Atorvastatin

Atorvastatin is a 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitor that lowers LDL cholesterol by 30% to 55% and triglycerides by 20% to 30%. It lowers heart attacks, strokes and death in people with established cardiovascular disease and in selected high risk people without it, including those with diabetes. It is one of the cheapest and most widely available statins in East Africa. It acts for 24 hours, so it can be taken at any time of day. Muscle symptoms and, rarely, liver injury are the main safety issues.

Classification. Statin; HMG CoA reductase inhibitor; high intensity at 40 to 80 mg.

Mechanism. Blocks the rate limiting step of hepatic cholesterol synthesis; the liver responds by raising LDL receptors and clearing more LDL from blood. It also stabilises plaque and lowers inflammation.

Pharmacodynamics. LDL cholesterol falls within 2 weeks, with the full effect at 4 weeks. Each doubling of dose adds about 6% more LDL reduction.

Pharmacokinetics. Oral bioavailability about 14%, with extensive first pass metabolism. Half life 14 hours (active metabolites 20 to 30 hours). Metabolised by CYP3A4. Highly protein bound (98%). Excreted in bile; little in urine.

Primary prevention of cardiovascular disease, adult. Start 10 to 20 mg once daily; titrate to the target.

Established cardiovascular disease (secondary prevention), acute coronary syndrome, adult. Start 40 to 80 mg once daily; usual maintenance 40 to 80 mg once daily; maximum 80 mg once daily.

Hypercholesterolaemia, adult. Start 10 to 20 mg once daily; titrate every 4 weeks; maximum 80 mg once daily.

Familial hypercholesterolaemia in children aged 10 years and over, specialist. 10 mg once daily; titrate every 4 weeks to a maximum of 20 mg once daily.

Dose adjustment for interactions. Clarithromycin, itraconazole, and ritonavir boosted protease inhibitors: use the lowest effective dose and do not exceed 20 mg daily (10 mg with itraconazole in some labels). Ciclosporin and gemfibrozil: avoid.

Kidney impairment. No adjustment.

Liver impairment. Contraindicated in active liver disease; use caution and a lower dose in stable impairment.

Contraindications. Active liver disease or unexplained persistent rise in transaminases; pregnancy; breastfeeding; hypersensitivity.

Warnings. Myopathy and rhabdomyolysis (higher with older age, low body weight, hypothyroidism, kidney impairment, high dose, and interacting drugs); immune mediated necrotising myopathy (rare); raised liver enzymes; new onset diabetes (small rise, benefit outweighs risk); haemorrhagic stroke signal at 80 mg after stroke (small); interstitial lung disease (rare); grapefruit juice in large amounts (over 1.2 L daily).

Adverse effects. Muscle aches, headache, nausea, diarrhoea, constipation, raised liver enzymes, raised blood glucose, insomnia, rash, memory complaints (rare).

Interactions. Raise statin levels: clarithromycin, erythromycin, itraconazole, ketoconazole, ritonavir boosted protease inhibitors, ciclosporin, gemfibrozil, fusidic acid (avoid together; stop statin during fusidic acid), verapamil, diltiazem, amiodarone, colchicine, grapefruit juice in large amounts. Lower levels: rifampicin, efavirenz, carbamazepine, phenytoin, St John's wort. Digoxin: small rise. Oral contraceptives: small rise in oestrogen and norethisterone levels. Warfarin: small INR effect.

Special groups.

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

• Breastfeeding: avoid.

• Patients of African ancestry: no dose change; effective in this population.

• Patients with HIV: considered for primary prevention, and the dose is limited with ritonavir boosted regimens.

• Older adults: start at a lower dose if frail; high risk groups benefit.

• Kidney impairment: no adjustment.

• Liver impairment: contraindicated in active disease.

Formulations. Tablets 10, 20, 40, 80 mg; chewable and oral suspension in some markets.

Administration. Oral once daily at any time of day, with or without food. Swallow the tablet whole with water.

Baseline. Fasting or non fasting lipid profile, alanine aminotransferase, creatine kinase if muscle symptoms or risk factors, thyroid function if suspected hypothyroidism, glucose or HbA1c, pregnancy status.

Monitoring. Lipid profile 4 to 12 weeks after starting or changing the dose, then every 6 to 12 months. Alanine aminotransferase at baseline, at 12 weeks and as needed. Creatine kinase only when muscle symptoms occur: stop if above 10 times the upper limit of normal or if symptoms are severe. Glucose in people with risk factors.

Stopping. Stop for creatine kinase above 10 times the upper limit of normal, rhabdomyolysis, transaminases above 3 times the upper limit of normal and persisting, or pregnancy. Restart at a lower dose after muscle symptoms settle.

Common prescribing errors. Giving more than 20 mg with clarithromycin or itraconazole; combining with gemfibrozil; continuing a statin during fusidic acid; omitting a baseline alanine aminotransferase; prescribing in pregnancy; stopping for mild muscle aches without checking creatine kinase and thyroid function.