Oral LD50 (rat): 1242 mg/kg, Oral LD50 (mouse): 100 mg/kg, lntraperitoneal LD50 (mouse): 500 mg/kg MSDS

Fenofibric acid is contraindicated for: (a) patients with severe renal impairment, including those receiving dialysis, (b) patients with active liver disease, including those with primary biliary cirrhosis and unexplained persistent liver function abnormalities, (c) patients with preexisting gallbladder disease, (d) patients with known hypersensitivity to fenofibric acid or Fenofibrate, and (e) nursing mothers FDA Label.

The relationship between the use of fenofibric acid and risk of mortality and coronary heart disease morbidity has not been formally established FDA Label. However, a number of studies involving fenofibrate and agents that are chemically and pharmacologically similar to fenofibrate demonstrate inconclusive results. In the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, 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 FDA Label. For the Coronary Drug Project, a large study of post myocardial infarction of patients treated for 5 years with clofibrate, there was a difference in the rate of cholelithiasis and cholecystitis requiring surgery between the clofibrate and placebo groups of 3.0% vs. 1.8%, respectively FDA Label. The World Health Organization (WHO) also conducted a study in which 5000 subjects without known coronary artery disease were treated with placebo or clofibrate for 5 years and followed for an additional year FDA Label. The results involved 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) in which excess mortality was due to a 33% increase in non-cardiovascular causes, including malignancy, post-cholecystectomy complications, and pancreatitis FDA Label. With the Helsinki Heart Study, 4081 middle aged men without a history of coronary artery disease were given either placebo or gemfibrozil for 5 years, with a 3.5 year open extension afterward FDA Label. Although total mortality was numerically higher in the gemfibrozil arm, it was statistically significant (p=0.19, 95% confidence interval for relative risk = 0.91-1.64). Finally, a secondary prevention component of the Helsinki Heart Study observed middle aged men not included in the primary prevention study because they had known or suspected coronary heart disease FDA Label. When these subjects were administered gemfibrozil or placebo therapy for 5 years, cardiac deaths trended higher in the gemfibrozil group but was ultimately not statistically significant (HR 2.2, 95% confidence interval: 0.94-5.05) FDA Label.

Fibrates facilitate the risk for myopathy and have been associated with rhabdomyolysis FDA Label. The risk for serious muscle toxicity appears to be increased in elderly patients and in patients with diabetes, renal failure, or hypothyroidism FDA Label. Myopathy should be considered in any patient with diffuse myalgia, muscle tenderness or weakness, and/or marked elevations of creatine phosphokinase levels FDA Label.

Fenofibrate administered across a range of doses with the higher dose equivalent to 105 mg fenofibric acid has been associated with increases in serum transaminases like AST (SGOT) and ALT (SGPT) FDA Label. In a pooled analysis of 10 placebo-controlled trials, increases to more than 3 times the upper limit of normal of ALT occurred in 5.3% of patients taking Fenofibrate versus 1.1% of patients treated with placebo FDA Label. If enzyme levels persist above three times the normal limit, therapy is to be discontinued FDA Label. After discontinuing fenofibrate treatment or during continued treatment a return to normal transaminase limits was usually observed FDA Label. The incidence of increases in transaminases observed with fenofibrate therapy appear to be dose related FDA Label. From 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 35 mg to 105 mg fenofibric acid per day and was comparatively 0% in those receiving placebo or doses equivalent to 35 mg or less fenofibric acid per day FDA Label. Hepatocellular, chronic active and cholestatic hepatitis associated with Fenofibrate therapy have been reported after exposures of weeks to several years FDA Label. In extremely rare cases, cirrhosis has been reported in associated with chronic active hepatitis FDA Label.

Increases in serum creatinine have been reported in patients on Fenofibrate FDA Label. These elevations tend to return to baseline following discontinuation of the drug FDA Label. Although the clinical significance of these observations is unknown, renal monitoring should be considered for patients with renal impairment and for patients at risk for renal insufficiency, perhaps like patients with diabetes or the elderly FDA Label.

Fenofibric acid may increase cholesterol excretion into the bile, leading to cholelithiasis FDA Label. If gallstones are found, fenofibric acid should be discontinued FDA Label.

Caution must be exercised over the ability of fenofibric acid to potentiate the anticoagulant effects of coumarin anticoagulants, resulting in prolongation of the prothrombin time/International Normalized Ratio (PT/INR) FDA Label.

Pancreatitis has also been reported in patients taking Fenofibrate FDA Label. This effect may be caused by the 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 FDA Label.

Mild to moderate hemoglobin, hematocrit, and white blood cell decreases have been observed in patients following the start of fenofibrate therapy FDA Label. However, although these levels tend to stabilize during long-term administration of the medication FDA Label, thrombocytopenia and agranulocytosis have been observed in patients treated with fenofibrates as well FDA Label. Scheduled monitoring of red and white blood cell counts during the first 12 months of fenofibric acid administration is subsequently recommended FDA Label.

Acute hypersensitivity reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis requiring patient hospitalization and treatment with steroids have been reported in patients treated with fenofibrates FDA Label.

In the fenofibrate arm during the FIELD trial, occurrences of pulmonary embolus (PE) and deep vein thrombosis (DVT) were recorded at higher rates when compared to the placebo group FDA Label. In particular, the placebo group had N=4900 and the fenofibrate group N=4895 FDA Label. For DVT there were 48 events (1%) in the placebo group and 67 (1%) in the fenofibrate group with p=0.074 FDA Label. While for PE, there were 32 (0.7%) events in the placebo group and 53 (1%) in the fenofibrate group with p=0.022 FDA Label. Likewise, in the Coronary Drug Project, a higher proportion of the clofibrate group reported definite or suspected fatal or nonfatal PE or thrombophlebitis when compared to the placebo group (5.2% vs 3.3% at 5 years with p<0.01) FDA Label.

Additionally there have been postmarketing and clinical trial reports of serious paradoxical decreases in HDL cholesterol levels to as low as 2 mg/dL happening in diabetic and non-diabetic patients initiated on fibrate therapy FDA Label. This decrease in HDL-C is accompanied by a decrease in apolipoprotein A1. Such decreases have been reported to occur within 2 weeks to years after initiation of fibrate therapy FDA Label. The HDL-C levels remain depressed until fibrate therapy has been withdrawn; the response to withdrawal of fibrate therapy is in fact rapid and sustained FDA Label. HDL-C levels are recommended to be checked within the first few months after initiation of fibrate therapy. In the case of severely depressed HDL-C levels being detected, fibrate therapy should be withdrawn and HDL-C levels monitored until it has returned to baseline with no intention or plan to re-initiate fibrate therapy FDA Label.

Adverse effects associated with the use of fenofibrate and fenofibric acid include abdominal pain, back pain, headache, nausea, constipation, abnormal liver tests, increased AST, increased ALT, increased creatine phosphokinase, respiratory disorder, rhinitis, diarrhea, dyspepsia, nasopharyngitis, sinusitis, upper respiratory tract infection, arthralgia, myalgia, pain in extremity, and/or dizziness FDA Label, L1526.

Adverse effects identified during the post-approval use period of fenofibrate include rhabdomyolysis, panrcreatitis, renal failure, muscle spasms, acute renal failure, hepatitis, cirrhosis, anemia, asthenia, and severely depressed HDL-cholesterol levels ^L1526.

As Fenofibric acid has the capability to potentiate the anticoagulant effect of coumarin anticoagulants (and subsequently prolong the PT/INR of patients), caution should be exercised when oral coumarin anticoagulants are given in conjunction with fenofibric acid. Frequent PT/INR determinations are therefore advisable until stabilized PT/INR readings are obtained
FDA Label, L1526.

Fenofibric acid should be administered to patients at least 1 hour before or 4 to 6 hours after a bile acid resin is given as such drugs may bind other agents being given concurrently and impede their absorption FDA Label, L1526.

Immunosuppressant medications like cyclosporine and tacrolimus can cause nephrotoxicity with decreases in creatinine clearance and rises in serum creatinine, and because renal excretion is the main elimination route for fenofibric acid, there exists a risk that an interaction could lead to deterioration of renal function FDA Label, L1526. As a consequence, the benefits and risks of using fenofibric acid with any other potentially nephrotoxic agents should be carefully considered and the lowest effective dose employed FDA Label, L1526.

Cases of myopathy, including rhabdomyolysis, have been reported with fenofibrates co-administered with colchicine, and caution should be exercised when considering the combination use of fenofibrates with colchicine FDA Label, L1526.

No well controlled studies regarding the use of fenofibric acid in pregnant women have been established FDA Label, L1526. Since the safety of fenofibric acid in pregnant women has not been formally elucidated, fenofibric acid should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus FDA Label, L1526.

Moreover, fenofibric acid should not be used in nursing mothers. Under the circumstances, a decision should be made between having to discontinue nursing or to discontinue the use of fenofibric acid, taking into perspective the importance of the drug therapy to the mother FDA Label, L1526.

The safety and effectiveness of fenofibric acid in paediatric patients has not been formally established FDA Label, L1526.

Fenofibric acid is predominantly excreted by the kidney system unchanged or as fenofibric acid glucuronide FDA Label, L1526. The risk of experiencing adverse reactions associated with exposure to fenofibric acid may consequently be greater in patients with impaired renal function FDA Label, L1526. Subsequently, because elderly patients may have a higher incidence of renal impairment, the dosage of fenofibric acid for geriatric patients should be based upon renal function, with normal renal function requiring no dosage modifications FDA Label, L1526. Renal function monitoring in elderly patients taking fenofibric acid is recommended FDA Label, L1526.

In patients with severe renal impairment, the use of fenofibric acid is to be avoided while dose reductions is necessary in patients with mild to moderate renal impairment FDA Label, L1526. Monitoring renal function in patients with renal impairment is recommended FDA Label, L1526.

The use of fenofibric acid has not been evaluated in patients with hepatic impairment FDA Label, L1526.

In a 24 month study, Wistar rats were dosed at various levels of fenofibrate. At a dose of 200mg/kg/day (6 times the maximum recommended human dose MRHD based on body surface area comparisons mg/m2), the incidence of liver carcinomas was significantly increased in both sexes of the rats FDA Label, L1526. At doses of 10 (0.3 times the MRHD) and 200 mg/kg/day, a statistically significant increase in pancreatic carcinomas was observed in males, and an increase in pancreatic adenomas and benign testicular interstitial cell tumours were observed at 200 mg/kg/day in males FDA Label, L1526. In a second 24 month study on the Sprague-Dawley strain of rats, doses of 10 and 60 mg/kg/day produced significant increases in the incidence of pancreatic acinar adenomas in both sexes of the rats and increases in interstitial cell tumours of the testes at 2 times the MRHD FDA Label, L1526.

In addition, fenofibrate 10 and 60 mg/kg/day, clofibrate 400 mg/kg/day (2 times the MRHD), and gemfibrozil 250 mg/kg/day (2 times the MRHD) are studied in a 117 week study in rats. Fenofibrate increased pancreatic acing adenomas in both sexes of the rats FDA Label, L1526. Clofibrate increased hepatocellular carcinoma and pancreatic acinar adenomas in males and hepatic neoplastic nodules in females FDA Label, L1526. And finally, gemfibrozil increased hepatic neoplastic nodules in males and females, while all three drugs increased testicular interstitial cell tumours in males FDA Label, L1526.

In a 21 month study with CF-1 mice, fenofibrate 10, 45, and 200 mg/kg/day (approximately 0.2, 1, and 3 times the MRHD) significantly increased the liver carcinomas in both sexes at 3 times the MRHD FDA Label, L1526. With a second 18 month study at 10, 60, and 200 mg/kg/day, fenofibrate significantly increased the liver carcinomas in male and female mice 3 times the MRHD FDA Label, L1526.

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 FDA Label, L1526

Fenofibrate was shown to be devoid of mutagenic potential in the Ames and micronucleus tests in vivo/rat FDA Label, L1526. In addition, fenofibric acid, has bee.n demonstrated to be devoid of mutagenic potential in the following tests: Ames, mouse lymphoma, chromosomal aberration and sister chromatid exchange in human lymphocytes, and unscheduled DNA synthesis in primary rat hepatocytes FDA Label, L1526.

In a fertility study, rats were given oral dietary doses of fenofibrate. Males received doses for 61 days prior to mating and females for 15 days prior to mating through weaning, which resulted in no adverse effect on fertility at doses up to 300 mg/kg/day (~10 times the MRHD, based on mg/m2 surface area comparisons) FDA Label, L1526.