fluvastatin 80 MG 24 HR Extended Release Oral Tablet

Generic Name: FLUVASTATIN SODIUM
Brand Name: LESCOL XL
  • Substance Name(s):
  • FLUVASTATIN SODIUM

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.

OVERDOSAGE

The approximate oral LD50 is greater than 2 g/kg in mice and greater than 0.7 g/kg in rats.

The maximum single oral dose of Lescol® (fluvastatin sodium) capsules received by healthy volunteers was 80 mg.

No clinically significant adverse experiences were seen at this dose.

The maximum dose administered with an extended-release formulation was 640 mg for two weeks.

This dose was not well tolerated and produced a variety of GI complaints and an increase in transaminase values (i.e., SGOT and SGPT).

There has been a single report of 2 children, one 2 years 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.

Should an accidental overdose occur, treat symptomatically and institute supportive measures as required.

The dialyzability of fluvastatin sodium and of its metabolites in humans is not known at present.

Information about the treatment of overdose can often be obtained from a certified Regional Poison Control Center.

Telephone numbers of certified Regional Poison Control Centers are listed in the Physicians’ Desk Reference®.*

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.

image of chemcial structure

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.

Figure 1.

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

image of figure 1 graph image of figure 2 chart image of figure 3 chart image of figure 4 chart

HOW SUPPLIED

Lescol ® XL (fluvastatin sodium) Extended-Release Tablets 80 mg Yellow, round, slightly biconvex film-coated tablet with beveled edges debossed with “Lescol XL” on one side and “80” on the other.

Bottles of 30 NDC 54868-4601-0 Store and Dispense Store at 25ºC (77ºF); excursions permitted to 15 -30ºC (59 -86ºF) [see USP Controlled Room Temperature].

Dispense in a tight container.

Protect from light.

INDICATIONS AND USAGE

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: LDL-C remains > 190 mg/dL or 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 (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 >130 (100-129: drug optional)†† 2+ Risk factors (10-year risk <20%) 130 10-year risk 10%-20%: >130 10-year risk 160 0-1 Risk factor††† 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 200 130 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.

DOSAGE AND ADMINISTRATION

The patient should be placed on a standard cholesterol-lowering diet before receiving Lescol® (fluvastatin sodium) or Lescol® XL (fluvastatin sodium) and should continue on this diet during treatment with Lescol or Lescol XL.

(See NCEP Treatment Guidelines for details on dietary therapy.) For patients requiring LDL-C reduction to a goal of ≥25%, the recommended starting dose is 40 mg as one capsule in the evening, 80 mg as one Lescol XL tablet administered as a single dose at any time of the day or 80 mg in divided doses of the 40 mg capsule given twice daily.

For patients requiring LDL-C reduction to a goal of <25% a starting dose of 20 mg may be used.

The recommended dosing range is 20-80 mg/day.

Lescol or Lescol XL may be taken without regard to meals, since there are no apparent differences in the lipid-lowering effects of fluvastatin sodium administered with the evening meal or 4 hours after the evening meal.

Do not break, crush or chew Lescol XL tablets or open Lescol capsules prior to administration.

Since the maximal reductions in LDL-C of a given dose are seen within 4 weeks, periodic lipid determinations should be performed and dosage adjustment made according to the patient’s response to therapy and established treatment guidelines.

The therapeutic effect of Lescol or Lescol XL is maintained with prolonged administration.

Heterozygous Familial Hypercholesterolemia in Pediatric Patients The recommended starting dose is one 20 mg Lescol capsule.

Dose adjustments, up to a maximum daily dose administered either as Lescol capsules 40 mg twice daily or one Lescol XL 80 mg tablet once daily, should be made at 6 week intervals.

Doses should be individualized according to the goal of therapy (see NCEP Pediatric Panel Guidelines and INDICATIONS AND USAGE.)1.

Concomitant Therapy Lipid-lowering effects on total cholesterol and LDL cholesterol are additive when immediate release Lescol is combined with a bile-acid binding resin or niacin.

When administering a bile-acid resin (e.g., cholestyramine) and fluvastatin sodium, Lescol should be administered at bedtime, at least 2 hours following the resin to avoid a significant interaction due to drug binding to resin.

(See also ADVERSE REACTIONS: Concomitant Therapy.) Dosage in Patients with Renal Insufficiency Since fluvastatin sodium is cleared hepatically with less than 6% of the administered dose excreted into the urine, 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.