FENOFIBRATE

Fenofibrate Capsules, USP (micronized) is a lipid regulating agent available as capsules for oral administration. The chemical name for fenofibrate is 2-[4-(4-chlorobenzoyl) phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester with the following structural formula: The empirical formula is C 20 H 21 O 4 Cl and the molecular weight is 360.83; fenofibrate, USP is very soluble in methylene chloride; slightly soluble in alcohol; practically insoluble in water. The melting point is 79 to 82°C. Fenofibrate, USP is a white or almost white crystalline powder which is stable under ordinary conditions. Each 67 mg capsule contains the following inactive ingredients: croscarmellose sodium, crospovidone, lactose monohydrate, magnesium stearate, povidone, pregelatinized starch, sodium lauryl sulfate, talc, D&C Red #28, FD&C Blue #1, FD&C Red #40, titanium dioxide, and gelatin. Each 134 mg capsule contains the following inactive ingredients: croscarmellose sodium, crospovidone, lactose monohydrate, magnesium stearate, povidone, pregelatinized starch, sodium lauryl sulfate, talc, D&C Red #28, FD&C Blue #1, titanium dioxide, and gelatin. Each 200 mg capsule contains the following inactive ingredients: croscarmellose sodium, crospovidone, lactose monohydrate, magnesium stearate, povidone, pregelatinized starch, sodium lauryl sulfate, talc, FD&C Red #40, D&C Red #28, FDA/E172 yellow iron oxide, titanium dioxide, and gelatin. Meets USP Dissolution Test 1. Chemical Structure

Treatment of Hypercholesterolemia Fenofibrate Capsules, USP (micronized) is indicated as adjunctive therapy to diet for the reduction of LDL-C, total-C, triglycerides, and apo B in adult patients with primary hypercholesterolemia or mixed dyslipidemia (Fredrickson Types IIa and IIb). Lipid altering agents should be used in addition to a diet restricted in saturated fat and cholesterol when response to diet and non-pharmacological interventions alone has been inadequate (see National Cholesterol Education Program [NCEP] Treatment Guidelines, below). Treatment of Hypertriglyceridemia Fenofibrate Capsules, USP (micronized) is also indicated as adjunctive therapy to diet for treatment of adult patients with hypertriglyceridemia (Fredrickson Types IV and V hyperlipidemia). Improving glycemic control in diabetic patients showing fasting chylomicronemia will usually reduce fasting triglycerides and eliminate chylomicronemia thereby obviating the need for pharmacologic intervention. 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 adequately studied. Drug therapy is not indicated for patients with Type I hyperlipoproteinemia, who have elevations of chylomicrons and plasma triglycerides, but who have normal levels of very low density lipoprotein (VLDL). Inspection of plasma refrigerated for 14 hours is helpful in distinguishing Types I, IV, and V hyperlipoproteinemia 2 . The initial treatment for dyslipidemia is dietary therapy specific for the type of lipoprotein abnormality. Excess body weight and excess alcoholic intake may be important factors in hypertriglyceridemia and should be addressed prior to any drug therapy. Physical exercise can be an important ancillary measure. Diseases contributory to hyperlipidemia, such as hypothyroidism or diabetes mellitus should be looked for and adequately treated. Estrogen therapy, like thiazide diuretics and beta-blockers, is sometimes associated with massive rises in plasma triglycerides, especially in subjects with familial hypertriglyceridemia. In such cases, discontinuation of the specific etiologic agent may obviate the need for specific drug therapy of hypertriglyceridemia. The use of drugs should be considered only when reasonable attempts have been made to obtain satisfactory results with non-drug methods. If the decision is made to use drugs, the patient should be instructed that this does not reduce the importance of adhering to diet (see WARNINGS and PRECAUTIONS ). Fredrickson Classification of Hyperlipoproteinemias Lipid Elevation Type Lipoprotein Elevated Major Minor C = cholesterol TG = triglycerides LDL = low density lipoprotein VLDL = very low density lipoprotein IDL = intermediate density lipoprotein I (rare) Chylomicrons TG ↑ ↔ C IIa LDL C — IIb LDL, VLDL C TG III (rare) IDL C, TG — IV VLDL TG ↑ ↔ C V (rare) Chylomicrons, VLDL TG ↑ ↔ The NCEP Treatment Guidelines Definite Atherosclerotic Disease Coronary heart disease or peripheral vascular disease (including symptomatic carotid artery disease). Two or More Other Risk Factors Other risk factors for coronary heart disease ( CHD) include: age (males: ≥45 years; females: ≥55 years or premature menopause without estrogen replacement therapy); family history of premature CHD; current cigarette smoking; hypertension; confirmed HDL-C <35 mg/dL (<0.91 mmol/L); and diabetes mellitus. Subtract I risk factor if HDL-C is ≥60 mg/dL (≥1.6 mmol/L). LDL-Cholesterol mg/dL (mmol/L) Initiation Level Goal No No ≥190 ( ≥4.9) < 160 (<4.1) No Yes ≥160 ( ≥4.1) < 130 (<3.4) Yes Yes or No ≥130 In CHD patients with LDL-C levels 100 to 129 mg/dL, the physician should exercise clinical judgment in deciding whether to initiate drug treatment. ( ≥3.4) < 100 (<2.6)

Patients should be placed on an appropriate lipid-lowering diet before receiving fenofibrate capsules (micronized) and should continue this diet during treatment with fenofibrate capsules (micronized). Fenofibrate capsules (micronized) should be given with meals, thereby optimizing the bioavailability of the medication. For the treatment of adult patients with primary hypercholesterolemia or mixed hyperlipidemia, the initial dose of fenofibrate capsules (micronized) is 200 mg per day. For adult patients with hypertriglyceridemia, the initial dose is 67 to 200 mg per day.Dosage should be individualized according to patient response and should be adjusted if necessary following repeat lipid determinations at 4 to 8 week intervals. The maximum dose is 200 mg per day. Treatment with fenofibrate capsules (micronized) should be initiated at a dose of 67 mg/day in patients having impaired renal function, and increased only after evaluation of the effects on renal function and lipid levels at this dose. In the elderly, the initial dose should likewise be limited to 67 mg/day. Lipid levels should be monitored periodically and consideration should be given to reducing the dosage of fenofibrate capsules (micronized) if lipid levels fall significantly below the targeted range.

Fenofibrate capsules (micronized) is contraindicated in patients who exhibit hypersensitivity to fenofibrate. Fenofibrate capsules (micronized) is contraindicated in patients with hepatic or severe renal dysfunction, including primary biliary cirrhosis, and patients with unexplained persistent liver function abnormality. Fenofibrate capsules (micronized) is contraindicated in patients with preexisting gallbladder disease (see WARNINGS ).

Clinical Studies 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. Adverse events reported by 2% or more of patients treated with fenofibrate during the double-blind, placebo-controlled trials, regardless of causality, are listed in the table below. 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 function tests were the most frequent events, causing discontinuation of fenofibrate treatment in 1.6% of patients in double-blind trials. Table 3: Adverse Reactions 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 200 mg Fenofibrate capsules (micronized) (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% Asthenia 2.1% 3.0% Flu Syndrome 2.1% 2.7% DIGESTIVE Liver Function Tests Abnormal 7.5% Significantly different from Placebo 1.4% Diarrhea 2.3% 4.1% Nausea 2.3% 1.9% Constipation 2.1% 1.4% METABOLIC AND NUTRITIONAL DISORDERS SPGT Increased 3.0% 1.6% Creatine Phosphokinase Increased 3.0% 1.4% SGOT Increased 3.4% 0.5% RESPIRATORY Respiratory Disorder 6.2% 5.5% Rhinitis 2.3% 1.1% 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 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 134 mg to 200 mg fenofibrate daily and was 0% in those receiving dosages equivalent to 34 mg to 67 mg fenofibrate daily or placebo. Post-Marketing Experience The following adverse reactions have been identified during post-approval use of fenofibrate: myalgia, rhabdomyolysis, pancreatitis, acute renal failure, muscle spasm, hepatitis, cirrhosis, increased total bilirubin, anemia, arthralgia, decreases in hemoglobin, decreases in hematocrit, white blood cell decreases, asthenia and interstitial lung disease. 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. To report SUSPECTED ADVERSE REACTIONS, contact Rhodes Pharmaceuticals at 1-888-827-0616 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Additional adverse events reported during postmarketing surveillance or by three or more patients in placebo-controlled trials or reported in other controlled or open trials, regardless of causality are listed below. BODY AS A WHOLE: Accidental injury, allergic reaction, chest pain, cyst, fever, hernia, infection, malaise, pain (unspecified), and photosensitivity reaction. CARDIOVASCULAR SYSTEM: Angina pectoris, arrhythmia, atrial fibrillation, cardiovascular disorder, coronary artery disorder, electrocardiogram abnormal, extrasystoles, hypertension, hypotension, migraine, myocardial infarct, palpitation, peripheral vascular disorder, phlebitis, tachycardia, varicose vein, vascular disorder, vasodilation, venous thromboembolic events (deep vein thrombosis, pulmonary embolus), and ventricular extrasystoles. DIGESTIVE SYSTEM: Anorexia, cholecystitis, cholelithiasis, colitis, diarrhea, duodenal ulcer, dyspepsia, eructation, esophagitis, flatulence, gamma glutamyl transpeptidase, gastritis, gastroenteritis, gastrointestinal disorder, increased appetite, liver fatty deposit, nausea, nausea and vomiting, peptic ulcer, rectal disorder, rectal hemorrhage, tooth disorder, and vomiting. ENDOCRINE SYSTEM: Diabetes mellitus. HEMIC AND LYMPHATIC SYSTEM: Anemia, ecchymosis, eosinophilia, leukopenia, lymphadenopathy, and thrombocytopenia. LABORATORY INVESTIGATIONS: Alkaline phosphatase increased, bilirubin increased, blood urea nitrogen increased, serum creatinine increased, gamma glutamyl transpeptidase increased, lactate dehydrogenase increased, SGOT and SGPT increased. METABOLIC AND NUTRITIONAL DISORDERS: Creatinine increased, edema, gout, hyperuricemia, hypoglycemia, peripheral edema, weight gain, and weight loss. MUSCULOSKELETAL SYSTEM: Arthralgia, arthritis, arthrosis, bursitis, joint disorder, leg cramps, myalgia, myasthenia, myositis, rhabdomyolysis, and tenosynovitis. NERVOUS SYSTEM: Anxiety or nervousness, depression, dizziness, dry mouth, hypertonia, insomnia, libido decreased, neuralgia, paresthesia, somnolence, and vertigo. RESPIRATORY SYSTEM: Allergic pulmonary alveolitis, asthma, bronchitis, cough increased, dyspnea, laryngitis, pharyngitis, pneumonia, sinusitis, and interstitial lung disease. SKIN AND APPENDAGES: Acne, alopecia, contact dermatitis, eczema, fungal dermatitis, herpes simplex, herpes zoster, maculopapular rash, nail disorder, photosensitivity reaction, pruritus, rash, skin disorder, skin ulcer, sweating, and urticaria. SPECIAL SENSES: Abnormal vision, amblyopia, cataract specified, conjunctivitis, ear pain, eye disorder, otitis media, and refraction disorder. UROGENITAL SYSTEM: Cystitis, dysuria, gynecomastia, kidney function abnormal, prostatic disorder, unintended pregnancy, urinary frequency, urolithiasis, and vaginal moniliasis. Photosensitivity reactions have occurred days to months after initiation; in some of these cases, patients reported a prior photosensitivity reaction to ketoprofen.

Oral Anticoagulants CAUTION SHOULD BE EXERCISED WHEN COUMARIN ANTICOAGULANTS ARE GIVEN IN CONJUNCTION WITH FENOFIBRATE CAPSULES (MICRONIZED). THE DOSAGE OF THE ANTICOAGULANTS SHOULD BE REDUCED TO MAINTAIN THE PROTHROMBIN TIME/INR AT THE DESIRED LEVEL TO PREVENT BLEEDING COMPLICATIONS. FREQUENT PROTHROMBIN TIME/INR DETERMINATIONS ARE ADVISABLE UNTIL IT HAS BEEN DEFINITELY DETERMINED THAT THE PROTHROMBIN TIME/INR HAS STABILIZED. HMG-CoA Reductase Inhibitors The combined use of fenofibrate and HMG-CoA reductase inhibitors should be avoided unless the benefit of further alterations in lipid levels is likely to outweigh the increased risk of this drug combination (see WARNINGS ). Resins Since bile acid sequestrants may bind other drugs given concurrently, patients should take fenofibrate capsules (micronized) at least 1 hour before or 4 to 6 hours after a bile acid binding resin to avoid impeding its absorption. Cyclosporine Because cyclosporine 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 fenofibrate, there is a risk that an interaction will lead to deterioration. The benefits and risks of using fenofibrate with immunosuppressants and other potentially nephrotoxic agents should be carefully considered, and the lowest effective dose employed.

STORAGE Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Keep out of the reach of children. Protect from moisture.