Triglide Tablets (First Horizon)

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DESCRIPTION

TRIGLIDE™ (fenofibrate) tablets, is a lipid-regulating agent available as tablets for oral administration.

Each tablet contains 50 mg or 160 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 C ₂₀ H ₂₁ O ₄ Cl and the molecular weight is 360.83; fenofibrate is insoluble in water.

The melting point is 79°C to 82°C. Fenofibrate is a white solid that is stable under ordinary conditions.

Inactive Ingredients:    Each tablet also contains crospovidone, lactose monohydrate, mannitol, maltodextrin, carboxymethylcellulose sodium, egg lecithin, croscarmellose sodium, sodium lauryl sulfate, colloidal silicon dioxide, magnesium stearate, and monobasic sodium phosphate.

CLINICAL PHARMACOLOGY

A variety of clinical studies have demonstrated that elevated levels of total cholesterol (TC), 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 A-I and apo A-II) are associated with the development of atherosclerosis. Epidemiologic investigations have established that cardiovascular morbidity and mortality vary directly with the level of TC, LDL-C, and triglycerides (TG), and inversely with the level of HDL-C. The independent effect of raising HDL-C or lowering 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 AII. 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 (alpha) (PPAR(alpha)). 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 TG 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 af[iuml ]nity for cholesterol receptors and are catabolized rapidly. Activation of PPAR(alpha) 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

Absorption

The absolute bioavailability of fenofibrate cannot be determined as the compound is virtually insoluble in aqueous media suitable for injection. However, after fenofibrate is dissolved, fenofibrate is well absorbed from the gastrointestinal tract.

Peak plasma levels of fenofibric acid occurs an average of 3 hours after administration.

TRIGLIDE 160 mg tablet exhibits a similar extent of absorption but 32% higher rate of absorption compared to the 200 mg micronized fenofibrate capsule under low-fat fed conditions.

Effect of Food on Absorption

Fenofibrate is insoluble in water and its bioavailability is optimized when taken with meals.

The extent of absorption of TRIGLIDE (AUC) is comparable between fed and fasted conditions. Food increases the rate of absorption of TRIGLIDE approximately 55%.

(See DOSAGE AND ADMINISTRATION .)

Distribution

In healthy volunteers administered nonmicronized formulation of fenofibrate, steady-state plasma levels of fenofibric acid were shown to be achieved within 5 days of daily dosing with single oral doses and did not demonstrate accumulation across time following multiple dose administration. Serum protein binding was approximately 99% bound to plasma proteins 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 of healthy subjects following fenofibrate administration. 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 radiolabeled 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 approximately 16 hours, allowing once daily administration in a clinical setting.

Pharmacokinetics in Special Populations

Geriatrics

TRIGLIDE has not been investigated in adequate and well-controlled trials in geriatric patients. However, a previous study using nonmicronized formulation shows that the oral clearance of fenofibric acid is similar to that of young adults. This indicates that a similar dosage regimen can be used in the elderly, without increasing accumulation of the drug or metabolites.

Pediatrics

TRIGLIDE 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

TRIGLIDE has not been investigated in patients with renal impairment. In a study using nonmicronized formulation 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. Therefore, the dosage of TRIGLIDE 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 with hepatic insufficiency.

Drug-Drug Interactions

In vitro studies using human liver microsomes indicate that fenofibrate and fenofibric acid are not inhibitors of cytochrome P450 (CYP) 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 4-6 hours after a bile acid binding resin to avoid impeding its absorption.

(See WARNINGS and PRECAUTIONS .)

CLINICAL TRIALS

In a single-dose pharmacokinetics study in healthy volunteers, TRIGLIDE 160 mg tablet was shown to have comparable bioavailability to a single dose of 200 mg fenofibrate capsule, micronized.

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

The effects of fenofibrate at a dose comparable to 200 mg micronized fenofibrate 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 191.0 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 end-point 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 (Goldberg et al., 1989) 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 200 mg micronized fenofibrate (comparable to 160 mg TRIGLIDE) 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).

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

INDICATIONS AND USAGE

Treatment of Hypercholesterolemia

TRIGLIDE is indicated as adjunctive therapy to diet for the reduction of LDL-C, Total-C, Triglycerides and Apo B in adult patients with primary hypercholesterolemia or mixed dyslipidemia (Fredrickson Types IIa and IIb).

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

Treatment of Hypertriglyceridemia

TRIGLIDE is 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 TRIGLIDE therapy on reducing this risk has not been 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 (Nikkila, 1983).

The initial treatment for dyslipidemia is dietary therapy specific for the type of lipoprotein abnormality. Excess body weight and excess alcohol intake may be important factors in hypertriglyceridemia and should be addressed prior to any drug therapy. Physical exercise can be an important ancillary measure.

Diseases contributory to hyperlipidemia, such as hypothyroidism or diabetes mellitus should be looked for and adequately treated. Estrogen therapy, like thiazide diuretics and beta-blockers, is sometimes associated with massive rises in plasma triglycerides, especially in subjects with familial hypertriglyceridemia.

In such cases, discontinuation of the specific etiologic agent may obviate the need for specific drug therapy of hypertriglyceridemia.

The use of drugs should be considered only when reasonable attempts have been made to obtain satisfactory results with non-drug methods. If the decision is made to use drugs, the patient should be instructed that this does not reduce the importance of adhering to diet. (See WARNINGS and PRECAUTIONS .)

CONTRAINDICATIONS

TRIGLIDE administration is contraindicated in the following conditions:

• Hypersensitivity to fenofibrate or any of the formulation components
• Severe renal dysfunction
• Hepatic dysfunction, including primary biliary cirrhosis and unexplained persistent liver function abnormality
• Pre-existing gallbladder disease

(See WARNINGS .)

WARNINGS

Liver Function:    Fenofibrate at doses equivalent to 134 mg to 200 mg micronized fenofibrate per day (at the highest dose, comparable to 160 mg TRIGLIDE) 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 transaminase 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 134 mg to 200 mg micronized fenofibrate per day and was 0% in those receiving dosages equivalent to 34 mg or 67 mg micronized fenofibrate per day, or placebo. Hepatocellular, chronic active and cholestatic hepatitis associated with fenofibrate therapy have been reported after exposures of weeks to several years. In extremely rare cases, cirrhosis has been reported in association with chronic active hepatitis.

Baseline and regular periodic monitoring of liver function, including serum ALT (SGPT) should be performed for the duration of therapy with TRIGLIDE, and therapy should be 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 and TRIGLIDE therapy should be discontinued if gallstones are found.

Concomitant Oral Anticoagulants:    Caution should be exercised when anticoagulants are given in conjunction with TRIGLIDE 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 (Statins): The combined use of TRIGLIDE 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.

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, may occasionally be associated with myositis, myopathy, or rhabdomyolysis. Patients receiving TRIGLIDE 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, TRIGLIDE therapy 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:    Because of chemical, pharmacological, and clinical similarities between fenofibrate and other products in this pharmacological class, adverse findings from other fibrate drugs (clofibrate and gemfibrozil) may also apply to fenofibrate products.

Clofibrate:   In one large randomized, placebo-controlled clinical study (Coronary Drug Project) conducted in patients with previous myocardial infarction, no differences in mortality between patients treated with clofibrate for 5 years (N=1103) and patients receiving placebo (N=2789) were reported, but twice as many patients given clofibrate developed cholelithiasis and cholecystisis (3.0% versus 1.8%). In another study conducted by the World Health Organization (WHO) in 5000 patients without known coronary heart disease who were treated with clofibrate for 5 years and followed 1 year beyond, a statistically significant higher age-adjusted total mortality in the group of patients treated with clofibrate compared to the placebo-treated control group (N=5000) was reported (5.70% versus 3.96%, p<0.01). The excess mortality causes included malignancy, post-cholecystectomy complications, and pancreatitis. A higher risk for gallbladder disease in patients administered clofibrate was reported.

In a follow-up study, which included almost 8 years of observation after the study ended, no differences in cancer rates were reported when both groups were standardized for age.

Gemfibrozil:   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=.91-1.64). Although cancer deaths trended higher in the gemfibrozil group (p=0.11), cancers (excluding basal cell carcinoma) were diagnosed with equal frequency in both study groups. Due to the limited size of the study, the relative risk of death from any cause was not shown to be different than that seen in the 9 year follow-up data from World Health Organization study (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 signficant (hazard ratio 2.2, 95% confidence interval: 0.94-5.05). 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).

PRECAUTIONS

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

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 administration.

Skeletal Muscle Changes:    Treatment with drugs of the fibrate class, including fenofibrate, 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 TRIGLIDE. 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 (Statins):   The combined use of TRIGLIDE 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 TRIGLIDE 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 TRIGLIDE, there is a risk that an interaction will lead to deterioration. The benefits and risks of using TRIGLIDE with immunosuppressants and other potentially nephrotoxic agents should be carefully considered, and the lowest effective dose employed.

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/meter ² of surface area). At a dose of 200 mg/kg/day (at 6 times the MRHD), the incidence of liver carcinoma was signficantly increased in both sexes. A statistically signifficant 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/meter ² 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 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/meter ² surface area). Fenofibrate increased pancreatic acinar adenomas in both sexes. Clofibrate increased hepatocellular carcinoma and pancreatic acinar adenomas in males and hepatic neoplastic nodules in females. Gemfibrozil increased hepatic neoplastic nodules in males and 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/meter ² 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 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 conducted, 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 four tests: Ames, mouse lymphoma, chromosomal aberration and unscheduled DNA synthesis.

Pregnancy:    Teratogenic Effects, 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/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 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, and a 0% survival of pups to weaning, and an increase in spina bifida.

Administration of approximately 10 times the MRHD of fenofibrate 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.

ADVERSE REACTIONS

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 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.

Laboratory Tests/Altered Laboratory Findings:    In patients treated with fenofibrate, the following has been reported:

• Increases in serum transaminase and isolated cases of hepatitis
• Decreases in plasma alkaline phosphatase
• Increases in plasma creatinine, urea, and creatine phosphokinase

OVERDOSAGE

There is no specific treatment for overdose with TRIGLIDE. 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.

DOSAGE AND ADMINISTRATION

Patients should be placed on an appropriate lipid-lowering diet before receiving TRIGLIDE and should continue on this diet during treatment with TRIGLIDE.

TRIGLIDE may be administered with or without food.

For the treatment of adult patients with primary hypercholesterolemia or mixed hyperlipidemia, the initial dose of TRIGLIDE is 160 mg per day.

For adult patients with hypertriglyceridemia, the initial dose is 50 mg to 160 mg once daily.

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 TRIGLIDE should be initiated at a dose of 50 mg/day in patients with 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 TRIGLIDE if lipid levels fall significantly below the targeted range.

HOW SUPPLIED

TRIGLIDE (fenofibrate) tablets, is available as a tablet in two strengths:

50 mg round off-white tablets debossed with "FH 50" are available in bottles of 90 tablets (NDC 59630-480-90).

160 mg round off-white tablets debossed with "FH 160" are available in bottles of 90 tablets (NDC 59630-485-90).

Storage: Store at 20 - 25°C (68 - 77°F); excursions permitted between 15 - 30°C (59 - 86°F). (See USP Controlled Room Temperature). Protect from light and moisture.

Manufactured for First Horizon Pharmaceutical® Corporation by Skyepharma Production SAS, France. Made in France.

Skyepharma

REFERENCES

• Goldberg AC, et al. Fenofibrate for the Treatment of Type IV and V Hyperlipoproteinemias: A Double-Blind, Placebo-Controlled Multicenter US Study. Clinical Therapeutics 1989; 11: 69-83.
• Nikkila EA. Familial lipoprotein lipase deficiency and related disorders of chylomicron metabolism. In: Stanbury JB, ed. The metabolic basis of inherited disease: McGraw-Hill, 1983; 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, 1986; 6: 670-678.

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FF-PI-1 Rev. 01/05

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