Antara

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 TG (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 . Fenofibrate did not reduce coronary heart disease morbidity and mortality in two large, randomized controlled trials of patients with type 2 diabetes mellitus . Antara is a peroxisome proliferator-activated 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). 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 TG (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. Fenofibrate did not reduce coronary heart disease morbidity and mortality in two large, randomized controlled trials of patients with type 2 diabetes mellitus.

Severe hypertriglyceridemia : 43 mg to 130 mg orally once daily; the dosage should be adjusted according to patient response Primary hyperlipidemia : 130 mg orally once daily. Administer as a single dose, at any time of day, with or without food. 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 2 months of treatment. Renal impairment : Initial dosage of 43 mg orally once daily. Geriatric patients : Select the dosage on the basis of renal function.

2.1Prior to Initiation of Antara Assess

lipid levels before initiating therapy. Identify other causes (e.g., diabetes mellitus, hypothyroidism, or medications) of high TG 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.

2.2Recommended Dosage and Administration

• Severe hypertriglyceridemia : ○ The recommended dosage of Antara is 43 mg or 130 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 130 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 2 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.

2.3Recommended Dosage in Patients with Renal Impairment

Assess renal function prior to initiation of Antara and periodically thereafter . Treatment with Antara should be initiated at a dosage of 43 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 dosage. 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 .

2.4Recommended Dosage in Geriatric Patients Dosage

selection for geriatric patients should be made on the basis of renal function

Hepatotoxicity : Serious drug-induced liver injury, including liver transplantation and death, has been reported with fenofibrates, including Antara. Monitor patient's liver function, including serum ALT, AST, and total bilirubin, at baseline and periodically for the duration of therapy. Discontinue if signs or symptoms of liver injury develop or if elevated enzyme levels persist. Myopathy and Rhabdomyolysis: Have been reported in patients taking fenofibrates. Risks are increased during co-administration with a statin, in geriatric patients and in patients with renal impairment, or hypothyroidism. Discontinue Antara if markedly elevated CK levels occur or if myopathy is either diagnosed or suspected. Temporarily discontinue Antara 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 the Antara dosage. Instruct patients to promptly report any unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. Increases in Serum creatinine : Monitor renal function in patients with renal impairment taking Antara. Consider monitoring renal function in patients at risk for renal impairment. Cholelithiasis : Fenofibrate may increase cholesterol excretion into the bile, leading to cholelithiasis. If cholelithiasis is suspected, gallbladder studies are indicated. Hypersensitivity Reactions : Acute hypersensitivity reactions, including anaphylaxis and angioedema, and delayed hypersensitivity reactions, including severe cutaneous adverse drug reactions have been reported postmarketing. Some cases were life-threatening and required emergency treatment. Discontinue Antara and treat appropriately if reactions occur.

5.1Mortality and Coronary Heart Disease Morbidity

Fenofibrate did not reduce cardiovascular disease morbidity or mortality in two large, randomized controlled trials of patients with type 2 diabetes mellitus . Because of chemical, pharmacological, and clinical similarities between fenofibrates, including Antara; pemafibrate; clofibrate; and gemfibrozil; the findings in 5 large randomized, placebo-controlled clinical trials with these other fibrate drugs may also apply to Antara. Pemafibrate did not reduce cardiovascular disease morbidity or mortality in a large, randomized, placebo-controlled trial of patients with type 2 diabetes mellitus on background statin therapy . In the Coronary Drug Project, a large trial conducted from 1965 to 1985 in men post myocardial infarction, there was no difference in mortality or nonfatal myocardial infarction between the clofibrate group and the placebo group after 5 years of treatment (NCT00000482). In a trial conducted by the World Health Organization (WHO) from 1965 to 1976, men without known coronary artery disease were treated with placebo or clofibrate for 5 years and followed for an additional 1 year.

There was a statistically significant, higher age-adjusted all-cause mortality in the clofibrate group compared with the placebo group (5.70% vs. 3.96%, p≤0.01). Excess mortality was due to a 33% increase in non-cardiovascular causes, including malignancy, post-cholecystectomy complications, and pancreatitis. The Helsinki Heart Study, conducted from 1982 to 1987, was a large (n=4,081) trial of middle-aged men without a history of coronary artery disease.

Subjects received either placebo or gemfibrozil for 5 years, with a 3.5-year open extension afterward. Total mortality was numerically but not statistically higher in the gemfibrozil randomization group versus placebo [95% confidence interval (CI) of the hazard ratio (HR) 0.91 to 1.64]. A secondary prevention component of the Helsinki Heart Study treated middle-aged men with gemfibrozil or placebo for 5 years.

The HR for cardiac deaths was 2.2, 95% CI, 0.94 to 5.05.

5.2Hepatotoxicity Serious

drug-induced liver injury (DILI), including liver transplantation and death, has been reported with postmarketing use of fenofibrates, including Antara. DILI has been reported within the first few weeks of treatment or after several months of therapy and in some cases has reversed with discontinuation of Antara treatment. Patients with DILI have experienced signs and symptoms including dark urine, abnormal stool, jaundice, malaise, abdominal pain, myalgia, weight loss, pruritus, and nausea.

Many patients had concurrent elevations of total bilirubin, serum alanine transaminase (ALT), and aspartate transaminase (AST). DILI has been characterized as hepatocellular, chronic active, and cholestatic hepatitis, and cirrhosis has occurred in association with chronic active hepatitis. In clinical trials, an intermediate daily dosage or the maximum recommended daily dosage of fenofibrate have been associated with increases in serum AST or ALT. The incidence of increases in transaminases may be dose related . Antara is contraindicated in patients with active liver disease, including those with unexplained persistent liver function abnormalities.

Monitor patient's liver function, including serum ALT, AST, and total bilirubin, at baseline and periodically for the duration of therapy with Antara. Discontinue Antara if signs or symptoms of liver injury develop or if elevated enzyme levels persist (ALT or AST > 3 times the upper limit of normal, or if accompanied by elevation of bilirubin). Do not restart Antara in these patients if there is no alternative explanation for the liver injury.

5.3Myopathy and Rhabdomyolysis Antara

may cause myopathy [muscle pain, tenderness, or weakness associated with elevated creatine kinase (CK)] and rhabdomyolysis. Risk Factors for Myopathy Risk factors for myopathy include age 65 years or older, uncontrolled hypothyroidism, renal impairment, and concomitant use with certain other drugs . Steps to Prevent or Reduce the Risk of Myopathy and Rhabdomyolysis Data from observational studies indicate that the risk for rhabdomyolysis is increased when fibrates, including fenofibrates, are co-administered with a statin. Avoid concomitant use unless the benefit of further alterations in TG levels is likely to outweigh the increased risk of this drug combination . Cases of myopathy, including rhabdomyolysis, have been reported with fenofibrates, including Antara, co-administered with colchicine.

Consider whether the benefit of using colchicine concomitantly with Antara outweighs the increased risk of myopathy. . Discontinue Antara if markedly elevated CK levels occur or if myopathy is either diagnosed or suspected. Muscle symptoms and CK elevations may resolve if Antara is discontinued. Temporarily discontinue Antara 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 or increasing the Antara dosage. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever.

5.4Increases in Serum Creatinine Increases in

serum creatinine have been reported in patients receiving fenofibrates. These increases tend to return to baseline following discontinuation of Antara. The clinical significance of this finding is unknown. Monitor renal function in patients with renal impairment taking Antara. Renal monitoring should also be considered for patients taking Antara at risk for renal insufficiency, such as geriatric patients and patients with diabetes.

Antara is contraindicated in patients with severe renal impairment, including those with end-stage renal disease (ESRD) and those receiving dialysis .

5.5Cholelithiasis Fenofibrate

may increase cholesterol excretion into the bile, leading to cholelithiasis. If cholelithiasis is suspected, gallbladder studies are indicated. Antara therapy should be discontinued if gallstones are found. Antara is contraindicated in patients with pre-existing gallbladder disease.

5.6Increased Bleeding Risk with Coumarin Anticoagulants

Exercise caution when co-administering anticoagulants with Antara because of the potentiation of coumarin-type anticoagulant effects in prolonging the prothrombin time/International Normalized Ratio (PT/INR). To prevent bleeding complications, monitor the PT/INR frequently and adjust the dosage of the anticoagulant until the PT/INR has stabilized .

5.7Pancreatitis Pancreatitis

has been reported in patients taking fenofibrates. This occurrence may represent a failure of efficacy in patients with severe hypertriglyceridemia, a direct drug effect, or a secondary phenomenon mediated through biliary tract stone or sludge formation with obstruction of the common bile duct.

5.8Hematologic Changes Mild to

moderate hemoglobin, hematocrit, and white blood cell decreases have been observed in patients following initiation of therapy with fenofibrates. However, these levels stabilize during long-term administration. Thrombocytopenia and agranulocytosis have been reported in individuals treated with Antara.

Periodic monitoring of red and white blood cell counts is recommended during the first 12 months of Antara administration.

5.9Hypersensitivity Reactions Acute Hypersensitivity Anaphylaxis

and angioedema have been reported with postmarketing use of fenofibrates. In some cases, reactions were life-threatening and required emergency treatment. If a patient develops signs or symptoms of an acute hypersensitivity reaction, advise them to seek immediate medical attention and discontinue Antara.

Antara is contraindicated in patients with a hypersensitivity to fenofibrate, fenofibric acid, or any of the ingredients in Antara. Delayed Hypersensitivity Severe cutaneous adverse drug reactions (SCAR), including Stevens-Johnson syndrome, Toxic Epidermal Necrolysis, and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), have been reported with post-marketing use of fenofibrates, occurring days to weeks after treatment initiation. The cases of DRESS were associated with cutaneous reactions (such as rash or exfoliative dermatitis) and a combination of eosinophilia, fever, systemic organ involvement (renal, hepatic, or respiratory).

Discontinue Antara and treat patients appropriately if SCAR is suspected.

5.10Venothromboembolic Disease In the Fenofibrate Intervention and Event

Lowering in Diabetes (FIELD) trial, pulmonary embolus (PE) and deep vein thrombosis (DVT) were observed at higher rates in the fenofibrate than the placebo-treated group. Of 9,795 patients enrolled in FIELD, there were 4,900 in the placebo group and 4,895 in the fenofibrate group. For DVT, there were 48 events (1%) in the placebo group and 67 (1.4%) in the fenofibrate group (p = 0.074); and for PE, there were 32 (0.7%) events in the placebo group and 53 (1.1%) in the fenofibrate group (p = 0.022).

In the Coronary Drug Project, a higher proportion of the clofibrate group experienced definite or suspected fatal or nonfatal pulmonary embolism or thrombophlebitis than the placebo group (5.2% vs. 3.3% at five years; p < 0.01). In the cardiovascular outcome trial with pemafibrate, pulmonary embolism was reported for 37 (0.7%) subjects in the pemafibrate group and 16 (0.3%) subjects in the placebo group. Deep vein thrombosis was reported for 36 (0.7%) subjects in the pemafibrate group and 13 (0.2%) subjects in the placebo group.

5.11Paradoxical Decrease in

HDL Cholesterol Levels There have been postmarketing and clinical trial reports of severe decreases in high-density lipoprotein cholesterol (HDL-C) levels (as low as 2 mg/dL) occurring in patients with and without diabetes initiated on fibrate therapy, including fenofibrate. The decrease in HDL-C is mirrored by a decrease in apolipoprotein A1. This decrease has been reported to occur within 2 weeks to years after initiation of fibrate therapy.

The HDL-C levels remain depressed until fibrate therapy has been withdrawn; the response to withdrawal of fibrate therapy is rapid and sustained. The clinical significance of this decrease in HDL-C is unknown. Check HDL-C levels within the first few months after initiation of Antara.

If a severely depressed HDL-C level is detected, discontinue Antara and monitor HDL-C until it has returned to baseline. Antara should not be re-initiated.

Severe renal impairment, including those with end-stage renal disease (ESRD) and those receiving dialysis Active liver disease, including those with unexplained persistent liver function abnormalities Pre-existing gallbladder disease Hypersensitivity to fenofibrate fenofibric acid, or any of the excipients in Antara Antara is contraindicated in patients with: Severe renal impairment, including those with end-stage renal disease (ESRD) and those receiving dialysis . Active liver disease, including those with unexplained persistent liver function abnormalities . Pre-existing gallbladder disease . Hypersensitivity to fenofibrate, fenofibric acid, or any of the excipients in Antara. Serious hypersensitivity reactions including anaphylaxis and angioedema have been reported with fenofibrate .

8.1Pregnancy Risk Summary Limited

available data with fenofibrate use in pregnant women are insufficient to determine a drug associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, no evidence of embryo-fetal toxicity was observed with oral administration of fenofibrate in rats and rabbits during organogenesis at doses less than or comparable to the maximum recommended clinical dosage of 130 mg of Antara daily, based on body surface area (mg/m 2 ). Adverse reproductive outcomes occurred at higher doses in the presence of maternal toxicity . Antara should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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 Animal Data In pregnant rats given oral dietary doses of 14 mg/kg/day, 127 mg/kg/day, and 361 mg/kg/day from gestation day 6 to 15 during the period of organogenesis, no adverse developmental findings were observed at 14 mg/kg/day (less than the clinical exposure at the maximum recommended human dose [MRHD] of 300 mg fenofibrate daily, comparable to 130 mg Antara daily, based on body surface area comparisons).

Increased fetal skeletal malformations were observed at maternally toxic doses (361 mg/kg/day, corresponding to 12 times the clinical exposure at the MRHD) that significantly suppressed maternal body weight gain. In pregnant rabbits given oral gavage doses of 15 mg/kg/day, 150 mg/kg/day, and 300 mg/kg/day from gestation day 6 to 18 during the period of organogenesis and allowed to deliver, no adverse developmental findings were observed at 15 mg/kg/day (a dose that approximates the clinical exposure at the MRHD, based on body surface area comparisons). Aborted litters were observed at maternally toxic doses (≥ 150 mg/kg/day, corresponding to ≥ 10 times the clinical exposure at the MRHD) that suppressed maternal body weight gain.

In pregnant rats given oral dietary doses of 15 mg/kg/day, 75 mg/kg/day, and 300 mg/kg/day from gestation day 15 through lactation day 21 (weaning), no adverse developmental effects were observed at 15 mg/kg/day (less than the clinical exposure at the MRHD, based on body surface area comparisons), despite maternal toxicity (decreased weight gain). Post-implantation loss was observed at ≥ 75 mg/kg/day (≥ 2 times the clinical exposure at the MRHD) in the presence of maternal toxicity (decreased weight gain). Decreased pup survival was noted at 300 mg/kg/day (10 times the clinical exposure at the MRHD), which was associated with decreased maternal body weight gain/maternal neglect.

8.2Lactation Risk Summary There

is no available information on the presence of fenofibrate in human milk, effects of the drug on the breastfed infant, or the effects on milk production. Fenofibrate is present in the milk of rats, and is therefore likely to be present in human milk. Because of the potential for serious adverse reactions in breastfed infants, such as disruption of infant lipid metabolism, women should not breastfeed during treatment with Antara and for 5 days after the final dose.

The following serious adverse reactions are described below and elsewhere in the labeling: Mortality and coronary heart disease morbidity Hepatoxicity Myopathy and Rhabdomyolysis Increases in Serum Creatinine Cholelithiasis Increased Bleeding Risk with Coumarin Anticoagulants Pancreatitis Hematologic Changes Hypersensitivity reactions Venothromboembolic disease Paradoxical Decreases in HDL Cholesterol Levels Adverse reactions (> 2% and greater than placebo) abnormal liver tests, increased AST, increased ALT, increased CPK, and rhinitis. 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 .

6.1Clinical 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 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" . Dosages of fenofibrate used in these trials were comparable to Antara 90 mg per day . Adverse reactions reported by 2% or more of patients treated with fenofibrate (and greater than placebo) during the double-blind, placebo-controlled trials are listed in Table 1 below. 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 either an intermediate or the maximum recommended daily dosage of fenofibrate versus 1.1% of patients treated with placebo.

In an 8-week trial, the incidence of ALT or AST elevations ≥ 3 times the upper limit of normal was 13% in patients receiving an intermediate daily dosage or the maximum recommended daily dosage of fenofibrate and was 0% in those receiving the lowest recommended daily dosage of fenofibrate or placebo .

6.2Postmarketing 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: Anemia, white blood cell decreases Gastrointestinal: Pancreatitis General: Asthenia Hepatobiliary: Increased total bilirubin, hepatitis, cirrhosis Immune System: Anaphylaxis, angioedema Lipid Disorders: Severely depressed HDL-cholesterol levels Musculoskeletal: Myalgia, muscle spasms, rhabdomyolysis, arthralgia Renal and Urinary: Acute renal failure Respiratory: Interstitial lung disease Skin and Subcutaneous Tissue: Photosensitivity reactions, days to months after initiation.

This may occur in patients who report a prior photosensitivity reaction to ketoprofen.