Fenofibrate

ADVERSE REACTIONS CLINICAL : 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% 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. * Dosage equivalent to 200 mg fenofibrate tablets. ** Significantly different from Placebo. BODY SYSETM Fenofibrate* Placebo Adverse Event (N = 489) (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% Flu Syndrome 2.1% 2.7% DIGESTIVE Liver Function Tests Abnormal 7.5% ** 1.4% Diarrhea 2.3% 4.1% Nausea 2.3% 1.9% Constipation 2.1% 1.4% METABOLIC AND NUTRITIONAL DISORDERS SGPT Increased 3% 1.6% Creatine Phosphokinase Increased 3% 1.4% SGOT Increased 3.4% ** 0.5% RESPIRATORY Respiratory Disorder 6.2% 5.5% Rhinitis 2.3% 1.1% Additional adverse events reported 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 : Chest pain, pain (unspecified), infection, malaise, allergic reaction, cyst, hernia, fever, photosensitivity reaction, and accidental injury. CARDIOVASCULAR SYSTEM : Angina pectoris, hypertension, vasodilatation, coronary artery disorder, electrocardiogram abnormal, ventricular extrasystoles, myocardial infarct, peripheral vascular disorder, migraine, varicose vein, cardiovascular disorder, hypotension, palpitation, vascular disorder, arrhythmia, phlebitis, tachycardia, extrasystoles, and atrial fibrillation. DIGESTIVE SYSTEM : Dyspepsia, flatulence, nausea, increased appetite, gastroenteritis, cholelithiasis, rectal disorder, esophagitis, gastritis, colitis, tooth disorder, vomiting, anorexia, gastrointestinal disorder, duodenal ulcer, nausea and vomiting, peptic ulcer, rectal hemorrhage, liver fatty deposit, cholecystitis, eructation, gamma glutamyl transpeptidase, and diarrhea. ENDOCRINE SYSTEM : Diabetes mellitus HEMIC AND LYMPHATIC SYSTEM : Anemia, leukopenia, ecchymosis, eosinophilia, lymphadenopathy, and thrombocytopenia. METABOLIC AND NUTRITIONAL DISORDERS : Creatinine increased, weight gain, hypoglycemia, gout, weight loss, edema, hyperuricemia, and peripheral edema. MUSCULOSKELETAL SYSTEM : Myositis, myalgia, arthralgia, arthritis, tenosynovitis, joint disorder, arthrosis, leg cramps, bursitis, and myasthenia. NERVOUS SYSTEM : Dizziness, insomnia, depression, vertigo, libido decreased, anxiety, paresthesia, dry mouth, hypertonia, nervousness, neuralgia, and somnolence. RESPIRATORY SYSTEM : Pharyngitis, bronchitis, cough increased, dyspnea, asthma, pneumonia, laryngitis, and sinusitis. SKIN AND APPENDAGES : Rash, pruritus, eczema, herpes zoster, urticaria, acne, sweating, fungal dermatitis, skin disorder, alopecia, contact dermatitis, herpes simplex, maculopapular rash, nail disorder, and skin ulcer. SPECIAL SENSES : Conjunctivitis, eye disorder, amblyopia, ear pain, otitis media, abnormal vision, cataract specified, and refraction disorder. UROGENITAL SYSTEM : Urinary frequency, prostatic disorder, dysuria, kidney function abnormal, urolithiasis, gynecomastia, unintended pregnancy, vaginal moniliasis, and cystitis.

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

DESCRIPTION Fenofibrate tablets, USP is a lipid regulating agent available as tablets for oral administration. Each tablet contains 54 mg or 160 mg of fenofibrate, USP. The chemical name for fenofibrate is 2-[4-(4-chlorobenzoyl) phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester with the following molecular structure: The molecular 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 alcohal and prectically insoluble in water. The melting point is 79 - 82° C. Fenofibrate, USP is a white or almost white crystalline powder. Inactive Ingredients : Each tablet contains colloidal silicon dioxide, crospovidone, lecithin (soya), microcrystalline cellulose, polyvinyl alcohol, povidone, pregelatinized starch, sodium lauryl sulfate, sodium stearyl fumarate, talc, titanium dioxide and xanthan gum. Meets USP Dissolution Test 2. structure

DOSAGE AND ADMINISTRATION Patients should be placed on an appropriate lipid-lowering diet before receiving fenofibrate tablets, and should continue this diet during treatment with fenofibrate tablets. Fenofibrate tablets 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 tablets is 160 mg per day. For adult patients with hypertriglyceridemia, the initial dose is 54 to 160 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 160 mg per day. Treatment with fenofibrate tablets should be initiated at a dose of 54 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 54 mg/day. Lipid levels should be monitored periodically and consideration should be given to reducing the dosage of fenofibrate tablets if lipid levels fall significantly below the targeted range.

INDICATIONS AND USAGE Treatment of Hypercholesterolemia Fenofibrate tablets, USP are indicated as adjunctive therapy to diet to reduce elevated LDL-C, Total-C, Triglycerides and Apo B, and to increase HDL-C 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 tablets, USP are 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 tablet, USP 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, thiazide diuretics and beta-blockers, are 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 C = cholesterol TG = triglycerides LDL = low density lipoprotein VLDL = very low density lipoprotein IDL = intermediate density lipoprotein Lipid Elevation Type Lipoprotein Elevated Major Minor 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 ↑↔ NCEP Treatment Guidelines: LDL-C Goals and Cutpoints for Therapeutic Lifestyle Changes and Drug Therapy in Different Risk Categories † CHD = coronary heart disease †† Some authorities recommend use of LDL-lowering drugs in this category if an LDL-C level of < 100 mg/dL cannot be achieved by therapeutic lifestyle changes. Others prefer use of drugs that primarily modify triglycerides and HDL-C, e.g., nicotinic acid or fibrate. Clinical judgment also may call for deferring drug therapy in this subcategory. ††† Almost all people with 0 to 1 risk factor have 10-year risk < 10%; thus, 10-year risk assessment in people with 0 to 1 risk factor is not necessary. Risk Category LDL Goal (mg/dL) LDL Level at Which to Initiate Therapeutic Lifestyle Changes (mg/dL) LDL Level at Which to Consider Drug Therapy (mg/dL) CHD † or CHD risk equivalents (10-years risk > 20%) < 100 ≥ 100 ≥ 130 (100 to 129: drug optional) †† 2+ Risk Factors (10-year risk ≤ 20%) < 130 ≥ 130 10-year risk 10% to 20%: ≥ 130 10-year risk < 10%: ≥ 160 0 to 1 Risk Factor ††† < 160 ≥ 160 ≥ 190 (160 to 189: LDL- lowering drug optional) After the LDL-C goal has been achieved, if the TG is still ≥ 200 mg/dL, non HDL-C (total-C minus HDL-C) becomes a secondary target of therapy. Non-HDL-C goals are set 30 mg/dL higher than LDL-C goals for each risk category.

WARNINGS Liver Function : Fenofibrate at doses equivalent to 107 mg to 160 mg fenofibrate tablets per day 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 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 related to fenofibrate therapy appears 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 107 mg to 160 mg of fenofibrate tablets per day and was 0% in those receiving dosages equivalent to 54 mg or less of fenofibrate 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. Regular periodic monitoring of liver function, including serum ALT (SGPT) should be performed for the duration of therapy with fenofibrate tablets, and therapy discontinued if enzyme levels persist above three times the normal limit. Cholelithiasis : Fenofibrate, like clofibrate and gemfibrozil, may increase cholesterol excretion into the bile, leading to cholelithiasis. If cholelithiasis is suspected, gallbladder studies are indicated. Fenofibrate tablet therapy should be discontinued if gallstones are found. Concomitant Oral Anticoagulants : Caution should be exercised when anticoagulants are given in conjunction with fenofibrate tablets because of the potentiation of coumarin-type anticoagulants in prolonging the prothrombin time/INR. The dosage of the anticoagulant 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. Concomitant HMG-CoA Reductase Inhibitors : The combined use of fenofibrate tablets 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. In a single-dose drug interaction study in 23 healthy adults the concomitant administration of fenofibrate tablets and pravastatin resulted in no clinically important difference in the pharmacokinetics of fenofibric acid, pravastatin or its active metabolite 3a-hydroxy iso-pravastatin when compared to either drug given alone. The combined use of fibric acid derivatives and HMG-CoA reductase inhibitors has been associated, in the absence of a marked pharmacokinetic interaction, in numerous case reports, with rhabdomyolysis, markedly elevated creatine kinase (CK) levels and myoglobinuria, leading in a high proportion of cases to acute renal failure. The use of fibrates alone, including fenofibrate tablets, may occasionally be associated with myositis, myopathy, or rhabdomyolysis. Patients receiving fenofibrate tablets and complaining of muscle pain, tenderness, or weakness should have prompt medical evaluation for myopathy, including serum creatine kinase level determination. If myopathy/myositis is suspected or diagnosed, fenofibrate tablets therapy should be stopped. Mortality : The effect of fenofibrate tablets on coronary heart disease morbidity and mortality and noncardiovascular mortality has not been established. Other Considerations : 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% vs. 1.8%). Because of chemical, pharmacological, and clinical similarities between fenofibrate tablets, Atromid-S (clofibrate), and Lopid (gemfibrozil), the adverse findings in 4 large randomized, placebo-controlled clinical studies with these other fibrate drugs may also apply to fenofibrate tablets. 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 World Health Organization study (RR = 1.29). Similarly, the numerical excess of gallbladder surgeries in the gemfibrozil group did not differ statistically from that observed in the WHO study. 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). The rate of gallbladder surgery was not statistically significant between study groups, but did trend higher in the gemfibrozil group, (1.9% vs 0.3%, p = 0.07). There was a statistically significant difference in the number of appendectomies in the gemfibrozil group (6/311 vs. 0/317, p = 0.029).

OVERDOSAGE There is no specific treatment for overdose with fenofibrate tablets. 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 fenofibrate is highly bound to plasma proteins, hemodialysis should not be considered.

Drug Interactions Oral Anticoagulants: CAUTION SHOULD BE EXERCISED WHEN COUMARIN ANTICOAGULANTS ARE GIVEN IN CONJUNCTION WITH FENOFIBRATE TABLETS. 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 tablets 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 tablets 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 tablets, there is a risk that an interaction will lead to deterioration. The benefits and risks of using fenofibrate tablets with immunosuppressants and other potentially nephrotoxic agents should be carefully considered, and the lowest effective dose employed.

CLINICAL PHARMACOLOGY A variety of clinical studies have demonstrated that elevated levels of total cholesterol (total-C), low density lipoprotein cholesterol (LDL-C), and apolipoprotein B (apo B), an LDL membrane complex, are associated with human atherosclerosis. Similarly, decreased levels of high density lipoprotein cholesterol (HDL-C) and its transport complex, apolipoprotein A (apo AI and apo AII) are associated with the development of atherosclerosis. Epidemiologic investigations have established that cardiovascular morbidity and mortality vary directly with the level of total-C, LDL-C, and triglycerides, and inversely with the level of HDL-C. The independent effect of raising HDL-C or lowering triglycerides (TG) on the risk of cardiovascular morbidity and mortality has not been determined. Fenofibric acid, the active metabolite of fenofibrate, produces reductions in total cholesterol, LDL cholesterol, apolipoprotein B, total triglycerides and triglyceride rich lipoprotein (VLDL) in treated patients. In addition, treatment with fenofibrate results in increases in high density lipoprotein (HDL) and apoproteins apoAI and apoAII. The effects of fenofibric acid seen in clinical practice have been explained in vivo in transgenic mice and in vitro in human hepatocyte cultures by the activation of peroxisome proliferator activated receptor α (PPARα). Through this mechanism, fenofibrate increases lipolysis and elimination of triglyceride-rich particles from plasma by activating lipoprotein lipase and reducing production of apoprotein C-III (an inhibitor of lipoprotein lipase activity). The resulting fall in triglycerides produces an alteration in the size and composition of LDL from small, dense particles (which are thought to be atherogenic due to their susceptibility to oxidation), to large buoyant particles. These larger particles have a greater affinity for cholesterol receptors and are catabolized rapidly. Activation of PPARα also induces an increase in the synthesis of apoproteins A-I, A-II and HDL-cholesterol. Fenofibrate also reduces serum uric acid levels in hyperuricemic and normal individuals by increasing the urinary excretion of uric acid. Pharmacokinetics/Metabolism Plasma concentrations of fenofibric acid after administration of 54 mg and 160 mg tablets are equivalent under fed conditions to 67 and 200 mg capsules, respectively. Absorption The absolute bioavailability of fenofibrate cannot be determined as the compound is virtually insoluble in aqueous media suitable for injection. However, fenofibrate is well absorbed from the gastrointestinal tract. Following oral administration in healthy volunteers, approximately 60% of a single dose of radiolabelled fenofibrate appeared in urine, primarily as fenofibric acid and its glucuronate conjugate, and 25% was excreted in the feces. Peak plasma levels of fenofibric acid occur within 6 to 8 hours after administration. The absorption of fenofibrate is increased when administered with food. With fenofibrate tablets, the extent of absorption is increased by approximately 35% under fed as compared to fasting conditions. Distribution In healthy volunteers, steady-state plasma levels of fenofibric acid were shown to be achieved within 5 days of dosing and did not demonstrate accumulation across time following multiple dose administration. Serum protein binding was approximately 99% in normal and hyperlipidemic subjects. Metabolism Following oral administration, fenofibrate is rapidly hydrolyzed by esterases to the active metabolite, fenofibric acid; no unchanged fenofibrate is detected in plasma. Fenofibric acid is primarily conjugated with glucuronic acid and then excreted in urine. A small amount of fenofibric acid is reduced at the carbonyl moiety to a benzhydrol metabolite which is, in turn, conjugated with glucuronic acid and excreted in urine. In vivo metabolism data indicate that neither fenofibrate nor fenofibric acid undergo oxidative metabolism (e.g., cytochrome P450) to a significant extent. Excretion After absorption, fenofibrate is mainly excreted in the urine in the form of metabolites, primarily fenofibric acid and fenofibric acid glucuronide. After administration of radiolabelled fenofibrate, approximately 60% of the dose appeared in the urine and 25% was excreted in the feces. Fenofibric acid is eliminated with a half-life of 20 hours, allowing once daily administration in a clinical setting. Special populations Geriatrics In elderly volunteers 77 to 87 years of age, the oral clearance of fenofibric acid following a single oral dose of fenofibrate was 1.2 L/h, which compares to 1.1 L/h in young adults. This indicates that a similar dosage regimen can be used in the elderly, without increasing accumulation of the drug or metabolites. Pediatrics Fenofibrate tablets have not been investigated in adequate and well-controlled trials in pediatric patients. Gender No pharmacokinetic difference between males and females has been observed for fenofibrate. Race The influence of race on the pharmacokinetics of fenofibrate has not been studied, however fenofibrate is not metabolized by enzymes known for exhibiting inter-ethnic variability. Therefore, inter-ethnic pharmacokinetic differences are very unlikely. Renal insufficiency In a study in patients with severe renal impairment (creatinine clearance < 50 mL/min), the rate of clearance of fenofibric acid was greatly reduced, and the compound accumulated during chronic dosage. However, in patients having moderate renal impairment (creatinine clearance of 50 to 90 mL/min), the oral clearance and the oral volume of distribution of fenofibric acid are increased compared to healthy adults (2.1 L/h and 95 L versus 1.1 L/h and 30 L, respectively). Therefore, the dosage of fenofibrate tablets should be minimized in patients who have severe renal impairment, while no modification of dosage is required in patients having moderate renal impairment. Hepatic insufficiency No pharmacokinetic studies have been conducted in patients having hepatic insufficiency. Drug-drug interactions In vitro studies using human liver microsomes indicate that fenofibrate and fenofibric acid are not inhibitors of cytochrome (CYP) P450 isoforms CYP3A4, CYP2D6, CYP2E1, or CYP1A2. They are weak inhibitors of CYP2C19 and CYP2A6, and mild-to-moderate inhibitors of CYP2C9 at therapeutic concentrations. Potentiation of coumarin-type anticoagulants has been observed with prolongation of the prothrombin time/INR. Bile acid sequestrants have been shown to bind other drugs given concurrently. Therefore, fenofibrate should be taken at least 1 hour before or 4 to 6 hours after a bile acid binding resin to avoid impeding its absorption. (See WARNINGS and PRECAUTIONS ). Clinical Trials Hypercholesterolemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia (Fredrickson Types IIa and IIb) The effects of fenofibrate at a dose equivalent to 160 mg of fenofibrate tablets per day 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 mg/dL. Fenofibrate tablet therapy lowered LDL-C, Total-C, and the LDL-C/HDL-C ratio. Fenofibrate tablet therapy also lowered triglycerides and raised HDL-C (see Table 1 ). Table 1 Mean Percent Change in Lipid Parameters at End of Treatment † † Duration of study treatment was 3 to 6 months. *p = < 0.05 vs. Placebo Treatment Group Total-C LDL-C HDL-C TG Pooled Cohort Mean baseline lipid values (n = 646) 306.9 mg/dL 213.8 mg/dL 52.3 mg/dL 191 mg/dL All FEN (n = 361) -18.7%* -20.6%* +11%* -28.9%* Placebo (n = 285) -0.4% -2.2% +0.7% +7.7% Baseline LDL-C > 160 mg/dL and TG < 150 mg/dL (Type IIa) Mean baseline lipid values (n = 334) 307.7 mg/dL 227.7 mg/dL 58.1 mg/dL 101.7 mg/dL All FEN (n = 193) -22.4%* -31.4%* +9.8%* -23.5%* Placebo (n = 141) +0.2% -2.2% +2.6% +11.7% Baseline LDL-C > 160 mg/dL and TG ≥ 150 mg/dL (Type IIb) Mean baseline lipid values (n = 242) 312.8 mg/dL 219.8 mg/dL 46.7 mg/dL 231.9 mg/dL All FEN (n = 126) -16.8%* -20.1%* +14.6%* -35.9%* Placebo (n = 116) -3% -6.6% +2.3% +0.9% In a subset of the subjects, measurements of apo B were conducted. Fenofibrate tablet 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). Hypertriglyceridemia (Fredrickson Type IV and V) The effects of fenofibrate on serum triglycerides were studied in two randomized, double-blind, placebo-controlled clinical trials 1 of 147 hypertriglyceridemic patients (Fredrickson Types IV and V). Patients were treated for eight weeks under protocols that differed only in that one 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 (Type IV/V hyperlipidemia), treatment with fenofibrate at dosages equivalent to 160 mg of fenofibrate tablets per day decreased primarily very low density lipoprotein (VLDL) triglycerides and VLDL cholesterol. Treatment of patients with Type IV hyperlipoproteinemia and elevated triglycerides often results in an increase of low density lipoprotein (LDL) cholesterol (see Table 2 ). Table 2 Effects of Fenofibrate Tablets in Patients With Fredrickson Type IV/V Hyperlipidemia *= p < 0.05 vs. Placebo Study 1 Placebo Fenofibrate Tablets Baseline TG level Baseline Endpoint % Change Baseline Endpoint % Change 350 to 499 mg/dL N (Mean) (Mean) (Mean) N (Mean) (Mean) (Mean) Triglycerides 28 449 450 -0.5 27 432 223 -46.2* VLDL Triglycerides 19 367 350 2.7 19 350 178 -44.1* Total Cholesterol 28 255 261 2.8 27 252 227 -9.1* HDL Cholesterol 28 35 36 4 27 34 40 19.6* LDL Cholesterol 28 120 129 12 27 128 137 14.5 VLDL Cholesterol 27 99 99 5.8 27 92 46 -44.7* Study 2 Placebo Fenofibrate Tablets Baseline TG level Baseline Endpoint % Change Baseline Endpoint % Change 500 to 1500 mg/dL N (Mean) (Mean) (Mean) N (Mean) (Mean) (Mean) Triglycerides 44 710 750 7.2 48 726 308 -54.5* VLDL Triglycerides 29 537 571 18.7 33 543 205 -50.6* Total Cholesterol 44 272 271 0.4 48 261 223 -13.8* HDL Cholesterol 44 27 28 5 48 30 36 22.9* LDL Cholesterol 42 100 90 -4.2 45 103 131 45* VLDL Cholesterol 42 137 142 11 45 126 54 -49.4* The effect of fenofibrate tablets on cardiovascular morbidity and mortality has not been determined.

20191101

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Fenofibrate Fenofibrate FENOFIBRATE FENOFIBRIC ACID SILICON DIOXIDE CROSPOVIDONE (15 MPA.S AT 5%) LECITHIN, SOYBEAN POLYVINYL ALCOHOL, UNSPECIFIED MICROCRYSTALLINE CELLULOSE POVIDONE, UNSPECIFIED STARCH, CORN SODIUM LAURETH-3 SULFATE SODIUM STEARYL FUMARATE TALC TITANIUM DIOXIDE XANTHAN GUM white to off-white biconvex RX901

Carcinogenesis, Mutagenesis, Impairment of Fertility: In a 24-month study in rats (10, 45, and 200 mg/kg; 0.3, 1, and 6 times the maximum recommended human dose on the basis of mg/meter 2 of surface area), the incidence of liver carcinoma was significantly increased at 6 times the maximum recommended human dose in males and females. A statistically significant increase in pancreatic carcinomas occurred in males at 1 and 6 times the maximum recommended human dose; there were also increases in pancreatic adenomas and benign testicular interstitial cell tumors at 6 times the maximum recommended human dose in males. In a second 24-month study in a different strain of rats (doses of 10 and 60 mg/kg; 0.3 and 2 times the maximum recommended human dose based on mg/meter 2 surface area), there were significant increases in the incidence of pancreatic acinar adenomas in both sexes and increases in interstitial cell tumors of the testes at 2 times the maximum recommended human dose. A comparative carcinogenicity study was done in rats comparing three drugs: fenofibrate (10 and 70 mg/kg; 0.3 and 1.6 times the maximum recommended human dose), clofibrate (400 mg/kg; 1.6 times the human dose), and gemfibrozil (250 mg/kg; 1.7 times the human dose) (multiples based on mg/meter 2 surface area). Pancreatic acinar adenomas were increased in males and females on fenofibrate; hepatocellular carcinoma and pancreatic acinar adenomas were increased in males and hepatic neoplastic nodules in females treated with clofibrate; hepatic neoplastic nodules were increased in males and females treated with gemfibrozil while testicular interstitial cell tumors were increased in males on all three drugs. In a 21-month study in mice at doses of 10, 45, and 200 mg/kg (approximately 0.2, 0.7 and 3 times the maximum recommended human dose on the basis of mg/meter 2 surface area), there were statistically significant increases in liver carcinoma at 3 times the maximum recommended human dose in both males and females. In a second 18-month study at the same doses, there was a significant increase in liver carcinoma in male mice and liver adenoma in female mice at 3 times the maximum recommended human dose. Electron microscopy studies have demonstrated peroxisomal proliferation following fenofibrate administration to the rat. An adequate study to test for peroxisome proliferation in humans has not been done, but changes in peroxisome morphology and numbers have been observed in humans after treatment with other members of the fibrate class when liver biopsies were compared before and after treatment in the same individual. Fenofibrate has been demonstrated to be devoid of mutagenic potential in the following tests: Ames, mouse lymphoma, chromosomal aberration and unscheduled DNA synthesis.

ANDA076635

Fenofibrate

Fenofibrate

63187-760

HUMAN PRESCRIPTION DRUG

ORAL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL RANBAXY NDC 63187-760-90 FENOFIBRATE TABLETS, USP 160 mg Rx only 90 Tablets 90's Bottle Label 63187-760-90

REFERENCES 1. GOLDBERG AC, et al. Fenofibrate for the Treatment of Type IV and V Hyperlipoproteinemias: A Double-Blind, Placebo-Controlled Multicenter US Study. Clinical Therapeutics, 11, pp. 69-83, 1989. 2. NIKKILA EA, Familial Lipoprotein Lipase Deficiency and Related Disorders of Chylomicron Metabolism. In Stanbury J.B., et al. (eds.): The Metabolic Basis of Inherited Disease, 5th edition, McGraw-Hill, 1983, Chap. 30, pp. 622-642. 3. BROWNWV, et al. Effects of Fenofibrate on Plasma Lipids: Double-Blind, Multicenter Study In Patients with Type IIA or IIB Hyperlipidemia. Arteriosclerosis. 6, pp. 670-678, 1986. Manufactured for: Ranbaxy Pharmaceuticals Inc. Jacksonville, FL 32257 USA Repackaged by: Proficient Rx LP Thousand Oaks, CA 91320 January 2013

Geriatric Use Fenofibric acid is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection.

Nursing Mothers Fenofibrate should not be used in nursing mothers. Because of the potential for tumorigenicity seen in animal studies, a decision should be made whether to discontinue nursing or to discontinue the drug.

Pediatric Use Safety and efficacy in pediatric patients have not been established.

Pregnancy Category C: Fenofibrate has been shown to be embryocidal and teratogenic in rats when given in doses 7 to 10 times the maximum recommended human dose and embryocidal in rabbits when given at 9 times the maximum recommended human dose (on the basis of mg/meter 2 surface area). There are no adequate and well-controlled studies in pregnant women. Fenofibrate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Administration of 9 times the maximum recommended human dose of fenofibrate to female rats before and throughout gestation caused 100% of dams to delay delivery and resulted in a 60% increase in post-implantation loss, a decrease in litter size, a decrease in birth weight, a 40% survival of pups at birth, a 4% survival of pups as neonates, and a 0% survival of pups to weaning, and an increase in spina bifida. Administration of 10 times the maximum recommended human dose to female rats on days 6 to 15 of gestation caused an increase in gross, visceral and skeletal findings in fetuses (domed head/hunched shoulders/rounded body/abnormal chest, kyphosis, stunted fetuses, elongated sternal ribs, malformed sternebrae, extra foramen in palatine, misshapen vertebrae, supernumerary ribs). Administration of 7 times the maximum recommended human dose to female rats from day 15 of gestation through weaning caused a delay in delivery, a 40% decrease in live births, a 75% decrease in neonatal survival, and decreases in pup weight, at birth as well as on days 4 and 21 post-partum. Administration of 9 and 18 times the maximum recommended human dose to female rabbits caused abortions in 10% of dams at 9 times and 25% of dams at 18 times the maximum recommended human dose and death of 7% of fetuses at 18 times the maximum recommended human dose.

HOW SUPPLIED Fenofibrate tablets, USP 160 mg are white to off-white, oval-shaped, biconvex, film-coated tablets, debossed with “ RX901 ” on one side and plain on the other side. They are supplied as follows. NDC 63187-760-30 Bottles of 30 NDC 63187-760-60 Bottles of 60 NDC 63187-760-90 Bottles of 90 Store at 20° - 25° C (68° - 77° F) [see USP Controlled Room Temperature]. Keep out of the reach of children. Protect from moisture. You may report side effects to FDA at 1-800-FDA-1088 .

PRECAUTIONS Initial Therapy : Laboratory studies should be done to ascertain that the lipid levels are consistently abnormal before instituting fenofibrate tablet therapy. Every attempt should be made to control serum lipids with appropriate diet, exercise, weight loss in obese patients, and control of any medical problems such as diabetes mellitus, and hypothyroidism that are contributing to the lipid abnormalities. Medications known to exacerbate hypertriglyceridemia (beta-blockers, thiazides, estrogens) should be discontinued or changed if possible prior to consideration of triglyceride-lowering drug therapy. Continued therapy : Periodic determination of serum lipids should be obtained during initial therapy in order to establish the lowest effective dose of fenofibrate tablets. Therapy should be withdrawn in patients who do not have an adequate response after two months of treatment with the maximum recommended dose of 160 mg per day. Pancreatitis: Pancreatitis has been reported in patients taking fenofibrate, gemfibrozil, and clofibrate. 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. Hypersensitivity Reactions : Acute hypersensitivity reactions including severe skin rashes requiring patient hospitalization and treatment with steroids have occurred very rarely during treatment with fenofibrate, including rare spontaneous reports of Stevens-Johnson syndrome, and toxic epidermal necrolysis. 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. Hematologic 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. Extremely rare spontaneous reports of thrombocytopenia and agranulocytosis have been received during post-marketing surveillance outside of the U.S. Periodic blood counts are recommended during the first 12 months of fenofibrate tablet administration. Skeletal muscle : The use of fibrates alone, including fenofibrate tablets may occasionally be associated with myopathy. Treatment with drugs of the fibrate class has been associated on rare occasions with rhabdomyolysis, usually in patients with impaired renal function. 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 fenofibrate therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed. Drug Interactions Oral Anticoagulants: CAUTION SHOULD BE EXERCISED WHEN COUMARIN ANTICOAGULANTS ARE GIVEN IN CONJUNCTION WITH FENOFIBRATE TABLETS. 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 tablets 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 tablets 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 tablets, there is a risk that an interaction will lead to deterioration. The benefits and risks of using fenofibrate tablets with immunosuppressants and other potentially nephrotoxic agents should be carefully considered, and the lowest effective dose employed. Carcinogenesis, Mutagenesis, Impairment of Fertility: In a 24-month study in rats (10, 45, and 200 mg/kg; 0.3, 1, and 6 times the maximum recommended human dose on the basis of mg/meter 2 of surface area), the incidence of liver carcinoma was significantly increased at 6 times the maximum recommended human dose in males and females. A statistically significant increase in pancreatic carcinomas occurred in males at 1 and 6 times the maximum recommended human dose; there were also increases in pancreatic adenomas and benign testicular interstitial cell tumors at 6 times the maximum recommended human dose in males. In a second 24-month study in a different strain of rats (doses of 10 and 60 mg/kg; 0.3 and 2 times the maximum recommended human dose based on mg/meter 2 surface area), there were significant increases in the incidence of pancreatic acinar adenomas in both sexes and increases in interstitial cell tumors of the testes at 2 times the maximum recommended human dose. A comparative carcinogenicity study was done in rats comparing three drugs: fenofibrate (10 and 70 mg/kg; 0.3 and 1.6 times the maximum recommended human dose), clofibrate (400 mg/kg; 1.6 times the human dose), and gemfibrozil (250 mg/kg; 1.7 times the human dose) (multiples based on mg/meter 2 surface area). Pancreatic acinar adenomas were increased in males and females on fenofibrate; hepatocellular carcinoma and pancreatic acinar adenomas were increased in males and hepatic neoplastic nodules in females treated with clofibrate; hepatic neoplastic nodules were increased in males and females treated with gemfibrozil while testicular interstitial cell tumors were increased in males on all three drugs. In a 21-month study in mice at doses of 10, 45, and 200 mg/kg (approximately 0.2, 0.7 and 3 times the maximum recommended human dose on the basis of mg/meter 2 surface area), there were statistically significant increases in liver carcinoma at 3 times the maximum recommended human dose in both males and females. In a second 18-month study at the same doses, there was a significant increase in liver carcinoma in male mice and liver adenoma in female mice at 3 times the maximum recommended human dose. Electron microscopy studies have demonstrated peroxisomal proliferation following fenofibrate administration to the rat. An adequate study to test for peroxisome proliferation in humans has not been done, but changes in peroxisome morphology and numbers have been observed in humans after treatment with other members of the fibrate class when liver biopsies were compared before and after treatment in the same individual. Fenofibrate has been demonstrated to be devoid of mutagenic potential in the following tests: Ames, mouse lymphoma, chromosomal aberration and unscheduled DNA synthesis. Pregnancy Category C: Fenofibrate has been shown to be embryocidal and teratogenic in rats when given in doses 7 to 10 times the maximum recommended human dose and embryocidal in rabbits when given at 9 times the maximum recommended human dose (on the basis of mg/meter 2 surface area). There are no adequate and well-controlled studies in pregnant women. Fenofibrate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Administration of 9 times the maximum recommended human dose of fenofibrate to female rats before and throughout gestation caused 100% of dams to delay delivery and resulted in a 60% increase in post-implantation loss, a decrease in litter size, a decrease in birth weight, a 40% survival of pups at birth, a 4% survival of pups as neonates, and a 0% survival of pups to weaning, and an increase in spina bifida. Administration of 10 times the maximum recommended human dose to female rats on days 6 to 15 of gestation caused an increase in gross, visceral and skeletal findings in fetuses (domed head/hunched shoulders/rounded body/abnormal chest, kyphosis, stunted fetuses, elongated sternal ribs, malformed sternebrae, extra foramen in palatine, misshapen vertebrae, supernumerary ribs). Administration of 7 times the maximum recommended human dose to female rats from day 15 of gestation through weaning caused a delay in delivery, a 40% decrease in live births, a 75% decrease in neonatal survival, and decreases in pup weight, at birth as well as on days 4 and 21 post-partum. Administration of 9 and 18 times the maximum recommended human dose to female rabbits caused abortions in 10% of dams at 9 times and 25% of dams at 18 times the maximum recommended human dose and death of 7% of fetuses at 18 times the maximum recommended human dose. Nursing Mothers Fenofibrate should not be used in nursing mothers. Because of the potential for tumorigenicity seen in animal studies, a decision should be made whether to discontinue nursing or to discontinue the drug. Pediatric Use Safety and efficacy in pediatric patients have not been established. Geriatric Use Fenofibric acid is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection.