Simvastatin is an oral HMG-CoA reductase inhibitor indicated as an adjunct to diet. It is a semi-synthetic derivative of lovastatin, the first FDA-approved statin. Simvastatin helps lower cholesterol production and reduce dyslipidemia associated complications. High concentrations of LDL cholesterol can lead to artery damage, potentially leading to cardiac complications and stroke.

FDA-Approved Indications

• Homozygous/heterozygous familial hypercholesterolemia
• Heterozygous NonFamilial hypercholesterolemia
• Hypertriglyceridemia
• Dysbetalipoproteinemia 
• Reduction of adverse cardiovascular events 

Simvastatin is also used off-label for prophylactic and therapeutic indications.

Non-FDA-Approved Indications

• Prophylaxis of adverse cardiovascular outcomes post-acute-coronary-syndrome hospitalization 
• Prophylaxis of atrial fibrillation among patients with stable coronary artery disease

Simvastatin is used as monotherapy and is available in combination products to treat dyslipidemia. Combination products include:

• Simvastatin/ezetimibe[1]
• Simvastatin/niacin extended-release (ER)

Clinicians prescribe statin therapy to lower cholesterol concentrations; simvastatin targets cholesterol production. Biosynthesis of this molecule consists of a multi-step pathway. The rate-limiting step in this pathway involves the 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase enzyme. Using acetyl-CoA as a substrate, mevalonic acid is formed, and subsequent reactions lead to the formation of cholesterol. Simvastatin acts on the rate-limiting step and serves as an HMG-CoA reductase inhibitor, consequently leading to decreased concentrations of cholesterol.

Statins also possess additional properties in addition to their ability to lower cholesterol concentrations. These include inhibition of platelet aggregation, reduction in inflammation at the site of atherosclerotic plaque, and improved endothelial function. These properties are commonly taken advantage of when prescribing statin therapy for individuals with normal cholesterol levels. Studies have shown that early statin therapy initiation has reduced the incidence of cardiovascular events, leading to reduced mortality.[2]

Simvastatin is approved for oral administration and is available in 5-mg, 10-mg, 20-mg, 40-mg, and 80-mg tablets. A suspension dosage form is also available for those with difficulty swallowing.

Recommended Dosages*

Homozygous Familial Hypercholesterolemia

• 40 mg once every evening

Heterozygous Familial Hypercholesterolemia

• Initial 10 to 20 mg once every evening; max dose 40 mg once every evening
• Pediatric patients age 10 to 17: Initial 10 mg once every evening; max dose 40 mg once every evening

Hypertriglyceridemia

• Initial 10 to 20 mg once every evening; max dose 40 mg once every evening

Reduction in Cardiovascular Events

• Initial 10 to 20 mg once every evening; max dose 40 mg once every evening
• In patients with coronary heart disease (CHD), the initial dose is 40 mg once every evening

A dose restriction exists for simvastatin 80 mg due to a higher risk of myopathy and possible rhabdomyolysis, especially within the first 12 months of use. Therefore, the 80-mg strength is restricted for only those patients who have been on the 80-mg regimen for 12 or more months with no reported myopathy. Simvastatin 80 mg is not recommended for patients with LDL targets that are not at goal even with the use of simvastatin 40 mg. Recommendations are to use a high-intensity statin instead. For patients who are stable on the simvastatin 80-mg dose, a change of therapy is necessary if initiating an interacting medication.

*Doses are adjusted to target goal LDL levels.

Dose Adjustments

Dose adjustments are necessary with simvastatin when taken concomitantly with certain pharmacotherapy. Adjustments in simvastatin strength reduce potential statin-associated toxicities, including fatigue and myopathy.

Potent CYP3A4 inhibitors (clarithromycin, HIV protease inhibitors, cyclosporine)

• Simvastatin is contraindicated:
  • Verapamil, Diltiazem, Dronedarone
    • Max dose is simvastatin 10 mg
  • Amiodarone, Amlodipine, Ranolazine
    • Max dose is simvastatin 20 mg

Common adverse effects include a headache, myalgia, abdominal pain, constipation, and upper respiratory infections. Rarer, yet more severe, causations include cardiovascular effects such as atrial fibrillation, hepatic abnormalities, including cholestatic hepatitis, greater than a 3-fold elevation in transaminases, jaundice, and potential liver failure. Adverse musculoskeletal effects include greater than a three-fold increase in creatine phosphokinase (CPK) levels, rhabdomyolysis, and compartment syndrome in the lower legs.[3][4]

Drug concentrations, and consequently, incidence and severity of adverse effects, are significantly increased when coadministered with CYP3A4 inhibitors. Concomitant medications administered with simvastatin should have an assessment performed for potential drug interactions to minimize the risk of adverse effects.

Patients contraindicated to simvastatin pharmacotherapy include those who have active liver disease, including those who have elevated hepatic enzymes, pregnancy, and women who may become pregnant or are breastfeeding. Concomitant use with certain medications (see above) is also a contraindication with simvastatin, and drug profiles should be carefully reviewed prior to initiation.

Pregnancy is a known secondary cause for dyslipidemia leading to a potential increase in triglyceride and LDL-C concentrations. Statin therapy is contraindicated during pregnancy resulting in limited options for dyslipidemia treatment during pregnancy. Alternative treatment options are necessary to treat elevated concentrations during pregnancy to minimize associated complications such as hypertriglyceridemia associated acute pancreatitis. Pregnancy has been delayed or avoided in reported cases to avoid the possible complications from untreated dyslipidemia.[5]

Although rare, a serious complication of statin therapy is liver toxicity with elevated levels of transaminases. Due to a potential increase in liver enzymes, patients with active liver disease and those with pre-existing elevated transaminases are excluded from simvastatin therapy. Simvastatin can transiently increase transaminase concentrations within the first few months of treatment. These subsequently return to baseline. The clinician should monitor liver function and enzymes while their patients are on simvastatin pharmacotherapy.[6]