FLUVASTATIN SODIUM ER

Fluvastatin sodium inhibits 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 g/mol and its structural formula is: Fluvastatin sodium is a white to pale yellow, hygroscopic powder soluble in water, ethanol and methanol. Fluvastatin sodium is supplied as extended-release tablets containing 84.24 mg of fluvastatin sodium, equivalent to 80 mg of fluvastatin, for oral use. Fluvastatin sodium extended-release tablets contain the following inactive ingredients: 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

Fluvastatin sodium extended-release tablets are indicated: • To reduce the risk of undergoing coronary revascularization procedures and slow the progression of coronary atherosclerosis in adults with clinically evident coronary heart disease. • As an adjunct to diet to reduce low-density lipoprotein cholesterol (LDL-C) in adults with primary hyperlipidemia. • As an adjunct to diet to reduce LDL-C in adults and pediatric patients 10 years of age and older with heterozygous familial hypercholesterolemia (HeFH) who require 80 mg of fluvastatin daily. Fluvastatin sodium extended-release tablets are indicated ( 1 ): • To reduce the risk of undergoing coronary revascularization procedures and slow the progression of coronary atherosclerosis in adults with clinically evident coronary heart disease. • As an adjunct to diet to reduce low-density lipoprotein cholesterol (LDL-C) in adults with primary hyperlipidemia. • As an adjunct to diet to reduce LDL-C in adults and pediatric patients 10 years of age and older with heterozygous familial hypercholesterolemia (HeFH) who require 80 mg

• Fluvastatin sodium extended-release tablets 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 fluvastatin sodium extended-release tablets prior to administration. ( 2.1 ) • Adults : The recommended starting dose is 80 mg (administered as one 80 mg fluvastatin sodium extended-release tablet once daily). ( 2.2 ) Children : The recommended dose is 80 mg once daily in pediatric patients 10 years of age and older who require 80 mg of fluvastatin. Fluvastatin sodium extended-release tablets are not recommended for dosage initiation in pediatric patients because the recommended starting dosage cannot be achieved with the available strength of 80 mg. ( 2.3 ) 2.1 Important Dosage Information • Take fluvastatin sodium extended-release tablets orally once daily as a single dose, with or without food. • Do not break, crush, or chew fluvastatin sodium extended-release tablets. • Fluvastatin sodium extended-release tablet is only available as an 80 mg tablet. Fluvastatin sodium extended-release tablets cannot be titrated [see Dosage and Administration (2.2, 2.3)] . • For patients that require a high-intensity statin or are unable to achieve their LDL-C goal receiving fluvastatin sodium extended-release tablets 80 mg daily, prescribe alternative LDL-C-lowering treatment. • Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating fluvastatin sodium extended-release tablets. 2.2 Recommended Dosage in Adult Patients The recommended dosage for fluvastatin sodium extended-release tablets is 80 mg once daily. 2.3 Recommended Dosage in Pediatric Patients Aged 10 Years of Age and Older with HeFH Fluvastatin sodium extended-release tablets are not recommended for dosage initiation in pediatric patients because the recommended starting dosage cannot be achieved with the available strength of 80 mg. Recommend use of another fluvastatin product to initiate dosing in pediatric patients. The recommended dosage of fluvastatin sodium extended-release tablets is 80 mg once daily in pediatric patients 10 years of age and older who require 80 mg of fluvastatin.

Fluvastatin sodium extended-release tablets are contraindicated in patients with: • Acute liver failure or decompensated cirrhosis [see Warnings and Precautions ( 5.3 )] . • Hypersensitivity to fluvastatin or any of the excipients in fluvastatin sodium extended-release tablets. Hypersensitivity reactions, including anaphylaxis, angioedema, and Stevens-Johnson syndrome have been reported [see Adverse Reactions ( 6.2 )] . • Acute liver failure or decompensated cirrhosis ( 4 ) • Hypersensitivity to fluvastatin or any excipient in fluvastatin sodium extended-release tablets ( 4 )

The following serious adverse reactions are discussed in greater detail in other sections of the label: • Myopathy and Rhabdomyolysis [see Warnings and Precautions ( 5.1 )] • Immune-Mediated Necrotizing Myopathy [see Warnings and Precautions ( 5.2 )] • Hepatic Dysfunction [see Warnings and Precautions ( 5.3 )] • Increases in HbA1c and Fasting Serum Glucose Levels [see Warnings and Precautions ( 5.4 )] Most frequent adverse reactions occurring in ≥ 2.5% of subjects treated with fluvastatin sodium extended-release tablets and more than placebo are: influenza-like symptoms, sinusitis, dyspepsia, urinary tract infection, bronchitis, 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 Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In the fluvastatin capsule, clinical trials there were 2326 patients treated with fluvastatin (age range, 18 to 75 years, 44% women, 94% White, 4% Black or African American, 2% other ethnicities) with a median treatment duration of 24 weeks. 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 tablets clinical trials there were 912 patients treated with fluvastatin sodium extended-release tablets (age range, 21 to 87 years, 52% women, 91% White, 4% Black of African American, 5% other ethnicities) with a median treatment duration of 24 weeks. 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%). Adverse reactions occurring in the fluvastatin capsules and fluvastatin sodium extended-release tablets controlled trials with a frequency ≥ 2% included the following: Table 1. Adverse Reactions Reported in ≥ 2% in Patients Treated with Fluvastatin Capsules/ Fluvastatin Sodium Extended-Release Tablets and at an Incidence Greater Than Placebo in Placebo-Controlled Trials Pooled Dosages Adverse reaction Placebo a N = 960 (%) Fluvastatin capsules a N = 2326 (%) Fluvastatin sodium extended-release tablets b N = 912 (%) Influenza-like symptoms 5.7 5.1 7.1 Headache 7.8 8.9 4.7 Myalgia 4.5 5.0 3.8 Abdominal pain 3.8 4.9 3.7 Dyspepsia 3.2 7.9 3.5 Sinusitis 1.9 2.6 3.5 Diarrhea 4.2 4.9 3.3 Arthropathy NA NA 3.2 Urinary tract infection 1.1 1.6 2.7 Nausea 2.0 3.2 2.5 Bronchitis 1.0 1.8 2.6 Fatigue 2.3 2.7 1.6 Flatulence 2.5 2.6 1.4 Arthritis 2.0 2.1 1.3 Allergy 2.2 2.3 1.0 Insomnia 1.4 2.7 0.8 a Controlled trials with fluvastatin capsules (20 mg and 40 mg daily and 40 mg twice daily) compared to placebo. b Controlled trials with fluvastatin sodium extended-release 80 mg tablets as compared to fluvastatin capsules. In the Fluvastatin Capsules Intervention Prevention Study (LIPS), the effect of fluvastatin capsules 40 mg, administered twice daily on the risk of recurrent cardiac events was assessed in 1677 patients with coronary heart disease who had undergone a percutaneous coronary intervention. This was a multicenter, randomized, double-blind, placebo-controlled trial, 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. Adverse Reactions Reported in ≥ 2% in Patients Treated with Fluvastatin Capsules/ Fluvastatin Sodium Extended-Release Tablets and at an Incidence Greater Than Placebo in the LIPS Trial Table 2. Adverse Reactions Reported in ≥ 2% in Patients Treated with Fluvastatin Capsules/ Fluvastatin Sodium Extended-Release Tablets and at an Incidence Greater Than Placebo in the LIPS Trial Adverse reaction Placebo N = 818 (%) Fluvastatin Capsules 40 mg twice daily N = 822 (%) Abdominal pain upper 4.5 6.3 Hypertension 4.2 5.8 Fatigue 3.8 4.7 Dyspepsia 4.0 4.5 Edema peripheral 2.9 4.4 Pain in extremity 2.7 4.1 Dizziness 3.5 3.9 Constipation 2.1 3.3 Nasopharyngitis 2.1 2.8 Dyspnea exertional 2.4 2.8 Gastric disorder 2.1 2.7 Nausea 2.3 2.7 Atrial fibrillation 2.0 2.4 Syncope 2.2 2.4 Bronchitis 2.0 2.3 Intermittent claudication 2.1 2.3 Myalgia 1.6 2.2 Arthralgia 1.8 2.1 Elevations in Liver Enzyme Tests Approximately 1.1% of patients treated with fluvastatin capsules in clinical trials developed dose-related, persistent elevations of serum transaminase levels to more than 3 times the ULN. 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 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 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 ALT/AST increased 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 24-week controlled trials, persistent transaminase elevation occurred in 1.9%, 1.8%, and 4.9% of patients treated with fluvastatin sodium extended-release tablets 80 mg, fluvastatin capsules 40 mg and fluvastatin capsules 40 mg twice daily, respectively. In 13 of 16 patients treated with fluvastatin sodium extended-release tablets the abnormality occurred within 12 weeks of initiation of treatment with fluvastatin sodium extended-release tablets 80 mg. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of fluvastatin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Musculoskeletal : Muscle cramps, myopathy, rhabdomyolysis, arthralgias, muscle spasms, muscle weakness, myositis. There have been rare reports of IMNM 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, 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 the use of 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). There have been rare reports of new-onset or exacerbation of myasthenia gravis, including ocular myasthenia, and reports of recurrence when the same or a different statin was administered. Psychiatric : Anxiety, 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, lichen planus, 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.

• Gemfibrozil : Avoid use with fluvastatin sodium extended-release tablets. ( 7.1 ) • Cyclosporine and Fluconazole : Avoid use with fluvastatin sodium extended-release tablets. ( 7.1 ) • Fibrates, Lipid-modifying doses (≥ 1 g/day) of Niacin, and Colchicine : Consider if the benefit of concomitant use with fluvastatin sodium extended-release tablets outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dose titration. ( 7.1 ) • Warfarin : Obtain an International Normalized Ratio (INR) before starting and frequently enough after initiation or discontinuation to ensure that no significant alteration in INR occurs. Once the INR is stable, monitor INR at regular intervals. ( 7.2 ) • Glyburide : Monitor blood glucose levels when fluvastatin sodium extended-release tablets are initiated. ( 7.2 ) • Phenytoin : Monitor plasma phenytoin levels when fluvastatin sodium extended-release tablets treatment is initiated. ( 7.2 ) 7.1 Drug Interactions that Increase the Risk of Myopathy and Rhabdomyolysis with Fluvastatin Sodium Extended-Release Tablets Table 3 includes a list of drugs that increase the risk of myopathy and rhabdomyolysis when used concomitantly with fluvastatin and instructions for preventing or managing them [see Warnings and Precautions ( 5.1 ), Clinical Pharmacology ( 12.3 )] . Table 3. Drug Interactions That Increase the Risk of Myopathy and Rhabdomyolysis with Fluvastatin Sodium Extended-Release Tablets Gemfibrozil Clinical impact There is an increased risk of myopathy/rhabdomyolysis when fluvastatin sodium extended-release tablets are administered with gemfibrozil Intervention Avoid concomitant use of gemfibrozil with fluvastatin sodium extended-release tablets. Cyclosporine Clinical impact Cyclosporine coadministration increases fluvastatin exposure. The risk of myopathy and rhabdomyolysis may be increased with concomitant use of cyclosporine with fluvastatin sodium extended-release tablets. Intervention Avoid concomitant use of cyclosporine with fluvastatin sodium extended-release tablets. Fluconazole Clinical impact Fluconazole coadministration increases fluvastatin exposure. The risk of myopathy and rhabdomyolysis may be increased with concomitant use of fluconazole with fluvastatin sodium extended-release tablets. Intervention Avoid concomitant use of fluconazole with fluvastatin sodium extended-release tablets. Niacin Clinical impact Risk of myopathy and rhabdomyolysis may be enhanced with concomitant use with lipid-modifying doses (≥ 1 g/day) of niacin with fluvastatin sodium extended-release tablets. Intervention Consider if the benefit of using lipid-modifying doses (≥ 1 g/day) of niacin concomitantly with fluvastatin sodium extended-release tablets outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dose titration. Fibrates Clinical impact Fibrates may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis may be increased with concomitant use of fibrates with fluvastatin sodium extended-release tablets. Intervention Consider if the benefit of using fibrates concomitantly with fluvastatin sodium extended-release tablets outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dose titration. Colchicine Clinical impact Cases of myopathy and rhabdomyolysis have been reported with concomitant use of colchicine with fluvastatin. Intervention Consider if the benefit of using colchicine concomitantly with fluvastatin sodium extended-release tablets outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dose titration. 7.2 Fluvastatin Sodium Extended-Release Tablets Effects on Other Drugs Table 4 presents fluvastatin sodium extended-release tablets’ effects on other drugs and instructions for preventing or managing them. Table 4. Fluvastatin Sodium Extended-Release Tablets’ Effects on Other Drugs Warfarin Clinical impact There are postmarketing reports of clinically evident bleeding and/or increased INR in patients taking concomitant statins and warfarin. Intervention In patients taking warfarin, obtain an INR before starting fluvastatin sodium extended-release tablets and frequently enough after initiation or discontinuation to ensure that no significant alteration in INR occurs. Once the INR is stable, monitor INR at regularly recommended intervals. Glyburide Clinical impact Concomitant administration of fluvastatin and glyburide increased glyburide exposures [see Clinical Pharmacology ( 12.3 )] . Intervention Monitor blood glucose levels when fluvastatin sodium extended-release tablets are initiated. Phenytoin Clinical impact Concomitant administration of fluvastatin and phenytoin increased phenytoin exposures [see Clinical Pharmacology ( 12.3 )] . Intervention Monitor plasma phenytoin levels when fluvastatin sodium extended-release tablets are initiated.