Lupin Pharmaceuticals, Inc.

Antara

Brand

Generic: Fenofibrate

ID: 27437010906

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FORM

Capsule

STRENGTH

43 mg

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TL;DR — Quick Summary

Key facts from the full medication guide below

RECENT MAJOR CHANGES 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Prior to Initiation of Antara 2.2 Recommended Dosage and Administration

🩺What it's for

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.

💊How to take it

Severe Hypertriglyceridemia: 43 mg to 130 mg orally once daily; the dose should be adjusted according to patient response (2.2) Primary hyperlipidemia: 130 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).

ℹ️Common side effects

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)]…

⚠️Serious risks

Hepatotoxicity: Serious drug-induced liver injury, including liver transplantation and death, has been reported with 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 (5.2). Myopathy and rhabdomyolysis: Have been reported in patients taking fenofibrate.

📋Interactions & cautions

📦Storage & missed dose

Antara capsules are supplied as follows: Strength Description NDC Package Size (capsules per bottle) 43 mg Imprinted with "43" and a segmented band, on the light green cap and "ANTARA" and "LUPIN" on the white to off-white body, available in bottles of 30. NDC 27437 - 109 06 30 130 mg Imprinted with "130" and a segmented band, on the dark green cap and "ANTARA" and "LUPIN" on the white body, available in bottles of 30.

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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.

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 130 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.

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).

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 130 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 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.

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 radio-labeled 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 occur within 4 to 8 hours after administration. There was less than dose-proportional increase in the systemic exposure of fenofibric acid from 43 mg and 130 mg of fenofibrate under fasting conditions. Doses of three-capsules of 43 mg Antara given concurrently were dose equivalent to single-capsule doses of 130 mg. 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% increase in AUC and 108% increase in Cmax of fenofibric acid from Antara 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. Table 3 Effects of Co-Administered Drugs on Fenofibric Acid Systemic Exposure from Antara or Fenofibrate Administration 1TriCor (fenofibrate) oral tablet 2TriCor (fenofibrate) oral micronized capsule Co-Administered Drug Dosage Regimen of Co-Administered Drug Dosage Regimen of Fenofibrate Changes in Fenofibric Acid Exposure AUC Cmax Lipid-lowing agents Atorvastatin 20 mg once daily for 10 days Fenofibrate 160 mg1 once daily for 10 days 2% 4% Pravastatin 40 mg as a single dose Fenofibrate 3 x 67 mg2 as a single dose 1% 2% Fluvastatin 40 mg as a single dose Fenofibrate 160 mg1 as a single dose 2% 10% Anti-diabetic agents Glimepiride 1 mg as a single dose Fenofibrate 145 mg1 once daily for 10 days 1% 1% Metformin 850 mg three times daily for 10 days Fenofibrate 54 mg1 three times daily for 10 days 9% 6% Rosiglitazone 8 mg once daily for 5 days Fenofibrate 145 mg1 once daily for 14 days 10% 3% Table 4 Effects of Antara or Fenofibrate on Systemic Exposure of Co-Administered Drugs 1TriCor (fenofibrate) oral tablet 2TriCor (fenofibrate) oral micronized capsule Dosage Regimen of Fenofibrate Dosage Regimen of Co-Administered Drug Changes in Co-Administered Drug Exposure Analyte AUC Cmax Lipid-lowing agents Fenofibrate 160 mg1 once daily for 10 days Atorvastatin, 20 mg once daily for 10 days Atorvastatin 17% 0% Fenofibrate 3 x 67 mg2 as a single dose Pravastatin, 40 mg as a single dose Pravastatin 13% 13% 3 -Hydroxyl-iso-pravastatin 26% 29% Fenofibrate 160 mg1 as a single dose Fluvastatin, 40 mg as a single dose (+)-3R, 5S-Fluvastatin 15% 16% Anti-diabetic agents Fenofibrate 145 mg1 once daily for 10 days Glimepiride, 1 mg once daily as a single dose Glimepiride 35% 18% Fenofibrate 54 mg1 three times daily for 10 days Metformin, 850 mg three times daily for 10 days Metformin 3% 6% Fenofibrate 145 mg1 once daily for 14 days Rosiglitazone, 8 mg once daily for 5 days Rosiglitazone 6% 1%

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/m2 surface 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/m2 surface 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 (approximately10 times the MRHD, based on mg/m2 surface area comparisons).

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). Table 5 Effects of Fenofibrate in Patients with Hypertriglyceridemia *p < 0.05 vs. placebo Study 1 Placebo Fenofibrate Baseline TG levels 350 to 499 mg/dL N Baseline (mean) Endpoint (mean) % Change (mean) N Baseline (mean) Endpoint (mean) % Change (mean) Triglycerides 28 449 450 -0.5 27 432 223 -46.2 * VLDL Triglycerides 19 367 350 2.7 19 350 178 -44.1 * Total Cholesterol 28 255 261 2.8 27 252 227 -9.1 * HDL Cholesterol 28 35 36 4 27 34 40 19.6 * LDL Cholesterol 28 120 129 1.2 27 128 137 14.5 VLDL Cholesterol 27 99 99 5.8 27 92 46 -44.7 * Study 2 Placebo Fenofibrate Baseline TG levels 500 to 1500 mg/dL N Baseline (mean) Endpoint (mean) % Change (mean) N Baseline (mean) Endpoint (mean) % Change (mean) Triglycerides 44 710 750 7.2 48 726 308 -54.5 * VLDL Triglycerides 29 537 571 18.7 33 543 205 -50.6 * Total Cholesterol 44 272 271 0.4 48 261 223 -13.8 * HDL Cholesterol 44 27 28 5 48 30 36 22.9 * LDL Cholesterol 42 100 90 -4.2 45 103 131 45* VLDL Cholesterol 42 137 142 11 45 126 54 -49.4 * 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 130 mg taken once daily with meals, a formulation of Antara comparable to 130 mg taken once daily between meals, or placebo. Antara 130 mg, whether taken with meals or between meals, had comparable effects on TG and all lipid parameters (See Table 6). Table 6. Antara Treatment in Patients with Hypertriglyceridemia * p 0.05 vs placebo ** p 0.05 vs placebo (log transformed data) Placebo (n =50) Antara with meals (n=54) Antara between meals (n=42) Baseline mg/dL (mean) % Change at endpoint (mean) Baseline mg/dL (mean) % Change at endpoint (mean) Baseline mg/dL (mean) % Change at endpoint (mean) Triglycerides 479 +0.7 475 -36.7 * 487 -36.6 * Total Cholesterol 237 -0.8 248 -5.1 241 -3.4 HDL Cholesterol 35 +0.8 36 +13.7 * 36 +14.3 * Non-HDL Cholesterol 202 -1.1 212 -8.2 ** 205 -6.6 ** LDL Cholesterol 115 +3.2 120 +15.4 * 122 +14.5 VLDL Cholesterol 87 -1.6 92 -34.4 * 83 -30.4 *

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.