Fenofibric Acid Drug Information

Prior to Initiation of Fenofibric Acid Delayed-Release Capsules • 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 fenofibric acid delayed-release capsules, and should continue this diet during treatment with fenofibric acid delayed-release capsules. • In patients with diabetes and fasting chylomicronemia, improve glycemic control prior to considering starting fenofibric acid delayed-release capsules.

Recommended Dosage and Administration •

• Severe hypertriglyceridemia: o The recommended dosage of fenofibric acid delayed-release capsule is 45 mg or 135 mg orally once daily. o 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: o The recommended dosage of fenofibric acid delayed-release capsule is 135 mg orally once daily. • Administer fenofibric acid delayed-release capsule as a single dose at any time of day, with or without food. • Advise patients to swallow fenofibric acid delayed-release capsules whole. Do not crush, break, dissolve, or chew capsules. • Assess TG when clinically appropriate, as early as 4 to 8 weeks after initiating fenofibric acid delayed-release capsules. Discontinue fenofibric acid delayed-release capsules 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 fenofibric acid delayed-release capsules at least 1 hour before or 4 hours to 6 hours after a bile acid binding resin to avoid impeding its absorption.

Recommended Dosage in Patients with Renal Impairment •

Assess renal function prior to initiation of fenofibric acid delayed-release capsules and periodically thereafter. • Treatment with fenofibric acid delayed-release capsules should be initiated at a dosage of 45 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. • Fenofibric acid delayed-release capsule 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.

Recommended Dosage in Geriatric Patients

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

Clinical 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 fenofibric acid delayed-release capsules 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 fenofibric acid delayed-release capsules 135 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. 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. Increases in Liver Enzymes In a pooled analysis of three 12-week, double-blind, controlled studies of fenofibric acid delayed-release capsules, increases in ALT and AST > 3 times the upper limit of normal on two consecutive occasions occurred in 1.9% and 0.2%, respectively, of patients receiving fenofibric acid delayed-release capsules 135 mg daily and placebo, without other lipid-altering drugs. 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 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. Clinical trials with fenofibric acid delayed-release capsules did not include a placebo-control arm. However, the adverse reaction profile of fenofibric acid delayed-release capsule was generally consistent with that of fenofibrate.

The following adverse reactions not listed above for fenofibrate were reported in ≥ 3% of patients taking fenofibric acid delayed-release capsules: Gastrointestinal: Diarrhea, dyspepsia General: Pain Infections: Nasopharyngitis, sinusitis, upper respiratory tract infection Musculoskeletal and Connective Tissue: Arthralgia, myalgia, pain in extremity Nervous System: Dizziness

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: Anemia Gastrointestinal: Pancreatitis General: Asthenia Hepatobiliary: Increased total bilirubin, hepatitis, cirrhosis Immune System: Anaphylaxis, angioedema Lipid Disorders: Severely depressed HDL-cholesterol levels Musculoskeletal: Muscle spasms, rhabdomyolysis 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.

Table 2 presents clinically important drug interactions with fenofibric acid delayed-release capsules. Table 2. Clinically Important Drug Interactions with Fenofibric Acid Delayed-Release Capsules 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. 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.

Consider the benefits and risks of concomitant use with immunosuppressants and other potentially nephrotoxic agents. Use the lowest effective dosage and monitor renal function. Administer fenofibric acid delayed-release capsules at least 1 hour before or 4 to 6 hours after a bile acid resin to avoid impeding its absorption.

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 dosage of 135 mg of fenofibric acid delayed-release capsules daily, based on body surface area (mg/m 2 ). Adverse reproductive outcomes occurred at higher doses in the presence of maternal toxicity (see Data).

Fenofibric acid delayed-release capsules 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 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 of 300 mg fenofibrate daily, comparable to 135 mg fenofibric acid delayed-release capsule 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.

Pediatric Use The safety and effectiveness of fenofibric acid delayed-release capsules have not been established in pediatric patients with severe hypertriglyceridemia or primary hyperlipidemia.

Fenofibric acid delayed-release capsules are 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 fenofibric acid, fenofibrate, or any of the excipients in fenofibric acid delayed-release capsules. Serious hypersensitivity reactions including anaphylaxis and angioedema have been reported with fenofibrate. Pre-existing gallbladder disease.

In the event of an overdose of fenofibric acid delayed-release capsules, consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations. There is no specific treatment for overdose with fenofibric acid delayed-release capsules. General supportive care of the patient is indicated, including monitoring of vital signs and observation of clinical status, should an overdose occur.

If indicated, elimination of unabsorbed drug should be achieved by emesis or gastric lavage; usual precautions should be observed to maintain the airway. Because fenofibric acid delayed-release capsules are highly bound to plasma proteins, hemodialysis should not be considered.