LIPOFEN™
(fenofibrate capsules)

Rx only

LIPOFEN™ (fenofibrate capsules), is a lipid regulating agent available as hard gelatin capsules for oral administration. Each hard gelatin capsule contains 50, 100 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 C₂₀H₂₁O₄C1 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.

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.

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

Clinical trials have not been conducted with LIPOFEN™.

Hypercholesterolemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia (Fredrickson Types IIa and IIb)

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 and raised HDL-C (see 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).

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 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 intervention alone has been inadequate (see National Cholesterol Education Program (NCEP) Treatment Guidelines, below).

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).

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.

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

LIPOFEN™ is contraindicated in patients with hepatitis 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).

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/m² 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 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 synthesis.

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 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 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.

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.

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 three 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 66277-246-02) and 90 (NDC 66277-246-03).

100 mg: Size 2 white opaque/white opaque gelatin capsule, imprinted in brown-red (rust) ink with “100” between lines on the body, “G 247” on the cap and containing a white to almost white paste, available in bottles of 30 (NDC 66277-247-02) and 90 (NDC 66277-247-03).

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 66277-248-02) and 90 (NDC 66277-248-03).

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

• 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.
• 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, 5^th edition, McGraw-Hill. 1983, Chap. 30, pp. 622-642.
• BROWN WV, 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.

March 2007

Galephar Pharmaceutical Research Inc.,

Juncos, Puerto Rico 00777-3873