Fenofibric acid delayed-release capsule is a peroxisome proliferator-activated receptor (PPAR) alpha agonist indicated as adjunctive therapy to diet to: Reduce TG in patients with severe hypertriglyceridemia ( 1.1 ). Reduce elevated LDL-C, Total-C, TG and Apo B, and to increase HDLC in patients with primary hypercholesterolemia or mixed dyslipidemia ( 1.2 ). Limitations of Use: Fenofibrate at a dose equivalent to 135 mg of fenofibric acid delayed-release capsule did not reduce coronary heart disease morbidity and mortality in patients with type 2 diabetes mellitus ( 5.1 ).
1.1Treatment of Severe Hypertriglyceridemia
Fenofibric acid delayed-release capsules are indicated as adjunctive therapy to diet to reduce triglycerides (TG) in patients with severe hypertriglyceridemia. Improving glycemic control in diabetic patients showing fasting chylomicronemia will usually obviate the need for pharmacological intervention. Markedly elevated levels of serum triglycerides (e.g. > 2,000 mg/dL) may increase the risk of developing pancreatitis.
The effect of fenofibric acid delayed-release capsules therapy on reducing this risk has not been adequately studied.
1.2Treatment of Primary Hypercholesterolemia or Mixed Dyslipidemia
Fenofibric acid delayed-release capsules are indicated as adjunctive therapy to diet to reduce elevated low-density lipoprotein cholesterol (LDL-C ), total cholesterol (Total-C), triglycerides (TG), and apolipoprotein B (Apo B), and to increase high-density lipoprotein cholesterol (HDL-C) in patients with primary hypercholesterolemia or mixed dyslipidemia.
1.3 Limitations of Use Fenofibrate at a dose equivalent to 135 mg of fenofibric acid delayed-release capsules did not reduce coronary heart disease morbidity and mortality in 2 large, randomized controlled trials of patients with type 2 diabetes mellitus [see Warnings and Precautions ( 5.1 )] .
1.4General Considerations for Treatment
Two medicines in one question?
Name two or more medicines and Osler runs an interaction check. A severe interaction is stated at the very top of the answer.
Laboratory studies should be performed to establish that lipid levels are abnormal before instituting fenofibric acid delayed-release capsules therapy. Every reasonable attempt should be made to control serum lipids with non-drug methods including appropriate diet, exercise, weight loss in obese patients, and control of any medical problems such as diabetes mellitus and hypothyroidism that may be contributing to the lipid abnormalities.
Medications known to exacerbate hypertriglyceridemia (beta-blockers, thiazides, estrogens) should be discontinued or changed if possible, and excessive alcohol intake should be addressed before triglyceride-lowering drug therapy is considered. If the decision is made to use lipid-altering drugs, the patient should be instructed that this does not reduce the importance of adhering to diet. Drug therapy is not indicated for patients who have elevations of chylomicrons and plasma triglycerides, but who have normal levels of VLDL.
Contraindications
Severe renal dysfunction, including patients receiving dialysis ( 4 , 12.3 ). Active liver disease ( 4 , 5.2 ). Gallbladder disease ( 4 , 5.5 ). Nursing mothers ( 4 , 8.2 ). Known hypersensitivity to fenofibric acid or fenofibrate ( 4 , 5.9 ) Fenofibric acid is contraindicated in: patients with severe renal impairment, including those receiving dialysis [see Clinical Pharmacology ( 12.3 )]. patients with active liver disease, including those with primary biliary cirrhosis and unexplained persistent liver function abnormalities [see Warnings and Precautions ( 5.3 )]. patients with preexisting gallbladder disease [see Warnings and Precautions ( 5.5 )]. nursing mothers [see Use in Specific Populations ( 8.2 )]. patients with hypersensitivity to fenofibric acid or fenofibrate [see Warnings and Precautions ( 5.9 )].
Warnings and precautions
Hepatotoxicity: Serious drug-induced liver injury, including liver transplantation and death, has been reported with fenofibric acid. 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 in elderly patients and patients with diabetes, renal failure, hypothyroidism, or statin co-administration ( 5.3 ). Serum creatinine: Fenofibric acid can reversibly increase serum creatinine levels ( 5.4 ). Monitor renal function periodically in patients with renal insufficiency ( 8.6 ). Cholelithiasis: Fenofibric acid increases cholesterol excretion into the bile, leading to risk of cholelithiasis.
If suspected, gallbladder studies are indicated ( 5.5 ). Coumarin anticoagulants: Use caution in concomitant treatment with oral coumarin anticoagulants. Adjust the dosage of coumarin anticoagulant to maintain the prothrombin time/INR at the desired level to prevent bleeding complications ( 5.6 ). 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 ).
5.1Mortality and Coronary Heart Disease Morbidity
The effect of fenofibric acid on coronary heart disease morbidity and mortality and non-cardiovascular mortality has not been established. Because of similarities between fenofibric acid and fenofibrate, clofibrate, and gemfibrozil, the findings in the following large randomized, placebo-controlled clinical studies with these fibrate drugs may also apply to fenofibric acid. The Action to Control Cardiovascular Risk in Diabetes Lipid (ACCORD Lipid) trial was a randomized placebo-controlled study of 5518 patients with type 2 diabetes mellitus on background statin therapy treated with fenofibrate.
The mean duration of follow-up was 4.7 years. Fenofibrate plus statin combination therapy showed a non-significant 8% relative risk reduction in the primary outcome of major adverse cardiovascular events (MACE), a composite of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular disease death (hazard ratio [HR] 0.92, 95% CI 0.79 to 1.08) (p=0.32) as compared to statin monotherapy. In a gender subgroup analysis, the hazard ratio for MACE in men receiving combination therapy versus statin monotherapy was 0.82 (95% CI 0.69 to 0.99), and the hazard ratio for MACE in women receiving combination therapy versus statin monotherapy was 1.38 (95% CI 0.98 to 1.94) (interaction p=0.01).
The clinical significance of this subgroup finding is unclear. The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study was a 5-year randomized, placebo-controlled study of 9795 patients with type 2 diabetes mellitus treated with fenofibrate. Fenofibrate demonstrated a non-significant 11 % relative reduction in the primary outcome of coronary heart disease events (hazard ratio [HR] 0.89, 95% CI 0.75 to 1.05, p = 0.16) and a significant 11% reduction in the secondary outcome of total cardiovascular disease events (HR 0.89 [0.80 to 0.99], p = 0.04).
There was a non-significant 11 % (HR 1.11 [0.95, 1.29], p = 0.18) and 19% (HR 1.19 [0.90, 1.57], p = 0.22) increase in total and coronary heart disease mortality, respectively, with fenofibrate as compared to placebo. In the Coronary Drug Project, a large study of post-myocardial infarction patients treated for 5 years with clofibrate, there was no difference in mortality seen between the clofibrate group and the placebo group.
There was, however, a difference in the rate of cholelithiasis and cholecystitis requiring surgery between the two groups (3.0% vs. 1.8%). In a study conducted by the World Health Organization (WHO), 5000 subjects 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. This appeared to confirm the higher risk of gallbladder disease seen in clofibrate-treated patients studied in the Coronary Drug Project. The Helsinki Heart Study was a large (N = 4081) study 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 higher in the gemfibrozil randomization group but did not achieve statistical significance (p = 0.19, 95% confidence interval for relative risk G:P = 0.91 to 1.64). Although cancer deaths trended higher in the gemfibrozil group (p = 0.11), cancers (excluding basal cell carcinoma) were diagnosed with equal frequency in both study groups. Due to the limited size of the study, the relative risk of death from any cause was not shown to be different than that seen in the 9 year follow-up data from WHO study (RR = 1.29).
A secondary prevention component of the Helsinki Heart Study enrolled middle-aged men excluded from the primary prevention study because of known or suspected coronary heart disease. Subjects received gemfibrozil or placebo for 5 years. Although cardiac deaths trended higher in the gemfibrozil group, this was not statistically significant (hazard ratio 2.2, 95% confidence interval: 0.94 to 5.05).
5.2Hepatotoxicity
Serious drug-induced liver injury (DILI), including liver transplantation and death, have been reported postmarketing with fenofibric acid. 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 fenofibric acid delayed-release capsules 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, fenofibric acid delayed-release capsules at a dose of 135 mg daily has been associated with increases in serum AST or ALT.
The incidence of increases in transaminases observed with fenofibrate therapy may be dose related [see Adverse Reactions ( 6.1 )] . Fenofibric acid delayed-release capsules is contraindicated in patients with active liver disease, including those with primary biliary cirrhosis and 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 fenofibric acid.
Discontinue fenofibric acid delayed-release capsules 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 fenofibric acid delayed-release capsules in these patients if there is no alternative explanation for the liver injury.
5.3Myopathy and Rhabdomyolysis
Fibrates increase the risk of myositis or myopathy and have been associated with rhabdomyolysis. The risk for serious muscle toxicity appears to be increased in elderly patients and in patients w
Our copy of this section ends here. The full text is in the official label at the FDA. Open Drugs@FDA
of coumarin-type anticoagulant effect has been observed with prolongation of the PT/INR . Caution should be exercised when oral coumarin anticoagulants are given in conjunction with fenofibric acid. The dosage of the anticoagulant 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 [see Warnings and Precautions ( 5.6 )].
7.2Bile Acid Binding Resins
Since bile acid binding resins may bind other drugs given concurrently, patients should take fenofibric acid at least 1 hour before or 4 to 6 hours after a bile acid resin to avoid impeding its absorption.
7.3Immunosuppressants
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 drugs of the fibrate class including fenofibric acid, there is a risk that an interaction will lead to deterioration of renal function. The benefits and risks of using fenofibric acid with immunosuppressants and other potentially nephrotoxic agents should be carefully considered, and the lowest effective dose employed.
7.4Colchicine Cases
of myopathy, including rhabdomyolysis, have been reported with fenofibrates co-administered with colchicine, and caution should be exercised when prescribing fenofibrate with colchicine.
Pregnancy and breastfeeding
8.1Pregnancy Risk Summary
Limited available data with fenofibrate use in pregnant women are insufficient to determine a drug associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, no evidence of embryo-fetal toxicity was observed with oral administration of fenofibrate in rats and rabbits during organogenesis at doses less than or equivalent to the maximum recommended clinical dose of 135 mg 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 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, 127, 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, equivalent to 135 mg fenofibric acid 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, 150, 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, 75, 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.
Adverse reactions
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 )] Pancreatitis [see Warnings and Precautions ( 5.7 )] Hypersensitivity reactions [see Warnings and Precautions ( 5.9 )] Venothromboembolic disease [see Warnings and Precautions ( 5.10 )] The most common adverse events reported during clinical trials with fenofibrate (≥ 2% and at least 1% greater than placebo) were abnormal liver tests, increased AST, increased ALT, increased CPK, and rhinitis ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-800-399-2561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
6.1Clinical Trials Experience
Because clinical 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 the rates observed in practice. Fenofibric acid is the active metabolite of fenofibrate. 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 events led to discontinuation of treatment in 5.0% of patients treated with fenofibrate and in 3.0% treated with placebo. Increases in liver tests were the most frequent events, causing discontinuation of fenofibrate treatment in 1.6% of patients in double-blind trials. Table 1. Adverse Events Reported by 2% or More of Patients Treated with Fenofibrate and Greater than Placebo During the Double-Blind, Placebo-Controlled Trials BODY SYSTEM Adverse Event Fenofibrate Dosage equivalent to 135 mg fenofibric acid ( N = 439 ) Placebo ( N = 365 ) BODY AS A WHOLE Abdominal Pain 4.6% 4.4% Back Pain 3.4% 2.5% Headache 3.2% 2.7% DIGESTIVE Nausea 2.3% 1.9% Constipation 2.1% 1.4% INVESTIGATIONS Abnormal Liver Tests 7.5% 1.4% Increased AST 3.4% 0.5% Increased ALT 3.0% 1.6% Increased Creatine Phosphokinase 3.0% 1.4% RESPIRATORY Respiratory Disorder 6.2% 5.5% Rhinitis 2.3% 1.1% 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.
Clinical trials with fenofibric acid did not include a placebo-control arm. However, the adverse event profile of fenofibric acid was generally consistent with that of fenofibrate. The following adverse events not listed above were reported in ≥ 3% of patients taking fenofibric acid alone: Gastrointestinal Disorders: Diarrhea, dyspepsia General Disorders and Administration Site Conditions: Pain Infections and Infestations: Nasopharyngitis, sinusitis, upper respiratory tract infection Musculoskeletal and Connective Tissue Disorders: Arthralgia, myalgia, pain in extremity Nervous System Disorders: Dizziness Increases in Liver Enzymes In a pooled analysis of three 12-week, double-blind, controlled studies of fenofibric acid, 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 fenofibrate 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 equivalent to 90 mg to 135 mg fenofibric acid daily and was 0% in those receiving dosages equivalent to 45 mg or less fenofibric acid delayed-release capsules daily or placebo.
6.2Postmarketing Experience
The following adverse reactions have been identified during postapproval 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: rhabdomyolysis, pancreatitis, renal failure, muscle spasms, acute renal failure, hepatitis, cirrhosis, increased total bilirubin, anemia, asthenia, severely depressed HDL-cholesterol levels, and interstitial lung disease.
Photosensitivity reactions to fenofibrate have occurred days to months after initiation; in some of these cases, patients reported a prior photosensitivity reaction to ketoprofen.
Composition
Active ingredients
CHOLINE FENOFIBRATE EQ 45MG FENOFIBRIC ACID
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
Prognia shows this product information for reference and learning. It is not treatment advice and can lag behind the official text. Always check the current product information and local protocols before prescribing.
