Fluvastatin Sodium

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. Fluvastatin capsules are 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 CHD ( 1.2 ) • Slow the progression of atherosclerosis in patients with CHD ( 1.2 ) Limitations of Use: • Fluvastatin capsules have 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 Fluvastatin capsules are 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 re-evaluated 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 CHD, fluvastatin capsules are indicated to: • reduce the risk of undergoing coronary revascularization procedures • slow the progression of coronary atherosclerosis 1.3 Limitations of Use Fluvastatin capsules have 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).

2 DOSAGE AND ADMINISTRATION • Dose range: 20 mg to 80 mg/day ( 2.1 ) • Fluvastatin capsules can be taken with or without food • Do not open fluvastatin capsules prior to administration ( 2.1 ) • Adults: the recommended starting dose is 40 mg to 80 mg (administered as one fluvastatin 40 mg capsule twice daily) ( 2.2 ) • Do not take two fluvastatin 40 mg capsules at one time • 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. Fluvastatin capsules can be administered orally as a single dose, with or without food. Do not open fluvastatin capsules prior to administration. Do not take two fluvastatin 40 mg capsules at one time. 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 40 mg as one capsule in the evening, 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. 2.2 Adult Patients with Hypercholesterolemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia Adult patients can be started on fluvastatin capsules. The recommended starting dose for fluvastatin capsules is one 40 mg capsule in the evening, or one fluvastatin 40 mg capsule twice daily. Do not take two fluvastatin 40 mg capsules at one time. 2.3 Pediatric Patients (10-16 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 as fluvastatin capsules 40 mg twice 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 b.i.d. fluvastatin in patients taking cyclosporine [see Drug Interactions (7.1) ]. 2.5 Use with Fluconazole Do not exceed a dose of 20 mg b.i.d. fluvastatin in patients taking fluconazole [see Drug Interactions (7.2) ].

3 DOSAGE FORMS AND STRENGTHS Fluvastatin Capsules, USP are available containing fluvastatin sodium, USP equivalent to 20 mg or 40 mg of fluvastatin. • The 20 mg capsules are hard-shell gelatin capsules with a pink opaque cap and an ivory opaque body filled with a light-yellow powder. The capsules are axially printed with MYLAN over 8020 in black ink on both the cap and the body. • The 40 mg capsules are hard-shell gelatin capsules with a pink opaque cap and an orange opaque body filled with a light-yellow powder. The capsules are axially printed with MYLAN over 8021 in black ink on both the cap and the body. • Fluvastatin Capsules: 20 mg, 40 mg ( 3 )

4 CONTRAINDICATIONS • Hypersensitivity to any component of this medication ( 4 ) • Active liver disease or unexplained, persistent elevations in serum transaminases ( 4 , 5.2 ) • Women who are pregnant or may become pregnant ( 4 , 8.1 ) • Nursing mothers ( 4 , 8.3 ) 4.1 Hypersensitivity to Any Component of This Medication Fluvastatin capsules are contraindicated in patients with hypersensitivity to any component of this medication. 4.2 Active Liver Disease Fluvastatin capsules are contraindicated in patients with active liver disease or unexplained, persistent elevations in serum transaminases [see Warnings and Precautions (5.2) ]. 4.3 Pregnancy Fluvastatin capsules are 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. Fluvastatin 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. Fluvastatin capsules 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, fluvastatin capsules 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 fluvastatin capsules should be advised not to breastfeed their infants [see Use In Specific Populations (8.3) ].

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 (5.2) ] . Most frequent adverse reactions (rate ≥ 2% and > placebo) are: headache, dyspepsia, myalgia, abdominal pain and nausea ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) 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 are conducted in varying study populations and study designs, the frequency of adverse reactions observed in the clinical studies of fluvastatin 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 capsules placebo-controlled clinical trials database of 2326 patients treated with fluvastatin capsules (age range 18-75 years, 44% women, 94% Caucasians, 4% Blacks, 2% other ethnicities) with a median treatment duration of 24 weeks, 3.4% of patients on fluvastatin 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%). Clinically relevant adverse experiences occurring in the fluvastatin capsules 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 and at an Incidence Greater than Placebo in Placebo-Controlled Trials Regardless of Causality (% of Patients) Pooled Dosages Fluvastatin Capsules Controlled trials with fluvastatin capsules (20 and 40 mg daily and 40 mg twice daily) compared to placebo N = 2326 (%) Placebo N = 960 (%) Musculoskeletal Myalgia 5.0 4.5 Arthritis 2.1 2.0 Arthropathy NA NA Respiratory Sinusitis 2.6 1.9 Bronchitis 1.8 1.0 Gastrointestinal Dyspepsia 7.9 3.2 Diarrhea 4.9 4.2 Abdominal pain 4.9 3.8 Nausea 3.2 2.0 Flatulence 2.6 2.5 Tooth disorder 2.1 1.7 Psychiatric Insomnia 2.7 1.4 Genitourinary Urinary tract infection 1.6 1.1 Headache 8.9 7.8 Influenza-like symptoms 5.1 5.7 Accidental Trauma 5.1 4.8 Fatigue 2.7 2.3 Allergy 2.3 2.2 Fluvastatin Capsules Intervention Prevention Study In the Fluvastatin Capsules Intervention Prevention Study, the effect of 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 and at an Incidence Greater than Placebo in the Trial Regardless of Causality (% of Patients) Fluvastatin 40 mg b.i.d. 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 Inte …

7 DRUG INTERACTIONS • Cyclosporine: Combination increases fluvastatin exposure. Limit fluvastatin capsules dose to 20 mg ( 2.4 , 7.1 ) • Fluconazole: Combination increases fluvastatin exposure. Limit fluvastatin capsules 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 fluvastatin ( 5.1 , 7.3 , 7.4 ) • Glyburide: Monitor blood glucose levels when fluvastatin dose is changed ( 7 ) • Phenytoin: Monitor plasma phenytoin levels when fluvastatin treatment is initiated or when the dosage is changed ( 7 ) • Warfarin and coumarin derivatives: Monitor prothrombin times when fluvastatin coadministration is initiated, discontinued, or the dosage changed ( 7 ) 7.1 Cyclosporine Cyclosporine coadministration increases fluvastatin exposure. Therefore, in patients taking cyclosporine, therapy should be limited to fluvastatin capsules 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 capsules 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 fluvastatin 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, fluvastatin 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.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category X: Fluvastatin is contraindicated in women who are or may become pregnant [see Contraindications (4) ] . 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 fluvastatin 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) ]. Fluvastatin should be administered to women of childbearing 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 fluvastatin capsules, 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 fluvastatin [see Contraindications (4) ] . 8.4 Pediatric Use The safety and efficacy of fluvastatin in children and adolescent patients 9-16 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, fluvastatin should be prescribed with caution in the elderly. 8.6 Hepatic Impairment Fluvastatin is 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) ] .

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.

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 Sodium (±)-(3 R *,5 S *,6 E )-7-[3-( p -fluorophenyl)-1-isopropylindol-2-yl]-3,5-dihydroxy-6-heptenoate. The molecular formula of fluvastatin sodium is C 24 H 25 FNNaO 4 , its molecular weight is 433.45 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, USP is an off-white to yellow, hygroscopic powder soluble in water, ethanol and methanol. Fluvastatin is supplied as capsules containing fluvastatin sodium, equivalent to 20 mg or 40 mg of fluvastatin, for oral administration. Active ingredient: fluvastatin sodium Inactive ingredients in capsules: corn starch, crospovidone, gelatin, magnesium stearate, red iron oxide, sodium lauryl sulfate, talc, titanium dioxide and yellow iron oxide. In addition, the black imprinting ink for the 20 mg and 40 mg capsules contains ammonium hydroxide, black iron oxide, propylene glycol and shellac glaze. Fluvastatin Structural Formula

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 tablets 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.

16 HOW SUPPLIED/STORAGE AND HANDLING Fluvastatin Capsules, USP are available containing fluvastatin sodium, USP equivalent to 20 mg or 40 mg of fluvastatin. The 20 mg capsules are hard-shell gelatin capsules with a pink opaque cap and an ivory opaque body filled with a light-yellow powder. The capsules are axially printed with MYLAN over 8020 in black ink on both the cap and the body. They are available as follows: NDC 0378-8020-93 bottles of 30 capsules NDC 0378-8020-77 bottles of 90 capsules The 40 mg capsules are hard-shell gelatin capsules with a pink opaque cap and an orange opaque body filled with a light-yellow powder. The capsules are axially printed with MYLAN over 8021 in black ink on both the cap and the body. They are available as follows: NDC 0378-8021-93 bottles of 30 capsules NDC 0378-8021-77 bottles of 90 capsules Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Protect from light. Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.