Fluvastatin

Fluvastatin
Clinical data
Trade names	Lescol, others
AHFS/Drugs.com	Monograph
MedlinePlus	a694010
Pregnancy; category	AU: D;
Routes of; administration	By mouth (capsules, tablets)
ATC code	C10AA04 (WHO) ;
Legal status
Legal status	AU: S4 (Prescription only); CA: ℞-only; UK: POM (Prescription only); US: ℞-only; In general: ℞ (Prescription only);
Pharmacokinetic data
Bioavailability	24–30%
Protein binding	>98%
Metabolism	Hepatic: CYP2C9 (75%), CYP3A4 (20%), CYP2C8 (5%)
Elimination half-life	1–3 hours (capsule), 9 hours (XR formulations)
Excretion	Faeces (95%), urine (5%)
Identifiers
	IUPAC name (3R,5S,6E)-7-[3-(4-Fluorophenyl)-1-(propan-2-yl)-1H-indol-2-yl]-3,5-dihydroxyhept-6-enoic acid;
CAS Number	93957-54-1 ;
PubChem CID	446155;
IUPHAR/BPS	2951;
DrugBank	DB01095 ;
ChemSpider	393587 ;
UNII	4L066368AS;
KEGG	D07983 ;
ChEBI	CHEBI:38565 ;
ChEMBL	ChEMBL1078 ;
CompTox Dashboard (EPA)	DTXSID201020962 DTXSID2020636, DTXSID201020962 ;
ECHA InfoCard	100.224.327
Chemical and physical data
Formula	C24H26FNO4
Molar mass	411.473 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES O=C(O)C[C@H](O)C[C@H](O)/C=C/c2c(c1ccccc1n2C(C)C)c3ccc(F)cc3;
	InChI InChI=1S/C24H26FNO4/c1-15(2)26-21-6-4-3-5-20(21)24(16-7-9-17(25)10-8-16)22(26)12-11-18(27)13-19(28)14-23(29)30/h3-12,15,18-19,27-28H,13-14H2,1-2H3,(H,29,30)/b12-11+/t18-,19-/m1/s1 ; Key:FJLGEFLZQAZZCD-MCBHFWOFSA-N ;
	(verify)

Fluvastatin is a member of the statin drug class, used to treat hypercholesterolemia and to prevent cardiovascular disease.

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It was patented in 1982 and approved for medical use in 1994.^[4] It is on the World Health Organization's List of Essential Medicines.^[5]

Adverse effects are comparable to other statins. Common are nausea, indigestion, insomnia and headache. Myalgia (muscle pain), and rarely rhabdomyolysis, characteristic side effects for statins, can also occur.^[6]

Contrary to lovastatin, simvastatin and atorvastatin, fluvastatin has no relevant interactions with drugs that inhibit the liver enzyme CYP3A4, and a generally lower potential for interactions than most other statins. Fluconazole, a potent inhibitor of CYP2C9, does increase fluvastatin levels.^[6]

Mechanism of action

Fluvastatin works by blocking the liver enzyme HMG-CoA reductase, which facilitates an important step in cholesterol synthesis.^[1]

Pharmacodynamics

In a Cochrane systematic review the dose-related magnitudes of fluvastatin on blood lipids was determined. Over the dose range of 10 to 80 mg/day total cholesterol was reduced by 10.7% to 24.9%, LDL cholesterol by 15.2% to 34.9%, and triglycerides by 3% to 17.5%.^[7]

Pharmacokinetics

The drug is quickly and almost completely (98%) absorbed from the gut. Food intake slows down absorption, but does not decrease it. Due to its first-pass effect, bioavailability is lower: about 24–30%^[2]^[1] according to different sources. Over 98% of the substance is bound to plasma proteins.^[1]

Several cytochrome P450 enzymes (mainly CYP2C9, but also CYP3A4 and CYP2C8)^[8] are involved in the metabolism of fluvastatin, which makes is less liable to interactions than most other statins. The main metabolite is inactive and is called "N-desisopropyl propionic acid" in the literature.^[1]^[6]

93–95% of the drug is excreted via the feces, less than 2% of which in form of the original substance.^[1]

Fluvastatin is the INN.^[9] Brandnames include Lescol, Canef, Vastin.

Data from the Cholesterol Treatment Trialists’ (CTT) publication^[10] was used to determine the effects of fluvastatin, atorvastatin and rosuvastatin on LDL cholesterol lowering and reduction of myocardial infarction. In two RCTs an average dose of 72 mg/day fluvastatin reduced LDL cholesterol by 31.9%, and reduced myocardial infarction, relative risk, 0.68 (95% CI 0.55 to 0.85) as compared to placebo. In five RCTs a mean atorvastatin dose of 26 mg/day reduced LDL cholesterol by 44.0% and reduced myocardial infarction, relative risk, 0.67 (95% CI 0.58 to 0.77) as compared to placebo. In four RCTs a mean rosuvastatin dose of 16 mg/day reduced LDL cholesterol by 48.8% and reduced myocardial infarction, relative risk, 0.82 (95% CI 0.73 to 0.93) as compared to placebo. Thus despite reducing LDL cholesterol by a much lesser amount with fluvastatin than atorvastatin and rosuvastatin, fluvastatin reduced myocardial infarction similarly to atorvastatin and to a greater degree than rosuvastatin.^[7]

[1]
Haberfeld H, ed. (2015). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag.
[2]
Neuvonen PJ, Backman JT, Niemi M (2008). "Pharmacokinetic comparison of the potential over-the-counter statins simvastatin, lovastatin, fluvastatin and pravastatin". Clinical Pharmacokinetics. 47 (7): 463–74. doi:10.2165/00003088-200847070-00003. PMID 18563955. S2CID 11716425.
[3]
"Lescol, Lescol XR (fluvastatin) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 18 March 2014.
[4]
Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 472. ISBN 9783527607495.
[5]
World Health Organization (2021). World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. hdl:10665/345533. WHO/MHP/HPS/EML/2021.02.
[6]
Dinnendahl, V, Fricke, U, eds. (2012). Arzneistoff-Profile (in German). Vol. 2 (26 ed.). Eschborn, Germany: Govi Pharmazeutischer Verlag. ISBN 978-3-7741-9846-3.
[7]
Adams SP, Sekhon SS, Tsang M, Wright JM (March 2018). "Fluvastatin for lowering lipids". The Cochrane Database of Systematic Reviews. 2018 (3). John Wiley & Sons, Ltd: CD012282. doi:10.1002/14651858.cd012282.pub2. PMC 6494196. PMID 29508377.
[8]
Lescol Monograph on Drugs.com.
[9]
"International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names (Rec. INN): List 30" (PDF). World Health Organization. 1990. Retrieved 29 November 2016.
[10]
Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, et al. (October 2005). "Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins". Lancet. 366 (9493): 1267–78. doi:10.1016/s0140-6736(05)67394-1. PMID 16214597. S2CID 10716362.

[AC-1] [1]
Haberfeld H, ed. (2015). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag.

[PK-2] [2]
Neuvonen PJ, Backman JT, Niemi M (2008). "Pharmacokinetic comparison of the potential over-the-counter statins simvastatin, lovastatin, fluvastatin and pravastatin". Clinical Pharmacokinetics. 47 (7): 463–74. doi:10.2165/00003088-200847070-00003. PMID 18563955. S2CID 11716425.

[MSR-3] [3]
"Lescol, Lescol XR (fluvastatin) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 18 March 2014.

[Fis2006-4] [4]
Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 472. ISBN 9783527607495.

[WHO22nd-5] [5]
World Health Organization (2021). World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. hdl:10665/345533. WHO/MHP/HPS/EML/2021.02.

[Dinnendahl-6] [6]
Dinnendahl, V, Fricke, U, eds. (2012). Arzneistoff-Profile (in German). Vol. 2 (26 ed.). Eschborn, Germany: Govi Pharmazeutischer Verlag. ISBN 978-3-7741-9846-3.

[Adams_2018-7] [7]
Adams SP, Sekhon SS, Tsang M, Wright JM (March 2018). "Fluvastatin for lowering lipids". The Cochrane Database of Systematic Reviews. 2018 (3). John Wiley & Sons, Ltd: CD012282. doi:10.1002/14651858.cd012282.pub2. PMC 6494196. PMID 29508377.

[8] [8]
Lescol Monograph on Drugs.com.

[INN-9] [9]
"International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names (Rec. INN): List 30" (PDF). World Health Organization. 1990. Retrieved 29 November 2016.

[10] [10]
Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, et al. (October 2005). "Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins". Lancet. 366 (9493): 1267–78. doi:10.1016/s0140-6736(05)67394-1. PMID 16214597. S2CID 10716362.

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Mechanism of action

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Fluvastatin

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