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 Sandoz Inc. at 1-800-525-8747 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 sodium extended-release tablets are conducted in varying study populations and study designs, the frequency of adverse reactions observed in the clinical studies of fluvastatin sodium extended-release tablets 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 immediate-release fluvastatin sodium placebo-controlled clinical trials database of 2326 patients treated with immediate-release fluvastatin sodium1 (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 immediate-release fluvastatin sodium 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 fluvastatin sodium extended-release tablet database of controlled clinical trials of 912 patients treated with fluvastatin sodium extended-release tablets (age range 21-87 years, 52% women, 91% Caucasians, 4% Blacks, 5% other ethnicities) with a median treatment duration of 24 weeks, 3.9% of patients on fluvastatin sodium extended-release tablets 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 immediate-release fluvastatin sodium and fluvastatin sodium extended-release tablets controlled studies with a frequency ≥2%, regardless of causality, included the following: Table 1: Clinical Adverse Events Reported in >2% in Patients Treated with Immediate-Release Fluvastatin Sodium / Fluvastatin Sodium Extended-Release Tablets and at an Incidence Greater than Placebo in Placebo-Controlled Trials Regardless of Causality (% of patients) Pooled Dosages Immediate-Release Fluvastatin Sodium1 N=2326 (%) Placebo1 N=960 (%) Fluvastatin Sodium Extended-Release Tablets2 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 1Controlled trials with immediate-release fluvastatin sodium (20 and 40 mg daily and 40 mg twice daily) compared to placebo 2Controlled trials with fluvastatin sodium extended-release tablets 80 mg as compared to immediate-release fluvastatin sodium Fluvastatin Sodium Intervention Prevention Study In the Fluvastatin Sodium Intervention Prevention Study, the effect of immediate-release fluvastatin sodium 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 immediate-release fluvastatin sodium 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 Immediate-Release Fluvastatin Sodium / Fluvastatin Sodium Extended-Release Tablets and at an Incidence Greater than Placebo in the Fluvastatin Intervention Prevention Study Trial Regardless of Causality (% of patients) Immediate-Release Fluvastatin Sodium 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 (9-16 years of age, 80% Caucasian, 19% Other [mixed ethnicity], 1% Asians) were treated with fluvastatin sodium administered as immediate-release fluvastatin sodium 20 mg - 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.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category X Fluvastatin sodium extended-release tablets are 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 extended-release tablets during pregnancy. Rare reports of congenital anomalies have been received following intrauterine exposure to other statins. In a review2 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 Non-Clinical Toxicology (13)]. Fluvastatin sodium extended-release tablets 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 extended-release tablets, 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 extended-release tablets [see Contraindications (4)]. 8.4 Pediatric Use The safety and efficacy of fluvastatin sodium extended-release tablets 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 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 extended-release tablets should be prescribed with caution in the elderly. 8.6 Hepatic Impairment Fluvastatin sodium extended-release tablets 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)].

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 extended-release tablets [see Contraindications (4)].