Simvastatin

Simvastatin is a statin given as an inactive lactone that the liver converts to the active acid. It lowers LDL cholesterol by 30% to 45% and triglycerides by 10% to 25%. It lowers heart attacks, strokes and death in people with cardiovascular disease and in selected high risk people. It is cleared by CYP3A4, so it has the largest number of dangerous interactions of any statin, and the dose is capped with several common heart drugs. It is cheap and widely available in East Africa.

Classification. Statin; HMG CoA reductase inhibitor; moderate intensity at 20 to 40 mg.

Mechanism. The active acid blocks the rate limiting step of hepatic cholesterol synthesis; the liver raises LDL receptors and clears more LDL.

Pharmacodynamics. LDL cholesterol falls within 2 weeks, with the full effect at 4 to 6 weeks. Cholesterol synthesis peaks at night, so evening dosing is more effective for this short acting statin.

Pharmacokinetics. Oral bioavailability under 5% (high first pass). Half life 2 to 3 hours (active metabolites longer). Metabolised by CYP3A4. Protein binding 95%. Excreted mostly in faeces.

Primary prevention and hypercholesterolaemia, adult. Start 10 to 20 mg once daily in the evening; titrate every 4 weeks; usual maintenance 20 to 40 mg once daily.

Established cardiovascular disease, high risk, adult. 40 mg once daily in the evening. The 80 mg dose is no longer started because of the risk of myopathy; it is used only in people who have already taken it for a year or more without muscle symptoms.

Homozygous familial hypercholesterolaemia, adult. 40 mg once daily in the evening (specialist).

Children aged 10 to 17 years with familial hypercholesterolaemia (specialist). Start 10 mg once daily in the evening; titrate every 4 weeks to a maximum of 40 mg.

Kidney impairment. Creatinine clearance under 30 mL/min: start 5 mg once daily and take care above 10 mg.

Interaction limits.

• Verapamil, diltiazem, dronedarone: maximum 10 mg daily.

• Amlodipine, amiodarone, ranolazine: maximum 20 mg daily.

• Lomitapide: maximum 20 mg daily.

• Contraindicated: itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, ritonavir boosted protease inhibitors, nefazodone, gemfibrozil, ciclosporin, danazol.

Contraindications. Active liver disease or unexplained persistent rise in transaminases; pregnancy; breastfeeding; concurrent strong CYP3A4 inhibitors (itraconazole, ketoconazole, clarithromycin, ritonavir boosted protease inhibitors); concurrent gemfibrozil, ciclosporin or danazol; hypersensitivity.

Warnings. Myopathy and rhabdomyolysis (risk rises with the 80 mg dose, age over 65 years, female sex, kidney impairment, hypothyroidism, and interacting drugs); raised liver enzymes; new onset diabetes (small rise); immune mediated necrotising myopathy (rare); interstitial lung disease (rare). In people of Chinese ancestry taking niacin (nicotinic acid) 1 g or more daily, the risk of myopathy is higher, so use with caution.

Adverse effects. Muscle aches, headache, nausea, constipation, abdominal pain, raised liver enzymes, rash.

Interactions. Raise levels: strong CYP3A4 inhibitors (itraconazole, ketoconazole, clarithromycin, erythromycin, ritonavir boosted protease inhibitors), ciclosporin, gemfibrozil, fusidic acid (stop the statin while on fusidic acid), amlodipine, verapamil, diltiazem, amiodarone, ranolazine, colchicine, grapefruit juice over 1 L daily. Lower levels: rifampicin, carbamazepine, phenytoin, efavirenz, St John's wort. Warfarin: raised INR.

Special groups.

• Pregnancy: stop when pregnancy is planned or confirmed; avoid.

• Breastfeeding: avoid.

• Patients of African ancestry: no dose change.

• Patients with HIV on ritonavir boosted regimens: avoid; use another statin.

• Older adults: use a lower dose; high risk groups still benefit.

• Kidney impairment: start 5 mg when creatinine clearance is under 30 mL/min.

• Liver impairment: contraindicated in active disease.

Formulations. Tablets 5, 10, 20, 40, 80 mg.

Administration. Oral once daily in the evening, with or without food. Avoid large amounts of grapefruit juice.

Baseline. Lipid profile, alanine aminotransferase, creatinine, creatine kinase if muscle symptoms or risk factors, thyroid function if suspected hypothyroidism, glucose or HbA1c, pregnancy status, a full list of other medicines.

Monitoring. Lipid profile 4 to 12 weeks after starting or changing the dose, then every 6 to 12 months. Alanine aminotransferase at baseline and as needed. Creatine kinase if muscle symptoms occur. Review the statin dose each time a new interacting drug is started.

Stopping. Stop for creatine kinase above 10 times the upper limit of normal, rhabdomyolysis, persistent transaminase rise above 3 times the upper limit of normal, pregnancy, or while taking a short course of clarithromycin or fusidic acid.

Common prescribing errors. Exceeding 20 mg with amlodipine or amiodarone; exceeding 10 mg with verapamil or diltiazem; giving it with clarithromycin or ritonavir; combining with gemfibrozil; starting the 80 mg dose; omitting evening dosing.