fluvastatin

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 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 Reduce the risk of undergoing revascularization procedures in patients with clinically evident CHD Slow the progression of atherosclerosis in patients with CHD 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). 1.1 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 to 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 to 199 110 to 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).

Dose range: 20 mg to 80 mg/day Fluvastatin capsules can be taken with or without food. Do not open fluvastatin capsules prior to administration Adults: the recommended starting dose is 40 mg to 80 mg (administered as one fluvastatin capsule, 40 mg twice daily) Do not take two fluvastatin capsules, 40 mg at one time Children with heterozygous familial hypercholesterolemia (ages 10 to 16, inclusive): the recommended starting dose is fluvastatin capsule, 20 mg once daily

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 capsules, 40 mg 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 capsule, 40 mg twice daily. Do not take two fluvastatin capsules, 40 mg at one time. 2.3 Pediatric Patients (10 to 16 Years of Age) With Heterozygous Familial Hypercholesterolemia The recommended starting dose is one fluvastatin capsule, 20 mg. 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 ] 1 . 1 National Cholesterol Education Program (NCEP): Highlights of the Report of the Expert Panel on Blood Cholesterol Levels in Children and Adolescents. Pediatrics. 89:495-501. 1992. 2.4 Use With Cyclosporine Do not exceed a dose of 20 mg b.i.d. fluvastatin capsules in patients taking cyclosporine [ see Drug Interactions ]. 2.5 Use With Fluconazole Do not exceed a dose of 20 mg b.i.d. fluvastatin capsules in patients taking fluconazole [ see Drug Interactions ].

12.1 Mechanism of Action Fluvastatin sodium 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.

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 ]. Liver Enzyme Abnormalities [ see Warnings and Precautions ]. Most frequent adverse reactions (rate ≥ 2% and > placebo) are: headache, dyspepsia, myalgia, abdominal pain and nausea To report SUSPECTED ADVERSE REACTIONS, contact Teva Pharmaceuticals USA, Inc at 1-888-838-2872 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 are conducted in varying study populations and study designs, the frequency of adverse reactions observed in the clinical studies of fluvastatin capsules 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 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%). 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 Capsules 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 (%) Musculoskeletal Myalgia 5.0

Arthritis 2.1

Arthropathy NA NA Respiratory Sinusitis 2.6

Bronchitis 1.8

Gastrointestinal Dyspepsia 7.9

Diarrhea 4.9

Abdominal pain 4.9

Nausea 3.2

Flatulence 2.6

Tooth disorder 2.1

Psychiatric Insomnia 2.7

Genitourinary Urinary tract infection 1.6

Miscellaneous Headache 8.9

Influenza-like symptoms 5.1

Accidental Trauma 5.1

Fatigue 2.7

Allergy 2.3 2.2 1.

Controlled trials with fluvastatin capsules (20 and 40 mg daily and 40 mg twice daily) compared to placebo 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 ]. Table 2: Clinical Adverse Events Reported in ≥ 2% in Patients Treated With Fluvastatin Sodium and at an Incidence Greater Than Placebo in the Trial Regardless of Causality (% of Patients) Fluvastatin Capsules, 40 mg b.i.d. N = 822 (%) Placebo N = 818 (%) Cardiac disorders Atrial fibrillation 2.4

Gastrointestinal disorders Abdominal pain upper 6.3

Constipation 3.3

Dyspepsia 4.5

Gastric disorder 2.7

Nausea 2.7

General disorders Fatigue 4.7

Edema peripheral 4.4

Infections and infestations Bronchitis 2.3

Nasopharyngitis 2.8

Musculoskeletal and connective tissue disorders Arthralgia 2.1

Myalgia 2.2

Pain in extremity 4.1

Nervous system disorders Dizziness 3.9

Syncope 2.4

Respiratory disorders Dyspnea exertional 2.8

Vascular disorders Hypertension 5.8

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 fluvastatin sodium extended-release tablets, 80 mg [ see Clinical Studies and Use in Specific Populations ]. 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 ]. 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.

Cyclosporine: Combination increases fluvastatin exposure. Limit fluvastatin dose to 20 mg Fluconazole: Combination increases fluvastatin exposure. Limit fluvastatin dose to 20 mg 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 Glyburide: Monitor blood glucose levels when fluvastatin dose is changed Phenytoin: Monitor plasma phenytoin levels when fluvastatin treatment is initiated or when the dosage is changed Warfarin and coumarin derivates: Monitor prothrombin times when fluvastatin coadministration is initiated, discontinued, or the dosage changed

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 and Clinical Pharmacology ]. 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 ] . 7.3 Gemfibrozil Due to an increased risk of myopathy/rhabdomyolysis when HMG-CoA reductase inhibitors are coadministered with gemfibrozil, concomitant administration of fluvastatin sodium 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 sodium should be administered with caution when used concomitantly with other fibrates [ see Warnings and Precautions and Clinical Pharmacology ]. 7.5 Niacin The risk of skeletal muscle effects may be enhanced when fluvastatin sodium is used in combination with lipid-modifying doses (≥ 1 g/day) of niacin; a reduction in fluvastatin sodium dosage should be considered in this setting [ see Warnings and Precautions ]. 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 ]. 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 ]. 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.

8.1 Pregnancy Pregnancy Category X Fluvastatin sodium is contraindicated in women who are or may become pregnant [ see Contraindications ]. 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 sodium 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 ]. Fluvastatin sodium 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 fluvastatin sodium, 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 sodium [ see Contraindications ]. 8.4 Pediatric Use The safety and efficacy of fluvastatin sodium 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 , Adverse Reactions , and Dosage and Administration ]. Adolescent females should be counseled on appropriate contraceptive methods while on fluvastatin sodium therapy [ see Contraindications ]. 8.5 Geriatric Use Fluvastatin exposures were not significantly different between the nonelderly and elderly populations (age ≥ 65 years) [ see Clinical Pharmacology ]. Since advanced age (≥ 65 years) is a predisposing factor for myopathy, fluvastatin sodium should be prescribed with caution in the elderly. 8.6 Hepatic Impairment Fluvastatin sodium is contraindicated in patients with active liver disease or unexplained, persistent elevations in serum transaminases [ see Clinical Pharmacology ]. 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 ].