Dosing & Uses
Dosage Forms & Strengths
tablet
- 5mg
- 10mg
- 20mg
- 40mg
- 80mg
Hypercholesterolemia
Usual dosage range: 5-40 mg PO qDay
Initial: 10-20 mg PO qDay in the evening
Patients at high CHD risk: Start 40 mg/day
Homozygous Familial Hypercholesterolemia
Recommended dose: 40 mg PO qDay in the evening
See limitations for 80 mg/day, listed below
Prevention of Coronary Events
5-40 mg PO qDay in the evening
Moderate reduction of LDL-C desired: 5-10 mg PO qDay in the evening; adjust dose to achieve goal
Reduction of >40% of LDL-C desired: 40 mg PO qDay in the evening; adjust dose to achieve goal
Presence of CHD or at high risk for cardiovascular events, including patients with diabetes, PVD, history of stroke or other cerebrovascular disease: 40 mg PO qDay in the evening adjunct to diet therapy (initiate simultaneously); adjust dose to achieve goal
Primary and secondary prevention of atheroschlerotic cardiovascular disease (ASCVD)
ACC/AHA Cholesterol Guideline Recommendations (2013) for adults ≥21 years
Primary prevention
- LDL-C ≥190 mg/dL: High-intensity therapy agent atorvastatin or rosuvastatin recommended
- Type 1 or 2 diabetes (40-75 years of age): Moderate-intensity therapy: 20-40 mg simvastatin PO qDay
- Type 1 or 2 diabetes (40-75 years of age and 10 year estimated risk of ASCVD ≥7.5%): High-intensity therapy agent atorvastatin or rosuvastatin recommended
- 40-75 years of age and 10 year estimated risk of ASCVD ≥7.5% : Moderate-intensity therapy: 20-40 mg simvastatin PO qDay; may consider high-intensity therapy agent atorvastatin or rosuvastatin
Secondary prevention
- Presence of ASCVD, including stroke/TIA or peripheral arterial disease believed to be of atherosclerotic origin or post-CABG
- ≤75 years: Treat with high-intensity therapy agent atorvastatin or rosuvastatin
- >75 years: Administer 20-40 mg simvastatin PO qDay (moderate-intensity therapy); not candidate for high-intensity therapy
Dosage Modifications
Severe renal impairment (CrCl <30 mL/min): 5 mg qDay initially
Coadministration with dronedarone, verapamil, or diltiazem: Do not exceed 10 mg/day
Coadministration with amiodarone, amlodipine, or ranolazine: Do not exceed 20 mg/day
Coadministration with lomitapide: Reduce simvastatin dose by 50%, and do not exceed 20 mg/day (or 40 mg/day in those previously tolerating 80 mg/day) when initiating lomitapide
Dosing Considerations
Lipid determinations should be performed after 4 weeks of therapy and periodically thereafter
Restricted dosing
- 80 mg/day should be used only for individuals who have been taking simvastatin 80 mg chronically (eg, ≥12 months) without evidence of myopathy or rhabdomyolysis
- Patients tolerating 80 mg who need to be initiated on an interacting drug that is contraindicated or associated with a maximum dose for simvastatin should be switched to an alternative statin with less potential for drug-drug interactions
- Patients unable to achieve their LDL-C goal utilizing 40 mg/day should not be titrated to 80 mg (increased risk for myopathy) but should instead be placed on alternative LDL-C-lowering treatment that provides greater LDL-C lowering
Overdose management
- Adverse drug reactions from overdose may include peripheral neuropathy, diarrhea, increased K+, myopathy, rhabdomyolysis, acute renal failure, elevated LFTs, and eye lens opacities
- Treatment is supportive
Dosage Forms & Strengths
tablet
- 5mg
- 10mg
- 20mg
- 40mg
- 80mg
Hypercholesterolemia
<10 years: Safety and efficacy not established
Heterozygous Familial Hypercholesterolemia
Adolescents aged 10-17 years
- Initial: 10 mg PO qDay in the evening; not to exceed 40 mg/day
- Recommended dosing range: 10-40 mg/day; adjustments should be made at intervals of 4 weeks or more
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Adverse Effects
1-10%
CPK elevation (>3x ULN) (5%)
Constipation (2%)
Upper respiratory infection (9%)
Flatulence (1-2%)
Transaminases increased (>3x ULN) (1%)
Headache (3-7%)
Myalgia (5%)
Eczema (5%)
Vertigo (5%)
Abdominal pain (7%)
<1%
Myalgia
Myopathy
Arthralgia
Arthritis
Eosinophilia
Chills
Angioedema
Rhabdomyolysis
Abdominal pain
Postmarketing Reports
Erectile dysfunction
Interstitial lung disease
Rare reports of cognitive impairment (eg, memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use
Warnings
Contraindications
Hypersensitivity to simvastatin
Active liver disease or unexplained transaminase elevation
Pregnancy
Nursing mothers
Strong CYP3A4 inhibitors (eg, itraconazole, ketoconazole, erythromycin, clarithromycin, posaconazole, voriconazole, HIV protease inhibitors, cobicistat, nefazodone), gemfibrozil, cyclosporine, and danazol
Cautions
Rule out secondary causes of hyperlipidemia prior to initiating therapy
Nonserious and reversible cognitive side effects may occur
Increased blood sugar and glycosylated hemoglobin (HbA1c) levels reported with statin intake
Heavy alcohol use, history of liver disease, renal failure
Monitor LFTs before initiating treatment and thereafter when clinically indicated; reports of fatal and nonfatal hepatic failure in patients taking statins
Discontinue if markedly elevated CPK levels occur or myopathy is diagnosed or suspected
Increases in HbA1c and fasting serum glucose levels reported with simvastatin
Severe electrolyte, endocrine, or metabolic disorders
Grapefruit juice increases simvastatin systemic exposure; avoid large quantities of grapefruit juice (ie, ≥1 quart/day)
Simvastatin and myopathy risk
- Myopathy/rhabdomyolysis with acute renal failure and/or myopathy reported; monitor patient closely
- Dose adjustment required when coadministered with niacin, amiodarone, verapamil, diltiazem, amlodipine, and ranolazine
- Predisposing factors for myopathy include advanced age (>65 years), uncontrolled hypothyroidism, and renal impairment
- Withhold or discontinue if myopathy, renal failure, or transaminase levels >3x ULN develop
- Risk of myopathy is greater in patients taking simvastatin 80 mg/day, especially in the 1st year of treatment
- Rare reports of immune-mediated necrotizing myopathy (IMNM), characterized by increased serum creatine kinase that persists despite discontinuing statin
- Risk for myopathy increased when coadministered with other lipid-lowering drugs (other fibrates, ≥1 g/day of niacin, or, for patients with HoFH, lomitapide), colchicine, amiodarone, dronedarone, verapamil, diltiazem, amlodipine, or ranolazine
-
Coadministration with niacin
- Myopathy/rhabdomyolysis observed with simvastatin coadministered with lipid-modifying niacin doses (ie, ≥1 g/day); also observed when coadministered with daptomycin
- Risk of myopathy is greater in Chinese patients, and therefore, coadministration of simvastatin with lipid-modifying niacin doses is not recommended in Chinese patients
- Unknown if this risk applies to other patients of Asian descent
Pregnancy & Lactation
Pregnancy
Contraindicated in women who are or may become pregnant
Lipid lowering drugs offer no benefit during pregnancy, because cholesterol and cholesterol derivatives are needed for normal fetal development
Atherosclerosis is a chronic process, and discontinuation of lipid-lowering drugs during pregnancy should have little impact on long-term outcomes of primary hypercholesterolemia therapy
There are no adequate and well-controlled studies of use with statins during pregnancy; however, there are rare reports of congenital anomalies in infants exposed to statins in utero
Lactation
Unknown if simvastatin excreted in human milk; because a small amount of another drug in this class is excreted in human milk and because of the potential for serious adverse reactions in nursing infants, women taking simvastatin should not breastfeed
A decision should be made whether to discontinue nursing or discontinue drug, taking into account the importance of the drug to the mother
Pregnancy Categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available.Pharmacology
Mechanism of Action
HMG-CoA reductase inhibitor; inhibits the rate-limiting step in cholesterol biosynthesis by competitively inhibiting HMG-CoA reductase
Absorption
Bioavailability: <5%
Onset of action: >3 days
Peak plasma time: 1.3-2.4 hr
Maximum effect: 4-6 weeks
Distribution
Protein bound: 95%
Metabolism
First pass in liver
Converted to maximally active simvastatin acid by nonenzymatic pathways and nonspecific enzymes
Metabolites: Beta-hydroxyacid and 6'-hydroxy, 6'-hydroxymethyl, and 6'-exomethylene derivatives (all active)
Simvastatin acid also converted to other active metabolites by CYP3A4
Elimination
Excretion: Feces (60%); urine (13%)
Pharmacogenomics
SLCO1B1 (OATP1B1) CC genotype significantly increases AUCs of parent drug and metabolites compared with the CT or TT genotypes
This polymorphism is proposed to reduce transport into the liver, the main site of statin metabolism and elimination, resulting in elevated plasma concentrations
SLCO1B1 polymorphism is thought to have a lesser effect on the more hydrophilic statins (eg, rosuvastatin, fluvastatin) compared with those that are more lipophilic (eg, atorvastatin, simvastatin)
Other genetic polymorphisms of elimination (eg, CYP450, P-glycoprotein) for each individual drug must also be considered, to explain variability for statin clearance among patients that exhibit SCLO1B1 polymorphism
SLCO1B1 CC genotype is most common in Caucasians and Asians (15%)
Risk of myopathy is 2.6- to 4.3-fold higher if the C allele is present and 16.9-fold higher in CC homozygotes than in TT homozygotes
Genetic testing laboratories
- Optivia Biotechnology, Inc (http://optiviabio.com)
Images
Patient Handout
Formulary
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