Lescol XL

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: Rhabdomyolysis with myoglobinuria and acute renal failure and myopathy (including myositis) [see Warnings and Precautions (5.1) ]. Liver Enzyme Abnormalities [see Warnings and Precautions (5.3) ]. Most frequent adverse reactions (rate ≥ 2% and > placebo) are headache, dyspepsia, myalgia, abdominal pain, and nausea ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Studies Experience in Adult Patients Because clinical studies on fluvastatin capsules/LESCOL XL are conducted in varying study populations and study designs, the frequency of adverse reactions observed in the clinical studies of fluvastatin capsules/LESCOL XL cannot be directly compared with that in the clinical studies of other statins and may not reflect the frequency of adverse reactions observed in clinical practice. In the fluvastatin capsule placebo-controlled clinical trials database of 2326 patients treated with fluvastatin 1 (age range 18 to 75 years, 44% women, 94% Caucasians, 4% Blacks, 2% other ethnicities) with a median treatment duration of 24 weeks, 3.4% of patients on fluvastatin capsules and 2.3% patients on placebo discontinued due to adverse reactions regardless of causality. The most common adverse reactions that led to treatment discontinuation and occurred at an incidence greater than placebo were: transaminase increased (0.8%), upper abdominal pain (0.3%), dyspepsia (0.3%), fatigue (0.2%), and diarrhea (0.2%). In the LESCOL XL database of controlled clinical trials of 912 patients treated with LESCOL XL (age range 21 to 87 years, 52% women, 91% Caucasians, 4% Blacks, 5% other ethnicities) with a median treatment duration of 24 weeks, 3.9% of patients on LESCOL XL discontinued due to adverse reactions regardless of causality. The most common adverse reactions that led to treatment discontinuation were abdominal pain (0.7%), diarrhea (0.5%), nausea (0.4%), dyspepsia (0.4%), and chest pain (0.3%). Clinically relevant adverse experiences occurring in the fluvastatin capsules and LESCOL XL controlled studies with a frequency ≥ 2%, regardless of causality, included the following: Table 1. Clinical Adverse Events Reported in ≥ 2% in Patients Treated With Fluvastatin Capsules/LESCOL XL and at an Incidence Greater Than Placebo in Placebo-Controlled Trials Regardless of Causality (% of patients) Pooled Dosages Fluvastatin capsules 1 N = 2326 (%) Placebo 1 N = 960 (%) LESCOL XL 2 N = 912 (%) Musculoskeletal Myalgia 5.0 4.5 3.8 Arthritis 2.1 2.0 1.3 Arthropathy NA NA 3.2 Respiratory Sinusitis 2.6 1.9 3.5 Bronchitis 1.8 1.0 2.6 Gastrointestinal Dyspepsia 7.9 3.2 3.5 Diarrhea 4.9 4.2 3.3 Abdominal pain 4.9 3.8 3.7 Nausea 3.2 2.0 2.5 Flatulence 2.6 2.5 1.4 Tooth disorder 2.1 1.7 1.4 Psychiatric Insomnia 2.7 1.4 0.8 Genitourinary Urinary tract infection 1.6 1.1 2.7 Miscellaneous Headache 8.9 7.8 4.7 Influenza-like symptoms 5.1 5.7 7.1 Accidental trauma 5.1 4.8 4.2 Fatigue 2.7 2.3 1.6 Allergy 2.3 2.2 1.0 1 Controlled trials with fluvastatin capsules (20 and 40 mg daily and 40 mg twice daily) compared to placebo. 2 Controlled trials with LESCOL XL 80 mg Tablets as compared to fluvastatin capsules. LESCOL Intervention Prevention Study In the LESCOL Intervention Prevention Study (LIPS), the effect of LESCOL (fluvastatin capsules) 40 mg, administered twice daily on the risk of recurrent cardiac events was assessed in 1677 patients with CHD who had undergone a percutaneous coronary intervention (PCI) procedure. This was a multicenter, randomized, double-blind, placebo-controlled study, patients were treated with dietary/lifestyle counseling and either fluvastatin capsules 40 mg (n = 844) or placebo (n = 833) given twice daily for a median of 3.9 years [see Clinical Studies (14.3) ]. Table 2. Clinical Adverse Events Reported in ≥ 2% in Patients Treated With Fluvastatin Capsules/LESCOL XL and at an Incidence Greater Than Placebo in the LIPS Trial Regardless of Causality (% of patients) Fluvastatin Capsules 40 mg twice daily N = 822 (%) Placebo N = 818 (%) Cardiac disorders Atrial fibrillation 2.4 2.0 Gastrointestinal disorders Abdominal pain upper 6.3 4.5 Constipation 3.3 2.1 Dyspepsia 4.5 4.0 Gastric disorder 2.7 2.1 Nausea 2.7 2.3 General disorders Fatigue 4.7 3.8 Edema peripheral 4.4 2.9 Infections and infestations Bronchitis 2.3 2.0 Nasopharyngitis 2.8 2.1 Musculoskeletal and connective tissue disorders Arthralgia 2.1 1.8 Myalgia 2.2 1.6 Pain in extremity 4.1 2.7 Nervous system disorders Dizziness 3.9 3.5 Syncope 2.4 2.2 Respiratory disorders Dyspnea exertional 2.8 2.4 Vascular disorders Hypertension 5.8 4.2 Intermittent claudication 2.3 2.1 6.2 Clinical Studies Experience in Pediatric Patients In patients aged < 18 years, efficacy and safety have not been studied for treatment periods longer than two years. In two open-label uncontrolled studies, 66 boys and 48 girls with heterozygous familial hypercholesterolemia (9 to 16 years of age, 80% Caucasian, 19% Other [mixed ethnicity], 1% Asians) were treated with fluvastatin sodium administered as fluvastatin capsules 20 mg to 40 mg twice daily, or LESCOL XL 80 mg extended-release tablet [see Clinical Studies (14.2) and Use in Specific Populations (8.4) ]. 6.3 Postmarketing Experience Because adverse reactions from spontaneous reports are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following effects have been reported with drugs in this class. Not all the effects listed below have necessarily been associated with fluvastatin sodium therapy. Musculoskeletal: muscle cramps, myalgia, myopathy, rhabdomyolysis, arthralgias, muscle spasms, muscle weakness, myositis. There have been rare reports of immune-mediated necrotizing myopathy associated with statin use [see Warnings and Precautions (5.2) ]. Neurological: dysfunction of certain cranial nerves (including alteration of taste, impairment of extra-ocular movement, facial paresis), tremor, dizziness, vertigo, paresthesia, hypoesthesia, dysesthesia, peripheral neuropathy, peripheral nerve palsy. There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks). Psychiatric: anxiety, insomnia, depression, psychic disturbances Respiratory: interstitial lung disease Hypersensitivity Reactions: An apparent hypersensitivity syndrome has been reported rarely which has included one or more of the following features: anaphylaxis, angioedema, lupus erythematosus-like syndrome, polymyalgia rheumatica, vasculitis, purpura, thrombocytopenia, leukopenia, hemolytic anemia, positive ANA, ESR (erythrocyte sedimentation rate) increase, eosinophilia, arthritis, arthralgia, urticaria, asthenia, photosensitivity reaction, fever, chills, flushing, malaise, dyspnea, toxic epidermal necrolysis, erythema multiforme, including Stevens-Johnson syndrome. Gastrointestinal: pancreatitis, hepatitis, including chronic active hepatitis, cholestatic jaundice, fatty change in liver, cirrhosis, fulminant hepatic necrosis, hepatoma, anorexia, vomiting, fatal, and non-fatal hepatic failure Skin: rash, dermatitis, including bullous dermatitis, eczema, alopecia, pruritus, a variety of skin changes (e.g., nodules, discoloration, dryness of skin/mucous membranes, changes to hair/nails) Reproductive: gynecomastia, loss of libido, erectile dysfunction Eye: progression of cataracts (lens opacities), ophthalmoplegia Laboratory abnormalities: elevated transaminases, alkaline phosphatase, gamma-glutamyl transpeptidase and bilirubin; thyroid function abnormalities

4 CONTRAINDICATIONS Hypersensitivity to any component of this medication ( 4.1 ) Active liver disease or unexplained, persistent elevations in serum transaminases ( 4.2 , 5.3 ) Women who are pregnant or may become pregnant ( 4.3 , 8.1 ) Nursing mothers ( 4.4 , 8.3 ) 4.1 Hypersensitivity to Any Component of This Medication LESCOL XL is contraindicated in patients with hypersensitivity to any component of this medication. 4.2 Active Liver Disease LESCOL XL is contraindicated in patients with active liver disease or unexplained, persistent elevations in serum transaminases [ see Warnings and Precautions (5.3) ]. 4.3 Pregnancy LESCOL XL is contraindicated in women who are pregnant or may become pregnant. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. LESCOL XL may cause fetal harm when administered to pregnant women. Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia. LESCOL XL 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 drug, LESCOL XL should be discontinued and the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1) ]. 4.4 Nursing Mothers Fluvastatin is secreted into the breast milk of animals and because HMG-CoA reductase inhibitors have the potential to cause serious adverse reactions in nursing infants, women who require treatment with LESCOL XL should be advised not to breastfeed their infants [see Use in Specific Populations (8.3) ].

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)-1 H -indol-2-yl]-3,5-dihydroxy-6-heptenoic acid, monosodium salt. The empirical formula of fluvastatin sodium is C 24 H 25 FNO 4 •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 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. Fluvastatin sodium structural formula

2 DOSAGE AND ADMINISTRATION Dose range: 20 mg to 80 mg/day ( 2.1 ) LESCOL XL can be taken with or without food and may be taken at any time of the day ( 2.1 ) Do not break, crush or chew LESCOL XL tablets prior to administration ( 2.1 ) Adults: the recommended starting dose is 80 mg (administered as one 80 mg LESCOL XL once daily) ( 2.2 ) Children with Heterozygous Familial Hypercholesterolemia (ages 10 to 16, inclusive): the recommended starting dose is fluvastatin capsule 20 mg once daily ( 2.3 ) 2.1 General Dosing Information Dose range: 20 mg to 80 mg/day. LESCOL XL can be administered orally as a single dose, with or without food. Do not break, crush or chew LESCOL XL tablets prior to administration. Since the maximal effect of a given dose is seen within 4 weeks, periodic lipid determinations should be performed at this time and dosage adjusted according to the patient’s response to therapy and established treatment guidelines. For patients requiring LDL-C reduction to a goal of ≥ 25%, the recommended starting dose is 80 mg as one LESCOL XL tablet administered as a single dose at any time of the day. For patients requiring LDL-C reduction to a goal of < 25%, a starting dose of 20 mg may be used. 2.2 Adult Patients With Hypercholesterolemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia The recommended starting dose for LESCOL XL is one 80 mg tablet administered as a single dose at any time of the day. 2.3 Pediatric Patients (10 to 16 years of age) With Heterozygous Familial Hypercholesterolemia The recommended starting dose is one 20 mg fluvastatin capsule. Dose adjustments, up to a maximum daily dose administered 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 Clinical Studies (14)] 1 . 1 National Cholesterol Education Program (NCEP): Highlights of the Report of the Expert Panel on Blood Cholesterol Levels in Children and Adolescents. Pediatrics. 89(3):495-501. 1992. 2.4 Use With Cyclosporine Do not exceed a dose of 20 mg twice-daily fluvastatin capsules in patients taking cyclosporine [see Drug Interactions (7.1)] . 2.5 Use With Fluconazole Do not exceed a dose of 20 mg twice-daily fluvastatin capsules in patients taking fluconazole [see Drug Interactions (7.2)] .

1 INDICATIONS AND USAGE Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Drug therapy is indicated as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other non-pharmacologic measures alone has been inadequate. LESCOL XL is an HMG-CoA reductase inhibitor (statin) indicated as an adjunctive therapy to diet to: Reduce elevated TC, LDL-C, Apo B, and TG, and to increase HDL-C in adult patients with primary hypercholesterolemia and mixed dyslipidemia ( 1.1 ) Reduce elevated TC, LDL-C, and Apo B levels in boys and post-menarchal girls, 10 to 16 years of age, with heterozygous familial hypercholesterolemia after failing an adequate trial of diet therapy ( 1.1 ) Reduce the risk of undergoing revascularization procedures in patients with clinically evident Coronary Heart Disease (CHD) ( 1.2 ) Slow the progression of atherosclerosis in patients with CHD ( 1.2 ) Limitations of Use: LESCOL XL has not been studied in conditions where the major abnormality is elevation of chylomicrons, VLDL, or IDL (i.e., hyperlipoproteinemia Types I, III, IV, or V) ( 1.3 ) 1.1 Hypercholesterolemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia LESCOL XL is indicated as an adjunct to diet to reduce elevated total cholesterol (Total-C), low-density lipoprotein cholesterol (LDL-C), triglyceride (TG) and apolipoprotein B (Apo B) levels, and to increase high-density lipoprotein cholesterol (HDL-C) in patients with primary hypercholesterolemia and mixed dyslipidemia (Fredrickson Type IIa and IIb). as an adjunct to diet to reduce Total-C, LDL-C, and Apo B levels in adolescent boys and adolescent girls who are at least one year post-menarche, 10-16 years of age, with heterozygous familial hypercholesterolemia 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 The NCEP classification of cholesterol levels in pediatric patients with a familial history of hypercholesterolemia or premature CVD is summarized below. Category Total-C (mg/ dL ) LDL-C (mg/ dL ) Acceptable < 170 < 110 Borderline 170-199 110-129 High ≥ 200 ≥ 130 Children treated with fluvastatin in adolescence should be reevaluated in adulthood and appropriate changes made to their cholesterol-lowering regimen to achieve adult treatment goals. 1.2 Secondary Prevention of Cardiovascular Disease In patients with clinically evident Coronary Heart Disease (CHD), LESCOL XL is indicated to: reduce the risk of undergoing coronary revascularization procedures slow the progression of coronary atherosclerosis 1.3 Limitations of Use LESCOL XL has not been studied in conditions where the major abnormality is elevation of chylomicrons, VLDL, or IDL (i.e., hyperlipoproteinemia Types I, III, IV, or V).

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.

7 DRUG INTERACTIONS Cyclosporine: Combination increases fluvastatin exposure. Limit fluvastatin dose to 20 mg ( 2.4 , 7.1 ) Fluconazole: Combination increases fluvastatin exposure. Limit fluvastatin dose to 20 mg ( 2.5 , 7.2 ) Concomitant lipid-lowering therapies : Use with fibrates or lipid-modifying doses (≥ 1 g/day) of niacin increases the risk of adverse skeletal muscle effects. Caution should be used when prescribing with LESCOL XL ( 5.1 , 7.3 , 7.4 ) Glyburide: Monitor blood glucose levels when fluvastatin dose is changed ( 7.6 ) Phenytoin: Monitor plasma phenytoin levels when fluvastatin treatment is initiated or when the dosage is changed ( 7.7 ) Warfarin and coumarin derivates: Monitor prothrombin times when fluvastatin coadministration is initiated, discontinued, or the dosage changed ( 7.8 ) 7.1 Cyclosporine Cyclosporine coadministration increases fluvastatin exposure. Therefore, in patients taking cyclosporine, therapy should be limited to fluvastatin 20 mg twice daily [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ]. 7.2 Fluconazole Administration of fluvastatin 40 mg single dose to healthy volunteers pre-treated with fluconazole for 4 days results in an increase of fluvastatin exposure. Therefore, in patients taking fluconazole, therapy should be limited to fluvastatin 20 mg twice daily [see Clinical Pharmacology (12.3) ]. 7.3 Gemfibrozil Due to an increased risk of myopathy/rhabdomyolysis when HMG-CoA reductase inhibitors are coadministered with gemfibrozil, concomitant administration of LESCOL XL with gemfibrozil should be avoided. 7.4 Other Fibrates Because it is known that the risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concurrent administration of other fibrates, LESCOL XL should be administered with caution when used concomitantly with other fibrates [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ]. 7.5 Niacin The risk of skeletal muscle effects may be enhanced when fluvastatin is used in combination with lipid-modifying doses (≥ 1 g/day) of niacin; a reduction in fluvastatin dosage should be considered in this setting [see Warnings and Precautions (5.1) ]. 7.6 Glyburide Concomitant administration of fluvastatin and glyburide increased glyburide exposures. Patients on concomitant therapy of glyburide and fluvastatin should continue to be monitored appropriately [ see Clinical Pharmacology (12.3) ]. 7.7 Phenytoin Concomitant administration of fluvastatin and phenytoin increased phenytoin exposures. Patients should continue to be monitored appropriately when fluvastatin therapy is initiated or when fluvastatin dose is changed [ see Clinical Pharmacology (12.3) ]. 7.8 Warfarin Bleeding and/or increased prothrombin times have been reported in patients taking coumarin anticoagulants concomitantly with other HMG-CoA reductase inhibitors. Therefore, patients receiving warfarin-type anticoagulants should have their prothrombin times closely monitored when fluvastatin sodium is initiated or the dosage of fluvastatin sodium is changed. 7.9 Colchicine Cases of myopathy, including rhabdomyolysis, have been reported with fluvastatin coadministered with colchicine, and caution should be exercised when prescribing fluvastatin with colchicine.

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 C max , an 11% decrease in AUC, and a more than 2-fold increase in T max 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 (T max 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 (VD ss ) 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 (t 1/2 ) of fluvastatin is approximately 3 hours. Specific Populations Renal Impairment In patients with moderate to severe renal impairment (CL Cr 10 to 40 mL/min), AUC and C max 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 C max 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 C max ** 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 C max ** 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%

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 C max , an 11% decrease in AUC, and a more than 2-fold increase in T max 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 (T max 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 (VD ss ) 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 (t 1/2 ) of fluvastatin is approximately 3 hours. Specific Populations Renal Impairment In patients with moderate to severe renal impairment (CL Cr 10 to 40 mL/min), AUC and C max 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 C max 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 C max ** 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 C max ** 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%

20230707

23

3 DOSAGE FORMS AND STRENGTHS LESCOL XL 80 mg tablets are yellow, round, slightly biconvex film-coated tablets with beveled edges debossed with “LESCOL XL” on one side and “80” on the other. LESCOL XL Tablets: 80 mg ( 3 )

Lescol XL fluvastatin sodium FLUVASTATIN SODIUM FLUVASTATIN HYDROXYPROPYL CELLULOSE HYPROMELLOSE 2208 (15000 MPA.S) FERRIC OXIDE YELLOW MAGNESIUM STEARATE CELLULOSE, MICROCRYSTALLINE POLYETHYLENE GLYCOL 8000 POTASSIUM BICARBONATE POVIDONE TITANIUM DIOXIDE Lescol;XL;80

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility A 2-year study was performed in rats at dose levels of 6, 9, and 18-24 (escalated after 1 year) mg/kg/day. These treatment levels represented plasma drug levels of approximately 9, 13, and 26-35 times the mean human plasma drug concentration after a 40 mg oral dose. A low incidence of forestomach squamous papillomas and 1 carcinoma of the forestomach at the 24 mg/kg/day dose level was considered to reflect the prolonged hyperplasia induced by direct contact exposure to fluvastatin sodium rather than to a systemic effect of the drug. In addition, an increased incidence of thyroid follicular cell adenomas and carcinomas was recorded for males treated with 18-24 mg/kg/day. The increased incidence of thyroid follicular cell neoplasm in male rats with fluvastatin sodium appears to be consistent with findings from other HMG-CoA reductase inhibitors. In contrast to other HMG-CoA reductase inhibitors, no hepatic adenomas or carcinomas were observed. The carcinogenicity study conducted in mice at dose levels of 0.3, 15 and 30 mg/kg/day revealed, as in rats, a statistically significant increase in forestomach squamous cell papillomas in males and females at 30 mg/kg/day and in females at 15 mg/kg/day. These treatment levels represented plasma drug levels of approximately 0.05, 2, and 7 times the mean human plasma drug concentration after a 40 mg oral dose. No evidence of mutagenicity was observed in vitro, with or without rat-liver metabolic activation, in the following studies: microbial mutagen tests using mutant strains of Salmonella typhimurium or Escherichia coli ; malignant transformation assay in BALB/3T3 cells; unscheduled DNA synthesis in rat primary hepatocytes; chromosomal aberrations in V79 Chinese Hamster cells; HGPRT V79 Chinese Hamster cells. In addition, there was no evidence of genotoxicity in vivo in either a rat chromosome aberration study or mouse micronucleus test. In a study in rats at dose levels for females of 0.6, 2 and 6 mg/kg/day and at dose levels for males of 2, 10 and 20 mg/kg/day, fluvastatin sodium had no adverse effects on the fertility or reproductive performance. Seminal vesicles and testes were small in hamsters treated for 3 months at 20 mg/kg/day (approximately three times the 40 mg human daily dose based on surface area, mg/m 2 ). There was tubular degeneration and aspermatogenesis in testes as well as vesiculitis of seminal vesicles. Vesiculitis of seminal vesicles and edema of the testes were also seen in rats treated for 2 years at 18 mg/kg/day (approximately 4 times the human C max achieved with a 40 mg daily dose). Fluvastatin sodium produced delays in skeletal development in rats at doses of 12 mg/kg/day and in rabbits at doses of 10 mg/kg/day. Malaligned thoracic vertebrae were seen in rats at 36 mg/kg, a dose that produced maternal toxicity. These doses resulted in 2 times (rat at 12 mg/kg) or 5 times (rabbit at 10 mg/kg) the 40 mg human exposure based on mg/m 2 surface area. A study in which female rats were dosed during the third trimester at 12 and 24 mg/kg/day resulted in maternal mortality at or near term and postpartum. In addition, fetal and neonatal lethality were apparent. No effects on the dam or fetus occurred at 2 mg/kg/day. A second study at levels of 2, 6, 12 and 24 mg/kg/day confirmed the findings in the first study with neonatal mortality beginning at 6 mg/kg. A modified Segment III study was performed at dose levels of 12 or 24 mg/kg/day with or without the presence of concurrent supplementation with mevalonic acid, a product of HMG-CoA reductase which is essential for cholesterol biosynthesis. The concurrent administration of mevalonic acid completely prevented the maternal and neonatal mortality but did not prevent low body weights in pups at 24 mg/kg on Days 0 and 7 postpartum.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility A 2-year study was performed in rats at dose levels of 6, 9, and 18-24 (escalated after 1 year) mg/kg/day. These treatment levels represented plasma drug levels of approximately 9, 13, and 26-35 times the mean human plasma drug concentration after a 40 mg oral dose. A low incidence of forestomach squamous papillomas and 1 carcinoma of the forestomach at the 24 mg/kg/day dose level was considered to reflect the prolonged hyperplasia induced by direct contact exposure to fluvastatin sodium rather than to a systemic effect of the drug. In addition, an increased incidence of thyroid follicular cell adenomas and carcinomas was recorded for males treated with 18-24 mg/kg/day. The increased incidence of thyroid follicular cell neoplasm in male rats with fluvastatin sodium appears to be consistent with findings from other HMG-CoA reductase inhibitors. In contrast to other HMG-CoA reductase inhibitors, no hepatic adenomas or carcinomas were observed. The carcinogenicity study conducted in mice at dose levels of 0.3, 15 and 30 mg/kg/day revealed, as in rats, a statistically significant increase in forestomach squamous cell papillomas in males and females at 30 mg/kg/day and in females at 15 mg/kg/day. These treatment levels represented plasma drug levels of approximately 0.05, 2, and 7 times the mean human plasma drug concentration after a 40 mg oral dose. No evidence of mutagenicity was observed in vitro, with or without rat-liver metabolic activation, in the following studies: microbial mutagen tests using mutant strains of Salmonella typhimurium or Escherichia coli ; malignant transformation assay in BALB/3T3 cells; unscheduled DNA synthesis in rat primary hepatocytes; chromosomal aberrations in V79 Chinese Hamster cells; HGPRT V79 Chinese Hamster cells. In addition, there was no evidence of genotoxicity in vivo in either a rat chromosome aberration study or mouse micronucleus test. In a study in rats at dose levels for females of 0.6, 2 and 6 mg/kg/day and at dose levels for males of 2, 10 and 20 mg/kg/day, fluvastatin sodium had no adverse effects on the fertility or reproductive performance. Seminal vesicles and testes were small in hamsters treated for 3 months at 20 mg/kg/day (approximately three times the 40 mg human daily dose based on surface area, mg/m 2 ). There was tubular degeneration and aspermatogenesis in testes as well as vesiculitis of seminal vesicles. Vesiculitis of seminal vesicles and edema of the testes were also seen in rats treated for 2 years at 18 mg/kg/day (approximately 4 times the human C max achieved with a 40 mg daily dose). Fluvastatin sodium produced delays in skeletal development in rats at doses of 12 mg/kg/day and in rabbits at doses of 10 mg/kg/day. Malaligned thoracic vertebrae were seen in rats at 36 mg/kg, a dose that produced maternal toxicity. These doses resulted in 2 times (rat at 12 mg/kg) or 5 times (rabbit at 10 mg/kg) the 40 mg human exposure based on mg/m 2 surface area. A study in which female rats were dosed during the third trimester at 12 and 24 mg/kg/day resulted in maternal mortality at or near term and postpartum. In addition, fetal and neonatal lethality were apparent. No effects on the dam or fetus occurred at 2 mg/kg/day. A second study at levels of 2, 6, 12 and 24 mg/kg/day confirmed the findings in the first study with neonatal mortality beginning at 6 mg/kg. A modified Segment III study was performed at dose levels of 12 or 24 mg/kg/day with or without the presence of concurrent supplementation with mevalonic acid, a product of HMG-CoA reductase which is essential for cholesterol biosynthesis. The concurrent administration of mevalonic acid completely prevented the maternal and neonatal mortality but did not prevent low body weights in pups at 24 mg/kg on Days 0 and 7 postpartum.

NDA021192

Lescol XL

fluvastatin sodium

0078-0354

HUMAN PRESCRIPTION DRUG

ORAL

PRINCIPAL DISPLAY PANEL NOVARTIS NDC 0078-0354-15 Lescol ® XL (fluvastatin sodium) Extended-Release Tablets equivalent to 80 mg per tablet fluvastatin 30 tablets Rx only PRINCIPAL DISPLAY PANEL NOVARTIS NDC 0078-0354-15 Lescol® XL fluvastatin sodium Extended-Release Tablets equivalent to 80 mg per tablet fluvastatin 30 tablets Rx only

Warnings and Precautions ( 5.2 ) 9/2020

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Patients taking LESCOL XL should be advised that high cholesterol is a chronic condition and they should adhere to their medication along with their National Cholesterol Education Program (NCEP)-recommended diet, a regular exercise program, and periodic testing of a fasting lipid panel to determine goal attainment. Patients should be advised about substances they should not take concomitantly with LESCOL XL [see Warnings and Precautions (5.1)] . Patients should also be advised to inform other healthcare professionals prescribing a new medication that they are taking LESCOL XL. Muscle Pain Patients starting therapy with LESCOL XL should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever or if these muscle signs or symptoms persist after discontinuing LESCOL XL. Liver Enzymes It is recommended that liver enzyme tests be performed before the initiation of LESCOL XL and if signs or symptoms of liver injury occur. All patients treated with LESCOL XL should be advised to report promptly any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice. Pregnancy Women of childbearing age should be advised to use an effective method of birth control to prevent pregnancy while using LESCOL XL. Discuss future pregnancy plans with your patients, and discuss when to stop taking LESCOL XL if they are trying to conceive. Patients should be advised that if they become pregnant they should stop taking LESCOL XL and call their healthcare professional. Breastfeeding Women who are breastfeeding should not use LESCOL XL. Patients who have a lipid disorder and are breastfeeding should be advised to discuss the options with their healthcare professional. T2020-132

14 CLINICAL STUDIES Figure 1. Primary Endpoint – Recurrent Cardiac Events (Cardiac Death, Nonfatal MI or Revascularization Procedure) (ITT Population) Figure 2. Lescol® Intervention Prevention Study - Primary and Secondary Endpoints Figure 3 Change in Minimum Lumen Diameter (mm) Figure 4 Change in % Diameter Stenosis 14.1 Hypercholesterolemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia 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 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 Active Controlled Trials (LESCOL XL) * Data for LESCOL XL 80 mg tablet from three 24-week controlled trials. Total Chol TG LDL Apo B HDL Dose N % ∆ N % ∆ N % ∆ N % ∆ N % ∆ All Patients LESCOL XL 80 mg * 750 -25 750 -19 748 -35 745 -27 750 +7 Baseline TG ≥ 200 mg/dL LESCOL XL 80 mg * 239 -25 239 -25 237 -33 235 -27 239 +11 14.2 Heterozygous Familial Hypercholesterolemia in Pediatric Patients Fluvastatin sodium was studied in two open-label, uncontrolled, dose-titration studies. The first study enrolled 29 pre-pubertal boys, 9 to 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 fluvastatin capsules 20 mg daily with dose adjustments every 6 weeks to 40 mg daily then 80 mg daily (40 mg twice daily) to achieve an LDL-C goal between 96.7 to 123.7 mg/dL. Endpoint analyses were performed at Year 2. Fluvastatin sodium 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 fluvastatin 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. Fluvastatin sodium 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 to 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 fluvastatin sodium therapy in childhood to reduce morbidity and mortality in adulthood has not been established. 14.3 Secondary Prevention of Cardiovascular Disease In the LESCOL Intervention Prevention Study (LIPS), the effect of fluvastatin capsules 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 fluvastatin 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. Fluvastatin capsules significantly reduced the risk of recurrent cardiac events (Figure 1) by 22% (p = 0.013, 181 patients in the fluvastatin capsules group versus 222 patients in the placebo group). Revascularization procedures comprised the majority of the initial recurrent cardiac events (143 revascularization procedures in the fluvastatin capsules 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 fluvastatin capsules 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 In the Lipoprotein and Coronary Atherosclerosis Study (LCAS), the effect of fluvastatin capsule 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 fluvastatin 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, fluvastatin capsules 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 fluvastatin capsules 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) Figure 4: Change in % Diameter Stenosis

15 REFERENCES 1. National Cholesterol Education Program (NCEP): Highlights of the Report of the Expert Panel on Blood Cholesterol Levels in Children and Adolescents. Pediatrics . 89(3):495-501.1992. 2. Manson, J.M., Freyssinges, C., Ducrocq, M.B., Stephenson, W.P., Postmarketing Surveillance of Lovastatin and Simvastatin Exposure During Pregnancy, Reproductive Toxicology, 10(6): 439-446, 1996.

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.

4.4 Nursing Mothers Fluvastatin is secreted into the breast milk of animals and because HMG-CoA reductase inhibitors have the potential to cause serious adverse reactions in nursing infants, women who require treatment with LESCOL XL should be advised not to breastfeed their infants [see Use in Specific Populations (8.3) ].

8.4 Pediatric Use The safety and efficacy of LESCOL XL in children and adolescent patients 9 to 16 years of age with heterozygous familial hypercholesterolemia have been evaluated in open-label, uncontrolled clinical trials for a duration of two years. The most common adverse events observed were influenza and infections. In these limited uncontrolled studies, there was no detectable effect on growth or sexual maturation in the adolescent boys or on menstrual cycle length in girls [see Clinical Studies (14.2), Adverse Reactions (6.3), and Dosage and Administration (2.2) ]. Adolescent females should be counseled on appropriate contraceptive methods while on fluvastatin therapy [see Contraindications (4) ].

4.3 Pregnancy LESCOL XL is contraindicated in women who are pregnant or may become pregnant. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. LESCOL XL may cause fetal harm when administered to pregnant women. Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia. LESCOL XL 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 drug, LESCOL XL should be discontinued and the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1) ].

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category X LESCOL XL is contraindicated in women who are or may become pregnant [ see Contraindications (4.3) ]. Lipid lowering drugs are contraindicated during pregnancy, because cholesterol and cholesterol derivatives are needed for normal fetal development. Serum cholesterol and triglycerides increase during normal pregnancy. Atherosclerosis is a chronic process, and discontinuation of lipid-lowering drugs during pregnancy should have little impact on long-term outcomes of primary hypercholesterolemia therapy. There are no adequate and well-controlled studies of use with LESCOL XL during pregnancy. Rare reports of congenital anomalies have been received following intrauterine exposure to other statins. In a review 2 of about 100 prospectively followed pregnancies in women exposed to other statins, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed the rate expected in the general population. The number of cases is adequate only to exclude a 3- to 4-fold increase in congenital anomalies over background incidence. In 89% of prospectively followed pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified. Teratology studies with fluvastatin in rats and rabbits showed maternal toxicity at high dose levels, but there was no evidence of embryotoxic or teratogenic potential [see Nonclinical Toxicology (13) ]. LESCOL XL should be administered to women of child-bearing potential only when such patients are highly unlikely to conceive and have been informed of the potential hazards. If a woman becomes pregnant while taking LESCOL XL, the drug should be discontinued and the patient advised again as to the potential hazards to the fetus. 8.3 Nursing Mothers Based on animal data, fluvastatin is present in breast milk in a 2:1 ratio (milk:plasma). Because of the potential for serious adverse reactions in nursing infants, nursing women should not take LESCOL XL [see Contraindications (4.4) ]. 8.4 Pediatric Use The safety and efficacy of LESCOL XL in children and adolescent patients 9 to 16 years of age with heterozygous familial hypercholesterolemia have been evaluated in open-label, uncontrolled clinical trials for a duration of two years. The most common adverse events observed were influenza and infections. In these limited uncontrolled studies, there was no detectable effect on growth or sexual maturation in the adolescent boys or on menstrual cycle length in girls [see Clinical Studies (14.2), Adverse Reactions (6.3), and Dosage and Administration (2.2) ]. Adolescent females should be counseled on appropriate contraceptive methods while on fluvastatin therapy [see Contraindications (4) ]. 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) ].

16 HOW SUPPLIED/STORAGE AND HANDLING 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 tablets…………………………………………………………………………………...NDC 0078-0354-15 Bottles of 100 tablets…………………………………………………………………………………...NDC 0078-0354-05 Store and Dispense Store at 20ºC to 25ºC (68ºF to 77ºF); excursions permitted between 15ºC and 30ºC (59ºF and 86ºF) [see USP Controlled Room Temperature]. Dispense in a tight container. Protect from light.