Fluvastatin


Thông tin thuốc gốc
Chỉ định và Liều dùng
Oral
Mixed dyslipidaemia, Primary hypercholesterolaemia
Adult: Doses are individualised according to the initial LDL-cholesterol (LDL-C) and goal of therapy. As an adjunct to diet: Patients requiring to achieve an LDL-C reduction of <25%: Initially, 20 mg once daily in the evening. Patients requiring to achieve an LDL-C reduction of ≥25%: Initially, 40 mg once daily in the evening. Doses may be up-titrated up to 80 mg, given either as a 40 mg conventional cap bid, or as an 80 mg extended-release tab once daily. Adjust dose at intervals of ≥4 weeks.

Oral
Heterozygous familial hypercholesterolaemia
Child: ≥9 years As an adjunct to diet: Initially, 20 mg daily. Doses are individualised according to the initial LDL-cholesterol (LDL-C) and goal of therapy. Max: 80 mg daily, given as a 40 mg conventional cap bid or as an 80 mg extended-release tab once daily. Adjust dose at intervals of 6 weeks. Dosage recommendations may vary among countries and individual products. Refer to specific product guidelines.

Oral
Secondary prevention in coronary heart disease
Adult: 80 mg once daily.
Nhóm bệnh nhân đặc biệt
Patients taking ciclosporin, fluconazole: 20 mg bid. Recommendations may vary among countries or individual products. Refer to specific product guidelines.

Pharmacogenomics:

Statin-associated musculoskeletal symptoms (SAMS) including myalgia, myopathy, or rhabdomyolysis may occur with fluvastatin use in relation to genes such as the SLCO1B1 and CYPC2C9 as variations in these genes may impair the systemic exposure to fluvastatin. Although available product information may not reference these genes, current international guidelines recommend that genetic testing may be considered to help identify those at significant risk, to reduce the risk of SAMS and to optimise fluvastatin therapy.

The SLCO1B1 gene encodes the organic anion transporting polypeptide 1B1 (OATP1B1) an influx transporter which enables the hepatic uptake of all statins and other exogenous and endogenous compounds (e.g. bilirubin). The CYP2C9 enzyme is vital for the Phase-I metabolism of multiple medicines including fluvastatin. A reduced function of the transporter and the genetic polymorphisms of CYP2C9 may cause an increased systemic exposure to statins, which is thought to be the contributor to SAMS. The data regarding the combination of SLCO1B1 and CYP2C9 genotypes are limited, and although the combinations of these genes are expected to cause an additive effect on fluvastatin pharmacokinetics, the combinatorial gene-based recommendations are rated as optional by the international guidelines.

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline as of February 2022:

Dosage recommendations based on SLCO1B1 phenotype:
Phenotype
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
Typical myopathy risk with ≤40 mg doses; increased exposure in comparison to SLCO1B1 normal function.
Initiate treatment at standard doses and adjust doses according to disease-specific guidelines.
SLCO1B1 possible decreased function
Patients carrying 1 non-functional allele and 1 unknown/uncertain functional allele e.g. *5/*6, *15/*10, *5/*43
Typical myopathy risk with ≤40 mg doses; increased exposure in comparison to SLCO1B1 normal function.
Initiate treatment at standard doses and adjust doses according to disease-specific guidelines.
SLCO1B1 poor function
Patients carrying 2 non-functional alleles e.g. *5/*5, *5/*15, *15/*15
Typical myopathy risk with standard doses; increased exposure in comparison to SLCO1B1 normal and decreased function.
Initiate treatment at a dose of ≤40 mg and adjust doses according to disease-specific guidelines. If the patient is tolerating 40 mg doses but a higher potency is needed, an alternative statin or combination therapy may be considered; refer to specific country guidelines. Although there may be an increased risk of myopathy, doses >40 mg may be considered.

Dosage recommendations based on CYP2C9 phenotype:
Phenotype
Genotype  Implications  Recommendations
CYP2C9 intermediate metaboliser
Patients carrying 1 normal functional allele and 1 decreased or 1 non-functional allele or patients carrying 2 decreased functional alleles e.g. *1/*2, *1/*3, *2/*2
Increased risk of myopathy; increased fluvastatin exposure in comparison to CYP2C9 normal metabolisers.
Initiate treatment at a dose of ≤40 mg and adjust doses according to disease-specific guidelines. If doses >40 mg are needed for the desired efficacy, an alternative statin or combination therapy may be considered; refer to specific country guidelines.
CYP2C9 poor metaboliser
Patients carrying 1 non-functional allele and 1 decreased functional allele or patients carrying 2 non-functional alleles e.g. *2/*3, *3/*3
Increased risk of myopathy; increased fluvastatin exposure in comparison to CYP2C9 normal and intermediate metabolisers.
Initiate treatment at a dose of ≤20 mg and adjust doses according to disease-specific guidelines. If doses >20 mg are needed for the desired efficacy, an alternative statin or combination therapy may be considered; refer to specific country guidelines.

Combinatorial gene-based recommendations based on SLCO1B1 and CYP2C9 phenotype:
Genotype combination
Recommendations
SLCO1B1 decreased/possible decreased function and CYP2C9 intermediate metaboliser
Initiate treatment at a dose of ≤20 mg and adjust doses according to disease-specific guidelines. If doses >20 mg are needed for the desired efficacy, an alternative statin or combination therapy may be considered; refer to specific country guidelines.
SLCO1B1 decreased/possible decreased function and CYP2C9 poor metaboliser
An alternative agent is recommended depending on the desired potency; refer to specific country guidelines.
SLCO1B1 poor function and CYP2C9 intermediate metaboliser
An alternative agent is recommended depending on the desired potency; refer to specific country guidelines.
SLCO1B1 poor function and CYP2C9 poor metaboliser
An alternative agent is recommended depending on the desired potency; refer to specific country guidelines.
Suy gan
Contraindicated.
Cách dùng
May be taken with or without food.
Chống chỉ định
Active liver disease, unexplained persistent elevation of serum transaminases. Pregnancy and lactation. Concomitant use and within 7 days of discontinuation of fusidic acid.
Thận trọng
Patient with a history of liver disease, predisposing factors for rhabdomyolysis (e.g. uncontrolled hypothyroidism, personal or familial history of hereditary muscle disorders, history of muscular toxicity with a statin or fibrate). Patients who consume large amounts of alcohol. Patient with SLCO1B1 gene polymorphisms, CYP2C9 intermediate and poor metabolisers, and/or those with combinations of SLCO1B1 and CYP2C9 genotypes; available product information may not reference pharmacogenomic information, refer to specific country guidelines for their respective considerations/recommendations. Renal impairment. Children and the elderly.
Tác dụng không mong muốn
Significant: Increased HbA1c, fasting blood glucose, serum transaminases; interstitial lung disease (particularly during prolonged use). Rarely, hepatitis, new-onset or exacerbation of myasthenia gravis, myopathy, myositis, rhabdomyolysis, immune-mediated necrotising myopathy.
Gastrointestinal disorders: Nausea, abdominal pain, dyspepsia.
Nervous system disorders: Headache.
Psychiatric disorders: Insomnia.
Potentially Fatal: Rarely, hepatic failure.
Chỉ số theo dõi
Monitor lipid profile at baseline, 4-12 weeks after initiation of treatment, then every 3-12 months thereafter. Monitor LFTs at baseline and during therapy (if symptoms suggest hepatotoxicity). Perform neuromuscular and serologic testing if immune-mediated necrotising myopathy is suspected. Assess for new-onset of diabetes mellitus.
Tương tác
May increase the risk of myopathy and rhabdomyolysis with colchicine, fibrates, nicotinic acid (≥1 g daily), and erythromycin. May increase the serum concentration and risk of myopathy/rhabdomyolysis with ciclosporin. May decrease the serum concentration with rifampicin, colestyramine. Reduced bioavailability with rifampicin. Increased exposure and peak concentration with fluconazole. Rarely, bleeding episodes and increased prothrombin time with warfarin and other coumarin anticoagulants.
Potentially Fatal: Increased risk of rhabdomyolysis with fusidic acid.
Tương tác với thức ăn
Alcohol may increase the risk of hepatic adverse effects.
Tác dụng
Description: Fluvastatin competitively inhibits HMG-CoA reductase, an enzyme essential for cholesterol synthesis. It reduces total cholesterol, triglycerides, LDL, and VLDL concentrations in plasma. It also increases HDL concentrations.
Pharmacokinetics:
Absorption: Rapidly and completely absorbed from the gastrointestinal tract. Bioavailability: 24% (conventional cap); approx 29% (extended-release tab). Time to peak plasma concentration: <1 hour (conventional cap); approx 3 hours (extended-release tab).
Distribution: Volume of distribution: 330 L. Plasma protein binding: >98%.
Metabolism: Undergoes extensive first-pass metabolism in the liver. Converted to inactive and active metabolites via oxidative metabolism mainly by the CYP2C9 isoenzyme and in small amounts by the CYP3A4 isoenzyme.
Excretion: Via faeces (93%; <2% as unchanged drug); urine (approx 6%). Elimination half-life: Approx 3 hours (conventional cap); 7.3-10.5 hours (extended-release tab).
Đặc tính

Chemical Structure Image
Fluvastatin

Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 446155, Fluvastatin. https://pubchem.ncbi.nlm.nih.gov/compound/Fluvastatin. Accessed May 27, 2022.

Bảo quản
Store below 25°C. Protect from light and moisture.
Phân loại MIMS
Thuốc trị rối loạn lipid máu
Phân loại ATC
C10AA04 - fluvastatin ; Belongs to the class of HMG CoA reductase inhibitors. Used in the treatment of hyperlipidemia.
Tài liệu tham khảo
Cooper-DeHoff R, Niemi M, Ramsey L et al. The Clinical Pharmacogenetics Implementation Consortium Guideline for SLCO1B1, ABCG2, and CYP2C9 Genotypes and Statin-Associated Musculoskeletal Symptoms. Clinical Pharmacology and Therapeutics. 2022 Feb;111(5):1007-2021. doi: 10.1002/cpt.2557. Accessed 13/05/2022. PMID: 35152405

Annotation of CPIC Guideline for Fluvastatin and CYP2C9, SLCO1B1. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org. Accessed 13/05/2022.

Anon. CYP2C9 - Fluvastatin (Pharmacogenomics). Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 13/05/2022.

Anon. Fluvastatin. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 08/02/2022.

Anon. SLCO1B1 - Fluvastatin (Pharmacogenomics). Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 13/05/2022.

Buckingham R (ed). Fluvastatin Sodium. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 08/02/2022.

Fluvastatin 20 mg Hard Capsules (Sandoz Limited). MHRA. https://products.mhra.gov.uk. Accessed 16/05/2022.

Fluvastatin 40 mg Capsule (Torrent Pharma [UK] Ltd). MHRA. https://products.mhra.gov.uk. Accessed 08/02/2022.

Fluvastatin Capsule (Teva Pharmaceuticals USA, Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed. Accessed 16/05/2022.

Joint Formulary Committee. Fluvastatin. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 08/02/2022.

Lescol Gelatin Capsules 20 mg and 40 mg, Lescol XL Prolonged Release 80 mg Tablets (Novartis Corporation [Malaysia] Sdn. Bhd.). National Pharmaceutical Regulatory Agency - Ministry of Health Malaysia. https://www.npra.gov.my. Accessed 08/02/2022.

Lescol XL 80 mg Prolonged-release Tablets (Novartis Pharmaceuticals UK Ltd). MHRA. https://products.mhra.gov.uk. Accessed 08/02/2022.

Lescol XL Tablet, Extended Release (Novartis Pharmaceuticals UK Ltd). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed. Accessed 08/02/2022.

The Clinical Pharmacogenetics Implementation Consortium Guideline for Statins and SLCO1B1, ABCG2, and CYP2C9. Clinical Pharmacogenetics Implementation Consortium (CPIC). https://cpicpgx.org. Accessed 13/05/2022.

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