Fluvastatin Sodium

1 INDICATIONS AND USAGE 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

2 DOSAGE AND ADMINISTRATION 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.

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 fluvastatin if markedly elevated creatine kinase (CK) levels occur, or myopathy is diagnosed or suspected. Temporarily discontinue fluvastatin 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 fluvastatin dosage. Instruct patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. (5.1) Immune-Mediated Necrotizing Myopathy (IMNM): Rare reports of IMNM, an autoimmune myopathy, have been reported with statin use. Discontinue fluvastatin if IMNM is suspected. (5.2) 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 fluvastatin sodium extended-release tablets (5.3) 5.1 Myopathy and Rhabdomyolysis Fluvastatin 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 fluvastatin. 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 [see Adverse Reactions (6.1)]. 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) [see Drug Interactions (7.1)]. Steps to Prevent or Reduce the Risk of Myopathy and Rhabdomyolysis Avoid concomitant use of fluvastatin with gemfibrozil, cyclosporin, and fluconazole. When used concomitantly with fluvastatin, lipid modifying doses (≥ 1 g/day) of niacin, fibrates, and colchicine may also increase the risk of myopathy and rhabdomyolysis [see Drug Interactions (7.1)]. Discontinue fluvastatin if markedly elevated CK levels occur or if myopathy is either diagnosed or suspected. Muscle symptoms and CK increases may resolve if fluvastatin is discontinued. Temporarily discontinue fluvastatin 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 fluvastatin. Instruct patients to promptly report any unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. 5.2 Immune-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 fluvastatin if IMNM is suspected. 5.3 Hepatic Dysfunction Increases in serum transaminases have been reported with use of fluvastatin [see Adverse Reactions (6.…

4 CONTRAINDICATIONS 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)

7 DRUG INTERACTIONS Gemfibrozil : Avoid use with fluvastatin. (7.1) Cyclosporine and Fluconazole : Avoid use with fluvastatin. (7.1) Fibrates, Lipid-modifying doses (≥ 1 g/day) of Niacin, and Colchicine : Consider if the benefit of concomitant use with fluvastatin 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 is initiated. (7.2) Phenytoin : Monitor plasma phenytoin levels when fluvastatin treatment is initiated. (7.2) 7.1 Drug Interactions That Increase the Risk of Myopathy and Rhabdomyolysis with Fluvastatin 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 Gemfibrozil Clinical impact There is an increased risk of myopathy/rhabdomyolysis when fluvastatin is administered with gemfibrozil Intervention Avoid concomitant use of gemfibrozil with fluvastatin. Cyclosporine Clinical impact Cyclosporine coadministration increases fluvastatin exposure. The risk of myopathy and rhabdomyolysis may be increased with concomitant use of cyclosporine with fluvastatin. Intervention Avoid concomitant use of cyclosporine with fluvastatin. Fluconazole Clinical impact Fluconazole coadministration increases fluvastatin exposure. The risk of myopathy and rhabdomyolysis may be increased with concomitant use of fluconazole with fluvastatin. Intervention Avoid concomitant use of fluconazole with fluvastatin 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. Intervention Consider if the benefit of using lipid-modifying doses (≥ 1 g/day) of niacin concomitantly with fluvastatin 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. Intervention Consider if the benefit of using fibrates concomitantly with fluvastatin 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 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 Effects on Other Drugs Table 4 presents fluvastatins effect on other drugs and instructions for preventing or managing them. Table 4. Fluvastatin 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 and frequently enough after initiation or dis…

8.1 Pregnancy Risk Summary Discontinue fluvastatin when pregnancy is recognized. Alternatively, consider the ongoing therapeutic needs of the individual patient. Fluvastatin decreases synthesis of cholesterol and possibly other biologically active substances derived from cholesterol; therefore, fluvastatin may cause fetal harm when administered to pregnant patients based on the mechanism of action [see Clinical Pharmacology (12.1)] . 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 fluvastatin use in pregnant women are insufficient to determine if there is a drug-associated risk of miscarriage (see Data). 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 ) (see Data). 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 1,152 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 w…

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 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 Lannett Company, Inc. at 1-844-834-0530 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 2,326 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 capsulesa N = 2,326 (%) 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 Capsule Intervention Prevention Study (LIPS), the effect of fluvastatin capsules 40 mg, administered twice daily on the risk of recurrent cardiac events was assessed in 1,677 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 Adverse reaction Placebo N = 818 (%) Fluvastatin Capsules 40 mg twice daily N = 8…