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All about: Lescol

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Generic Name: fluvastatin sodium
Dosage Form: Extended release tablets, capsules

Lescol®                                                  

(fluvastatin sodium)                                        

Capsules

Lescol® XL

(fluvastatin sodium)

Extended-Release Tablets

Rx only

Prescribing Information

Lescol Description

Lescol® (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 C24H25FNO4•Na, its molecular weight is 433.46 and its structural formula is:

      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 is supplied as capsules containing fluvastatin sodium, equivalent to 20 mg or 40 mg of fluvastatin, for oral administration. Lescol® XL (fluvastatin sodium) 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 capsules: gelatin, magnesium stearate, microcrystalline cellulose, pregelatinized starch (corn), red iron oxide, sodium lauryl sulfate, talc, titanium dioxide, yellow iron oxide, and other ingredients.

Capsules may also include: benzyl alcohol, black iron oxide, butylparaben, carboxymethylcellulose sodium, edetate calcium disodium, methylparaben, propylparaben, silicon dioxide and sodium propionate.

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

Lescol - Clinical Pharmacology

A variety of clinical studies have demonstrated that elevated levels of total cholesterol (Total-C), low density lipoprotein cholesterol (LDL-C), triglycerides (TG) and apolipoprotein B (a membrane transport complex for LDL-C) promote human atherosclerosis. Similarly, decreased levels of HDL-cholesterol (HDL-C) and its transport complex, apolipoprotein A, are associated with the development of atherosclerosis. Epidemiologic investigations have established that cardiovascular morbidity and mortality vary directly with the level of Total-C and LDL-C and inversely with the level of HDL-C.

      Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including VLDL, IDL and remnants, can also promote atherosclerosis. Elevated plasma triglycerides are frequently found in a triad with low HDL-C levels and small LDL particles, as well as in association with non-lipid metabolic risk factors for coronary heart disease. As such, total plasma TG has not consistently been shown to be an independent risk factor for CHD. Furthermore, the independent effect of raising HDL or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined.

      In patients with hypercholesterolemia and mixed dyslipidemia, treatment with Lescol® (fluvastatin sodium) or Lescol® XL (fluvastatin sodium) reduced Total-C, LDL-C, apolipoprotein B, and triglycerides while producing an increase in HDL-C. Increases in HDL-C are greater in patients with low HDL-C (<35 mg/dL). Neither agent had a consistent effect on either Lp(a) or fibrinogen. The effect of Lescol or Lescol XL induced changes in lipoprotein levels, including reduction of serum cholesterol, on cardiovascular mortality has not been determined.

Mechanism of Action

Lescol is a competitive inhibitor of HMG-CoA reductase, which is responsible for the conversion of 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/Metabolism

Oral Absorption

Fluvastatin is absorbed rapidly and completely following oral administration of the capsule, with peak concentrations reached in less than 1 hour. Following administration of a 10 mg dose, the absolute bioavailability is 24% (range 9%-50%). Administration with food reduces the rate but not the extent of absorption. At steady state, administration of fluvastatin with the evening meal results in a two-fold decrease in Cmax and more than two-fold increase in tmax as compared to administration 4 hours after the evening meal. No significant differences in extent of absorption or 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 higher than expected plasma fluvastatin concentrations.

      Fluvastatin has two optical enantiomers, an active 3R,5S and an inactive 3S,5R form. In vivo studies showed that stereo-selective hepatic binding of the active form occurs during the first pass resulting in a difference in the peak levels of the two enantiomers, with the active to inactive peak concentration ratio being about 0.7. The approximate ratio of the active to inactive approaches unity after the peak is seen and thereafter the two enantiomers decline with the same half-life. After an intravenous administration, bypassing the first-pass, metabolism, the ratios of the enantiomers in plasma were similar throughout the concentration-time profiles.

      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%. Once Lescol XL begins to be absorbed, fluvastatin concentrations rise rapidly. The maximum concentration seen after a high-fat meal is much less than the peak concentration following a single dose or twice daily dose of the 40 mg Lescol capsule. Overall variability in the pharmacokinetics of Lescol XL is large (42%-64% CV for Cmax and AUC), and especially so after a high-fat meal (63%-89% for Cmax and AUC). Intrasubject variability in the pharmacokinetics of Lescol XL under fasting conditions (about 25% for Cmax and AUC) tends to be much smaller as compared to the overall variability. Multiple peaks in plasma fluvastatin concentrations have been observed after Lescol XL administration.

Distribution

Fluvastatin is 98% bound to plasma proteins. The mean volume of distribution (VDss) is estimated at 0.35 L/kg. The parent drug is targeted to the liver and no active metabolites are present systemically. 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. Both enantiomers of fluvastatin are metabolized in a similar manner.

      In vitro studies demonstrated that fluvastatin undergoes oxidative metabolism, predominantly via 2C9 isozyme systems (75%). Other isozymes that contribute to fluvastatin metabolism are 2C8 (~5%) and 3A4 (~20%). (See PRECAUTIONS: Drug Interactions Section).

Elimination

Fluvastatin is primarily (about 90%) eliminated in the feces as metabolites, with less than 2% present as unchanged drug. Urinary recovery is about 5%. After a radiolabeled dose of fluvastatin, the clearance was 0.8 L/h/kg. Following multiple oral doses of radiolabeled compound, there was no accumulation of fluvastatin; however, there was a 2.3- fold accumulation of total radioactivity.

      Steady-state plasma concentrations show no evidence of accumulation of fluvastatin following immediate release capsule administration of up to 80 mg daily, as evidenced by a beta-elimination half-life of less than 3 hours. However, under conditions of maximum rate of absorption (i.e., fasting) systemic exposure to fluvastatin is increased 33% to 53% compared to a single 20 mg or 40 mg dose of the immediate- release capsule. Following once daily administration of the 80 mg Lescol XL tablet for 7 days, systemic exposure to fluvastatin is increased (20%-30%) compared to a single dose of the 80 mg Lescol XL tablet. Terminal half-life of Lescol XL was about 9 hours as a result of the slow-release formulation.

      Single-dose and steady-state pharmacokinetic parameters in 33 subjects with hypercholesterolemia for the capsules and in 35 healthy subjects for the extended-release tablets are summarized below:

Table 1 Single-Dose and Steady-State Pharmacokinetic Parameters
Cmax 
(ng/mL)
mean±SD
(range)
AUC
(ng·h/mL)
mean±SD
(range)
tmax 
(hr)
mean±SD
(range)
CL/F
(L/hr)
mean±SD
(range)
t1/2
(hr)
mean±SD
(range)
Capsules
20 mg single
dose (n=17)
166±106 207±65 0.9±0.4 107±38.1 2.5±1.7
(48.9-517) (111-288) (0.5-2.0) (69.5-181) (0.5-6.6)
20 mg twice daily
(n=17)
200±86 275±111 1.2±0.9 87.8±45 2.8±1.7
(71.8-366) (91.6-467) (0.5-4.0) (42.8-218) (0.9-6.0)
40 mg single
dose (n=16)
273±189 456±259 1.2±0.7 108±44.7 2.7±1.3
(72.8-812) (207-1221) (0.75-3.0) (32.8-193) (0.8-5.9)
40 mg twice daily
(n=16)
432±236 697±275 1.2±0.6 64.2±21.1 2.7±1.3
(119-990) (359-1559) (0.5-2.5) (25.7-111) (0.7-5.0)
Extended-Release Tablets 80 mg single dose (n=24)
80 mg single dose,
fasting (n=24)
126±53 579±341 3.2± 2.6 - -
(37-242) (144-1760) (1-12)
80 mg single dose,
fed state high- fat
meal (n=-24)
183±163 861±632 6 - -
(21-733) (199-3132) (2-24)
Extended-Release Tablets 80 mg following 7 days dosing (steady-state) (n=11)
80 mg once daily,
fasting (n=11)
102±42 630±326 2.6±0.91 - -
(43.9-181) (247-1406) (1.5-4)

Special Populations

Renal Insufficiency:

No significant (<6%) renal excretion of fluvastatin occurs in humans.

Hepatic Insufficiency:

Fluvastatin is subject to saturable first-pass metabolism/sequestration by the liver and is eliminated primarily via the biliary route. Therefore, the potential exists for drug accumulation in patients with hepatic insufficiency. Caution should therefore be exercised when fluvastatin sodium is administered to patients with a history of liver disease or heavy alcohol ingestion (see WARNINGS).

      Fluvastatin AUC and Cmax values increased by about 2.5- fold in hepatic insufficiency patients. This result was attributed to the decreased presystemic metabolism due to hepatic dysfunction. The enantiomer ratios of the two isomers of fluvastatin in hepatic insufficiency patients were comparable to those observed in healthy subjects.

Age:

Plasma levels of fluvastatin are not affected by age.

Gender:

Women tend to have slightly higher (but statistically insignificant) fluvastatin concentrations than men for the immediate- release capsule. This is most likely due to body weight differences, as adjusting for body weight decreases the magnitude of the differences seen. For Lescol XL, there are 67% and 77% increases in systemic availability for women over men under fasted and high- fat meal conditions.

Pediatric:

Pharmacokinetic data in the pediatric population are not available. 

Clinical Studies

Hypercholesterolemia (heterozygous familial and nonfamilial) and Mixed Dyslipidemia

In 12 placebo-controlled studies in patients with Type IIa or IIb hyperlipoproteinemia, Lescol® (fluvastatin sodium) alone 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. After 24 weeks of treatment, daily doses of 20 mg, 40 mg, and 80 mg (40 mg twice daily) resulted in median LDL-C reductions of 22% (n=747), 25% (n=748) and 36% (n=257), respectively. Lescol treatment produced dose-related reductions in Apo B and in triglycerides and increases in HDL-C. The median (25th, 75th percentile) percent changes from baseline in HDL-C after 12 weeks of treatment with Lescol at daily doses of 20 mg, 40 mg and 80 mg (40 mg twice daily) were +2 (-4,+10), +5 (-2,+12), and +4 (-3,+12), respectively. In a subgroup of patients with primary mixed dyslipidemia, defined as baseline TG levels ≥200 mg/dL, treatment with Lescol also produced significant decreases in Total-C, LDL-C, TG and Apo B and variable increases in HDL-C. The median (25th, 75th percentile) percent changes from baseline in HDL-C after 12 weeks of treatment with Lescol at daily doses of 20 mg, 40 mg and 80 mg (40 mg twice daily) in this population were +4 (-2,+12), +8 (+1,+15), and +4 (-3,+13), respectively.

      In a long-term open-label free titration study, after 96 weeks LDL-C decreases of 25% (20 mg, n=68), 31% (40 mg, n=298) and 34% (80 mg, n=209) were seen. No consistent effect on Lp(a) was observed.

      Lescol® XL (fluvastatin sodium) Extended-Release Tablets have been studied in five controlled studies of patients with Type IIa or IIb hyperlipoproteinemia. 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. Therapeutic response is well established within two weeks, and a maximum response is achieved within four weeks. After four weeks of therapy, the median decrease in LDL-C was 38% and at Week 24 endpoint the median LDL-C decrease was 35%. Significant increases in HDL-C were also observed. The median (25th and 75th percentile) percent changes from baseline in HDL-C for Lescol XL were +7(+0,+15) after 24 weeks of treatment.

Table 2 Median Percent Change in Lipid Parameters from Baseline to Week 24 Endpoint All Placebo-Controlled Studies (Lescol®) and Active Controlled Trials (Lescol® XL)
Total Chol. TG LDL Apo B HDL
Dose N % ∆ N % ∆ N % ∆ N % ∆ N % ∆
All Patients
      Lescol 20 mg1 747 -17 747 -12 747 -22 114 -19 747 +3
      Lescol 40 mg1 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

1 Data for Lescol from 12 placebo- controlled trials

2 Data for Lescol XL 80 mg tablet from three 24- week controlled trials

      In patients with primary mixed dyslipidemia (Fredrickson Type IIb) as defined by baseline plasma triglycerides levels ≥200 mg/dL, Lescol XL 80 mg produced a median reduction in triglycerides of 25%. In these patients, Lescol XL 80 mg produced median (25th and 75th percentile) percent change from baseline in HDL-C of +11(+3,+20). Significant decreases in Total-C, LDL-C, and Apo B were also achieved. In these studies, patients with triglycerides >400 mg/dL were excluded.

Heterozygous Familial Hypercholesterolemia in Pediatric Patients

Fluvastatin sodium was studied in two open-label, uncontrolled, dose-titration studies which enrolled pediatric patients with heterozygous familial hypercholesterolemia. 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 bid) to achieve an LDL-C goal of 96.7 to 123.7 mg/dL. Endpoint analyses were performed at Year 2. 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.

      In the first study, Lescol 20 mg to 80 mg daily doses 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). In the second study, Lescol 20 mg to 80 mg daily doses 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.

Reduction in the Risk of Recurrent Cardiac Events

In the Lescol Intervention Prevention Study, 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 coronary heart disease 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. At baseline patients had total cholesterol between 100 and 367 mg/dL (mean 201 mg/dL), LDL-C between 42 and 243 mg/dL (mean 132 mg/dL), triglycerides between 15 and 270 mg/dL (mean 70 mg/dL) and HDL-C between 8 and 174 mg/dL (mean 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.

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).

Atherosclerosis

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 coronary artery disease 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. These baseline levels 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.

      Lescol significantly slowed the progression of coronary atherosclerosis. Compared to placebo, Lescol significantly slowed the progression of lesions as measured by within-patient per-lesion change in minimum lumen diameter (MLD), the primary endpoint (see 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). Additionally, 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.

Indications and Usage for Lescol

Therapy with lipid-altering agents should be used in addition to a diet restricted in saturated fat and cholesterol (see National Cholesterol Education Program [NCEP] Treatment Guidelines, below).

Hypercholesterolemia (heterozygous familial and nonfamilial) and Mixed Dyslipidemia

Lescol® (fluvastatin sodium) and Lescol® XL (fluvastatin sodium) are indicated to reduce elevated total cholesterol (Total-C), LDL-C, TG and Apo B levels, and to increase HDL-C in patients with primary hypercholesterolemia and mixed dyslipidemia (Fredrickson Type IIa and IIb) whose response to dietary restriction of saturated fat and cholesterol and other nonpharmacological measures has not been adequate.

Heterozygous Familial Hypercholesterolemia in Pediatric Patients

Lescol and Lescol XL are indicated as an adjunct to diet to reduce Total-C, LDL-C, and Apo B levels in adolescent boys and girls who are at least one year post-menarche, 10-16 years of age, with heterozygous familial hypercholesterolemia whose response to dietary restriction has not been adequate and the following findings are present:

  1. LDL-C remains ≥ 190 mg/dL or
  2. LDL-C remains ≥ 160 mg/dL and:
    • there is a positive family history of premature cardiovascular disease or
    • two or more other cardiovascular disease risk factors are present.

      Therapy with lipid-altering agents should be considered only after secondary causes for hyperlipidemia such as poorly controlled diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinemias, obstructive liver disease, other medication, or alcoholism, have been excluded. Prior to initiation of fluvastatin sodium, a lipid profile should be performed to measure Total-C, HDL-C and TG. For patients with TG <400 mg/dL (<4.5 mmol/L), LDL-C can be estimated using the following equation:

LDL-C = Total-C - HDL-C - 1/5 TG

      For TG levels >400 mg/dL (>4.5 mmol/L), this equation is less accurate and LDL-C concentrations should be determined by ultracentrifugation. In many hypertriglyceridemic patients LDL-C may be low or normal despite elevated Total-C. In such cases, Lescol is not indicated.

      Lipid determinations should be performed at intervals of no less than 4 weeks and dosage adjusted according to the patient’s response to therapy.

      The National Cholesterol Education Program (NCEP) Treatment Guidelines are summarized below:

Table 3 NCEP Treatment Guidelines: LDL-C Goals and Cutpoints for Therapeutic Lifestyle Changes and Drug Therapy in Different Risk Categories
Risk Category LDL Goal
(mg/dL)
LDL Level at Which to
Initiate Therapeutic
Lifestyle Changes
(mg/dL)
LDL Level at Which to Consider
Drug
Therapy
(mg/dL)
CHD† or CHD risk
equivalents
(10-year risk >20%)
<100 ≥100 ≥130

(100-129: drug optional)††
2+ Risk factors
(10-year risk ≤20%)
<130 ≥130 10-year risk 10%-20%: ≥130 
10-year risk <10%: ≥160
0-1 Risk factor††† <160 ≥160 ≥190
(160-189: LDL-lowering
drug optional)

CHD, coronary heart disease

††Some authorities recommend use of LDL-lowering drugs in this category if an LDL-C level of <100mg/dL cannot be achieved by therapeutic lifestyle changes. Others prefer use of drugs that primarily modify triglycerides and HDL-C, e.g., nicotinic acid or fibrate. Clinical judgement also may call for deferring drug therapy in this subcategory.

†††Almost all people with 0-1 risk factor have 10-year risk <10%; thus, 10-year risk assessment in people with 0-1 risk factor is not necessary.

      After the LDL-C goal has been achieved, if the TG is still ≥200 mg/dL, non-HDL-C (Total-C minus HDL-C) becomes a secondary target of therapy. Non-HDL-C goals are set 30 mg/dL higher than LDL-C goals for each risk category.

      At the time of hospitalization for an acute coronary event, consideration can be given to initiating drug therapy at discharge if the LDL-C level is ≥130 mg/dL (NCEP-ATP II).

      Since the goal of treatment is to lower LDL-C, the NCEP recommends that the LDL-C levels be used to initiate and assess treatment response. Only if LDL-C levels are not available, should the Total-C be used to monitor therapy.

Table 4 Classification of Hyperlipoproteinemias
      Lipid Elevations
Type Lipoproteins
Elevated
Major Minor
I (rare) Chylomicrons TG ↑→C
IIa LDL C
IIb LDL, VLDL C TG
III (rare) IDL C/TG
IV VLDL TG ↑→C
V (rare) Chylomicrons, VLDL TG ↑→C

C = cholesterol, TG = triglycerides, LDL = low density lipoprotein, VLDL = very low density lipoprotein,

IDL = intermediate density lipoprotein

      Neither Lescol nor Lescol XL have been studied in conditions where the major abnormality is elevation of chylomicrons, VLDL, or IDL (i.e., hyperlipoproteinemia Types I, III, IV, or V).

      The NCEP classification of cholesterol levels in pediatric patients with a familial history of hypercholesterolemia or premature cardiovascular disease is summarized below:

Category Total-C (mg/dL) LDL-C (mg/dL)
Acceptable
Borderline
High
<170
170-199
≥200
<110
110-129
≥130

      Children treated with fluvastatin in adolescence should be re-evaluated in adulthood and appropriate changes made to their cholesterol-lowering regimen to achieve adult treatment goals.

Secondary Prevention of Coronary Events

In patients with coronary heart disease, Lescol and Lescol XL are indicated to reduce the risk of undergoing coronary revascularization procedures.

Atherosclerosis

Lescol and Lescol XL are also indicated to slow the progression of coronary atherosclerosis in patients with coronary heart disease as part of a treatment strategy to lower total and LDL cholesterol to target levels.

Contraindications

Hypersensitivity to any component of this medication. Lescol® (fluvastatin sodium) and Lescol® XL (fluvastatin sodium) are contraindicated in patients with active liver disease or unexplained, persistent elevations in serum transaminases (see WARNINGS).

Pregnancy and Lactation

Atherosclerosis is a chronic process and discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia. Cholesterol and other products of cholesterol biosynthesis are essential components for fetal development (including synthesis of steroids and cell membranes). Since HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, they may cause fetal harm when administered to pregnant women. Therefore, HMG-CoA reductase inhibitors are contraindicated during pregnancy and in nursing mothers. Fluvastatin sodium should be administered to women of childbearing age only when such patients are highly unlikely to conceive and have been informed of the potential hazards. If the patient becomes pregnant while taking this class of drug, therapy should be discontinued and the patient apprised of the potential hazard to the fetus.

Warnings

Liver Enzymes

Biochemical abnormalities of liver function have been associated with HMG-CoA reductase inhibitors and other lipid-lowering agents. Approximately 1.1% of patients treated with Lescol® (fluvastatin sodium) capsules in worldwide trials developed dose-related, persistent elevations of transaminase levels to more than 3 times the upper limit of normal. Fourteen of these patients (0.6%) were discontinued from therapy. In all clinical trials, a total of 33/2969 patients (1.1%) had persistent transaminase elevations with an average fluvastatin exposure of approximately 71.2 weeks; 19 of these patients (0.6%) were discontinued. The majority of patients with these abnormal biochemical findings were asymptomatic.

      In a pooled analysis of all placebo-controlled studies in which Lescol capsules were used, persistent transaminase elevations (>3 times the upper limit of normal [ULN] on two consecutive weekly measurements) occurred in 0.2%, 1.5%, and 2.7% of patients treated with 20, 40, and 80 mg (titrated to 40 mg twice daily) Lescol capsules, respectively. Ninety-one percent of the cases of persistent liver function test abnormalities (20 of 22 patients) occurred within 12 weeks of therapy and in all patients with persistent liver function test abnormalities there was an abnormal liver function test present at baseline or by Week 8.

      In the pooled analysis of the 24-week controlled trials, persistent transaminase elevation occurred in 1.9%, 1.8% and 4.9% of patients treated with Lescol® XL (fluvastatin sodium) 80 mg, Lescol 40 mg and Lescol 40 mg twice daily, respectively. In 13 of 16 patients treated with Lescol XL the abnormality occurred within 12 weeks of initiation of treatment with Lescol XL 80 mg.

      It is recommended that liver function tests be performed before the initiation of therapy and at 12 weeks following initiation of treatment or elevation in dose. Patients who develop transaminase elevations or signs and symptoms of liver disease should be monitored to confirm the finding and should be followed thereafter with frequent liver function tests until the levels return to normal. Should an increase in AST or ALT of three times the upper limit of normal or greater persist (found on two consecutive occasions) withdrawal of fluvastatin sodium therapy is recommended.

      Active liver disease or unexplained transaminase elevations are contraindications to the use of Lescol and Lescol XL (see CONTRAINDICATIONS). Caution should be exercised when fluvastatin sodium is administered to patients with a history of liver disease or heavy alcohol ingestion (see CLINICAL PHARMACOLOGY: Pharmacokinetics/Metabolism). Such patients should be closely monitored.

Skeletal Muscle

Rhabdomyolysis with renal dysfunction secondary to myoglobinuria has been reported with fluvastatin and with other drugs in this class. Myopathy, defined as muscle aching or muscle weakness in conjunction with increases in creatine phosphokinase (CPK) values to greater than 10 times the upper limit of normal, has been reported.

     Myopathy should be considered in any patients with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of CPK. Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. Fluvastatin sodium therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. Fluvastatin sodium therapy should also be temporarily withheld in any patient experiencing an acute or serious condition predisposing to the development of renal failure secondary to rhabdomyolysis, e.g., sepsis; hypotension; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy.

      The risk of myopathy and/or rhabdomyolysis during treatment with HMG-CoA reductase inhibitors has been reported to be increased if therapy with either cyclosporine, gemfibrozil, erythromycin, or niacin is administered concurrently. Isolated cases of myopathy have been reported during post-marketing experience with concomitant administration of fluvastatin and colchicine. No information is available on the pharmacokinetic interaction between fluvastatin and colchicine. However, myotoxicity, including muscle pain and weakness and rhabdomyloysis, have been reported anecdotally with concomitant administration of colchicine.

      Myopathy was not observed in a clinical trial in 74 patients involving patients who were treated with fluvastatin sodium together with niacin.

      Uncomplicated myalgia has been observed infrequently in patients treated with Lescol at rates indistinguishable from placebo.

      The use of fibrates alone may occasionally be associated with myopathy. The combined use of HMG-CoA reductase inhibitors and fibrates should generally be avoided.

Precautions

General

Before instituting therapy with Lescol® (fluvastatin sodium) or Lescol® XL (fluvastatin sodium), an attempt should be made to control hypercholesterolemia with appropriate diet, exercise, and weight reduction in obese patients, and to treat other underlying medical problems (see INDICATIONS AND USAGE).

      The HMG-CoA reductase inhibitors may cause elevation of creatine phosphokinase and transaminase levels (see WARNINGS and ADVERSE REACTIONS). This should be considered in the differential diagnosis of chest pain in a patient on therapy with fluvastatin sodium.

Homozygous Familial Hypercholesterolemia

HMG-CoA reductase inhibitors are reported to be less effective in patients with rare homozygous familial hypercholesterolemia, possibly because these patients have few functional LDL receptors.

Information for Patients

Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever.

      Women should be informed that if they become pregnant while receiving Lescol or Lescol XL the drug should be discontinued immediately to avoid possible harmful effects on a developing fetus from a relative deficit of cholesterol and biological products derived from cholesterol. In addition, Lescol or Lescol XL should not be taken during nursing. (See CONTRAINDICATIONS.)

Drug Interactions

The below listed drug interaction information is derived from studies using immediate- release fluvastatin. Similar studies have not been conducted using the Lescol XL tablet.

Immunosuppressive Drugs, Gemfibrozil, Niacin (Nicotinic Acid), Erythromycin

(See WARNINGS: Skeletal Muscle).

      In vitro data indicate that fluvastatin metabolism involves multiple Cytochrome P450 (CYP) isozymes. CYP2C9 isoenzyme is primarily involved in the metabolism of fluvastatin (~75%), while CYP2C8 and CYP3A4 isoenzymes are involved to a much less extent, i.e., ~5% and ~20%, respectively. If one pathway is inhibited in the elimination process of fluvastatin other pathways may compensate.

      In vivo drug interaction studies with CYP3A4 inhibitors/substrates such as cyclosporine, erythromycin, and itraconazole result in minimal changes in the pharmacokinetics of fluvastatin, confirming less involvement of CYP3A4 isozyme. Concomitant administration of fluvastatin and phenytoin increased the levels of phenytoin and fluvastatin, suggesting predominant involvement of CYP2C9 in fluvastatin metabolism.

Niacin/Propranolol:

Concomitant administration of immediate- release fluvastatin sodium with niacin or propranolol has no effect on the bioavailability of fluvastatin sodium.

Cholestyramine:

Administration of immediate- release fluvastatin sodium concomitantly with, or up to 4 hours after cholestyramine, results in fluvastatin decreases of more than 50% for AUC and 50%-80% for Cmax. However, administration of immediate- rel

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