Simvastatin


Thông tin thuốc gốc
Chỉ định và Liều dùng
Oral
Cardiovascular risk reduction
Adult: Patients with atherosclerotic CV disease or diabetes mellitus: 20-40 mg once daily in the evening. May increase dose at intervals of at least 4 weeks. Max: 80 mg daily.

Oral
Hyperlipidaemias
Adult: Initially, 10-20 mg once daily. Patients requiring large reduction in cholesterol or with high CV risk: Initially, 40 mg once daily. Patients with homozygous familial hypercholesterolaemia: Initially, 40 mg once daily. All doses to be taken in the evening. Max: 80 mg daily. Adjust dose according to patient response at intervals of at least 4 weeks. Patients should be placed on a cholesterol-lowering diet and other lifestyle modification prior and during drug therapy.
Child: Heterozygous familial hypercholesterolaemia: 10-17 years Initially, 10 mg once daily. Recommended dose: 10-40 mg daily. Adjust dose according to the recommended goal of therapy at intervals of at least 4 weeks. All doses to be taken in the evening.  Max: 40 mg daily. Patients should be placed on a cholesterol-lowering diet and other lifestyle modification prior and during drug therapy.
Special Patient Group
Patients taking fibrates (except fenofibrate): Max: 10 mg daily.

Patients taking amiodarone, amlodipine, ranolazine, verapamil, diltiazem, elbasvir, grazoprevir: Max: 20 mg daily.

Patients taking lomitapide: Max: 40 mg daily.

Pharmacogenomics:

Simvastatin, a prodrug, is converted to its active metabolite simvastatin acid (SVA), which is a substrate of the organic anion transporter protein OATP1B1. OATP1B1 mediates the hepatic uptake of statins and other endogenous compounds (e.g. bilirubin) for subsequent elimination. SLCO1B1 gene encodes OATP1B1, certain polymorphism in the SLCO1B1 gene (e.g. 521T>C polymorphism), can produce a less active form of OATP1B1. This change in the function of the transporter protein leads to reduced SVA reuptake thus increasing SVA concentration which is thought to be the contributor to statin-associated myopathy. Genetic testing may be helpful in identifying those at significant risk to reduce simvastatin-induced myopathy and optimise patient adherence.

Intermediate function heterozygous SLCO1B1 phenotype (carriers of 1 normal-function allele plus 1 deceased-function allele *1/*5, *1/*15, *1/*17, TC genotype)

Patient may have intermediate myopathy risk. CPIC recommends initiation of therapy at a lower dose or considering use of alternative statins (e.g. rosuvastatin). Perform routine creatinine kinase test.

Low function homozygous SLCO1B1 phenotype (carriers of 2 deceased-function allele *5/*5, *5/*15, *5/*17, CC genotype)

Patient may have high myopathy risk. CPIC recommends initiation of therapy at a lower dose or considering use of alternative statins (e.g. rosuvastatin). Perform routine creatinine kinase test.
Renal Impairment
CrCl (mL/min): Dosage
<30
Initially, 5 mg once daily with close monitoring. 
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, myopathy secondary to other lipid-lowering agents. Concurrent use with potent CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, clarithromycin, erythromycin, telithromycin, nefazodone, HIV protease inhibitors, cobicistat containing products, fusidic acid), ciclosporin, danazol and gemfibrozil. Pregnancy and lactation.
Thận trọng
Patients with diabetes mellitus, predisposing factors for myopathy/rhabdomyolysis (e.g. uncontrolled hypothyroidism, personal or family history of muscular disorders, history of muscular toxicity with a statin or fibrate, alcohol abuse). Renal and hepatic impairment. Children and elderly. Patients with SLCO1B1 gene polymorphism. Coadministration of niacin (≥1 g) in patients of Chinese descent. A dose of 80 mg should be restricted to patients who have been taking simvastatin 80 mg for 12 months or more. Temporarily discontinue simvastatin prior to elective major surgery.
Phản ứng phụ
Significant: Increased serum transaminase.
Blood and lymphatic system disorders: Anaemia.
Gastrointestinal disorders: Constipation, abdominal pain, flatulence, dyspepsia, diarrhoea, nausea, acid regurgitation, vomiting, pancreatitis.
Hepatobiliary disorders: Hepatitis, jaundice.
Immune system disorders: Hypersensitivity reactions.
Metabolism and nutrition disorders: Hyperglycaemia.
Musculoskeletal and connective tissue disorders: Myalgia, arthralgia. muscle cramps.
Nervous system disorders: Headache, paraesthesia, dizziness, peripheral neuropathy.
Psychiatric disorders: Insomnia, depression.
Respiratory, thoracic and mediastinal disorders: Upper respiratory infection, bronchitis, interstitial lung disease.
Reproductive system and breast disorders: Erectile dysfunction.
Skin and subcutaneous tissue disorders: Rash, pruritus, alopecia.
Potentially Fatal: Myopathy, rhabdomyolysis with or without acute renal failure, hepatic failure.
Thông tin tư vấn bệnh nhân
This drug may cause dizziness, if affected, do not drive or operate machinery.
MonitoringParameters
Monitor lipid profile, LFT and creatine kinase. Monitor for signs and symptoms of myopathy and rhabdomyolysis.
Tương tác
May increase risk of myopathy and rhabdomyolysis with concurrent use with amiodarone, amlodipine, verapamil, diltiazem, lomitapide, daptomycin, and colchicine. May increase serum concentrations of elbasvir and grazoprevir. May increase prothrombin time with coumarin anticoagulants.
Potentially Fatal: Increased risk of myopathy including rhabdomyolysis with potent CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, clarithromycin, erythromycin, telithromycin, nefazodone, HIV protease inhibitors, nelfinavir, boceprevir, telaprevir, cobicistat containing products), gemfibrozil, ciclosporin, danazol and fusidic acid.
Food Interaction
Increased plasma concentrations resulting to increased risk of myopathy and rhabdomyolysis with grapefruit juice. May enhance hepatic side hepatic effects with alcohol.
Tác dụng
Description: Simvastatin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the enzyme that catalyses the conversion of HMG-CoA to produce mevalonate, an early and rate-limiting step in cholesterol biosynthesis, resulting to reduced total cholesterol, LDL-cholesterol and triglycerides, and increases HDL-cholesterol levels.
Onset:  >3 days.
Pharmacokinetics:
Absorption: Well absorbed from the gastrointestinal tract (85%). Bioavailability: <5%. Time to peak plasma concentration: 1.3-2.4 hours.
Distribution: Plasma protein binding: Approx 95%.
Metabolism: Metabolised in the liver by CYP3A4 to active β-hydroxyacid (active metabolite). Undergoes extensive first-pass metabolism.
Excretion: Mainly via faeces (60% as metabolites); urine (13%, inactive form). Elimination half-life: 1.9 hour (active metabolite).
Đặc tính

Chemical Structure Image
Simvastatin

Source: National Center for Biotechnology Information. PubChem Database. Simvastatin, CID=54454, https://pubchem.ncbi.nlm.nih.gov/compound/Simvastatin (accessed on Jan. 23, 2020)

Bảo quản
Tablet: Store below 30°C. Suspension: Store between 20-25°C. Protect from heat.
Phân loại MIMS
Phân loại ATC
C10AA01 - simvastatin ; Belongs to the class of HMG CoA reductase inhibitors. Used in the treatment of hyperlipidemia.
References
Ramsey LB, Johnson SG, Caudle KE, et al. The Clinical Pharmacogenetics Implementation Consortium Guideline for SLCO1B1 and Simvastatin-Induced Myopathy: 2014 Update. CPIC Update:1-6. doi: 10.1038/clpt.2014.125. Accessed 19/09/2018

Anon. Simvastatin. AHFS Clinical Drug Information [online]. Bethesda, MD. American Society of Health-System Pharmacists, Inc. https://www.ahfscdi.com. Accessed 06/11/2019.

Anon. Simvastatin. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 06/11/2019.

Anon. SLCO1B1 – Simvastatin (Pharmacogenomics). Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 19/09/2018.

Buckingham R (ed). Simvastatin. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 06/11/2019.

Clinical Annotation for rs4149056 Related to Simvastatin – Toxicity (1A). Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 10/19/2018.

Joint Formulary Committee. Simvastatin. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 06/11/2019.

Simvastatin Tablet (Micro Labs Limited). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 19/11/2019.

Simvastatin Tablet, Film Coated (Teva Pharmaceuticals USA, Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 06/11/2019.

The Clinical Pharmacogenetics Implementation Consortium Guideline for SLCO1B1 and Simvastatin-Induced Myopathy: 2014 Update. Clinical Pharmacogenetics Implementation Consortium (CPIC). https://cpicpgx.org/. Accessed 19/09/2018.

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