Lescol XL

1 INDICATIONS AND USAGE LESCOL XL is 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. LESCOL XL is 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

2 DOSAGE AND ADMINISTRATION • LESCOL XL 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 LESCOL XL tablets prior to administration. ( 2.1 ) • Adults : The recommended starting dose is 80 mg (administered as one 80 mg LESCOL XL 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. LESCOL XL is 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 LESCOL XL tablets orally once daily as a single dose, with or without food. • Do not break, crush, or chew LESCOL XL tablets. • LESCOL XL is only available as an 80 mg tablet. LESCOL XL 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 LESCOL XL 80 mg daily, prescribe alternative LDL-C-lowering treatment. • Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating LESCOL XL. 2.2 Recommended Dosage in Adult Patients The recommended dosage for LESCOL XL is 80 mg once daily. 2.3 Recommended Dosage in Pediatric Patients Aged 10 Years of Age and Older with HeFH LESCOL XL is 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 LESCOL XL is 80 mg once daily in pediatric patients 10 years of age and older who require 80 mg of fluvastatin.

4 CONTRAINDICATIONS LESCOL XL is 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 LESCOL XL. 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 LESCOL XL ( 4 )

Not available.

6 ADVERSE REACTIONS 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 LESCOL XL 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 LESCOL XL clinical trials there were 912 patients treated with LESCOL XL (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 LESCOL XL controlled trials with a frequency ≥ 2% included the following: Table 1. Adverse Reactions Reported in ≥ 2% in Patients Treated with Fluvastatin Capsules/LESCOL XL and at an Incidence Greater Than Placebo in Placebo-Controlled Trials Pooled Dosages Adverse reaction Placebo a N = 960 (%) Fluvastatin capsules a N = 2326 (%) LESCOL XL 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 LESCOL XL 80 mg Tablets as compared to fluvastatin capsules. In the LESCOL Intervention Prevention Study (LIPS), the effect of LESCOL (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/LESCOL XL and at an Incidence Greater Than Placebo in the LIPS Trial Table 2. Adverse Reactions Reported in ≥ 2% in Patients Treated with Fluvastatin Capsules/LESCOL XL 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 LESCOL 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 LESCOL XL 80 mg, fluvastatin capsules 40 mg and fluvastatin capsules 40 mg twice daily, respectively. In 13 of 16 patients treated with LESCOL XL the abnormality occurred within 12 weeks of initiation of treatment with LESCOL XL 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.