Lescol XL (Page 4 of 7)

8.5 Geriatric Use

Fluvastatin exposures were not significantly different between the nonelderly and elderly populations (age ≥ 65 years) [see Clinical Pharmacology (12.3) ]. Since advanced age (> 65 years) is a predisposing factor for myopathy, LESCOL XL should be prescribed with caution in the elderly.

8.6 Hepatic Impairment

LESCOL XL are contraindicated in patients with active liver disease or unexplained, persistent elevations in serum transaminases [see Clinical Pharmacology (12.3) ].

8.7 Renal Impairment

Dose adjustments for mild to moderate renal impairment are not necessary. Fluvastatin has not been studied at doses greater than 40 mg in patients with severe renal impairment; therefore, caution should be exercised when treating such patients at higher doses [see Clinical Pharmacology (12.3) ].

10 OVERDOSAGE

To date, there has been limited experience with overdosage of fluvastatin. If an overdose occurs, it should be treated symptomatically with laboratory monitoring and supportive measures should be instituted as required. The dialyzability of fluvastatin sodium and of its metabolites in humans is not known at present [see Warnings and Precautions (5) ].

In the pediatric population, there have been reports of overdosage with fluvastatin sodium in children, including a 2 year-old and the other 3 years of age, either of whom may have possibly ingested fluvastatin sodium. The maximum amount of fluvastatin sodium that could have been ingested was 80 mg (4 x 20 mg capsules). Vomiting was induced by ipecac in both children and no capsules were noted in their emesis. Neither child experienced any adverse symptoms and both recovered from the incident without problems.

In the postmarketing experience there have been reports of accidental ingestion of fluvastatin capsules in infants up to 3 years of age. In one case, increased serum CPK values were noted. There have been reports of intentional overdose in adolescents with the development of hepatic enzyme elevations, convulsions and gastroenteritis/vomiting/diarrhea. One case of intentional overdose as suicide attempt in a 15 year-old female reported ingestion of 2,800 mg LESCOL XL with hepatic enzyme elevation.

11 DESCRIPTION

Fluvastatin sodium is a water-soluble cholesterol lowering agent which acts through the inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase.

Fluvastatin sodium is [R *,S *-(E)]-(±)-7-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H -indol-2-yl]-3,5-dihydroxy-6-heptenoic acid, monosodium salt. The empirical formula of fluvastatin sodium is C24 H25 FNO4 •Na, its molecular weight is 433.46 and its structural formula is:

Fluvastatin sodium structural formula

This molecular entity is the first entirely synthetic HMG-CoA reductase inhibitor, and is in part structurally distinct from the fungal derivatives of this therapeutic class.

Fluvastatin sodium is a white to pale yellow, hygroscopic powder soluble in water, ethanol and methanol. LESCOL XL is supplied as extended-release tablets containing fluvastatin sodium, equivalent to 80 mg of fluvastatin, for oral administration.

Active Ingredient: fluvastatin sodium

Inactive Ingredients in extended-release tablets: hydroxypropyl cellulose, hydroxypropyl methyl cellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol 8000, potassium bicarbonate, povidone, titanium dioxide, and yellow iron oxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Fluvastatin 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.

12.3 Pharmacokinetics

Absorption

Following oral administration of the capsule, fluvastatin reaches peak concentrations in less than 1 hour. The absolute bioavailability is 24% (range 9% to 50%) after administration of a 10 mg dose.

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 2-fold increase in Tmax as 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.

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% to 66%) compared to that of the fluvastatin 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 fluvastatin capsule.

Distribution

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.

Metabolism

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.

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.

Excretion

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.

Specific Populations

Renal Impairment

In patients with moderate to severe renal impairment (CLCr 10 to 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.

Hepatic Impairment

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.

Geriatric

Plasma levels of fluvastatin are not significantly different in patients age > 65 years compared to patients age 21 to 49 years.

Gender

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 to 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.

Pediatric

Pharmacokinetic data in the pediatric population are not available.

Drug-Drug Interactions

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.

The below listed drug interaction information is derived from studies using fluvastatin capsules. Similar studies have not been conducted using the LESCOL XL tablet.

Table 3. Effect of Coadministered Drugs on Fluvastatin Systemic Exposure
*Single dose unless otherwise noted.**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. †Considered clinically significant [see Dosage and Administration (2) and Drug Interactions (7)].
Coadministered Drug and Dosing Regimen Fluvastatin
Dose (mg) * Change in AUC ** Change in Cmax **
Cyclosporine – stable dose (twice daily) 20 mg QD for 14 weeks ↑ 90% ↑ 30%
Fluconazole 400 mg QD Day 1, 200 mg b.i.d. Day 2-4 40 mg QD ↑ 84% ↑ 44%
Cholestyramine 8 g QD 20 mg QD administered 4 hrs after a meal plus cholestyramine ↓ 51% ↓ 83%
Rifampicin 600 mg QD for 6 days 20 mg QD ↓ 53% ↓ 42%
Cimetidine 400 mg twice daily for 5 days, QD on Day 6 20 mg QD ↑ 30% ↑ 40%
Ranitidine 150 mg twice daily for 5 days, QD on Day 6 20 mg QD ↑ 10% ↑ 50%
Omeprazole 40 mg QD for 6 days 20 mg QD ↑ 20% ↑ 37%
Phenytoin 300 mg QD 40 mg twice daily for 5 days ↑ 40 % ↑ 27%
Propranolol 40 mg twice daily for 3.5 days 40 mg QD ↓ 5% No change
Digoxin 0.1 – 0.5 mg QD for 3 weeks 40 mg QD No change ↑ 11%
Diclofenac 25 mg QD 40 mg QD for 8 days ↑50 % ↑ 80%
Glyburide 5 – 20 mg QD for 22 days 40 mg twice daily for 14 days ↑ 51% ↑ 44%
Warfarin 30 mg QD 40 mg QD for 8 days ↑ 30% ↑ 67%
Clopidogrel 300 mg loading dose on Day 10, 75 mg QD on Days 11-19 80 mg XL QD for 19 days ↓ 2% ↑ 27%

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.

Table 4. Effect of Fluvastatin Coadministration on Systemic Exposure of Other Drugs
*Single dose unless otherwise noted.**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.†Considered clinically significant [see Dosage and Administration (2) and Drug Interactions (7)].
Fluvastatin Dosage Regimen Coadministered Drug
Name and Dose (mg) * Change in AUC ** Change in Cmax **
40 mg QD for 5 days Phenytoin 300 mg QD ↑ 20% ↑ 5%
40 mg twice daily for 21 days Glyburide 5 – 20 mg QD for 22 days ↑ 70% ↑ 50%
40 mg QD for 8 days Diclofenac 25 mg QD ↑ 25% ↑ 60%
40 mg QD for 8 days Warfarin 30 mg QD S-warfarin: ↑ 7% S-warfarin: ↑ 10%
R-warfarin: no change R-warfarin: ↑ 6%

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