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| __NOTOC__
| | #REDIRECT [[Fluvastatin]] |
| {{fluvastatin}}
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| {{CMG}}; {{AE}} {{SS}}
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| ==Clinical Pharmacology==
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| ===Mechanism of Action===
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| LESCOL is a competitive inhibitor of HMG-CoA reductase, the rate limiting enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) to mevalonate, a precursor of sterols, including cholesterol. The inhibition of cholesterol biosynthesis reduces the cholesterol in hepatic cells, which stimulates the synthesis of LDL receptors and thereby increases the uptake of LDL particles. The end result of these biochemical processes is a reduction of the plasma cholesterol concentration.
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| ===Pharmacokinetics===
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| ====Absorption:====
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| Following oral administration of the capsule, fluvastatin reaches peak concentrations in less than 1 hour. The absolute bioavailability is 24% (range 9%-50%) after administration of a 10 mg dose.
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| At steady state, administration of fluvastatin with the evening meal results in a 50% decrease in Cmax, an 11% decrease in AUC, and a more than two-fold increase in tmaxas compared to administration 4 hours after the evening meal. No significant differences in the lipid-lowering effects were observed between the two administrations. After single or multiple doses above 20 mg, fluvastatin exhibits saturable first-pass metabolism resulting in more than dose proportional plasma fluvastatin concentrations.
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| Fluvastatin administered as LESCOL XL 80 mg tablets reaches peak concentration in approximately 3 hours under fasting conditions, after a low-fat meal, or 2.5 hours after a low-fat meal. The mean relative bioavailability of the XL tablet is approximately 29% (range: 9%-66%) compared to that of the LESCOL immediate-release capsule administered under fasting conditions. Administration of a high-fat meal delayed the absorption (Tmax: 6h) and increased the bioavailability of the XL tablet by approximately 50%. However, the maximum concentration of LESCOL XL seen after a high-fat meal is less than the peak concentration following a single dose or twice daily dose of the 40 mg LESCOL capsule.
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| ====Distribution:====
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| Fluvastatin is 98% bound to plasma proteins. The mean volume of distribution (VDss) is estimated at 0.35 L/kg. At therapeutic concentrations, the protein binding of fluvastatin is not affected by [[warfarin]], [[salicylic acid]] and [[glyburide]].
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| ====Metabolism:====
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| Fluvastatin is metabolized in the liver, primarily via hydroxylation of the indole ring at the 5- and 6-positions. N-dealkylation and beta-oxidation of the side-chain also occurs. The hydroxy metabolites have some pharmacologic activity, but do not circulate in the blood. Fluvastatin has two enantiomers. Both enantiomers of fluvastatin are metabolized in a similar manner. | |
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| In vitro data indicate that fluvastatin metabolism involves multiple Cytochrome P450 (CYP) isozymes. CYP2C9 isoenzyme is primarily involved in the metabolism of fluvastatin (approximately 75%), while CYP2C8 and CYP3A4 isoenzymes are involved to a much less extent, i.e. approximately 5% and approximately 20%, respectively.
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| ====Excretion:====
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| Following oral administration, fluvastatin is primarily (about 90%) excreted in the feces as metabolites, with less than 2% present as unchanged drug. Approximately 5% of a radiolabeled oral dose were recovered in urine. The elimination half-life (t1/2) of fluvastatin is approximately 3 hours.
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| ====Specific Populations====
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| ====Renal Impairment=====
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| In patients with moderate to severe renal impairment (CLCr 10-40 mL/min), AUC and Cmax increased approximately 1.2-fold after administration of a single dose of 40 mg fluvastatin compared to healthy volunteers. In patients with end-stage renal disease on hemodialysis, the AUC increased by approximately 1.5-fold. LESCOL XL was not evaluated in patients with renal impairment. However, systemic exposures after administration of LESCOL XL are lower than after the 40 mg immediate release capsule.
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| =====Hepatic Impairment=====
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| In patients with hepatic impairment due to liver cirrhosis, fluvastatin AUC and Cmax increased approximately 2.5- fold compared to healthy subjects after administration of a single 40 mg dose. The enantiomer ratios of the two isomers of fluvastatin in hepatic impairment patients were comparable to those observed in healthy subjects.
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| =====Geriatric=====
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| Plasma levels of fluvastatin are not significantly different in patients age > 65 years compared to patients age 21 to 49 years.
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| ====Gender====
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| In a study evaluating the effect of age and gender on fluvastatin pharmacokinetics, there were no significant differences in fluvastatin exposures between males and females, except between younger females and younger males (both ages 21-49 years), where there was an approximate 30% increase in AUC in females. Adjusting for body weight decreases the magnitude of the differences seen. For LESCOL XL, the AUC increases 67% and 77% for women compared to men under fasted and high- fat meal fed conditions, respectively.
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| ====Pediatric====
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| Pharmacokinetic data in the pediatric population are not available.
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| ====Drug-Drug Interactions====
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| Data from drug-drug interactions studies involving coadministration of [[gemfibrozil]], [[niacin]], [[itraconazole]], [[erythromycin]],[[ tolbutamide]] or [[clopidogrel ]]indicate that the PK disposition of fluvastatin is not significantly altered when fluvastatin is coadministered with any of these drugs.
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| The below listed drug interaction information is derived from studies using LESCOL. Similar studies have not been conducted using the LESCOL XL tablet.
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| {|
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| |[[File:fluvastatin04.jpg|thumb|800px]]
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| <SMALL><SMALL><SMALL>*Single dose unless otherwise noted</SMALL></SMALL></SMALL>
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| <SMALL><SMALL><SMALL>**Mean ratio (with/without coadministered drug and no change = 1-fold) or % change (with/without coadministered drug and no change = 0%); symbols of ↑ and ↓ indicate the exposure increase and decrease, respectively.</SMALL></SMALL></SMALL>
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| † Considered clinically significant [see Dosage and Administration (2) and Drug Interactions (7)]
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| Data from drug-drug interaction studies involving fluvastatin and coadministration of either gemfibrozil, tolbutamide or losartan indicate that the PK disposition of either gemfibrozil, tolbutamide or losartan is not significantly altered when coadministered with fluvastatin.
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| {|
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| |[[File:fluvastatin05.jpg|thumb|800px]]
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| |}
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| <SMALL><SMALL><SMALL>*Single dose unless otherwise noted</SMALL></SMALL></SMALL>
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| <SMALL><SMALL><SMALL>**Mean ratio (with/without coadministered drug and no change = 1-fold) or % change (with/without coadministered drug and no change = 0%); symbols of ↑ and ↓ indicate the exposure increase and decrease, respectively.</SMALL></SMALL></SMALL>
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| † Considered clinically significant [see Dosage and Administration (2) and Drug Interactions (7)]
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| <ref name="dailymed.nlm.nih.gov">{{Cite web | last = | first = | title = LESCOL (FLUVASTATIN SODIUM) CAPSULE LESCOL XL (FLUVASTATIN SODIUM) TABLET, EXTENDED RELEASE [NOVARTIS PHARMACEUTICALS CORPORATION] | url = http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=8a1823e7-26fb-4858-bac7-9e152e5ea16a | publisher = | date = | accessdate = 12 February 2014 }}</ref>
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| ==References==
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| {{Reflist|2}}
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| {{Statins}}
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| [[Category:Statins]]
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| [[Category:Diols]]
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| [[Category:Indoles]]
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| [[Category:Carboxylic acids]]
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| [[Category:Organofluorides]]
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| [[Cardiovasular Druf]]
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| [[Drug]]
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