Usual Adult Dose for Prevention of Cardiovascular Disease

Initial dose: 10 to 20 mg orally once a day

• High-risk patients may initiate at 40 mg orally once a day

Maintenance dose: 5 to 40 mg orally once a day
Maximum dose: 40 mg/day

Restricted Use (due to myopathy risk): 80 mg/day should only be used in patients who have been taking this drug chronically (e.g. for 12 months or more) without evidence of muscle toxicity

Comments:

• Lipids should be checked 4 weeks after initiating therapy; patients unable to achieve LDL-C goal with 40 mg/day should be placed on alternative LDL-C lowering therapy.
• High risk patients include those at high risk for coronary heart disease (CHD) events due to existing CHD, diabetes, peripheral vessel disease, history of stroke or other cerebrovascular disease; in these patients, therapy can be initiated at a higher dose simultaneously with diet (restricted in saturated fat and cholesterol).

Uses: As one component of multiple risk factor intervention in individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia, specifically:

• This drug is indicated in patients at high risk of CHD events: to reduce the risk of total mortality by reducing CHD deaths; to reduce the risk of nonfatal myocardial infarction and stroke; and to reduce the need for coronary and non-coronary revascularization procedures.
• This drug is indicated in patients with hyperlipidemia: to reduce elevated total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (ApoB), triglycerides (TG), and increase high-density lipoprotein cholesterol (HDL-C) in patients with primary hyperlipidemia (Fredrickson type IIa, heterozygous familial and nonfamilial) or mixed dyslipidemia (Fredrickson type IIb); to reduce elevated TG in patients with hypertriglyceridemia (Fredrickson type IV hyperlipidemia); and to reduce elevated TG and VLDL-C in patients with primary dysbetalipoproteinemia (Fredrickson type III hyperlipidemia).

Usual Adult Dose for Cardiovascular Risk Reduction

Initial dose: 10 to 20 mg orally once a day

• High-risk patients may initiate at 40 mg orally once a day

Maintenance dose: 5 to 40 mg orally once a day
Maximum dose: 40 mg/day

Restricted Use (due to myopathy risk): 80 mg/day should only be used in patients who have been taking this drug chronically (e.g. for 12 months or more) without evidence of muscle toxicity

Comments:

• Lipids should be checked 4 weeks after initiating therapy; patients unable to achieve LDL-C goal with 40 mg/day should be placed on alternative LDL-C lowering therapy.
• High risk patients include those at high risk for coronary heart disease (CHD) events due to existing CHD, diabetes, peripheral vessel disease, history of stroke or other cerebrovascular disease; in these patients, therapy can be initiated at a higher dose simultaneously with diet (restricted in saturated fat and cholesterol).

Uses: As one component of multiple risk factor intervention in individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia, specifically:

• This drug is indicated in patients at high risk of CHD events: to reduce the risk of total mortality by reducing CHD deaths; to reduce the risk of nonfatal myocardial infarction and stroke; and to reduce the need for coronary and non-coronary revascularization procedures.
• This drug is indicated in patients with hyperlipidemia: to reduce elevated total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (ApoB), triglycerides (TG), and increase high-density lipoprotein cholesterol (HDL-C) in patients with primary hyperlipidemia (Fredrickson type IIa, heterozygous familial and nonfamilial) or mixed dyslipidemia (Fredrickson type IIb); to reduce elevated TG in patients with hypertriglyceridemia (Fredrickson type IV hyperlipidemia); and to reduce elevated TG and VLDL-C in patients with primary dysbetalipoproteinemia (Fredrickson type III hyperlipidemia).

Usual Adult Dose for Homozygous Familial Hypercholesterolemia

40 mg orally once a day
Maximum dose: 40 mg/day

Restricted Use (due to myopathy risk): 80 mg/day should only be used in patients who have been taking this drug chronically (e.g. for 12 months or more) without evidence of muscle toxicity

Comments:

• Exposure to this drug is approximately doubled with concomitant use of lomitapide; therefore, if initiating lomitapide, reduce simvastatin by 50% or for patients who have tolerated 80 mg/day chronically, simvastatin should be decreased to 40 mg/day.

Use: To reduce total-C and LDL-C in patients with homozygous familial hypercholesterolemia (HoFH) as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are unavailable.

Usual Pediatric Dose for Heterozygous Familial Hypercholesterolemia

10 years or older:
Initial dose: 10 mg orally once a day in the evening
Maintenance dose: 10 to 40 mg orally once a day in the evening
Maximum dose: 40 mg orally once a day in the evening

Comments:

• Doses should be individualized according to the goal of therapy; dose adjustments should be made at intervals of 4 weeks or more.
• The minimum goal of treatment in pediatric and adolescent patients is to achieve a mean LDL-C less than 130 mg/dL.
• The optimal age at which to initiate lipid-lowering therapy to decrease the risk of symptomatic adulthood CAD has not been determined.

Uses: As an adjunct to diet to reduce total-C, LDL-C, and Apo B levels in adolescent boys and girls who are at least one year postmenarche (10 to 17 years) with heterozygous familial hypercholesterolemia (HeFH), if after an adequate trial of diet therapy the following findings are present:

• LDL cholesterol remains 190 mg/dL or greater, OR
• LDL cholesterol remains 160 mg/dL or greater and there is a positive family history of premature cardiovascular disease (CVD), OR two or more other CVD risk factors are present

Renal Dose Adjustments

Mild to moderate renal dysfunction: No adjustment recommended
Severe renal dysfunction: Initial dose: 5 mg orally once a day; monitor closely

Liver Dose Adjustments

Active liver disease or unexplained transaminase elevations: Contraindicated

• Substantial alcohol ingestion and/or past history of liver disease: Use with caution

Interrupt therapy if serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice develop; investigate cause, if an alternative etiology is not found, do not restart

Dose Adjustments

Restricted Use of Simvastatin 80 mg/day:

• Simvastatin 80 mg dose should only be used in patients who have taken this dose chronically (e.g., for 12 months or more) without evidence of muscle toxicity
• If a patient on simvastatin 80 mg/day needs to initiate an interacting drug (one that will increase simvastatin concentrations); simvastatin should be switched to an alternative statin with less potential for drug-drug interaction.

• Coadministration of Strong CYP450 3A4 Inhibitors: Contraindicated; avoid consuming grapefruit juice during therapy
• Coadministration with Niacin 1 g/day or more: Not recommended for Chinese patients
• Coadministration with Verapamil, Diltiazem, or Dronedarone: Simvastatin dose should not exceed 10 mg/day
• Coadministration with Amiodarone, Amlodipine, or Ranolazine: Simvastatin dose should not exceed 20 mg/day
• Coadministration of Lomitapide: Simvastatin dose should not exceed 20 mg/day in patients with HoFH (for patients who have tolerated simvastatin 80 mg/day chronically, a dose of simvastatin 40 mg may be used)

Clinical Pharmacogenetics Implementation Consortium Guideline (CPIC):

• Normal Function SLCO1B1 Phenotype: Follow prescribed dosing guidelines and adjust doses based on disease-specific guidelines
• Intermediate and Low Function SLCO1B1 Phenotype: Initiate therapy with a lower dose or consider an alternative statin (e.g. pravastatin or rosuvastatin); consider routine CK monitoring

Precautions

CONTRAINDICATIONS:

• Hypersensitivity to active substance or any component of product
• Active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels
• Pregnancy
• Lactation
• Concomitant administration of strong CYP450 3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors, boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, nefazodone, and cobicistat containing products)
• Concomitant administration of gemfibrozil, cyclosporine, or danazol

Safety and efficacy have not been established in patients younger than 10 years, nor in pre-menarchal girls.

Consult WARNINGS section for dosing related precautions.

Dialysis

Data not available

Other Comments

Administration advice:

• Take orally once a day in the evening

Oral Suspension:

• Take on an empty stomach
• Shake well for at least 20 seconds before measuring dose
• Use an accurate measuring dose; a household teaspoon is not an accurate measuring device

Storage:

• Oral Suspension: Store at room temperature (68F to 77F [20C to 25C]); Protect from heat; do not freeze or refrigerate; Use within 30 days after opening

General:

• This drug has not been studied in patients with Fredrickson Types I and V dyslipidemias.

Monitor:

• Obtain liver function tests prior to initiating therapy and as clinically indicated
• Periodic creatine kinase determinations may be considered to monitor for myopathy, however, there is no assurance that such monitoring will prevent myopathy
• Patients with severe renal impairment should be closely monitored
• Chinese patients may be a higher risk of myopathy and should be closely monitored

Patient advice:

• Patients should be instructed to read the patient labeling.
• Patients should be advised to adhere to a diet and exercise program.
• Patients should be instructed to discuss all medication use including herbal products and over the counter products with their healthcare professional; patients should be advised to avoid grapefruit juice during therapy.
• Patients should understand the risk of myopathy and should be instructed to report unexplained muscle pain promptly, especially if accompanied by malaise or fever.
• Patients should be instructed to report any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice.
• Women of childbearing potential should be advised to use an effective method of birth control.

Frequently asked questions

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