Adult: As an adjunct to diet: Initially, 10-20 mg once daily. For patients who require a large decrease (>45%) in LDL-cholesterol (LDL-C): Initially, 20-40 mg once daily. Adjust dose according to patient response at intervals of at least 4 weeks. Max: 80 mg once daily. All doses to be taken in the evening.
Oral Cardiovascular risk reduction
Adult: In patients at high risk of CHD, with or without hyperlipidaemia: Usual dose: 20-40 mg once daily in the evening. Adjust dose according to patient response at intervals of at least 4 weeks.
Oral Heterozygous familial hypercholesterolaemia
Child: In boys Tanner stage 2 and above and girls who are at least 1 year post menarche, 10-17 years Initially, 10 mg once daily in the evening. Dosage is individualised and adjusted according to the recommended goal of therapy at intervals of at least 4 weeks. Max: 40 mg once daily in the evening. Patients should be placed on a cholesterol-lowering diet prior to and during drug therapy.
Nhóm bệnh nhân đặc biệt
Patients taking fibrates (except fenofibrate), ciclosporin, gemfibrozil, lipid-lowering doses of nicotinic acid (≥1g daily): Max: 10 mg daily. Dosage recommendations may vary among countries or individual products. Refer to specific product guidelines.
Patients taking verapamil, diltiazem, amiodarone, amlodipine, ranolazine, dronedarone, elbasvir or grazoprevir containing products: Max: 20 mg daily. Dosage recommendations may vary among countries or individual products. Refer to specific product guidelines.
Patients taking ticagrelor; lomitapide (in patients with homozygous familial hypercholesterolaemia): Max: 40 mg daily. Dosage recommendations may vary among countries or individual products. Refer to specific product guidelines.
Pharmacogenomics:
Simvastatin, a prodrug, is converted to its active metabolite simvastatin acid (SVA), which is a substrate of the organic anion transporter protein OATP1B1. SLCO1B1 gene encodes OATP1B1 which mediates the hepatic uptake of statins and other exogenous and endogenous compounds (e.g. bilirubin and 17-β-glucuronosyl estradiol) for subsequent elimination. Certain polymorphisms in the SLCO1B1 gene (e.g. 521T>C [rs4149056] polymorphism) can produce a less active form of OATP1B1. The reduced function of this transporter leads to an increased statin systemic exposure which is thought to be the contributor to statin-associated myopathy/statin-associated musculoskeletal symptoms (SAMS). Genetic testing may help identify those at significant risk, reducing simvastatin-induced myopathy and optimising 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 and 1 non-functional allele e.g. *1/*5, *1/*15
Increased risk of myopathy; increased SVA exposure in comparison to SLCO1B1 normal function.
An alternative agent is recommended depending on the desired potency; refer to specific country guidelines. If simvastatin treatment is desired, limit the dose to <20 mg daily.
SLCO1B1 possible decreased function
Patients carrying 1 non-functional allele and 1 unknown/uncertain functional allele e.g. *5/*6, *15/*10, *5/*43
Increased risk of myopathy; increased SVA exposure in comparison to SLCO1B1 normal function.
An alternative agent is recommended depending on the desired potency; refer to specific country guidelines. If simvastatin treatment is desired, limit the dose to <20 mg daily.
SLCO1B1 poor function
Patients carrying 2 non-functional alleles e.g. *5/*5, *5/*15, *15/*15
Highly increased risk of myopathy; increased SVA exposure in comparison to SLCO1B1 normal and decreased function.
An alternative agent is recommended depending on the desired potency; refer to specific country guidelines.
Royal Dutch Pharmacists Association - Pharmacogenetics Working Group (DPWG) Guideline as of August 2020:
Genotype
Implications
Recommendations
SLCO1B1 521 CC
30-fold to 18% increased risk of myopathy and 48-fold to 12% increased risk of severe myopathy with 80 mg daily doses; 7-fold to 1% increased risk of myopathy and 11-fold to 0.68% increased risk of severe myopathy with 40 mg daily doses.
Choose an alternative agent. Additional risk factors for myopathy should be considered.
SLCO1B1 521 TC
5-fold to 3% increased risk of moderately severe to severe myopathy and 1.3% increased risk of severe myopathy with 80 mg daily doses; 2.6-fold to 0.39% increased risk of moderately severe to severe myopathy and 0.17% increased risk of severe myopathy with 40 mg daily doses.
Choose an alternative agent. Additional risk factors for myopathy should be considered. If simvastatin treatment is desired, avoid doses >40 mg daily.
Suy thận
CrCl (mL/min):
Dosage
15-29
Initially, 5 mg once daily.
Cách dùng
May be taken with or without food. Take in the evening. Avoid excessive consumption (>1 L/day) of grapefruit juice.
Chống chỉ định
Active liver disease or unexplained persistent elevations of serum transaminases. Pregnancy and lactation. Concurrent use with potent CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, voriconazole, posaconazole, telithromycin, erythromycin, clarithromycin, nefazodone, HIV protease inhibitors, telaprevir, boceprevir, cobicistat), ciclosporin, gemfibrozil, danazol; concomitant use and within 7 days of discontinuation of fusidic acid.
Thận trọng
Patient with predisposing factors for rhabdomyolysis (e.g. uncontrolled hypothyroidism, personal or familial history of hereditary muscular disorders, previous history of muscular toxicity with a statin or fibrate, alcohol abuse); at risk of diabetes mellitus (e.g. fasting glucose of 5.6-6.9 mmol/L, BMI >30 kg/m2, hypertension, elevated triglycerides), history of liver disease. Patient with SLCO1B1 gene polymorphism. Not recommended for coadministration with niacin (≥1 g/day) in patients of Asian descent, particularly Chinese patients. Patient undergoing major surgery. The 80 mg dose is only recommended in patients at high risk of CV complications who have not achieved their treatment goals on lower doses and when the benefits are expected to outweigh the potential risks. Renal impairment. Children and elderly.
Tác dụng không mong muốn
Significant: Increased HbA1c, fasting blood glucose, serum transaminases; interstitial lung disease (prolonged use). Rarely, exacerbation of myasthenia gravis. Very rarely, immune-mediated necrotising myopathy (IMNM). Blood and lymphatic system disorders: Rarely, anaemia. Gastrointestinal disorders: Rarely, nausea, vomiting, diarrhoea, constipation, abdominal pain, pancreatitis. General disorders and administration site conditions: Rarely, asthenia. Hepatobiliary disorders: Rarely, hepatitis or jaundice. Immune system disorders: Rarely, hypersensitivity syndrome. Musculoskeletal and connective tissue disorders: Myalgia, muscle cramps. Nervous system disorders: Rarely, headache, dizziness, paraesthesia, peripheral neuropathy. Skin and subcutaneous tissue disorders: Rarely, rash, pruritus, alopecia. Potentially Fatal: Rarely, myopathy, rhabdomyolysis with or without acute renal failure; hepatic failure.
Monitor fasting or non-fasting lipid profile before treatment initiation; fasting lipid profile 4-12 weeks post initiation and 3-12 months thereafter; LFT at baseline and as clinically indicated; creatine phosphokinase at baseline (in high-risk patients or those suggestive of myopathy); prothrombin time at baseline, following dose changes, or frequently during early treatment (in patients taking coumarin anticoagulants). Assess for new-onset diabetes mellitus. If immune-mediated necrotising myopathy is suspected, consider performing neuromuscular and serologic testing. Monitor signs and symptoms of myopathy or rhabdomyolysis.
Tương tác
Increased risk of myopathy and rhabdomyolysis with lomitapide, amiodarone, verapamil, diltiazem, amlodipine, dronedarone, ranolazine, nicotinic acid (≥1 g daily), daptomycin, fibrates (except fenofibrate), fluconazole, acipimox, and colchicine. Increased serum concentration with elbasvir, grazoprevir, and ticagrelor. Enhanced effect of coumarin anticoagulants. Decreased serum concentration with rifampicin. Potentially Fatal: Increased risk of myopathy and rhabdomyolysis with fusidic acid, potent CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, voriconazole, posaconazole, telithromycin, erythromycin, clarithromycin, nefazodone, HIV protease inhibitors, telaprevir, boceprevir, cobicistat containing products), including ciclosporin, gemfibrozil, and danazol.
Tương tác với thức ăn
Increased serum concentration and risk of myopathy and rhabdomyolysis with grapefruit juice; avoid concurrent intake.
Tác dụng
Description: Simvastatin is a competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyses the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in cholesterol biosynthesis. Onset: >3 days. Pharmacokinetics: Absorption: Well absorbed from the gastrointestinal tract. Bioavailability: <5% (β-hydroxyacid). Time to peak plasma concentration: 1.3-2.4 hours. Distribution: Plasma protein binding: >95%. Metabolism: Metabolised in the liver by the CYP3A4 isoenzyme into β-hydroxyacid and other metabolites; undergoes extensive first-pass effect. Excretion: Mainly via faeces (60%); urine (13%). Elimination half-life: 1.9 hours (β-hydroxyacid).
Đặc tính
Simvastatin Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 54454, Simvastatin. https://pubchem.ncbi.nlm.nih.gov/compound/54454. Accessed July 26, 2022.
Bảo quản
Tab: Store below 30°C. Protect from moisture. Oral susp: Store between 20-25°C. Do not freeze or refrigerate. Protect from heat.
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