ANTARA

Antara (fenofibrate) Capsule, is a peroxisome proliferator-activated receptor (PPAR) alpha agonist available as capsules for oral administration. Each capsule contains 30 mg or 90 mg of micronized fenofibrate. The chemical name for fenofibrate is 2-[4-(4-chlorobenzoyl) phenoxy] 2-methyl-propanoic acid, l-methylethyl ester with the following structural formula: Fenofibrate The empirical formula is C 20 H 21 O 4 Cl and the molecular weight is 360.83; fenofibrate is insoluble in water. The melting point is 79°C to 82°C. Fenofibrate is a white solid which is stable under ordinary conditions. Inactive Ingredients : Each gelatin capsule contains hypromellose, simethicone emulsion, sodium lauryl sulphate, sugar spheres and talc. The capsule shell contains the following inactive ingredients: black iron oxide, D & C Yellow 10, potassium hydroxide, propylene glycol, gelatin, shellac, sodium lauryl sulphate, titanium dioxide. The 30 mg capsule shell contains following additional inactive ingredients: FD & C Blue 2, yellow iron oxide. The 90 mg capsule shell contains following additional inactive ingredients: FD & C Blue 1, FD & C Yellow 6. Fenofibrate

Antara is indicated as adjunctive therapy to diet: To reduce triglyceride (TG) levels in adults with severe hypertriglyceridemia (TG greater than or equal to 500 mg/dL). To reduce elevated low-density lipoprotein cholesterol (LDL-C) in adults with primary hyperlipidemia when use of recommended LDL-C lowering therapy is not possible. Limitations of Use Markedly elevated levels of serum triglycerides (e.g., > 2,000 mg/dL) may increase the risk of developing pancreatitis. The effect of fenofibrate therapy on reducing this risk has not been determined [see Warnings and Precautions ( 5.7 )] . Fenofibrate did not reduce coronary heart disease morbidity and mortality in two large, randomized controlled trials of patients with type 2 diabetes mellitus [see Warnings and Precautions ( 5.1 ) and Clinical Studies ( 14.4 ) ]. Antara is a peroxisome proliferator receptor (PPAR) alpha agonist indicated as an adjunct to diet: To reduce triglyceride (TG) levels in adults with severe hypertriglyceridemia (TG greater than or equal to 500 mg/dL). (1). To reduce elevated low-density lipoprotein cholesterol (LDL-C) in adults with primary hyperlipidemia when use of recommended LDL-C lowering therapy is not possible (1). Limitations of Use: Markedly elevated levels of serum triglycerides (e.g., > 2,000 mg/dL) may increase the risk of developing pancreatitis. The effect of fenofibrate therapy on reducing this risk has not been determined. (1) Fenofibrate did not reduce coronary heart disease morbidity and mortality in two large, randomized controlled trials of patients with type 2 diabetes mellitus. (1)

Severe Hypertriglyceridemia : 30 mg to 90 mg orally once daily; the dose should be adjusted according to patient response ( 2.2 ). Primary hyperlipidemia : 90 mg orally once daily ( 2.2 ). Administer as a single dose, at any time of day, with or without food ( 2.2 ). Assess TG when clinically appropriate, as early as 4 to 8 weeks after initiating Antara. Discontinue Antara in patients who do not have an adequate response after two months of treatment ( 2.2 ). Renal impairment : Initial dosage of 30 mg orally once daily ( 2.3 ). Geriatric patients : Select the dosage on the basis of renal function ( 2.4 ). 2.1 Prior to Initiation of Antara Assess lipid levels before initiating therapy. Identify other causes (e.g., diabetes mellitus, hypothyroidism, or medications) of high triglyceride levels and manage as appropriate. Patients should be placed on an appropriate lipid-lowering diet before receiving Antara and should continue this diet during treatment with Antara. In patients with diabetes and fasting chylomicronemia, improve glycemic control prior to considering starting Antara. 2.2 Recommended Dosage and Administration • Severe hypertriglyceridemia : ○ The recommended dosage of Antara is 30 mg or 90 mg orally once daily. ○ Dosage should be individualized according to patient response, and should be adjusted if necessary following repeat lipid determinations at 4 to 8 week intervals. • Primary hyperlipidemia : ○ The recommended dosage of Antara is 90 mg orally once daily. • Administer Antara as a single dose at any time of day, with or without food. • Advise patients to swallow Antara capsules whole. Do not crush, break, dissolve, or chew capsules. • Assess TG when clinically appropriate, as early as 4 to 8 weeks after initiating Antara. Discontinue Antara in patients who do not have an adequate response after two months of treatment. • If a dose is missed, advise patients not to take an extra dose. Resume treatment with the next dose. • Advise patients to take Antara at least 1 hour before or 4 hours to 6 hours after a bile acid binding resin to avoid impeding its absorption. 2.3 Recommended Dosage in Patients with Renal Impairment Assess renal function prior to initiation of Antara and periodically thereafter [see Warnings and Precautions ( 5.4 )]. Treatment with Antara should be initiated at a dosage of 30 mg orally once daily in patients with mild to moderately impaired renal function (eGFR 30 to <60 mL/min/1.73m 2 ), and increased only after evaluation of the effects on renal function and TG levels at this dose. Antara is contraindicated in patients with severe renal impairment (eGFR <30 mL/min/ 1.73m 2 ), including those with end-stage renal disease (ESRD) and those receiving dialysis [see Contraindications ( 4 ), Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 ) ] 2.4 Recommended Dosage in Geriatric Patients Dosage selection for the elderly should be made on the basis of renal function [see Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 ) ].

Severe renal impairment, including those with end-stage renal disease (ESRD) and those receiving dialysis ( 4 ) Active liver disease, including those with unexplained persistent liver function abnormalities ( 4 ) Pre-existing gallbladder disease ( 4 ) Hypersensitivity to fenofibrate fenofibric acid, or any of the excipients in Antara ( 4 ) Antara is contraindicated in the following conditions: Severe renal impairment, including those with end-stage renal disease (ESRD) and those receiving dialysis [see Clinical Pharmacology ( 12.3 ) ]. Active liver disease, including those with unexplained persistent liver function abnormalities [see Warnings and Precautions ( 5.2 ) ]. Pre-existing gallbladder disease [see Warnings and Precautions ( 5.5 ) ]. Hypersensitivity to fenofibric acid, fenofibrate, or any of the excipients in Antara. Serious hypersensitivity reactions including anaphylaxis and angioedema have been reported with fenofibrate [see Warnings and Precautions ( 5.9 ) ].

The following serious adverse reactions are described below and elsewhere in the labeling: Mortality and coronary heart disease morbidity [see Warnings and Precautions ( 5.1 )] Hepatoxicity [see Warnings and Precautions ( 5.2 )] Myopathy and Rhabdomyolysis [see Warnings and Precautions ( 5.3 )] Increases in Serum Creatinine [see Warnings and Precautions ( 5.4 )] Cholelithiasis [see Warnings and Precautions ( 5.5 )] Increased Bleeding Risk with Coumarin Anticoagulants [see Warnings and Precautions ( 5.6 )] Pancreatitis [see Warnings and Precautions ( 5.7 )] Hematologic Changes [see Warnings and Precautions ( 5.8 )] Hypersensitivity reactions [see Warnings and Precautions ( 5.9 )] Venothromboembolic disease [see Warnings and Precautions ( 5.10 )] Most common adverse reactions (> 2% and greater than 1% in placebo) are abnormal liver tests, increased AST, increased ALT, increased CPK, and rhinitis ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-800-399-2561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect rates observed in clinical practice. The Safety of Antara has been established in adults with hypertriglyceridemia or primary hyperlipidemia based on adequate and well-controlled trials of other formulations of fenofibrate, referenced below as "fenofibrate" [see Clinical Studies ( 14 )]. Dosages of fenofibrate used in these trials were comparable to Antara 90 mg per day [see Clinical Pharmacology ( 12.3 )]. Adverse events reported by 2% or more of patients treated with fenofibrate (and greater than placebo) during double-blind, placebo-controlled trials are listed in Table 1. Adverse reactions led to discontinuation of treatment in 5% of patients treated with fenofibrate and in 3% treated with placebo. Increases in liver function tests were the most frequent events, causing discontinuation of fenofibrate treatment in 1.6% of patients in double-blind trials. Table 1 Adverse Reactions Reported by 2% or More of Patients Treated with Fenofibrate and Greater than Placebo During the Double-Blind, Placebo-Controlled Trials Adverse Reaction Placebo (N=365) Fenofibrate (N=439) Abnormal Liver Tests 1% 8% Abdominal Pain 4% 5% Increased ALT 2% 3% Increased AST 1% 3% Increased Creatine Phosphokinase 1% 3% Constipation 1% 2% Rhinitis 1% 2% Other Adverse Reactions Urticaria Urticaria was seen in 1.1 vs. 0%, and rash in 1.4 vs. 0.8% of fenofibrate and placebo patients, respectively, in controlled trials. Increases in Liver Enzymes In a pooled analysis of 10 placebo-controlled trials, increases to >3 times the upper limit of normal in ALT occurred in 5.3% of patients taking fenofibrate at doses comparable to 90 mg Antara daily versus 1.1% of patients treated with placebo. In an 8-week study, the incidence of ALT or AST elevations ≥ 3 times the upper limit of normal was 13% in patients receiving dosages comparable to 60 mg to 90 mg Antara daily and was 0% in those receiving dosages comparable to 30 mg or less Antara daily or placebo. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of fenofibrate. 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. Blood Disorders: Anemia Gastrointestinal Disorders: Pancreatitis General Disorder: Asthenia Hepatobiliary Disorders: Increased total bilirubin, hepatitis, cirrhosis Immune System Disorders: Anaphylaxis, angioedema Lipid Disorders: Severely depressed HDL-cholesterol levels Musculoskeletal Disorders: Myalgia, muscle spasms, rhabdomyolysis, arthralgia Renal and Urinary Disorders: Acute renal failure Respiratory Disorders: Interstitial lung disease Skin and Subcutaneous Tissue Disorders: Photosensitivity reactions. This may occur in patients who report a prior photosensitivity reaction to ketoprofen.

Table 2. Clinically Important Drug Interactions with Antara Statins Clinical Impact: Fibrates may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of fibrates with statins. Intervention: Consider if the benefit of using Antara concomitantly with statin therapy 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 of statin therapy. Colchicine Clinical Impact: Cases of myopathy and rhabdomyolysis have been reported with concomitant use of colchicine with fenofibrates. Intervention: Consider if the benefit of using colchicine concomitantly with Antara 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 dosage titration of colchicine. Coumarin Anticoagulants Clinical Impact: Fibrates may cause potentiation of coumarin-type anticoagulant effects with prolongation of the PT/INR. Intervention: Caution should be exercised when coumarin anticoagulants are given in conjunction with Antara. The dosage of the anticoagulants should be reduced to maintain the PT/INR at the desired level to prevent bleeding complications. Frequent PT/INR determinations are advisable until it has been definitely determined that the PT/INR has stabilized Immunosuppressants Clinical Impact: Immunosuppressants such as cyclosporine and tacrolimus can produce nephrotoxicity with decreases in creatinine clearance and rises in serum creatinine, and because renal excretion is the primary elimination route of fibrate drugs including Antara, there is a risk that an interaction will lead to deterioration of renal function. Intervention: The benefits and risks of using Antara with immunosuppressants and other potentially nephrotoxic agents should be carefully considered, and the lowest effective dosage employed and renal function monitored. Bile-Acid Binding Resins Clinical Impact: Bile-acid binding resins may bind other drugs given concurrently. Intervention: In patients taking a bile acid resin, administer Antara at least 1 hour before or 4 to 6 hours after the bile acid resin to avoid impeding its absorption. Consider if the benefit of concomitant use of statins or colchicine outweighs the increased risk of myopathy and rhabdomyolysis. Monitor patients for signs and symptoms of myopathy ( 7 ) Exercise caution in concomitant treatment with coumarin anticoagulants. Reduce the dosage of coumarin to maintain the PT/INR at the desired level to prevent bleeding complications ( 7 ). Consider the benefits and risks of concomitant use with immunosuppressants and other potentially nephrotoxic agents. Use the lowest effective dosage and monitor renal function ( 7 ). Administer Antara at least 1 hour before or 4 to 6 hours after the bile acid resins to avoid impeding its absorption ( 7 ).