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Drug Reference

simvastatin

HMG-CoA reductase inhibitor· Brands: Zocor, Simvador, Simvastatin Sandoz, Simvastatin TevaPO

Mechanism of action
Simvastatin is a prodrug that is hydrolyzed to its active beta-hydroxyacid form. It competitively inhibits HMG-CoA reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate, an early rate-limiting step in cholesterol biosynthesis. Reduced hepatic cholesterol synthesis upregulates LDL receptors on hepatocytes, increasing clearance of LDL cholesterol from the plasma. It also decreases hepatic production of VLDL, leading to reductions in serum triglycerides and modest increases in HDL cholesterol.
Pharmacokinetics
Simvastatin is administered orally and undergoes extensive first-pass metabolism. It is a lactone prodrug that is hydrolyzed to the active form, primarily by esterases and CYP3A4. Peak plasma concentrations occur within 1 to 2 hours. It is highly protein-bound. The active form is metabolized by CYP3A4 and to a lesser extent by CYP2C8. The drug and its metabolites are excreted mainly in bile and faeces, with approximately 10-15% in urine. The elimination half-life of the active metabolite is about 1 to 3 hours, but the pharmacological effect lasts longer. Because of extensive presystemic metabolism, systemic availability is low (about 5%).
Indications & dosing

Primary hypercholesterolaemia and mixed dyslipidaemia

Take in the evening. Reduce dose to 10-20 mg if used with certain calcium channel blockers or amiodarone. Avoid with strong CYP3A4 inhibitors.

  • adult · PO: 10–40 mg once daily · Take in the evening. Reduce dose to 10-20 mg if used with certain calcium channel blockers or amiodarone. Avoid with strong CYP3A4 inhibitors.

Cardiovascular risk reduction

Used in patients with existing atherosclerotic cardiovascular disease or high risk.

  • adult · PO: 20–40 mg once daily · Used in patients with existing atherosclerotic cardiovascular disease or high risk.

Heterozygous familial hypercholesterolaemia

May increase to 80 mg if necessary, but only if no interacting drugs.

  • adult · PO: 20–40 mg once daily · May increase to 80 mg if necessary, but only if no interacting drugs.

Heterozygous familial hypercholesterolaemia

For adolescents aged 10-17 years with familial hypercholesterolaemia.

  • pediatric · PO: 10–40 mg once daily · For adolescents aged 10-17 years with familial hypercholesterolaemia.

Homozygous familial hypercholesterolaemia

Usually used in combination with other lipid-lowering therapy.

  • adult · PO: 20–40 mg once daily · Usually used in combination with other lipid-lowering therapy.
Contraindications & precautions
  • Active liver disease or unexplained persistent elevation of serum transaminases · Simvastatin is hepatotoxic; use is contraindicated in the presence of active liver disease or persistent unexplained transaminase elevations.
  • Pregnancy · Statins may cause fetal harm; discontinue simvastatin before conception or if pregnancy occurs.
  • Breastfeeding · Safety during breastfeeding is not established; alternative lipid-lowering therapy is advised.
  • Concurrent use of strong CYP3A4 inhibitors · Includes itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, and nefazodone. Co-administration markedly increases myopathy risk.
  • Concomitant use of gemfibrozil · Gemfibrozil substantially increases simvastatin plasma concentrations and the risk of myopathy/rhabdomyolysis.
  • Hypersensitivity to simvastatin or any excipient · Anaphylactic or severe allergic reactions are rare but contraindicate further use.
  • Measure liver function tests before initiating simvastatin and subsequently as clinically indicated; discontinue therapy if transaminase levels rise persistently without alternative explanation.
  • Advise patients to promptly report unexplained muscle pain, tenderness, weakness, or dark urine, and to seek medical attention if these symptoms occur; consider monitoring creatine kinase if myopathy is suspected.
  • Use with caution in patients with renal impairment, hypothyroidism, or a history of previous myopathy on statins, and in the elderly, as these predispose to myopathy.
  • Avoid excessive alcohol intake and maintain awareness that grapefruit juice may increase exposure; limit intake to small quantities.
  • Be vigilant for drug interactions: avoid strong CYP3A4 inhibitors, and use caution with other drugs that increase myopathy risk, such as fibrates, niacin, amiodarone, verapamil, diltiazem, and macrolides; adhere to dose limits.
Adverse effects
  • Myalgia
  • Myopathy (elevated creatine kinase with muscle symptoms)serious
  • Rhabdomyolysisserious
  • Hepatotoxicity (elevated transaminases, hepatitis, jaundice)serious
  • Headache
  • Constipation
  • Diarrhoea
  • Nausea
  • Pancreatitisserious
  • Memory impairment
Interactions
  • diltiazemmajorAvoid concomitant use if possible. If co-prescription is necessary, limit the simvastatin dose to a maximum of 10 mg daily, as recommended by regulatory guidelines. Monitor patients for signs of myopathy, and consider measuring creatine kinase at baseline and if symptoms develop. Advise patients to report unexplained muscle pain or weakness promptly.
  • amiodaronemajorAvoid concomitant use if possible. If combination is necessary, limit simvastatin dose to no more than 20 mg daily and monitor patients for signs of myopathy, including creatine kinase levels. Consider alternative statins less dependent on CYP3A4, such as pravastatin or rosuvastatin.
  • amlodipinemajorIf the combination is necessary, limit the simvastatin dose to 20 mg daily, or use an alternative statin that is less dependent on CYP3A4, such as pravastatin or rosuvastatin. Monitor patients for signs of myopathy, and consider measuring creatine kinase if symptoms develop. Do not exceed the recommended dose.
  • fluconazolemajorAvoid concurrent use of simvastatin and fluconazole. If necessary, consider alternative antifungal agents that do not inhibit CYP3A4, or use a statin that is not metabolised by CYP3A4, such as pravastatin or rosuvastatin. If co-administration is unavoidable, reduce the simvastatin dose and monitor creatine kinase levels and symptoms of myopathy.
  • verapamilmajorAvoid co-prescribing verapamil with simvastatin doses above 10 mg daily. If combination is necessary, limit simvastatin to 10 mg/day and monitor for muscle symptoms and creatine kinase levels.
  • cyclosporinecontraindicatedCo-prescription is contraindicated. Do not use simvastatin with cyclosporine. If a statin is needed, consider an alternative with lower interaction risk, such as pravastatin, under specialist advice.
  • erythromycincontraindicatedCo-administration is contraindicated. If erythromycin is required, alternative lipid-lowering therapy should be considered, such as pravastatin or rosuvastatin, which are less dependent on CYP3A4 metabolism. If temporary treatment with erythromycin is unavoidable, simvastatin should be withheld during the course of antibiotic therapy.
  • clarithromycincontraindicatedAvoid co-prescription of clarithromycin and simvastatin. If an antibiotic is required, consider an alternative macrolide (e.g., azithromycin) or another antibiotic that does not inhibit CYP3A4. If a statin is required, consider a statin not metabolised by CYP3A4, such as pravastatin or rosuvastatin. If temporary combination is deemed absolutely necessary, simvastatin should be withheld during clarithromycin therapy; however, this approach is rarely acceptable given the contraindication.
  • carbamazepinemajorAvoid the combination if possible. If a statin is needed, consider a statin not metabolised by CYP3A4, such as pravastatin or rosuvastatin. If the combination is unavoidable, monitor lipid levels regularly and adjust the simvastatin dose accordingly, with careful consideration of the risk of myopathy when carbamazepine is stopped. Patients should be counselled to report unexplained muscle pain, tenderness, or weakness.
  • ticagrelormajorAvoid concomitant use, or if deemed necessary, limit the simvastatin dose to a maximum of 40 mg daily. Alternatively, consider a statin that is not extensively metabolised by CYP3A4, such as pravastatin or rosuvastatin. Monitor patients for symptoms of myopathy and check creatine kinase levels if symptoms develop.
  • colchicinemajorAvoid concomitant use where possible. If the combination is necessary, use the lowest effective doses and monitor for muscle symptoms and serum creatine kinase. Consider alternative statins that are not metabolised by CYP3A4, such as pravastatin or rosuvastatin. In patients with renal impairment, dose adjustment of colchicine is essential.
Renal & hepatic adjustment
  • eGFR 0–29: Use with caution; do not exceed 10 mg/day in severe renal impairment.
  • eGFR 30–300: No dose adjustment required.
  • Hepatic impairment (mild): No dose adjustment usually required. Monitor liver function tests.
  • Hepatic impairment (moderate): Use with caution; consider dose reduction in moderate hepatic impairment.
  • Hepatic impairment (severe): Contraindicated in active liver disease or unexplained persistent transaminase elevations. (avoid)
Monitoring, pregnancy & toxicity
  • Fasting lipid profile (LDL, HDL, total cholesterol, triglycerides) · At baseline, 4-12 weeks after initiation or dose adjustment, then periodically.
  • Liver function tests (ALT, AST) · At baseline and periodically thereafter.
  • Creatine kinase (CK) · If symptoms of myopathy occur.
  • Signs and symptoms of myopathy (muscle pain, tenderness, weakness) · At each visit, especially in high-risk patients or when on interacting drugs.
  • Pregnancy: Simvastatin is contraindicated during pregnancy. It should be discontinued as soon as pregnancy is recognized, as statins may cause fetal harm.
  • Toxicity: Myopathy and rhabdomyolysis (muscle pain, tenderness, weakness, dark urine, elevated CK). · Discontinue simvastatin; monitor CK, renal function, and urine output; manage with IV fluids and supportive care.
  • Toxicity: Hepatotoxicity (elevated transaminases, jaundice, hepatomegaly). · Discontinue simvastatin; monitor LFTs; treat symptomatically.
  • Toxicity: Overdose (gastrointestinal symptoms, potential myopathy). · No specific antidote; treat symptomatically; monitor for myopathy and hepatic injury.
Clinical notes
Simvastatin is used in the management of hypercholesterolaemia and mixed dyslipidaemia to reduce LDL cholesterol and the risk of cardiovascular events. It is also indicated for primary and secondary prevention of cardiovascular disease. The usual starting dose is 10 to 20 mg once daily at night, with a maximum of 80 mg daily (although 80 mg is associated with increased myopathy risk and is reserved for patients with severe hypercholesterolaemia). Dose adjustments are required in patients with renal impairment and for concomitant use of certain interacting drugs. Simvastatin is contraindicated in pregnancy, active liver disease, and with strong CYP3A4 inhibitors. Muscle toxicity is a key concern; patients should be advised to report unexplained muscle pain or weakness. It is a substrate of CYP3A4, so interactions with grapefruit juice, azole antifungals, macrolides, and cyclosporine are important. Monitor liver function, lipids, and creatine kinase as appropriate. In patients of Chinese descent, the risk of myopathy is increased, so the 80 mg dose is not recommended.

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BNF; local formulary