Fenofibric acid

Tell your doctor about all prescription, nonprescription, illegal, recreational, herbal, nutritional, or dietary drugs you're taking, especially:

• Neoral, Sandimmune, or Gengraf (cyclosporine)
• Blood thinners, such as Coumadin (warfarin)
• Diuretics (water pills)
• Oral contraceptives (birth control pills)
• Estrogen or other hormone replacement therapy (HRT)
• Beta-blockers, such as Tenormin (atenolol), Coreg (carvedilol), Lopressor or Toprol (metoprolol), Inderal or InnoPran (propranolol), and others

Also, if you take Questran (cholestyramine), Welchol (colesevelam), or Colestid (colestipol), take them at least four to six hours before, or one hour after, taking Trilipix.

You can take statins (another group of cholesterol-lowering medicines) at the same time you take Trilipix.

Trilipix and Alcohol

Drinking alcohol while taking Trilipix may increase your risk of liver damage.

Avoid alcohol while using this medicine.

Your pharmacist can provide more information about fenofibric acid.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

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Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

You may take fenofibric acid with or without food.

If you also take cholestyramine (Questran), colesevelam (Welchol), or colestipol (Colestid), take these medicines at least 1 hour after taking fenofibric acid, or 4 to 6 hours before taking fenofibric acid. Do not take any of these medicines at the same time you take fenofibric acid.

"Statin" cholesterol-lowering medications may be taken at the same time as fenofibric acid.

Fenofibric acid is only part of a complete program of treatment that may also include diet, exercise, weight control, and other medications. Follow your diet, medication, and exercise routines very closely.

Use all medications as directed by your doctor. Read the medication guide or patient instructions provided with each medication. Do not change your doses or medication schedule without your doctor's advice.

To be sure this medicine is helping your condition and is not causing harmful effects, your blood will need to be tested often. Your liver, kidney, and gallbladder function may also need to be tested. Visit your doctor regularly.

Store at room temperature away from moisture and heat.

It is very important that your doctor check your progress at regular visits. This will allow your doctor to see if the medicine is working properly to lower your cholesterol and triglyceride (fats) levels and to decide if you should continue to take it. Blood and urine tests may be needed to check for unwanted effects.

Check with your doctor right away if you have unexplained muscle pain, tenderness, or weakness, especially if you also have unusual tiredness or a fever. These could be symptoms of a serious muscle problem called myopathy.

Check with your doctor right away if you have dark-colored urine, diarrhea, a fever, muscle cramps or spasms, muscle pain or stiffness, or feel very tired or weak. These could be symptoms of a serious muscle problem called rhabdomyolysis, which can cause kidney problems.

fenofibric acid may increase your risk of gallstones. Call your doctor right away if you have severe stomach pain with nausea and vomiting.

Pancreatitis may occur while you are using fenofibric acid. Tell your doctor right away if you have sudden and severe stomach pain, chills, constipation, nausea, vomiting, fever, or lightheadedness.

Serious skin reactions can occur with fenofibric acid. Check with your doctor right away if you have blistering, peeling, or loosening of the skin, red skin lesions, severe acne or skin rash, sores or ulcers on the skin, or fever or chills while you are using fenofibric acid.

Check with your doctor right away if you have signs of a fever, chills, cough, sore throat, unusual bleeding, bruising, or weakness. These could be symptoms of an infection resulting from low white blood cell counts, which may be caused by fenofibric acid.

Do not stop taking fenofibric acid without first checking with your doctor. When you stop taking fenofibric acid, your blood fat levels may increase again. Your doctor may want you to follow a special diet to help prevent that.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Body aches or pain
• chills
• cough
• difficulty with breathing
• ear congestion
• fever
• headache
• loss of voice
• nasal congestion
• runny nose
• sneezing
• sore throat
• unusual tiredness or weakness

• Bladder pain
• bloody or cloudy urine
• blurred vision
• cough producing mucus
• diarrhea
• difficult, burning, or painful urination
• difficulty with moving
• dizziness
• frequent urge to urinate
• general feeling of discomfort or illness
• joint pain
• loss of appetite
• lower back or side pain
• muscle aching or cramping
• muscle or bone pain
• muscle pain or stiffness
• muscle spasms
• nausea
• nervousness
• pain in the arms or legs
• pounding in the ears
• shivering
• slow or fast heartbeat
• sweating
• swollen joints
• tightness in the chest
• trouble sleeping
• vomiting

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Acid or sour stomach
• belching
• difficulty having a bowel movement (stool)
• heartburn
• indigestion
• pain or tenderness around the eyes and cheekbones
• stomach discomfort, upset, or pain

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Severe Hypertriglyceridemia

Fenofibric Acid tablets is indicated as adjunctive therapy to diet for treatment of severe hypertriglyceridemia (≥ 500 mg/dL). Improving glycemic control in diabetic patients showing fasting chylomicronemia will usually obviate the need for pharmacologic intervention.

Markedly elevated levels of serum triglycerides > 2000 mg/dL may increase the risk of developing pancreatitis. The effect of fenofibrate therapy on reducing this risk has not been adequately studied.

Primary Hypercholesterolemia or Mixed Dyslipidemia

Fenofibric Acid tablets is 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.

Important Limitations of Use

Fenofibrate at a dose equivalent to 105 mg of Fenofibric Acid tablets was not shown to reduce coronary heart disease morbidity and mortality in patients with type 2 diabetes mellitus [see Warnings and Precautions (5.1)].

• 35-mg: White, round tablets. Debossed "AR 787".
• 105-mg: White, modified oval tablets. Debossed "AR 788".

Fenofibric Acid tablets 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)].
• patients with known hypersensitivity to Fenofibric Acid or fenofibrate [see Warnings and Precautions (5.9)].
• nursing mothers [see Use in Specific Populations (8.3)].

Mortality and Coronary Heart Disease Morbidity

The effect of Fenofibric Acid tablets on coronary heart disease morbidity and mortality and non-cardiovascular mortality has not been established.

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 0.79–1.08) (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 0.69–0.99), and the hazard ratio for MACE in women receiving combination therapy versus statin monotherapy was 1.38 (95% CI 0.98–1.94) (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 0.75–1.05, p=0.16) and a significant 11% reduction in the secondary outcome of total cardiovascular disease events (HR 0.89 [0.80–0.99], 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.

Because of chemical, pharmacological, and clinical similarities between fenofibrate, clofibrate, and gemfibrozil, the adverse findings in 4 large randomized, placebo-controlled clinical studies with these other fibrate drugs may also apply to Fenofibric Acid.

In the Coronary Drug Project, a large study of post myocardial infarction of 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 = 0.91–1.64). 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 World Health Organization study (relative risk=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 (HR 2.2, 95% confidence interval: 0.94–5.05).

Skeletal Muscle

Fibrates increase the risk for myopathy and have been associated with rhabdomyolysis. The risk for serious muscle toxicity appears to be increased in elderly patients and in patients with diabetes, renal failure, or hypothyroidism.

Data from observational studies suggest that the risk for rhabdomyolysis is increased when fibrates, in particular gemfibrozil, are co-administered with an HMG-CoA reductase inhibitor (statin). The combination should be avoided unless the benefit of further alterations in lipid levels is likely to outweigh the increased risk of this drug combination [see Clinical Pharmacology (12.3)].

Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevations of creatine phosphokinase levels.

Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. CPK levels should be assessed in patients reporting these symptoms, and Fenofibric Acid tablets therapy should be discontinued if markedly elevated CPK levels occur or myopathy/myositis is suspected or diagnosed.

Cases of myopathy, including rhabdomyolysis, have been reported with fenofibrates co-administered with colchicine, and caution should be exercised when prescribing fenofibrate with colchicine [see Drug Interactions (7.4)].

Liver Function

Fenofibrate (administered over a range of doses with the higher dose equivalent to 105 mg Fenofibric Acid) has been associated with increases in serum transaminases [AST (SGOT) or ALT (SGPT)].

In a pooled analysis of 10 placebo-controlled trials, increases to > 3 times the upper limit of normal of ALT occurred in 5.3% of patients taking fenofibrate versus 1.1% of patients treated with placebo.

When transaminase determinations were followed either after discontinuation of treatment or during continued treatment, a return to normal limits was usually observed. The incidence of increases in transaminases observed with fenofibrate therapy appear to be dose related. In an 8-week dose-ranging study, the incidence of ALT or AST elevations to at least three times the upper limit of normal was 13% in patients receiving dosages equivalent to 35 mg to 105 mg Fenofibric Acid tablets per day and was 0% in those receiving dosages equivalent to 35 mg or less Fenofibric Acid tablets per day, or placebo.

Hepatocellular, chronic active and cholestatic hepatitis associated with fenofibrate therapy have been reported after exposures of weeks to several years. In extremely rare cases, cirrhosis has been reported in association with chronic active hepatitis.

Baseline and regular, periodic monitoring of liver function, including ALT (SGPT) should be performed for the duration of therapy with Fenofibric Acid tablets, and therapy discontinued if enzyme levels persist above three times the normal limit.

Serum Creatinine

Elevations in serum creatinine have been reported in patients on fenofibrate. These elevations tend to return to baseline following discontinuation of fenofibrate. The clinical significance of these observations is unknown. Renal monitoring should be considered for patients with renal impairment and for patients at risk for renal insufficiency, such as the elderly and patients with diabetes.

Cholelithiasis

Fenofibric Acid tablets, like fenofibrate, clofibrate and gemfibrozil, may increase cholesterol excretion into the bile, leading to cholelithiasis. If cholelithiasis is suspected, gallbladder studies are indicated. Fenofibric Acid tablets therapy should be discontinued if gallstones are found.

Coumarin Anticoagulants

Caution should be exercised when coumarin anticoagulants are given in conjunction with Fenofibric Acid tablets. Fenofibric Acid tablets may potentiate the anticoagulant effects of these agents resulting in prolongation of the prothrombin time/International Normalized Ratio (PT/INR). To prevent bleeding complications, frequent monitoring of PT/INR and dose adjustment of the anticoagulant are recommended until the PT/INR has stabilized [see Drug Interactions (7.1)].

Pancreatitis

Pancreatitis has been reported in patients taking fenofibrate. 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.

Hematological Changes

Mild-to-moderate hemoglobin, hematocrit, and white blood cell decreases have been observed in patients following initiation of fenofibrate therapy. However, these levels stabilize during long-term administration. Thrombocytopenia and agranulocytosis have been reported in individuals treated with fenofibrate. Periodic monitoring of red and white blood cell counts is recommended during the first 12 months of Fenofibric Acid tablets administration.

Hypersensitivity Reactions

Acute hypersensitivity reactions including severe skin rashes such as Stevens-Johnson syndrome and toxic epidermal necrolysis requiring patient hospitalization and treatment with steroids have been reported in individuals treated with fenofibrate.

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.

Venothromboembolic Disease

In the 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%) in the fenofibrate group (p=0.074); and for PE, there were 32 (0.7%) events in the placebo group and 53 (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).

Paradoxical Decreases 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 diabetic and non-diabetic patients 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. It is recommended that HDL-C levels be checked within the first few months after initiation of fibrate therapy. If a severely depressed HDL-C level is detected, fibrate therapy should be withdrawn, and the HDL-C level monitored until it has returned to baseline, and fibrate therapy should not be re-initiated.

Fenofibric Acid tablets is a lipid regulating agent available as tablets for oral administration. Each tablet contains 35 mg or 105 mg of Fenofibric Acid. The chemical name for Fenofibric Acid is 2-[4-(4-chlorobenzoyl)phenoxy]-2-methylpropanoic acid with the following structural formula:

Fenofibric Acid is a white to almost white crystalline powder that is stable under ordinary conditions, and has a melting point of 179 – 183°C. Its empirical formula is C17H15ClO4 and molecular weight 318.75. Fenofibric Acid is insoluble in water; its solubility increases with pH in buffered media.

Inactive Ingredients: Each tablet contains copovidone, crospovidone, magnesium stearate and microcrystalline cellulose.

Severe Hypertriglyceridemia

The effects of fenofibrate on serum triglycerides were studied in two randomized, double-blind, placebo-controlled clinical trials of 147 hypertriglyceridemic patients. Patients were treated for eight weeks under protocols that differed only in that one protocol entered patients with baseline triglyceride (TG) levels of 500 to 1500 mg/dL, and the other TG levels of 350 to 500 mg/dL.

In patients with hypertriglyceridemia and normal cholesterolemia with or without hyperchylomicronemia, treatment with fenofibrate at dosages equivalent to 105 mg of Fenofibric Acid tablets decreased primarily very low density lipoprotein (VLDL) triglycerides and VLDL cholesterol. Treatment of some with elevated triglycerides often results in an increase of low density lipoprotein (LDL) cholesterol (see Table 4).

Primary Hypercholesterolemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia

The effects of fenofibrate at doses equivalent to 105 mg of Fenofibric Acid tablets were assessed from four randomized, placebo-controlled, double-blind, parallel-group studies including patients with the following mean baseline lipid values: Total-C 306.9 mg/dL; LDL-C 213.8 mg/dL; HDL-C 52.3 mg/dL; and triglycerides 191.0 mg/dL. Fenofibrate therapy lowered LDL-C, Total-C, and the LDL-C/HDL-C ratio. Fenofibrate therapy also lowered triglycerides and raised HDL-C (see Table 5).

In a subset of the subjects, measurement of Apo B was conducted. Fenofibrate treatment significantly reduced Apo B from baseline to endpoint as compared with placebo (-25.1% vs. 2.4%, p < 0.0001, n=213 and 143 respectively).

The effect of Fenofibric Acid tablets on cardiovascular morbidity and mortality has not been determined.

Applies to fenofibric acid: oral capsule delayed release, oral tablet

Along with its needed effects, fenofibric acid may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking fenofibric acid:

• Body aches or pain
• chills
• cough
• difficulty with breathing
• ear congestion
• fever
• headache
• loss of voice
• nasal congestion
• runny nose
• sneezing
• sore throat
• unusual tiredness or weakness

• Bladder pain
• bloody or cloudy urine
• blurred vision
• cough producing mucus
• diarrhea
• difficult, burning, or painful urination
• difficulty with moving
• dizziness
• frequent urge to urinate
• general feeling of discomfort or illness
• joint pain
• loss of appetite
• lower back or side pain
• muscle aching or cramping
• muscle or bone pain
• muscle pain or stiffness
• muscle spasms
• nausea
• nervousness
• pain in the arms or legs
• pounding in the ears
• shivering
• slow or fast heartbeat
• sweating
• swollen joints
• tightness in the chest
• trouble sleeping
• vomiting

Some side effects of fenofibric acid may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Acid or sour stomach
• belching
• difficulty having a bowel movement (stool)
• heartburn
• indigestion
• pain or tenderness around the eyes and cheekbones
• stomach discomfort, upset, or pain