simvastatin (Rx)

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

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

Immune-mediated necrotizing myopathy

• Immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, reported with statin use
• IMNM is characterized by muscle biopsy showing necrotizing myopathy without significant inflammation improvement with immunosuppressive agents, proximal muscle weakness, and elevated serum creatine kinase, which persist despite discontinuation of statin treatment
• Treatment with immunosuppressive agents may be required
• Advice all patients starting therapy or whose dose is being increased, about the risk of myopathy, including rhabdomyolysis
• Patients should report promptly any unexplained muscle pain, tenderness, or weakness particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing therapy; additional neuromuscular and serologic testing may be necessary
• Therapy should be discontinued immediately if myopathy is diagnosed or suspected
• Discontinue therapy if markedly elevated creatine kinase (CK) levels occur or if myopathy diagnosed or suspected
• Therapy should be temporarily withheld in any patient experiencing an acute or serious condition predisposing to development of renal failure secondary to rhabdomyolysis, eg, sepsis; hypotension; dehydration; major surgery; trauma; severe metabolic, endocrine, and electrolyte disorders; or uncontrolled epilepsy
• Consider risk of IMNM carefully prior to initiation of a different statin
• If therapy is initiated with a different statin, monitor for signs and symptoms of IMNM
• Additional neuromuscular and serologic testing may be necessary
• Treatment with immunosuppressive agents may be required
• Consider risk of IMNM carefully prior to initiation of a different statin
• If therapy is initiated with a different statin, monitor for signs and symptoms of IMNM

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

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.

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)