ANTARA (fenofibrate 43 mg) Dailymed

Recent Major Changes

Indications and Usage (1) 07/2024

Dosage and Administration (2) 07/2024

Warnings and Precautions, Mortality and Coronary Heart Disease Morbidity (5.1) 07/2024

1 Indications And Usage

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: 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).
• Renal impairment:  Initial dosage of 43 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 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 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 43 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) ]

3 Dosage Forms And Strengths

• Capsules: 43 mg and 130 mg (3).

Antara Capsules:

• 43 mg; capsules, imprinted with "43" and a segmented band, on the light green cap and "ANTARA" and "LUPIN" on the white to off-white body.
• 130 mg; capsules, imprinted with "130" and a segmented band, on the dark green cap and "ANTARA" and "LUPIN" on the white body.

4 Contraindications

• 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)].

5 Warnings And Precautions

• 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. Risks are increased during co-administration with a statin, particularly in elderly patients and patients with diabetes, renal failure, or uncontrolled 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 (5.3).
• Serum creatinine: Increases in serum creatinine have been reported in patients on Antara. Monitor renal function in patients with renal impairment taking Antara. Consider monitoring renal function in patients at risk for renal impairment (5.4).
• Cholelithiasis: Fenofibrate increases cholesterol excretion into the bile, leading to risk of cholelithiasis. If cholelithiasis is suspected, gallbladder studies are indicated (5.5).
• 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 fenofibrate and treat patients appropriately if reactions occur (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 43 mg or 130 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.