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.

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 = 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 33/2,969 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.

12.3 Pharmacokinetics Absorption Fluvastatin administered as fluvastatin sodium extended-release 80 mg tablets reaches peak concentration in approximately 3 hours under fasting conditions, after a low-fat meal, or 2.5 hours after a low-fat meal. The mean relative bioavailability of the extended-release tablet is approximately 29% (range, 9% to 66%) compared to that of the fluvastatin immediate-release capsule administered under fasting conditions. Administration of a high-fat meal delayed the absorption (Tmax 6h) and increased the bioavailability of the extended-release tablet by approximately 50%. However, the maximum concentration of fluvastatin sodium extended-release tablets seen after a high-fat meal is less than the peak concentration following a single dose or twice daily dose of the 40 mg fluvastatin capsule. Distribution Fluvastatin is 98% bound to plasma proteins. The mean volume of distribution (VDss) is estimated at 0.35 L/kg. At therapeutic concentrations, the protein binding of fluvastatin is not affected by warfarin, salicylic acid and glyburide. Elimination Metabolism Fluvastatin is metabolized in the liver, primarily via hydroxylation of the indole ring at the 5- and 6-positions. N-dealkylation and beta-oxidation of the side-chain also occurs. The hydroxy metabolites have some pharmacologic activity, but do not circulate in the blood. Fluvastatin has two enantiomers. Both enantiomers of fluvastatin are metabolized in a similar manner. In vitro data indicate that fluvastatin metabolism involves multiple Cytochrome P450 (CYP) isozymes. CYP2C9 isoenzyme is primarily involved in the metabolism of fluvastatin (approximately 75%), while CYP2C8 and CYP3A4 isoenzymes are involved to a much less extent, i.e., approximately 5% and approximately 20%, respectively. Excretion Following oral administration, fluvastatin is primarily (about 90%) excreted in the feces as metabolites, with less than 2% present as unchanged drug. Approximately 5% of a radiolabeled oral dose were recovered in urine. The elimination half-life (t 1/2 ) of fluvastatin is approximately 3 hours. Specific Populations Geriatric Patients Plasma levels of fluvastatin are not significantly different in patients age > 65 years compared to patients age 21 to 49 years. Gender In a study evaluating the effect of age and gender on fluvastatin pharmacokinetics, there were no significant differences in fluvastatin exposures between males and females, except between younger females and younger males (both ages 21-49 years), where there was an approximate 30% increase in area under the curve (AUC) in females. Adjusting for body weight decreases the magnitude of the differences seen. For fluvastatin sodium extended-release tablets, the AUC increases 67% and 77% for women compared to men under fasted and high-fat meal fed conditions, respectively. Pediatric Patients Pharmacokinetic data in the pediatric population are not available. Patients with Renal Impairment In patients with moderate to severe renal impairment (CLCr 10-40 mL/min), AUC and Cmax increased approximately 1.2-fold after administration of a single dose of 40 mg fluvastatin compared to healthy volunteers. In patients with end-stage renal disease on hemodialysis, the AUC increased by approximately 1.5-fold. Fluvastatin sodium extended-release tablets were not evaluated in patients with renal impairment [see Use in Specific Populations (8.6)]. However, systemic exposures after administration of fluvastatin sodium extended-release tablets are lower than after the 40 mg immediate release capsule. Patients with Hepatic Impairment In patients with hepatic impairment due to liver cirrhosis, fluvastatin AUC and Cmax increased approximately 2.5-fold compared to healthy subjects after administration of a single 40 mg dose [see Use in Specific Populations (8.7)]. The enantiomer ratios of the two isomers of fluvastatin in hepatic impairment patients were comparable to those observed in healthy subjects. Drug Interaction Studies Data from drug-drug interactions studies involving coadministration of gemfibrozil, niacin, itraconazole, erythromycin, tolbutamide or clopidogrel indicate that the PK disposition of fluvastatin is not significantly altered when fluvastatin is coadministered with any of these drugs. The below listed drug interaction information is derived from studies using fluvastatin capsules. Similar studies have not been conducted using the fluvastatin sodium extended-release tablets. Table 5. Effect of Coadministered Drugs on Fluvastatin Systemic Exposure Coadministered drug and dosing regimen Fluvastatin Dose (mg) a Change in AUC b Change in Cmax b Cyclosporine – stable dose (twice daily) c 20 mg once daily for 14 weeks ↑90% ↑30% Fluconazole 400 mg once daily 1,200 mg twice daily 2 to 4 c 40 mg once daily ↑84% ↑44% Cholestyramine 8 g once daily 20 mg once daily administered 4 hrs after a meal plus cholestyramine ↓51% ↓83% Rifampicin 600 mg once daily for 6 days 20 mg once daily ↓53% ↓42% Cimetidine 400 mg twice daily for 5 days, once daily on Day 6 20 mg once daily ↑30% ↑40% Ranitidine 150 mg twice daily for 5 days, once daily on Day 6 20 mg once daily ↑10% ↑50% Omeprazole 40 mg once daily for 6 days 20 mg once daily ↑20% ↑37% Phenytoin 300 mg once daily 40 mg twice daily for 5 days ↑40% ↑27% Propranolol 40 mg twice daily for 3.5 days 40 mg once daily ↓5% No change Digoxin 0.1 to 0.5 mg once daily for 3 weeks 40 mg once daily No change ↑11% Diclofenac 25 mg once daily 40 mg once daily for 8 days ↑50% ↑80% Glyburide 5 mg to 20 mg once daily for 22 days 40 mg twice daily for 14 days ↑51% ↑44% Warfarin 30 mg once daily 40 mg once daily for 8 days ↑30% ↑67% Clopidogrel 300 mg loading dose on Day 10, 75 mg once daily on Days 11 to 19 80 mg extended-release once daily for 19 days ↓2% ↑27% Abbreviation: AUC, area under the curve. a Single dose unless otherwise noted. b Mean ratio (with/without coadministered drug and no change = 1-fold) or % change (with/without coadministered drug and no change = 0%); symbols of ↑ and ↓ indicate the exposure increase and decrease, respectively. c Considered clinically significant [see Dosage and Administration (2.4), Drug Interactions (7.1)]. Data from drug-drug interaction studies involving fluvastatin and coadministration of either gemfibrozil, tolbutamide or losartan indicate that the PK disposition of either gemfibrozil, tolbutamide or losartan is not significantly altered when coadministered with fluvastatin. Table 6. Effect of Fluvastatin Coadministration on Systemic Exposure of Other Drugs Co-administered drug Fluvastatin dosage regimen Name and dose (mg) a Change in AUC b Change in Cmax b 40 mg once daily for 5 days Phenytoin 300 mg once daily c ↑20% ↑5% 40 mg twice daily for 21 days Glyburide 5 to 20 mg once daily for 22 days c ↑70% ↑50% 40 mg once daily for 8 days Diclofenac 25 mg once daily ↑25% ↑60% 40 mg once daily for 8 days Warfarin 30 mg once daily S-warfarin: ↑7% S-warfarin: ↑10% R-warfarin: no change R-warfarin: ↑6% Abbreviation: AUC, area under the curve. a Single dose unless otherwise noted. b Mean ratio (with/without coadministered drug and no change = 1-fold) or % change (with/without coadministered drug and no change = 0%); symbols of ↑ and ↓ indicate the exposure increase and decrease, respectively. c Considered clinically significant [see Drug Interactions (7.2)].