LIPOFEN® (fenofibrate capsules), is a lipid regulating agent available as hard gelatin capsules for oral administration. Each hard gelatin capsule contains 50 or 150 mg of fenofibrate. 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 C₂₀H₂₁O₄CI and the molecular weight is 360.83; fenofibrate is insoluble in water. The melting point is 79-82°C. Fenofibrate is a white solid which is stable under ordinary conditions.

Inactive Ingredients: Each hard gelatin capsule contains Gelucire 44/14 (lauroyl macrogol glyceride type 1500), polyethylene glycol 20,000, polyethylene glycol 8000, hydroxypropylcellulose, sodium starch glycolate, gelatin, titanium dioxide, shellac, propylene glycol, may also contain black iron oxide, FD&C Blue #1, FD&C Blue #2, FD&C Red #40, D&C Yellow #10.

Last updated on RxList: 2/4/2009

Treatment of Hypercholesterolemia

LIPOFEN® is 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 Ha and Hb).

Lipid-altering agents should be used in addition to a diet restricted in saturated fat and cholesterol when response to diet and non-pharmacological intervention alone has been inadequate (see National Cholesterol Education Program (NCEP) Treatment Guidelines, below).

Treatment of Hypertriglyceridemia

LIPOFEN® 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 LIPOFEN® 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 hyperlipoproteinemia2.

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

NCEP Treatment Guidelines: LDL-C Goals and Cutpoints for Therapeutic Lifestyle Changes and Drug TherapyinDifferentRiskCategories.

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.

Patients should be placed on an appropriate lipid-lowering diet before receiving LIPOFEN®, and should continue this diet during treatment with LIPOFEN®. LIPOFEN® capsules should be given with meals, thereby optimizing the absorption of the medication.

For the treatment of adult patients with primary hypercholesterolemia or mixed hyperlipidemia, the initial dose of LIPOFEN® is 150 mg per day.

For adult patients with hypertriglyceridemia, the initial dose is 50 to 150 mg per day. Dosage should be individualized according to patient response, and should be adjusted if necessary following repeat lipid determination at 4 to 8 week intervals. The maximum dose is 150 mg per day.

Treatment with LIPOFEN® should be initiated at a dose of 50 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 50 mg/day.

Lipid levels should be monitored periodically and consideration should be given to reducing the dosage of LIPOFEN® if lipid levels fall significantly below the targeted range.

LIPOFEN® (fenofibrate capsules) is available in two strengths:

50 mg: Size 3 white opaque/white opaque gelatin capsule, imprinted in black ink with : '50" between lines on the body, "G 246" on the cap and containing a white to almost white paste, available in bottles of 30 (NDC 66869-137-20).

150 mg: Size 1 white opaque/white opaque gelatin capsule, imprinted in green ink with : '150" between lines on the body, "G 248" on the cap and containing a white to almost white paste, available in bottles of 30 (NDC 66869-147-20) and 90 (NDC 66869-147-30).

Storage

Store at controlled room temperature, 15°-30°C (59°-86°F). Keep out of the reach of children. Protect from moisture and light.

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. NTKKILA 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. BROWN WV, et al. Effects of Fenofibrate on Plasma Lipids: Double-Blind, Multicenter Study In Patients with Type TJA or HB Hyperlipidemia. Arteriosclerosis. 6, pp. 670-678,1986.

Rev. 062008. Manufactured by: Galephar Pharmaceutical Research Inc. Tuncos, PR00777-3873. Manufactured for: Kowa Pharmaceuticals America, Inc. Montgomery, AL 36117 1 (877) 334-3464. FDA rev date: 12/12/2009

Last updated on RxList: 2/4/2009

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 5.0% 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.

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 infarction, 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, esophagjtis, 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.

To report SUSPECTED ADVERSE REACTIONS, contact Kowa Pharmaceuticals America, Inc. at 1 (877) 334-3464 or FDA at 1 (888) 463-6332 or via the web at www.fda.gov/medwatch/index.html for voluntary reporting of adverse reactions.

Oral Anticoagulants: CAUTION SHOULD BE EXERCISED WHEN COUMARIN ANTICOAGULANTS ARE GIVEN IN CONJUNCTION WITH LIPOFEN®. 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 LIPOFEN® andHMG-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 LIPOFEN® at least 1 hour before or 4-6 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 LIPOFEN®, there is a risk that an interaction will lead to deterioration. The benefits and risks of using LIPOFEN ® with immunosuppressants and other potentially nephrotoxic agents should be carefully considered, and the lowest effective dose employed.

Last updated on RxList: 2/4/2009

Liver Function: Fenofibrate at doses equivalent to 100 mg to 150 mg LIPOFEN ® 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 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 100 mg to 150 mg LIPOFEN® per day and was 0% in those receiving dosages equivalent to 50 mg or less LIPOFEN® 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 functions, including serum ALT (SGPT) should be performed for the duration of therapy with LIPOFEN®, 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. LIPOFEN® therapy should be discontinued if gallstones are

Concomitant Oral Anticoagulants: Caution should be exercised when anticoagulants are given in conjunction with LIPOFEN® 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 LIPOFEN® 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 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 LIPOFEN®, may occasionally be associated with myositis, myopathy, or rhabdomyolysis. Patients receiving LIPOFEN® 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, LIPOFEN® should be stopped.

Mortality: The effect of fenofibrate on coronary heart disease morbidity and mortality and non-cardiovascular mortality has not been established.

Other Considerations

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 (HR0.89 [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.

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%).

Because of chemical, pharmacological, and clinical similarities between LIPOFEN® (fenofibrate capsules), 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 LIPOFEN®.

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^081) 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=0.91-1.64). 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 the WHO 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 second 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: 0.94-5.05). The rate of gallbladder surgery was not statistically significant between the 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).

Initial Therapy: Laboratory studies should be done to ascertain that the lipid levels are consistently abnormal before instituting LIPOFEN® (fenofibrate capsules) 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 LIPOFEN®. Therapy should be withdrawn in patients who do not have an adequate response after two months of treatment with the maximum recommended dose of 150 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.

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 5 years; pO.01).

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 LIPOFEN® administration.

Skeletal Muscle: The use of fibrates alone, including LIPOFEN®, 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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Two dietary carcinogenicity studies have been conducted in rats with fenofibrate. In the first 24-month study, rats were dosed with fenofibrate at 10, 45 and 200 mg/kg/day, approximately 0.3, 1, and 6 times the maximum recommended human dose (MRHD, based on mg/m² of surface area). At a dose of 200 mg/kg/day (at 6 times MRHD), the incidence of liver carcinoma was significantly increased in both sexes. A statistically significant increase in pancreatic carcinomas was observed in males at 1 and 6 times the MRHD; an increase in pancreatic adenomas and benign testicular interstitial cell tumors was observed at 6 times the MRHD in males. In a second 24-month study in a different strain of rats, doses of 10 and 60 mg/kg/day (0.3 and 2 times the MRHD based on mg/m' surface area) produced significant increases in the incidence of pancreatic acinar adenomas in both sexes and increases in testicular interstitial cell tumors in males at 2 times the MRHD (200 mg/kg/day).

A 117-week carcinogenicity study was conducted in rats comparing three drugs: fenofibrate 10 and 60 mg/kg/day (0.3 and 2 times the MRHD), clofibrate (400 mg/kg; 2 times the human dose), and gemfibrozil (250 mg/kg; 2 times the human dose, multiples based on mg/m² surface area). Fenofibrate increased pancreatic acinar adenomas in both sexes. Clofibrate increased hepatocellular nodules in females. Gemfibrozil increased hepatic neoplastic nodules in females, while all three drugs increased testicular interstitial cell tumors in males.

In a 21-month study in mice, fenofibrate 10, 45 and 200 mg/kg/day (approximately 0.2. 0.7, and 3 times the MRHD on the basis of mg/m² surface area) significantly increased the liver carcinomas in both sexes at 3 times the MRHD. In a second 18 month study at the same doses, fenofibrate 10, 45 and 200 mg/kg/day (approximately 0.2, 0.7 and 3 times the MRHD on the basis of mg/m² surface area) significantly increased the liver carcinomas in both sexes at 3 times the MRHD. In a second 18 month study at the same doses, fenofibrate significantly increased the liver carcinomas in male mice and liver adenomas in female mice at 3 times the MRHD.

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

Pregnancy Category C

Safety in pregnant women has not been established. Fenofibrate has been shown to be embryocidal and teratogenic in rats when given in doses 7 to 10 times the maximum recommended human dose (MRHD) and embryocidal in rabbits when given at 9 times the MRHD (on the basis of mg/m² 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 approximately 9 times the MRHD 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, a 0% survival of pups to weaning, and an increase in spina bifida

Administration of approximately 10 times the MRHD to female rats on days 6-15 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 approximately 7 times the MRHD 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 fenofibrate at 9 to 18 times the MRHD to female rabbits caused abortions in 10% to 25% of dams, and death in 7% of fetuses at 18 times the MRHD.

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.

Last updated on RxList: 2/4/2009

There is no specific treatment for overdose with LIPOFEN®. 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.

LIPOFEN® is contraindicated in patients who exhibit hypersensitivity to fenofibrate.

LIPOFEN® is contraindicated in patients with hepatic or severe renal dysfunction, including primary biliary cirrhosis, and patients with unexplained persistent liver function abnormality.

LIPOFEN® is contraindicated in patients with preexisting gallbladder disease (see WARNINGS).

Last updated on RxList: 2/5/2009

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 All) 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 apo AI and apo AH.

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 a (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-m (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-H 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

The extent and rate of absorption of fenofibric acid after administration of 150 mg LIPOFEN® capsules are equivalent under low-fat andhigh-fat fed conditions to 160 mg Tricor® tablets.

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 radiolabeled fenofibrate appeared in urine, primarily as fenofibric acid and its glucuronate conjugate, and 25% was excreted in the feces.

The absorption of fenofibrate is increased when administered with food

With LIPOFEN®, the extent of absorption is increased by approximately 58% and 25% under high-fat fed and low-fat fed conditions as compared to fasting conditions, respectively.

In a single dose and multiple dose bioavailability study with LIPOFEN® capsules 200 mg, the extent of absorption (AUG) of fenofibric acid, the principal metabolite of fenofibrate, was 42% larger at steady state compared to single-dose administration. The rate of absorption (Cms*) of fenofibric acid was 73% greater after multiple-dose than after single-dose administration.

The extent of absorption of LIPOFEN® in terms of AUC value of fenofibric acid increased in a less than proportional manner while the rate of absorption in terms of Cmai value of fenofibric acid increased proportionally related to dose.

Distribution

In healthy volunteers, steady-state plasma levels of fenofibric acid were shown to be achieved after 5 days of once a day dosing and demonstrated a mean 2.4-fold accumulation following multiple dose administration. Steady-state plasma levels of fenofibrate demonstrated no accumulation. 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; unchanged fenofibrate is detected at low concentrations in plasma compared to fenofibric acid over most of the single dose and multiple dosing periods.

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 excretedin urine.

In vivo metabolism data indicate that neither fenofibrate nor fenofibric acid undergo oxidative metabolism (e.g., cytochrome P450) to a significant degree.

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 radiolabeled fenofibrate, approximately 60% of the dose appeared in the urine and 25% was excreted in feces.

Fenofibric acid is eliminated with a half-life between 10 and 35 hours (mean approximately 20 hours) allowing once daily administration in a clinical setting.

Special Populations

Geriatrics

In elderly volunteers 77-87 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 has 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 of 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 LIPOFEN® 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, LIPOFEN® should be taken at least 1 hour before or 4-6 hours after a bile acid binding resin to avoid impeding its absorption (see WARNINGS and PRECAUTIONS).

Clinical Trials

Clinical trials have not been conducted with LIPOFEN®.

Hypercholesterolemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia (Fredrickson Types lla and lib)

The effects of fenofibrate at a dose equivalent to 150 mg per day of LIPOFEN® 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 andraised HDL-C (see Table 1).

Table 1

In a subset of the subjects, measurements of apo B were 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).

Hypertriglyceridemia (Fredrickson Types IV and V]

The effects of fenofibrate on serum triglycerides were studied in two randomized, double-blind, placebo-controlled clinical trials1 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 150 mg LIPOFEN® 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 Fenofibrale in Patients With Fredrickson TyperV/VHyperlipidemia

The effect of fenofibrate on cardiovascular morbidity and mortality has not been determined.

Last updated on RxList: 2/4/2009

No information provided. Please refer to the WARNINGS and PRECAUTIONS sections.

Last updated on RxList: 2/4/2009

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

FENOFIBRATE - ORAL

(fen-oh-FYE-brate)

COMMON BRAND NAME(S): Tricor, Triglide

USES: Fenofibrate is used along with diet and exercise to help control levels of blood fats. It can help lower "bad" cholesterol (LDL) and triglycerides and raise "good" cholesterol (HDL). In general, this drug is used after your blood fat levels have not been fully controlled by non-drug treatments (e.g., diet changes, exercise, decreasing alcohol intake, weight loss if overweight, and controlling blood sugar if diabetic).

Lowering "bad" cholesterol and triglycerides may help decrease the risk for strokes and heart attacks. Fenofibrate is a lipid-lowering agent (fibrate). It works by increasing the natural substance (enzyme) that breaks down fats in the blood.

HOW TO USE: Take this medication by mouth, usually once daily or as directed by your doctor. Fenofibrate comes in capsules and different types of tablets. These dosage forms are not interchangeable. Do not switch between different forms or brands of this medication without talking with your doctor because they may not provide the same amount of medication. Some forms of this drug should be taken with food while some may be taken with or without food. It is important to take this medication correctly to be sure the drug has the greatest benefit. Check with your pharmacist about your brand of fenofibrate.

Swallow the tablet whole. Do not take broken or chipped tablets.

Take fenofibrate at least 1 hour before or 4-6 hours after certain other cholesterol-lowering medications (bile acid-binding resin drugs such as colestipol/cholestyramine). These products can react with fenofibrate, preventing its full absorption.

Dosage is based on your medical condition and response to therapy. Use this medication regularly to get the most benefit from it. Remember to use it at the same time each day. It is important to continue taking this medication even if you feel well. Most people with high cholesterol/triglycerides do not feel sick.

It is very important to continue to follow your doctor's advice about diet and exercise. It may take up to 2 months to get the full benefits of this drug.

SIDE EFFECTS: Upset stomach and constipation may occur. If these effects persist or worsen, notify your doctor promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

This medication may infrequently cause gallstones and liver problems. If you notice any of the following unlikely but very serious side effects, tell your doctor immediately: persistent nausea/vomiting, severe stomach/intestinal pain, dark urine, yellowing eyes/skin.

This drug may infrequently cause muscle pain, tenderness, or weakness (which can rarely lead to a very serious condition called rhabdomyolysis). Seek immediate medical attention if you develop these muscle problems (especially with fever or unusual tiredness). This side effect is more likely if you are also taking a "statin" (e.g., atorvastatin, pravastatin) to lower your cholesterol.

Tell your doctor immediately if any of these rare but very serious side effects occur: easy bleeding/bruising, black/tarry stool, vomit that looks like coffee grounds, signs of infection (e.g., fever, persistent sore throat), change in amount of urine.

A very serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction may include: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking fenofibrate, tell your doctor or pharmacist if you are allergic to it; or to other "fibrates" (e.g., gemfibrozil); or if you have any other allergies. Some Canadian brands of this medication may contain ingredients that come from a soybean source. If you are allergic to soybeans/peanuts, check with your pharmacist about your particular brand.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: gallbladder disease, liver disease (e.g., biliary cirrhosis, hepatitis).

Before using this medication, tell your doctor or pharmacist your medical history, especially of: alcohol use, diabetes, kidney disease, history of muscle problems (e.g., myopathy), underactive thyroid (hypothyroidism).

Kidney function declines as you grow older. This medication is removed by the kidneys. Therefore, elderly people may be more sensitive to the effects of this drug, especially muscle problems.

For the U.S. product, the manufacturer states this medication should be used only when clearly needed during pregnancy. Discuss the risks and benefits with your doctor.

For the Canadian product, the manufacturer states this medication must not be used during pregnancy. If you become pregnant or think you may be pregnant, inform your doctor immediately. Women of childbearing age should use an effective form of birth control. Stop using this drug for several months before becoming pregnant.

It is not known whether this drug passes into breast milk. Breast-feeding while using this drug is not recommended. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: See also How to Use section.

Your healthcare professionals (e.g., doctor or pharmacist) may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop or change the dosage of any medicine before checking with them first.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially: "blood thinners" (e.g., warfarin), ezetimibe, drugs which can increase triglycerides (e.g., beta blockers, certain "water pills" such as thiazide diuretics, estrogens), drugs that may be harmful to the kidneys (e.g., cyclosporine, injectable aminoglycosides such as tobramycin, NSAIDs such as ibuprofen, vancomycin).

Use caution if the following drugs are combined with fenofibrate because serious side effects such as muscle injury (myopathy) infrequently could occur: "statins" (e.g., lovastatin, pravastatin), high-dose niacin (1 gram or more per day).

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US national poison hotline at 1-800-222-1222. Canadian residents should call their local poison control center directly.

NOTES: Do not share this medication with others.

Laboratory and/or medical tests (e.g., kidney/liver tests, blood count, lipid levels) may be performed to monitor your progress or check for side effects. Consult your doctor for more details.

For best results, this medication should be used along with a low saturated fat/low cholesterol diet, exercise, and weight control. Consult your doctor about other ways to lower your heart disease risk.

MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature away from light and moisture. Storage temperature ranges differ according to different manufacturers, so consult your pharmacist for more information. Keep all medicines away from children and pets.

Store the tablets in the original bottle with the desiccant to protect against moisture. Discard any broken or chipped tablets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised September 2008 Copyright(c) 2008 First DataBank, Inc.