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/1.73m2), 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/ 1.73m2), 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)].

Antara capsules:

• 30 mg; size '4' capsules with opaque light green cap and opaque light green body, imprinted with LUPIN logo and "ANTARA"  in black ink on body, and "30" in black ink on cap, containing white to off-white pellets.
• 90 mg; size '3' capsules with opaque dark green cap and opaque white body, imprinted with LUPIN logo and "ANTARA"  in black ink on body, and "90" in black ink on cap, containing white to off-white pellets.

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)].

5.1 Mortality 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 [see Clinical Studies (14.4)].

Because of chemical, pharmacological, and clinical similarities between Antara, pemafibrate, clofibrate, and gemfibrozil, 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 [see Clinical Studies (14.4)].

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 one 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.

5.2 Hepatotoxicity

Serious drug-induced liver injury (DILI), including liver transplantation and death, has been reported postmarketing with 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, fenofibrate at dosages comparable to 30 mg or 90 mg of Antara per day has been associated with increases in serum AST or ALT.  The incidence of increases in transaminases may be dose related [see Adverse Reactions (6.1)]. 

Antara is contraindicated in patients with active liver disease, including those with unexplained persistent liver function abnormalities [see Contraindications (4)]. 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.

5.3 Myopathy 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 greater, uncontrolled hypothyroidism, renal impairment, and concomitant use with certain other drugs [see Drug Interaction (7) and Uses in Specific Populations (8.6)].

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 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 [see Drug Interactions (7) and Clinical Pharmacology (12.3)].

Cases of myopathy, including rhabdomyolysis, have been reported with Antara co-administered with colchicine. Consider whether the benefit of using colchicine concomitantly with Antara outweighs the increased risk of myopathy [see Drug Interactions (7)].

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.

5.4 Increases in Serum Creatinine

Increases in serum creatinine have been reported in patients on Antara. 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 the elderly 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 [see Dosage and Administration (2.3), Contraindications (4), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].

5.5 Cholelithiasis

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.

5.6 Increased Bleeding Risk with Coumarin Anticoagulants

Caution should be exercised when anticoagulants are given in conjunction with Antara because of the potentiation of coumarin-type anti-coagulants in prolonging the prothrombin time/International Normalized Ratio (PT/INR). To prevent bleeding complications, frequent monitoring of PT/INR and dosage adjustment of the anticoagulant are recommended until PT/INR has stabilized [see Drug Interactions (7)].

5.7 Pancreatitis

Pancreatitis has been reported in patients taking Antara. 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.

5.8 Hematologic Changes

Mild to moderate hemoglobin, hematocrit, and white blood cell decreases have been observed in patients following initiation of Antara. 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.

5.9 Hypersensitivity Reactions

Acute Hypersensitivity

Anaphylaxis and angioedema have been reported postmarketing with fenofibrate. 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 postmarketing, occurring days to weeks after initiation of Antara. 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 fenofibrate and treat patients appropriately if SCAR is suspected.

5.10 Venothromboembolic 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.

5.11 Paradoxical Decrease in HDL Cholesterol Levels

There have been postmarketing and clinical trial reports of severe decreases in HDL cholesterol levels (as low as 2 mg/dL) occurring in patients with and without diabetes initiated on fibrate therapy. 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.

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.

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.

8.1 Pregnancy

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 dose of 90 mg of Antara daily, based on body surface area (mg/m2). Adverse reproductive outcomes occurred at higher doses in the presence of maternal toxicity (see Data). 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 90 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.

8.2 Lactation

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 [see Contraindications (4)].

8.4 Pediatric Use

The safety and effectiveness of Antara have not been established in pediatric patients with severe hypertriglyceridemia or primary hyperlipidemia.

8.5 Geriatric Use

Assess renal function in elderly patients and follow contraindications and dosing recommendations for patients with renal impairment [see Contraindications (4), Warnings and Precautions (5.3, 5.4), and Use in Specific Populations (8.6)]. While fenofibric acid exposure is not influenced by age, elderly patients are more likely to have renal impairment, and fenofibric acid is substantially excreted by the kidney [see Clinical Pharmacology (12.3)].

Consider monitoring renal function in elderly patients taking Antara.

8.6 Renal Impairment

Antara is contraindicated in patients with severe renal impairment (eGFR <30 mL/min/1.73m2), including those with end-stage renal disease (ESRD) and those receiving dialysis [see Contraindications (4)]. Dose reduction is required in patients with mild to moderate renal impairment [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)]. Patients with severe renal impairment have 2.7-fold higher exposure of fenofibric acid and increased accumulation of fenofibric acid during chronic dosing compared with healthy volunteers. Renal impairment is a risk factor for myopathy and rhabdomyolysis [see Warnings and Precautions (5.3, 5.4), and Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

The use of Antara has not been evaluated in subjects with hepatic impairment. Antara is contraindicated in patients with active liver disease, including those with unexplained persistent liver function abnormalities [see Contraindications (4) and Clinical Pharmacology (12.3)].

12.1 Mechanism of Action

The active moiety of Antara is fenofibric acid. The pharmacological effects of fenofibric acid in both animals and humans have been studied through oral administration of fenofibrate.

The lipid-modifying effects of fenofibric acid seen in clinical practice have been explained in vivo in transgenic mice and in vitro in human hepatocyte cultures by the activation of PPAR alpha receptor. Through this mechanism, fenofibrate increases lipolysis and elimination of triglyceride-rich particles from plasma by activating lipoprotein lipase and reducing production of apoprotein C-III (an inhibitor of lipoprotein lipase activity).

12.2 Pharmacodynamics

Fenofibric acid, the active metabolite of fenofibrate, produces reductions in total cholesterol, total triglycerides, and triglyceride-rich lipoprotein (VLDL) in treated patients with severe hypertriglyceridemia.

12.3 Pharmacokinetics

Fenofibrate is a pro-drug of the active chemical moiety fenofibric acid. Fenofibrate is converted by ester hydrolysis in the body to fenofibric acid which is the active constituent measurable in the circulation.

Absorption: The absolute bioavailability of fenofibrate cannot be determined as the compound is virtually insoluble in aqueous media suitable for injection. Fenofibrate is insoluble in water and its bioavailability is optimized when taken with meals. However, after fenofibrate is dissolved, fenofibrate is well absorbed from the gastrointestinal tract. Following oral administration in healthy volunteers, approximately 60% of a single dose of  radiolabeled fenofibrate appeared in urine, primarily as fenofibric acid and its glucuronate conjugate, and 25% was excreted in the feces. Peak plasma levels of fenofibric acid from Antara capsules 90 mg occur within 2 to 6 hours after administration.

Effect of Food

The extent of absorption of fenofibric acid was unaffected when Antara was taken either in fasted state or with a low-fat meal. However, the Cmax of Antara increased in the presence of a low-fat meal. Tmax was unaffected in the presence of a low-fat meal. In the presence of a high-fat meal, there was a 26.7% increase in AUC and 15.35% increase in Cmax of fenofibric acid from Antara capsule 30mg relative to fasting state.

Distribution: In healthy volunteers, steady-state plasma levels of fenofibric acid were shown to be achieved within a week of dosing and did not demonstrate accumulation across time following multiple dose administration. Serum protein binding was approximately 99% in normal and hyperlipidemic subjects.

Elimination

Metabolism: Following oral administration, fenofibrate is rapidly hydrolyzed by esterases to the active metabolite, fenofibric acid; no unchanged fenofibrate is detected in plasma.

Fenofibric acid is primarily conjugated with glucuronic acid and then excreted in urine. A small amount of fenofibric acid is reduced at the carbonyl moiety to a benzhydrol metabolite which is, in turn, conjugated with glucuronic acid and excreted in urine.

In vivo metabolism data indicate that neither fenofibrate nor fenofibric acid undergo oxidative metabolism (e.g., cytochrome P450) to a significant extent.

Excretion: After absorption, fenofibrate is mainly excreted in the urine in the form of metabolites, primarily fenofibric acid and fenofibric acid glucuronide. After administration of radio-labelled fenofibrate, approximately 60% of the dose appeared in the urine and 25% was excreted in the feces. Fenofibric acid is eliminated with a half-life of 23 hours, allowing once daily dosing.

Specific Populations

Geriatric Patients: In elderly volunteers aged 77 to 87 years, the oral clearance of fenofibric acid following a single oral dose of fenofibrate was 1.2 L/h, which compares to 1.1 L/h in young adults. This indicates that a similar dosage regimen can be used in the elderly with normal renal function, without increasing accumulation of the drug or metabolites [see Dosage and Administration (2.4) and Use in Special Populations (8.5)].

Pediatric Patients: Pharmacokinetics of Antara has not been studied in pediatric patients.

Male and Female Patients: No pharmacokinetic difference between males and females has been observed for fenofibrate.

Racial and Ethnic Groups: The influence of race on the pharmacokinetics of fenofibrate has not been studied; however, fenofibrate is not metabolized by enzymes known for exhibiting inter-ethnic variability.

Patients with Renal Impairment: The pharmacokinetics of fenofibric acid was examined in patients with mild, moderate, and severe renal impairment. Patients with severe renal impairment [creatinine clearance(CrCl) ≤ 30 mL/min or estimated glomerular filtration rate(eGFR) < 30 mL/min/1.73m2] showed 2.7-fold increase in exposure for fenofibric acid and increased accumulation of fenofibric acid during chronic dosing compared to that of healthy subjects. Patients with mild to moderate renal impairment (CrCl 30 mL/min to 80 mL/min or eGFR 30 mL/min/1.73m2to 59 mL/min/1.73m2) had similar exposure but an increase in the half-life for fenofibric acid compared to that of healthy subjects. Based on these findings, the use of Antara is contraindicated in patients with severe renal impairment, including end-stage renal disease (ESRD) or those receiving dialysis.  Dose reduction is required in patients having mild to moderate renal impairment [see Dosage and Administration (2.4)].

Patients with Hepatic Impairment: No pharmacokinetic studies have been conducted in patients having hepatic impairment.

Drug-Drug Interaction Studies: In vitro studies using human liver microsomes indicate that fenofibrate and fenofibric acid are not inhibitors of cytochrome (CYP) P450 isoforms CYP3A4, CYP2D6, CYP2E1, or CYP1A2. They are weak inhibitor of CYP2C8, CYP2C19 and CYP2A6, and mild-to-moderate inhibitors of CYP2C9 at therapeutic concentrations.

Table 3 describes the effects of co-administered drugs on fenofibric acid systemic exposure.

Table 4 describes the effects of co-administered fenofibric acid on exposure to other drugs.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis: Two dietary carcinogenicity studies have been conducted in rats with fenofibrate. In the first 24-month study, Wistar rats were dosed with fenofibrate at 10 mg/kg/day, 45 mg/kg/day, and 200 mg/kg/day, approximately 0.3 times, 1 times, and 6 times the maximum recommended human dose (MRHD), based on body surface area comparisons (mg/m2). At a dose of 200 mg/kg/day (at 6 times the MRHD), the incidence of liver carcinoma was significantly increased in both sexes. A statistically significant increase in pancreatic carcinomas was observed in males at 1 and 6 times the MRHD; an increase in pancreatic adenomas and benign testicular interstitial cell tumors was observed in males at 6 times the MRHD. In a second 24-month study in a different strain of rats (Sprague-Dawley), doses of 10 mg/kg/day and 60 mg/kg/day (0.3 and 2 times the MRHD) produced significant increases in the incidence of pancreatic acinar adenomas in both sexes and increases in testicular interstitial cell tumors in males at 2 times the MRHD.

A 117-week carcinogenicity study was conducted in rats comparing three drugs: fenofibrate 10 mg/kg/day and 60 mg/kg/day (0.3 and 2 times the MRHD), clofibrate (400 mg/kg/day; 2 times the human dose), and gemfibrozil (250 mg/kg/day; 2 times the human dose, based on mg/m2surface area). Fenofibrate increased pancreatic acinar adenomas in both sexes. Clofibrate increased hepatocellular carcinomas in males and hepatic neoplastic nodules in females. Gemfibrozil increased hepatic neoplastic nodules in males and females, while all three drugs increased testicular interstitial cell tumors in males.

In a 21-month study in CF-1 mice, fenofibrate 10 mg/kg/day, 45 mg/kg/day, and 200 mg/kg/day (approximately 0.2 times, 1 times, and 3 times the MRHD on the basis of mg/m2surface area) significantly increased the liver carcinomas in both sexes at 3 times the MRHD. In a second 18-month study at 10 mg/kg/day, 60 mg/kg/day, and 200 mg/kg/day, fenofibrate significantly increased the liver carcinomas in male mice and liver adenomas in female mice at 3 times the MRHD.

Electron microscopy studies have demonstrated peroxisomal proliferation following fenofibrate administration to the rat. An adequate study to test for peroxisome proliferation in humans has not been done, but changes in peroxisome morphology and numbers have been observed in humans after treatment with other members of the fibrate class when liver biopsies were compared before and after treatment in the same individual.

Mutagenesis: Fenofibrate has been demonstrated to be devoid of mutagenic potential in the following tests: Ames, mouse lymphoma, chromosomal aberration and unscheduled DNA synthesis in primary rat hepatocytes.

Impairment of Fertility: In fertility studies rats were given oral dietary doses of fenofibrate, males received 61 days prior to mating and females 15 days prior to mating through weaning which resulted in no adverse effect on fertility at doses up to 300 mg/kg/day (approximately 10 times the MRHD, based on mg/m2surface area comparisons).

14.1 Overview of Clinical Trials

The effectiveness 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 [see Clinical Pharmacology (12.3)].

14.2 Clinical Trials in Adults with Hypertriglyceridemia

The effects of fenofibrate on serum triglycerides were studied in two randomized, double-blind, placebo-controlled clinical trials of 147 patients with hypertriglyceridemia. Patients were treated for eight weeks under protocols that differed only in that one entered patients with baseline TG levels of 500 to 1,500 mg/dL, and the other TG levels of 350 to 499 mg/dL. In patients with hypertriglyceridemia and normal cholesterolemia with or without hyperchylomicronemia, treatment with fenofibrate decreased primarily very low-density lipoprotein (VLDL) triglycerides and VLDL cholesterol. Treatment of patients with elevated triglycerides often results in an increase of LDL-C (See Table 5).

The effect of Antara on serum triglycerides was studied in a double-blind, randomized, 3 arm parallel-group trial of 146 patients. The study population was comprised of 61% male and 39% female patients. Approximately 70% of patients had hypertension and 32% had diabetes. Patients were treated for eight weeks with either a formulation of Antara comparable to 90 mg taken once daily with meals, a formulation of Antara comparable to 90 mg taken once daily between meals, or placebo. Antara, whether taken with meals or between meals, had comparable effects on TG and all lipid parameters (See Table 6).

14.3 Clinical Trials in Adults with Primary Hyperlipidemia

The effects of fenofibrate were assessed in four randomized, placebo-controlled, double-blind, parallel group trials in patients with hyperlipidemia and mixed dyslipidemia. Fenofibrate therapy reduced LDL-C, Total-C, and triglycerides, and increased HDL-C (See Table 7).

14.4 Lack of Efficacy in Cardiovascular Outcomes Trials

Fenofibrate did not reduce cardiovascular disease morbidity or mortality in two large, randomized controlled trials of patients with type 2 diabetes mellitus.

The Action to Control Cardiovascular Risk in Diabetes Lipid (ACCORD Lipid) (NCT00000620) trial was a randomized placebo-controlled trial of 5,518 patients (2,765 assigned to receive fenofibrate) with type 2 diabetes mellitus on background statin therapy treated with fenofibrate. The mean age at baseline was 62 years and 31% were female. Overall, 68% were White, 15% were Black or African American; 7% identified as Hispanic or Latino. The mean duration of follow-up was 4.7 years. The primary outcome of major adverse cardiovascular events (MACE), a composite of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular disease death was a HR of 0.92 (95% CI, 0.79 to 1.08) for fenofibrate plus statin combination therapy as compared to statin monotherapy.

The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial was a 5-year randomized, placebo-controlled trial of 9,795 patients (4,895 assigned to receive fenofibrate) with type 2 diabetes mellitus treated with fenofibrate. The mean age at baseline was 62 years, 37% were female, and 93% were White. The primary outcome of coronary heart disease events was a HR of 0.89, (95% CI 0.75 to 1.05) with fenofibrate compared to placebo. The HR for total and coronary heart disease mortality, respectively, was 1.11 (95% CI, 0.95 to 1.29) and 1.19 (95% CI, 0.90 to 1.57) with fenofibrate as compared to placebo.

Because of chemical, pharmacological, and clinical similarities between fenofibrate and pemafibrate, findings in a large randomized, placebo-controlled clinical trial with pemafibrate are relevant for 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 (NCT03071692). The trial was a randomized placebo-controlled trial of 10,497 patients (5,240 assigned to receive pemafibrate) with type 2 diabetes mellitus on background lipid-lowering therapy. The median age at baseline was 64 years and 28% were female. Overall, 86% were White, 5% were Asian, 3% were Black or African American; 19% identified as Hispanic or Latino. The median duration of follow-up was 3.4 years. The primary outcome of major adverse cardiovascular events (MACE), a composite of non-fatal myocardial infarction, non-fatal ischemic stroke, coronary revascularization, and death from cardiovascular causes, was a HR of 1.03 (95% CI, 0.91 to 1.15) for pemafibrate plus statin combination therapy as compared to statin monotherapy.

Manufactured for:

Lupin Pharmaceuticals, Inc

Baltimore, Maryland 21202

United States.

Manufactured by:

Lupin Limited

Goa - 403 722

India

Or

Lupin Limited

Pithampur (M.P.) - 454 775

India

Or

Lupin Limited

Nagpur - 441 108

India

For medical inquiries, call Lupin Pharmaceuticals, Inc. at 1-800-399-2561.

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