Child: Dose is individualised according to baseline LDL-C levels, the goal of therapy, and patient response. As an adjunct to diet: 10-17 years Initially, 10 mg daily; may be adjusted according to response at intervals of at least 4 weeks. Usual range: 10-20 mg once daily.
Adult: Dose is individualised according to baseline LDL-cholesterol (LDL-C) levels, the goal of therapy, and patient response. As an adjunct to diet: Usual initial dose: 10 mg or 20 mg once daily; patients who require >45% reduction in LDL-C may initiate at 40 mg once daily. Usual range: 10-80 mg once daily. Max: 80 mg once daily. Evaluate lipid levels within 2-4 weeks after initiation and/or upon titration, then adjust dose accordingly.
Oral Homozygous familial hypercholesterolaemia
Adult: Dose is individualised according to baseline LDL-C levels, the goal of therapy, and patient response. As an adjunct to other lipid-lowering treatments (e.g. LDL apheresis): 10-80 mg daily.
Oral Prophylaxis of cardiovascular events in high-risk patients
Adult: Dose is individualised according to baseline LDL-C levels, the goal of therapy, and patient response. Primary prevention: Initially, 10 mg daily. Higher doses may be required to attain LDL-C levels according to current guidelines.
Special Patient Group
Patients taking clarithromycin, itraconazole, fosamprenavir, ritonavir (plus darunavir, fosamprenavir, or saquinavir), elbasvir/grazoprevir combination, or letermovir: Use the lowest necessary atorvastatin dose. Max: 20 mg daily.
Patients taking boceprevir, nelfinavir: Use the lowest necessary atorvastatin dose. Max: 40 mg daily. Dosage recommendations may vary among countries and individual products (refer to specific product guidelines).
Pharmacogenomics:
SLCO1B1 gene encodes the organic anion transporting polypeptide 1B1 (OATP1B1; also known as SLCO1B1 or OATP-C), an influx transporter that facilitates the hepatic uptake of statins and other exogenous and endogenous compounds (e.g. bilirubin). Polymorphism in the SLCO1B1 gene (e.g. c.521T>C [rs4149056]) that encodes OATP1B1 may cause increased systemic exposure to statins which is thought to be the contributor to statin-associated musculoskeletal symptoms (SAMS). Genetic testing may be considered in identifying those at significant risk, to reduce the incidence of SAMS and optimise patient adherence.
Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline as of January 2022:
Phenotype and Genotype
Implications
Recommendations
SLCO1B1 decreased function
Patients carrying 1 normal or increased functional allele plus 1 non-functional allele (e.g. *1/*5, *1/*15)
Increased myopathy risk due to increased atorvastatin exposure in comparison with normal function.
Initiate treatment at a dose of ≤40 mg and adjust doses according to disease-specific guidelines. Monitor for myopathy, particularly with 40 mg dose. If >40 mg dose is needed for desired efficacy, may consider combination therapy with a non-statin guideline-directed medical therapy; refer to specific country guidelines.
Increased myopathy risk due to increased atorvastatin exposure in comparison with normal function.
Initiate treatment at a dose of ≤40 mg and adjust doses according to disease-specific guidelines. Monitor for myopathy, particularly with 40 mg dose. If >40 mg dose is needed for desired efficacy, may consider combination therapy with a non-statin guideline-directed medical therapy; refer to specific country guidelines.
Increased myopathy risk due to increased atorvastatin exposure in comparison to normal and decreased function.
Initiate treatment at a dose of ≤20 mg and adjust doses according to disease-specific guidelines. If >20 mg dose is needed for desired efficacy, may consider an alternative statin (rosuvastatin) or combination therapy with a non-statin guideline-directed medical therapy; refer to specific country guidelines.
Administration
May be taken with or without food. Avoid excessive consumption (>1 L/day) of grapefruit juice.
Contraindications
Active liver disease or unexplained persistent serum transaminase elevation. Pregnancy and lactation. Concomitant use with glecaprevir/pibrentasvir combination, systemic fusidic acid or within 7 days of stopping fusidic acid treatment, telaprevir, ciclosporin, and tipranavir/ritonavir combination.
Special Precautions
Patient with predisposing factors for rhabdomyolysis (e.g. hypothyroidism, personal or family history of hereditary muscular disorders, history of muscular toxicity with statin or fibrate), history of liver disease, recent stroke or TIA. Patients who consume large quantities of alcoholic beverages. Patient taking clarithromycin, itraconazole, fosamprenavir, ritonavir (plus darunavir, fosamprenavir, or saquinavir), elbasvir/grazoprevir combination, letermovir, boceprevir and nelfinavir. Patient with known SLCO1B1 gene polymorphism. Renal impairment. Children and elderly.
Adverse Reactions
Significant: Myalgia, myositis, myopathy; increased serum transaminase, serum creatine kinase, HbA1c and fasting blood sugar levels. Rarely, immune-mediated necrotising myopathy (IMNM), interstitial lung disease, worsen or precipitate myasthenia gravis. Gastrointestinal disorders: Diarrhoea, constipation, flatulence, dyspepsia, nausea. General disorders and administration site conditions: Malaise, asthenia, fatigue, pyrexia. Hepatobiliary disorders: Hepatitis. Immune system disorders: Allergic reactions. Investigations: Abnormal LFT. Musculoskeletal and connective tissue disorders: Arthralgia, muscle spasms, back pain, joint swelling, pain in extremity. Nervous system disorders: Headache, dizziness, paraesthesia, hypoaesthesia, amnesia. Psychiatric disorders: Insomnia, nightmares. Respiratory, thoracic and mediastinal disorders: Nasopharyngitis, pharyngolaryngeal pain, epistaxis. Skin and subcutaneous tissue disorders: Rash, pruritus, urticaria, alopecia. Potentially Fatal: Rhabdomyolysis (with or without acute renal failure secondary to myoglobinuria), hepatic failure.
Obtain lipid profile (fasting or non-fasting) before treatment initiation; fasting lipid profile during treatment. Monitor LFTs at baseline and periodically thereafter. May perform baseline creatine phosphokinase measurement for those at risk for myopathy. Assess for signs and symptoms of myopathy or rhabdomyolysis; new-onset diabetes mellitus.
Drug Interactions
May increase the risk of myopathy and rhabdomyolysis with moderate or potent CYP3A4 inhibitors (e.g. clarithromycin, erythromycin, ketoconazole, voriconazole, itraconazole, posaconazole, diltiazem, verapamil, certain antivirals for hepatitis C, HIV protease inhibitors), transport protein inhibitors (e.g. letermovir), gemfibrozil or other fibric acid derivatives, niacin, ezetimibe, and colchicine. Decreased plasma concentrations with CYP3A4 inducers (e.g. efavirenz, rifampicin), Al- and Mg-containing antacid, colestipol. May increase the plasma concentration of digoxin, norethisterone and ethinylestradiol. Potentially Fatal: Concomitant use with systemic fusidic acid may significantly increase the risk for muscle toxicities, including rhabdomyolysis. Increased plasma concentrations with glecaprevir/pibrentasvir, telaprevir, ciclosporin, and tipranavir/ritonavir, which may increase the risk of myopathy or rhabdomyolysis.
Food Interaction
Decreased plasma concentration with St. John's wort. May increase serum concentration with grapefruit juice.
Action
Description: Mechanism of Action: Atorvastatin selectively and competitively inhibits 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in cholesterol synthesis. This action results in a compensatory increase in the expression of LDL receptors on hepatocyte membranes and, subsequently, increased hepatic uptake and clearance of LDL-C from the blood. Onset: 3-5 days (initial changes); 2-4 weeks (Max reduction in plasma cholesterol and triglycerides). Pharmacokinetics: Absorption: Rapidly absorbed from the gastrointestinal tract. Bioavailability: Approx 14% (atorvastatin); approx 30% (atorvastatin and equipotent metabolites). Time to peak plasma concentration: Approx 1-2 hours. Distribution: Volume of distribution: Approx 381 L. Plasma protein binding: ≥98%. Metabolism: Metabolised in the liver by CYP3A4 isoenzyme into active ortho- and parahydroxylated derivatives and various β-oxidation products. Undergoes extensive first-pass metabolism in the gastrointestinal mucosa and liver. Excretion: Mainly via the bile; urine (<2% as unchanged drug). Elimination half-life: Approx 14 hours (atorvastatin); approx 20-30 hours (equipotent metabolites).
Chemical Structure
Atorvastatin Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 60823, Atorvastatin. https://pubchem.ncbi.nlm.nih.gov/compound/60823. Accessed July 28, 2022.
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