Fluvastatin

Fluvastatin
Clinical data
Trade names	Lescol, others
AHFS/Drugs.com	Monograph
MedlinePlus	a694010
Pregnancy; category	AU: D ; US: X (Contraindicated) ;
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%[1][2]
Protein binding	>98%[2]
Metabolism	Hepatic: CYP2C9 (75%), CYP3A4 (20%), CYP2C8 (5%)[2][3]
Elimination half-life	1–3 hours (capsule), 9 hours (XR formulations)[2][3]
Excretion	Faeces (95%), urine (5%)[2]
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)	DTXSID2020636 ;
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.

It was patented in 1982 and approved for medical use in 1994.[4]

Adverse effects

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.[5]

Interactions

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.[5]

Pharmacology

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%.[6]

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)[7] 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][5]

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

Names

Fluvastatin is the INN.[8] Brandnames include Lescol, Canef, Vastin.

Research

Data from the Cholesterol Treatment Trialists’ (CTT) publication[9] 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.[6]

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References

Haberfeld H, ed. (2015). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag.
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.
"Lescol, Lescol XR (fluvastatin) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 18 March 2014.
Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 472. ISBN 9783527607495.
Dinnendahl, V, Fricke, U, eds. (2012). Arzneistoff-Profile (in German). 2 (26 ed.). Eschborn, Germany: Govi Pharmazeutischer Verlag. ISBN 978-3-7741-9846-3.
Adams SP, Sekhon SS, Tsang M, Wright JM (March 2018). "Fluvastatin for lowering lipids". The Cochrane Database of Systematic Reviews. John Wiley & Sons, Ltd. 3: CD012282. doi:10.1002/14651858.cd012282.pub2. PMC 6494196. PMID 29508377.
Lescol Monograph on Drugs.com.
"International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names (Rec. INN): List 30" (PDF). World Health Organization. 1990. Retrieved 29 November 2016.
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.

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

[PK-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.

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

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

[Dinnendahl-5] Dinnendahl, V, Fricke, U, eds. (2012). Arzneistoff-Profile (in German). 2 (26 ed.). Eschborn, Germany: Govi Pharmazeutischer Verlag. ISBN 978-3-7741-9846-3.

[:0-6] Adams SP, Sekhon SS, Tsang M, Wright JM (March 2018). "Fluvastatin for lowering lipids". The Cochrane Database of Systematic Reviews. John Wiley & Sons, Ltd. 3: CD012282. doi:10.1002/14651858.cd012282.pub2. PMC 6494196. PMID 29508377.

[7] Lescol Monograph on Drugs.com.

[INN-8] "International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names (Rec. INN): List 30" (PDF). World Health Organization. 1990. Retrieved 29 November 2016.

[9] 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.