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 ( 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 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).

20 mg are hard gelatin capsules with ivory opaque body and pink opaque cap, filled with an off-white to yellowish powder with small agglomerates. Cap imprinted with “TEVA” and body imprinted with “7442”. 40 mg are hard gelatin capsules with yellow opaque body and pink opaque cap, filled with an off-white to yellowish powder with small agglomerates. Cap imprinted with “TEVA” and body imprinted with “7443”. Capsules: 20 mg, 40 mg ( 3 )

Hypersensitivity to any component of this medication ( 4 ) Active liver disease or unexplained, persistent elevations in serum transaminases ( 4 , 5.3 ) 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 ( 5.3 )] .

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 capsules 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 )] .

Skeletal muscle effects (e.g., myopathy and rhabdomyolysis): Risks increase with advanced age (≥ 65), uncontrolled hypothyroidism, renal impairment, and combination use with cyclosporine,or gemfibrozil. Advise patients to promptly report to their physician unexplained and/or persistent muscle pain, tenderness, or weakness and discontinue fluvastatin if myopathy is diagnosed or suspected. ( 5.1 , 8.5 , 8.7 ) Patients should be advised to report promptly any symptoms of myopathy. Fluvastatin capsules therapy should be discontinued if myopathy is diagnosed or suspected ( 5.1 ) Immune-Mediated Necrotizing Myopathy (IMNM): There have been rare reports of IMNM, an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; positive anti-HMG CoA reductase antibody; muscle biopsy showing necrotizing myopathy; and improvement with immunosuppressive agents. ( 5.2 ) Liver enzyme abnormalities: Persistent elevations in hepatic transaminases can occur. Check liver enzyme tests before initiating therapy and as clinically indicated thereafter ( 5.3 )

5.1 Skeletal Muscle Rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with fluvastatin capsules and other drugs in this class. Fluvastatin capsules should be prescribed with caution in patients with predisposing factors for myopathy. These factors include advanced age (> 65 years), renal impairment, and inadequately treated hypothyroidism. The risk of myopathy and/or rhabdomyolysis with statins is increased with concurrent therapy with cyclosporine, erythromycin, fibrates or niacin. Myopathy was not observed in a clinical trial in 74 patients involving patients who were treated with fluvastatin sodium together with niacin. Isolated cases of myopathy have been reported during postmarketing experience with concomitant administration of fluvastatin sodium and colchicine. No information is available on the pharmacokinetic interaction between fluvastatin sodium and colchicine. Uncomplicated myalgia has also been reported in fluvastatin sodium-treated patients [see Adverse Reactions ( 6 )] . In clinical trials, uncomplicated myalgia has been observed infrequently in patients treated with fluvastatin sodium at rates indistinguishable from placebo. Myopathy, defined as muscle aching or muscle weakness in conjunction with increases in CPK values to greater than 10 times the upper limit of normal, was < 0.1% in fluvastatin clinical trials. Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of CPK. All patients should be advised to promptly report to their physician unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing fluvastatin. Fluvastatin sodium therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. Fluvastatin sodium therapy should also be temporarily withheld in any patient experiencing an acute or serious condition predisposing to the development of renal failure secondary to rhabdomyolysis, e.g., sepsis; hypotension; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy.

5.2 Immune-Mediated Necrotizing Myopathy There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; positive anti-HMG CoA reductase antibody; muscle biopsy showing necrotizing myopathy; and improvement with immunosuppressive agents. Additional neuromuscular and serologic testing may be necessary. Treatment with immunosuppressive agents may be required. Consider risk of IMNM carefully prior to initiation of a different statin. If therapy is initiated with a different statin, monitor for signs and symptoms of IMNM.

5.3 Liver Enzymes Increases in serum transaminases (aspartate aminotransferase [AST]/serum glutamic-oxaloacetic transaminase, or alanine aminotransferase [ALT]/serum glutamic-pyruvic transaminase) have been reported with HMG-CoA reductase inhibitors, including fluvastatin sodium. In most cases, the elevations were transient and resolved or improved on continued therapy or after a brief interruption in therapy. Approximately 1.1% of patients treated with fluvastatin capsules in worldwide trials developed dose-related, persistent elevations of serum transaminase levels to more than 3 times the upper limit of normal. Fourteen of these patients (0.6%) were discontinued from therapy. In all clinical trials, a total of 33/2969 patients (1.1%) had persistent transaminase elevations with an average fluvastatin sodium exposure of approximately 71.2 weeks; 19 of these patients (0.6%) were discontinued. The majority of patients with these abnormal biochemical findings were asymptomatic. In a pooled analysis of all placebo-controlled studies in which fluvastatin capsules were used, persistent transaminase elevations (> 3 times the upper limit of normal [ULN] on two consecutive weekly measurements) occurred in 0.2%, 1.5%, and 2.7% of patients treated with daily doses of 20, 40, and 80 mg (titrated to 40 mg twice daily) fluvastatin capsules, respectively. Ninety-one percent of the cases of persistent liver function test abnormalities (20 of 22 patients) occurred within 12 weeks of therapy and in all patients with persistent liver function test abnormalities there was an abnormal liver function test present at baseline or by Week 8. In the pooled analysis of the 24 week controlled trials, persistent transaminase elevation occurred in 1.8% and 4.9% of patients treated with fluvastatin capsules, 40 mg and fluvastatin capsules, 40 mg twice daily, respectively. It is recommended that liver enzyme tests be performed prior to the initiation of fluvastatin sodium, and if signs or symptoms of liver injury occur. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including fluvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with fluvastatin sodium, promptly interrupt therapy. If an alternate etiology is not found do not restart fluvastatin sodium. In very rare cases, possibly drug-related hepatitis was observed that resolved upon discontinuation of treatment. 1 Active liver disease or unexplained serum transaminase elevations are contraindications to the use of fluvastatin sodium [see Contraindications ( 4 ) and Warnings and Precautions ( 5.3 )] . Caution should be exercised when fluvastatin sodium is administered to patients with a history of liver disease or heavy alcohol ingestion [see Clinical Pharmacology ( 12.3 )] . Such patients should be closely monitored.

5.4 Endocrine Effects Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including fluvastatin sodium. Statins interfere with cholesterol synthesis and lower circulating cholesterol levels and, as such, might theoretically blunt adrenal or gonadal steroid hormone production. Fluvastatin sodium exhibited no effect upon non-stimulated cortisol levels and demonstrated no effect upon thyroid metabolism as assessed by measurement of thyroid stimulating hormone (TSH). Small declines in total serum testosterone have been noted in treated groups, but no commensurate elevation in LH occurred, suggesting that the observation was not due to a direct effect upon testosterone production. No effect upon FSH in males was noted. Due to the limited number of premenopausal females studied to date, no conclusions regarding the effect of fluvastatin sodium upon female sex hormones may be made. […]

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 Teva 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

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 Miscellaneous 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 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 ( 14.3 )]. 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

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 fluvastatin sodium extended-release tablets, 80 mg [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 ( 5.1 )]. 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 ( 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 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 derivates: 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 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 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 ( 5.1 ) and Clinical Pharmacology ( 12.3 )].

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 ( 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.

8.1 Pregnancy Pregnancy Category X Fluvastatin sodium 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 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 ( 13 )]. 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 ( 4 )].

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 ( 14.2 ), Adverse Reactions ( 6.3 ), and Dosage and Administration ( 2.2 )] . Adolescent females should be counseled on appropriate contraceptive methods while on fluvastatin sodium 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 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 ( 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 )].

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.