reductase inhibitor, which is not metabolized by CYP3A4 (eg, fluvastatin), may be less likely to interact and may be a safer alternative.St. John's wort
Coadministration may result in decreased simvastatin levels, possibly decreasing efficacy. Avoid coadministration if possible.Ticagrelor
Simvastatin plasma concentrations, pharmacologic effects, and risk of adverse reactions may be increased by coadministration of ticagrelor. The daily dose of simvastatin should not exceed 40 mg in patients receiving ticagrelor.
Atrial fibrillation (6%).
Headache (7%); vertigo (5%); insomnia (4%); asthenia, depression, dizziness, memory impairment, paresthesia, peripheral neuropathy (postmarketing).
Eczema (5%); alopecia, pruritus, rash, skin changes (eg, change in hair/nails, discoloration, dryness of the skin/mucous membranes, nodules) (postmarketing).
Abdominal pain, constipation (7%); gastritis, nausea (5%); diarrhea, dyspepsia, flatulence, pancreatitis, vomiting (postmarketing).
UTI (3%); erectile dysfunction (postmarketing).
Increased serum hepatic transaminases (1%); hepatic failure, hepatitis/jaundice, (postmarketing).
Hypersensitivity syndrome, including anaphylaxis, angioedema, arthralgia, arthritis, asthenia, chills, dermatomyositis, dyspnea, eosinophilia, erythema multiforme, erythrocyte sedimentation rate increase, fever, flushing, hemolytic anemia, leukopenia, lupus erythematous like syndrome, malaise, photosensitivity, polymyalgia rheumatica, positive antinuclear antibody, purpura, Stevens-Johnson syndrome, thrombocytopenia, toxic epidermal necrolysis, urticaria, vasculitis (postmarketing).
Elevated creatine kinase (5%); alkaline phosphatase elevated, bilirubin elevated, GGT elevated, thyroid function abnormalities.
Diabetes mellitus (4%); edema/swelling (3%).
Myalgia (4%); myopathy (1%); rhabdomyolysis (less than 1%); muscle cramps (postmarketing).
Upper respiratory tract infection (9%); bronchitis (7%); sinusitis (2%); interstitial lung disease (postmarketing).
Monitor LFTs before initiation of treatment and periodically thereafter. Monitor patients who develop elevated transaminases levels with a second liver function evaluation to confirm the finding and follow thereafter with frequent LFTs until the abnormality returns to normal. Check lipid profile after 4 wk of therapy and periodically thereafter. Monitor all patients for myopathy (eg, unexplained muscle pain, weakness, tenderness). Monitor CPK levels periodically.
Category X . Contraindicated in women who are pregnant or who may become pregnant. Lipid-lowering drugs offer no benefit during pregnancy because cholesterol and cholesterol derivatives are needed for healthy fetal development.
Undetermined. Contraindicated in breast-feeding mothers.
Safety and efficacy not established in children younger than 10 y or in premenarchal girls.
Use with caution; elderly patients have an increased risk of myopathy, including rhabdomyolysis.
Use with caution in severe renal impairment.
Contraindicated in active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels. Use with caution in patients who consume substantial quantities of alcohol and/or have history of liver disease.
Persistent increases (to more than 3 times the ULN) in serum transaminases have occurred.
Skeletal muscle effects
Myopathy, manifested as muscle pain, tenderness, or weakness with creatine kinase more than 10 times the ULN, may occur. Rhabdomyolysis, with or without acute renal failure secondary to myoglobinuria, and rare fatalities, have occurred. The risk is greater in patients taking simvastatin 80 mg, concomitant use of potent CYP3A4 inhibitors, advanced age, women, uncontrolled hyperthyroidism, and renal impairment.
Temporarily stop therapy for a few days prior to elective major surgery and when any major medical or surgical condition supervenes.
Doses up to 3.6 g have been taken without sequelae.
- Advise patients to adhere to their NCEP-recommended diet and a regular exercise program.
- Advise patients about substances they should not take concomitantly with simvastatin. Also advise patients to inform their other health care providers prescribing a new medication or increasing the dose of an existing medication that they are taking simvastatin.
- Advise all patients of the risk of myopathy, including rhabdomyolysis, and to promptly report any unexplained muscle pain, tenderness, or weakness.
- Inform patients using the 80 mg dose that the risk of myopathy, including rhabdomyolysis, is increased with use of the 80 mg dose. The risk of myopathy, including rhabdomyolysis, occurring with use of simvastatin is increased when taking certain types of medication or consuming larger quantities of grapefruit juice. Instruct patients to discuss all medications, both prescription and OTC, with their health care provider.
- Inform patients that fasting lipid panels and liver function tests should be preformed before the initiation of therapy and thereafter when clinically indicated.
- Advise women of childbearing age to use an effective method of birth control to prevent pregnancy while using simvastatin. Discuss future pregnancy plans with patients, and discuss when to stop taking simvastatin if they are trying to conceive. Advise patients that if they become pregnant, they should stop taking simvastatin immediately and contact their health care provider.
- Advise women who are breast-feeding to not use simvastatin.
Copyright © 2009 Wolters Kluwer Health.
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