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: • 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. • Do not break, crush or chew LESCOL XL tablets prior to administration. • Adults : The recommended starting dose is 80 mg (administered as one 80 mg LESCOL XL once daily). 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.

2.1Important 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 . • 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.

2.2Recommended Dosage in Adult Patients The

recommended dosage for LESCOL XL is 80 mg once daily.

2.3Recommended 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.

5 WARNINGS AND PRECAUTIONS • Myopathy and Rhabdomyolysis : Risk factors include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, and concomitant use with certain other drugs. Discontinue LESCOL XL if markedly elevated creatine kinase (CK) levels occur, or myopathy is diagnosed or suspected. Temporarily discontinue LESCOL XL in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis. Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing LESCOL XL dosage. Instruct patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. • Immune-Mediated Necrotizing Myopathy (IMNM) : Rare reports of IMNM, an autoimmune myopathy, have been reported with statin use. Discontinue LESCOL XL if IMNM is suspected. • Hepatic Dysfunction : Increases in serum transaminases have occurred, some persistent. Rare reports of fatal and non-fatal hepatic failure have occurred. Consider testing liver enzyme before initiating therapy and as clinically indicated thereafter. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue LESCOL XL

5.1Myopathy and Rhabdomyolysis

LESCOL XL may cause myopathy (muscle pain, tenderness, or weakness associated with elevated creatine kinase [CK]) and rhabdomyolysis. Acute kidney injury secondary to myoglobinuria and rare fatalities have occurred as a result of rhabdomyolysis with statins, including LESCOL XL. Myopathy, defined as muscle aching or muscle weakness in conjunction with increases in CK, values to greater than 10 times the upper limit of normal (ULN) was < 0.1% in fluvastatin clinical trials . Risk Factors for Myopathy Risk factors for myopathy include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, and concomitant use with certain other drugs (including other lipid-lowering therapies) . Steps to Prevent or Reduce the Risk of Myopathy and Rhabdomyolysis Avoid concomitant use of LESCOL XL with gemfibrozil, cyclosporin, and fluconazole. When used concomitantly with LESCOL XL, lipid modifying doses (≥ 1 g/day) of niacin, fibrates, and colchicine may also increase the risk of myopathy and rhabdomyolysis . Discontinue LESCOL XL if markedly elevated CK levels occur or if myopathy is either diagnosed or suspected.

Muscle symptoms and CK increases may resolve if LESCOL XL is discontinued. Temporarily discontinue LESCOL XL in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis, e.g., sepsis, shock, severe hypovolemia, major surgery, trauma, severe metabolic, endocrine, or electrolyte disorders, or uncontrolled epilepsy. Inform patients of the risk of myopathy and rhabdomyolysis when starting LESCOL XL. Instruct patients to promptly report any unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever.

5.2Immune-Mediated Necrotizing Myopathy There

have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use, including reports of recurrence when the same or a different statin was administered. IMNM is characterized by proximal muscle weakness and elevated serum CK, 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. Discontinue LESCOL XL if IMNM is suspected.

5.3Hepatic Dysfunction Increases in

serum transaminases have been reported with use of LESCOL XL . In most cases, these changes appeared soon after initiation, were transient, were not accompanied by symptoms, and resolved or improved on continued therapy or after a brief interruption in therapy. Persistent increases to more than three times the ULN in serum transaminases have occurred in approximately 1.1% of patients receiving fluvastatin in clinical trials. Marked persistent increases of hepatic transaminases have also occurred with fluvastatin.

There have been rare post-marketing reports of fatal and non-fatal hepatic failure in patients taking statins, including LESCOL XL. Patients who consume substantial quantities of alcohol and/or have a history of liver disease may be at increased risk for hepatic injury. Consider liver enzyme testing before LESCOL XL initiation and thereafter, when clinically indicated. LESCOL XL is contraindicated in patients with acute liver failure or decompensated cirrhosis . If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue LESCOL XL.

5.4Increases in HbA1c and Fasting Serum Glucose

Levels Increases in HbA1c and fasting serum glucose levels have been reported with statins, including LESCOL XL. Optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices.

4 CONTRAINDICATIONS LESCOL XL is contraindicated in patients with: • Acute liver failure or decompensated cirrhosis . • Hypersensitivity to fluvastatin or any of the excipients in LESCOL XL. Hypersensitivity reactions, including anaphylaxis, angioedema, and Stevens-Johnson syndrome have been reported . • Acute liver failure or decompensated cirrhosis • Hypersensitivity to fluvastatin or any excipient in LESCOL XL

8 USE IN SPECIFIC POPULATIONS • Pregnancy: May cause fetal harm • Lactation: Breastfeeding not recommended during treatment with LESCOL XL

8.1Pregnancy Risk Summary Discontinue

LESCOL XL when pregnancy is recognized. Alternatively, consider the ongoing therapeutic needs of the individual patient. LESCOL XL decreases synthesis of cholesterol and possibly other biologically active substances derived from cholesterol; therefore, LESCOL XL may cause fetal harm when administered to pregnant patients based on the mechanism of action . In addition, treatment of hyperlipidemia is not generally necessary during pregnancy.

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 hyperlipidemia for most patients. Available data from case series and prospective and retrospective observational cohort studies over decades of use with statins in pregnant women have not identified a drug-associated risk of major congenital malformations. Published data from prospective and retrospective observational cohort studies with LESCOL XL use in pregnant women are insufficient to determine if there is a drug-associated risk of miscarriage . In animal reproduction studies, no adverse developmental effects were observed in pregnant rats or rabbits orally administered fluvastatin during the period of organogenesis at doses that resulted in 2 and 5 times, respectively, the human exposure at the maximum recommended human dosage of 40 mg/day, based on body surface area (mg/m 2 ) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Human Data A Medicaid cohort linkage study of 1152 statin-exposed pregnant women compared to 886,996 controls did not find a significant teratogenic effect from maternal use of statins in the first trimester of pregnancy, after adjusting for potential confounders, including maternal age, diabetes mellitus, hypertension, obesity, and alcohol and tobacco use using propensity score-based methods. The relative risk of congenital malformations between the group with statin use and the group with no statin use in the first trimester was 1.07 (95% CI: 0.85 to 1.37) after controlling for confounders, particularly preexisting diabetes mellitus.

There were also no statistically significant increases in any of the organ-specific malformations assessed after accounting for confounders. In the majority of pregnancies, statin treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified. Study limitations include reliance on physician coding to define the presence of a malformation, lack of control for certain confounders such as body mass index, use of prescription dispensing as verification for the use of a statin, and lack of information on non-live births.

Animal Data Fluvastatin sodium given to rats during organogenesis at doses of 12 mg/kg/day and in rabbits at doses of 10 mg/kg/day produced delays in skeletal development. These doses resulted in 2 times (rat at 12 mg/kg) or 5 times (rabbit at 10 mg/kg) the 40 mg human exposure based on mg/m 2 surface area. Malaligned thoracic vertebrae were seen in rats at 36 mg/kg, a dose that produced significant maternal toxicity.

A study in which female rats were given fluvastatin during the third trimester at 12 and 24 mg/kg/day resulted in maternal mortality at or near term and postpartum. In addition, fetal and neonatal lethality were apparent. No effects on the dam or fetus occurred at 2 mg/kg/day. A second study at levels of 2, 6, 12 and 24 mg/kg/day confirmed the findings in the first study with neonatal mortality beginning at 6 mg/kg.

Rats were given fluvastatin from Gestation Day 15 to Lactation Day 21 at doses of 12 or 24 mg/kg/day with or without the presence of concurrent supplementation with mevalonic acid, a product of HMG-CoA reductase which is essential for cholesterol biosynthesis. The concurrent administration of mevalonic acid completely prevented the maternal and neonatal mortality but did not prevent low body weights in pups at 24 mg/kg on Days 0 and 7 postpartum.

8.2Lactation Risk Summary There

is no information about the presence of fluvastatin in human milk, the effects of the drug on the breastfed infant or the effects of the drug on milk production. However, it has been shown that another drug in this class passes into human milk. Studies in rats have shown that fluvastatin and/or its metabolites are present in the milk of lactating rats.

When a drug is present in animal milk, it is likely that the drug will be present in human milk . Statins, including LESCOL XL, decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol and may cause harm to the breastfed infant. Because of the potential for serious adverse reactions in a breastfed infant, based on the mechanism of action, advise patients that breastfeeding is not recommended during treatment with LESCOL XL . Data Following a single oral administration of 1 mg/kg of radioactive fluvastatin to lactating rats, the concentration of total radioactivity was determined. Fluvastatin and/or its metabolites were measured in the breast milk at a 2:1 ratio (milk:plasma).

8.4Pediatric Use The

safety and effectiveness of LESCOL XL as an adjunct to diet to reduce LDL-C have been established in pediatric patients 10 years of age and older with HeFH. Use of LESCOL XL for this indication is based on open-label, uncontrolled clinical trials in 114 pediatric patients 9 years of age and older with HeFH. In these limited uncontrolled studies, there was no significant effect on growth or sexual maturation in the males or females, or on menstrual cycle length in females. The safety and effectiveness of LESCOL XL have not been established in pediatric patients younger than 10 years of age with HeFH or in pediatric patients with other types of hyperlipidemia (other than HeFH).

8.5Geriatric Use Fluvastatin

exposures were not significantly different between the nonelderly and elderly populations (age ≥ 65 years) . Advanced age (≥ 65 years) is a risk factor for LESCOL XL-associated myopathy and rhabdomyolysis. Dose selection for an elderly patient should be cautious, recognizing the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of myopathy. Monitor geriatric patients receiving LESCOL XL for the increased risk of myopathy .

8.6Renal Impairment Renal

impairment is a risk factor for myopathy and rhabdomyolysis. 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, use LESCOL XL with caution in patients with severe renal impairment.

Monitor all patients with renal impairment for development of myopathy .

8.7Hepatic Impairment

LESCOL XL is contraindicated in patients with acute liver failure or decompensated cirrhosis .

The following serious adverse reactions are discussed in greater detail in other sections of the label: • Myopathy and Rhabdomyolysis • Immune-Mediated Necrotizing Myopathy • Hepatic Dysfunction • Increases in HbA1c and Fasting Serum Glucose Levels 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. 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.

6.1Clinical 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

7.1Headache

7.8 8.9

4.7Myalgia

4.5 5.0

3.8Abdominal

pain 3.8 4.9

3.7Dyspepsia

3.2 7.9

3.5Sinusitis

1.9 2.6

3.5Diarrhea

4.2 4.9

3.3Arthropathy

NA NA

3.2Urinary

tract infection 1.1 1.6

2.7Nausea

2.0 3.2

2.5Bronchitis

1.0 1.8

2.6Fatigue

2.3 2.7

1.6Flatulence

2.5 2.6

1.4Arthritis

2.0 2.1

1.3Allergy

2.2 2.3

1.0Insomnia

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 .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

6.3Hypertension

4.2

5.8Fatigue

3.8

4.7Dyspepsia

4.0

4.5Edema

peripheral 2.9

4.4Pain in

extremity 2.7

4.1Dizziness

3.5

3.9Constipation

2.1

3.3Nasopharyngitis

2.1

2.8Dyspnea

exertional 2.4

2.8Gastric

disorder 2.1

2.7Nausea

2.3

2.7Atrial

fibrillation 2.0

2.4Syncope

2.2

2.4Bronchitis

2.0

2.3Intermittent

claudication 2.1

2.3Myalgia

1.6

2.2Arthralgia

1.8

2.1Elevations 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.

6.2Postmarketing 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 . 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.