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Lescol

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Lescol

CLINICAL PHARMACOLOGY

Mechanism of Action

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.

Pharmacokinetics

Absorption

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.

At steady state, administration of fluvastatin with the evening meal results in a 50% decrease in Cmax, a 11% decrease in AUC, and a more than two-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%-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.

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 (t½) of fluvastatin is approximately 3 hours.

Specific Populations

Renal Impairment

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.

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 was 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.

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 LESCOL. Similar studies have not been conducted using the LESCOL XL tablet.

Table 3 : Effect of Co-administered Drugs on Fluvastatin Systemic Exposure

Co-administered drug and dosing regimen Fluvastatin    
  Dose (mg)* Change in AUC ** Change in Cmax **
Cyclosporine – stable dose (b.i.d,)† 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 b.i.d. for 5 days, QD on Day 6 20 mg QD ↑30% ↑ 40%
Ranitidine 150 mg b.i.d. 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 b.i.d. for 5 days ↑ 40 % ↑27%
Propranolol 40 mg b.i.d. 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 b.i.d for 14 days ↓ 51% ↑ 44%
*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 and DRUG INTERACTIONS]

Data from drug-drug interaction studies involving fluvastatin and coadministration of either gemfibrozil, tolbutamide or lorsartan indicate that the PK disposition of either gemfibrozil, tolbutamide or lorsartan is not significantly altered when coadministered with fluvastatin.

Table 4 : Effect of Fluvastatin Co-Administration on Systemic Exposure of Other Drugs

Fluvastatin dosage regimen Co-administered drug    
  Name and Dose (mg)* Change in AUC* Change in Cmax*
40 mg QD for 5 days Phenytoin 300 mg QDf ↑ 20% ↑5%
40 mg b.i.d. for 21 days Glyburide 5 - 20 mg QD for 22 days f ↑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%
R-warfarin: no change
S-warfarin: ↑ 10%
R-warfarin: ↑ 6%
*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 and DRUG INTERACTIONS]

Clinical Studies

Hypercholesterolemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia

In 12 placebo-controlled studies in patients with primary hypercholesterolemia and mixed dyslipidemia, LESCOL was administered to 1621 patients in daily dose regimens of 20 mg, 40 mg, and 80 mg (40 mg twice daily) for at least 6 weeks duration (Table 5). After 24 weeks of treatment, treatment with LESCOL resulted in significantly reduced plasma LDL-C, TC, TG, and Apo B compared to placebo and was associated with variable increases in HDL-C across the dose range.

LESCOL XL has been studied in five controlled studies of patients with primary hypercholesterolemia and mixed dyslipidemia. LESCOL XL was administered to over 900 patients in trials from 4 to 26 weeks in duration. In the three largest of these studies, LESCOL XL given as a single daily dose of 80 mg significantly reduced Total-C, LDL-C, TG and Apo B and resulted in increases in HDL-C (Table 5).

In patients with primary mixed dyslipidemia as defined by baseline plasma TG levels ≥ 200 mg/dL and < 400 mg/dL, treatment with LESCOL/LESCOL XL produced significant decreases in Total-C, LDL-C, TG and Apo B and variable increases in HDL-C (Table 5).

Table 5 : Median Percent Change in Lipid Parameters from Baseline to Week 24 Endpoint All Placebo-Controlled Studies (LESCOL) and Active Controlled Trials (LESCOL XL)

Dose Total Chol TG LDL Apo B HDL
N % Δ N N % Δ N % Δ N
All Patients
  LESCOL 20 mg1 747 -17 747 -12 747 -22 114 -19 747 3
  LESCOL 40 mg 1 748 -19 748 -14 748 -25 125 -18 748 4
  LESCOL 40 mg twice daily1 257 -27 257 -18 257 -36 232 -28 257 6
  LESCOL XL 80 mg2 750 -25 750 -19 748 -35 745 -27 750 7
Baseline TG ≥ 200 mg/dL
  LESCOL 20 mg1 148 -16 148 -17 148 -22 23 -19 148 6
  LESCOL 40 mg1 179 -18 179 -20 179 -24 47 -18 179 7
  LESCOL 40 mg twice daily1 76 -27 76 -23 76 -35 69 -28 76 9
  LESCOL XL 80 mg2 239 -25 239 -25 237 -33 235 -27 239 11
1Data for LESCOL from 12 placebo-controlled trials
2Data for LESCOL XL 80 mg tablet from three 24-week controlled trials

Heterozygous Familial Hypercholesterolemia in Pediatric Patients

LESCOL was studied in two open-label, uncontrolled, dose-titration studies. The first study enrolled 29 pre-pubertal boys, 9-12 years of age, who had an LDL-C level > 90th percentile for age and one parent with primary hypercholesterolemia and either a family history of premature ischemic heart disease or tendon xanthomas. The mean baseline LDL-C was 226 mg/dL (range: 137-354 mg/dL). All patients were started on LESCOL capsules 20 mg daily with dose adjustments every 6 weeks to 40 mg daily then 80 mg daily (40 mg b.i.d.) to achieve an LDL-C goal between 96.7 – 123.7 mg/dL. Endpoint analyses were performed at Year 2. LESCOL decreased plasma levels of Total-C and LDL-C by 21% and 27%, respectively. The mean achieved LDL-C was 161 mg/dL (range: 74-336 mg/dL).

The second study enrolled 85 male and female patients, 10 to 16 years of age, who had an LDL-C > 190 mg/dL or LDL-C > 160 mg/dL and one or more risk factors for coronary heart disease, or LDL-C > 160 mg/dL and a proven LDL-receptor defect. The mean baseline LDL-C was 225 mg/dL (range: 148-343 mg/dL). All patients were started on LESCOL capsules 20 mg daily with dose adjustments every 6 weeks to 40 mg daily then 80 mg daily (LESCOL 80 mg XL tablet) to achieve an LDL-C goal of < 130 mg/dL. Endpoint analyses were performed at Week 114. LESCOL decreased plasma levels of Total-C and LDL-C by 22% and 28%, respectively. The mean achieved LDL-C was 159 mg/dL (range: 90-295 mg/dL).

The majority of patients in both studies (83% in the first study and 89% in the second study) were titrated to the maximum daily dose of 80 mg. At study endpoint, 26% to 30% of patients in both studies achieved a targeted LDL-C goal of < 130 mg/dL. The long-term efficacy of LESCOL or LESCOL XL therapy in childhood to reduce morbidity and mortality in adulthood has not been established.

Secondary Prevention of Cardiovascular Disease

In the LESCOL Intervention Prevention Study (LIPS), the effect of LESCOL 40 mg administered twice daily on the risk of recurrent cardiac events (time to first occurrence of cardiac death, nonfatal myocardial infarction, or revascularization) was assessed in 1677 patients with CHD who had undergone a percutaneous coronary intervention (PCI) procedure (mean time from PCI to randomization=3 days). In this multicenter, randomized, double-blind, placebo-controlled study, patients were treated with dietary/lifestyle counseling and either LESCOL 40 mg (n=844) or placebo (n=833) given twice daily for a median of 3.9 years. The study population was 84% male, 98% Caucasian, with 37% > 65 years of age. Mean baseline lipid concentrations were: total cholesterol 201 mg/dL, LDL-C 132 mg/dL, triglycerides 70 mg/dL and HDL-C 39 mg/dL.

LESCOL significantly reduced the risk of recurrent cardiac events (Figure 1) by 22% (p=0.013, 181 patients in the LESCOL group vs. 222 patients in the placebo group). Revascularization procedures comprised the majority of the initial recurrent cardiac events (143 revascularization procedures in the LESCOL group and 171 in the placebo group). Consistent trends in risk reduction were observed in patients > 65 years of age.

Figure 1 : Primary Endpoint – Recurrent Cardiac Events (Cardiac Death, Nonfatal MI or Revascularization Procedure) (ITT Population)

Primary Endpoint – Recurrent Cardiac Events - Illustration

Outcome data for the LESCOL Intervention Prevention Study are shown in Figure 2. After exclusion of revascularization procedures (CABG and repeat PCI) occurring within the first 6 months of the initial procedure involving the originally instrumental site, treatment with LESCOL was associated with a 32% (p=0.002) reduction in risk of late revascularization procedures (CABG or PCI occurring at the original site > 6 months after the initial procedure, or at another site).

Figure 2 : LESCOL® Intervention Prevention Study -Primary and Secondary Endpoints

Intervention Prevention Study -Primary and Secondary Endpoints - Illustration

In the Lipoprotein and Coronary Atherosclerosis Study (LCAS), the effect of LESCOL therapy on coronary atherosclerosis was assessed by quantitative coronary angiography (QCA) in patients with CAD and mild to moderate hypercholesterolemia (baseline LDL-C range 115-190 mg/dL). In this randomized double-blind, placebo-controlled trial, 429 patients were treated with conventional measures (Step 1 AHA Diet) and either LESCOL 40 mg/day or placebo. In order to provide treatment to patients receiving placebo with LDL-C levels ≥ 160 mg/dL at baseline, adjunctive therapy with cholestyramine was added after Week 12 to all patients in the study with baseline LDL-C values of ≥ 160 mg/dL which were present in 25% of the study population. Quantitative coronary angiograms were evaluated at baseline and 2.5 years in 340 (79%) angiographic evaluable patients.

Compared to placebo, LESCOL significantly slowed the progression of coronary atherosclerosis as measured by within-patient per-lesion change in minimum lumen diameter (MLD), the primary endpoint (Figure 3 below), percent diameter stenosis (Figure 4), and the formation of new lesions (13% of all fluvastatin patients versus 22% of all placebo patients). A significant difference in favor of LESCOL was found between all fluvastatin and all placebo patients in the distribution among the three categories of definite progression, definite regression, and mixed or no change. Beneficial angiographic results (change in MLD) were independent of patients' gender and consistent across a range of baseline LDL-C levels.

Figure 3 : Change in Minimum Lumen Diameter (mm)

Change in Minimum Lumen Diameter - Illustration

Figure 4 : Change in % Diameter Stenosis

Change in % Diameter Stenosis - Illustration

Last reviewed on RxList: 3/12/2012
This monograph has been modified to include the generic and brand name in many instances.

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