Dosing & Uses
Dosage Forms & Strengths
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
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
Patients of Chinese descent taking lipid-modifying doses of niacin (ie, ≥1 g/day): Increased risk of myopathy with simvastatin 40 mg/day; consider lower dose
Patients of Asian descent should not receive simvastatin 80 mg coadministered with lipid-modifying doses of niacin-containing products
Lipid determinations should be performed after 4 weeks of therapy and periodically thereafter
- 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
- 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
<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
Serious - Use Alternative
Significant - Monitor Closely
CPK elevation (>3x ULN) (5%)
Upper respiratory infection (9%)
Transaminases increased (>3x ULN) (1%)
Abdominal pain (7%)
Interstitial lung disease
Rare reports of cognitive impairment (eg, memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use
Hypersensitivity to simvastatin
Active liver disease or unexplained transaminase elevation
Strong CYP3A4 inhibitors (eg, itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, posaconazole, voriconazole, HIV protease inhibitors, cobicistat, nefazodone, boceprevir, telaprevir), gemfibrozil, cyclosporine, and danazol
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
- 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
- Increased risk for myopathy in Chinese patients coadministered niacin >1 g/day; they should not receive simvastatin 80 mg coadministered with lipid-modifying doses of niacin-containing products
- 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
- See Contraindications for list of drugs contraindicated because of increased risk for myopathy when coadministered with simvastatin
- See Adult Dosing for dose limitations and modifications
Pregnancy & Lactation
Pregnancy category: X
Lactation: Contraindicated; potentially unsafe
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.
Mechanism of Action
HMG-CoA reductase inhibitor; inhibits the rate-limiting step in cholesterol biosynthesis by competitively inhibiting HMG-CoA reductase
Onset of action: >3 days
Peak plasma time: 1.3-2.4 hr
Maximum effect: 4-6 weeks
Protein bound: 95%
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
Excretion: Feces (60%); urine (13%)
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)
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