Two dietary carcinogenicity studies have been conducted in rats with fenofibrate. In the first 24-month study, Wistar 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 body surface area comparisons (mg/m2). At a dose of 200 mg/kg/day (at 6 times the MRHD), the incidence of liver carcinomas 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 rat carcinogenicity study in a different strain of rats (Sprague-Dawley), doses of 10 and 60 mg/kg/day (0.3 and 2 times the MRHD) 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.
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/day; 2 times the human dose), and gemfibrozil (250 mg/kg/day; 2 times the human dose, based on mg/m2 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 CF-1 mice, fenofibrate 10, 45, and 200 mg/kg/day (approximately 0.2, 1, 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 10, 60, and 200 mg/kg/day, 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 in primary rat hepatocytes.
Impairment of Fertility
In fertility studies rats were given oral dietary doses of fenofibrate, males received 61 days prior to mating and females 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).
The effects of fenofibrate at a dose equivalent to 90 mg Antara 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 4).
† Duration of study treatment was 3 to 6 months.
|Treatment Group||Total – C||LDL – C||HDL – C||TG|
|Mean baseline lipid values (N=646)||306.9 mg/dL||213.8 mg/dL||52.3 mg/dL||191.0 mg/dL|
|All FEN (n=361)||-18.7%*||-20.6%*||+11.0%*||-28.9%*|
|Baseline LDL – C > 160 mg / dL and TG < 150 mg / dL ( Type IIa )|
|Mean baseline lipid values (N=334)||307.7 mg/dL||227.7 mg/dL||58.1 mg/dL||101.7 mg/dL|
|All FEN (n=193)||-22.4%*||-31.4%*||+9.8%*||-23.5%*|
|Baseline LDL – C > 160 mg / dL and TG ≥ 150 mg / dL ( Type IIb )|
|Mean baseline lipid values (N=242)||312.8 mg/dL||219.8 mg/dL||46.7 mg/dL||231.9 mg/dL|
|All FEN (n=126)||-16.8%*||-20.1%*||+14.6%*||-35.9%*|
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).
The effects of fenofibrate on serum triglycerides were studied in two randomized, double-blind, placebo-controlled clinical trials of 147 hypertriglyceridemic patients. Patients were treated for eight weeks under protocols that differed only in that one entered patients with baseline TG levels of 500 to 1500 mg/dL, and the other TG levels of 350 to 499 mg/dL. In patients with hypertriglyceridemia and normal cholesterolemia with or without hyperchylomicronemia , treatment with fenofibrate at dosages equivalent to 90 mg Antara per day decreased primarily very low density lipoprotein (VLDL) triglycerides and VLDL cholesterol Treatment of patients with elevated triglycerides often results in an increase of LDL-C (See Table 5).
|Baseline TG levels 350 to 499 mg/dL||N||Baseline (mean)||Endpoint (mean)||% Change (mean)||N||Baseline (mean)||Endpoint (mean)||% Change (mean)|
|Baseline TG levels 500 to 1500 mg/dL||N||Baseline (mean)||Endpoint (mean)||% Change (mean)||N||Baseline (mean)||Endpoint (mean)||% Change (mean)|
The effect of Antara on serum triglycerides was studied in a double-blind, randomized, 3 arm parallel-group trial of 146. The study population was comprised of 61 % male and 39% female patients. Approximately 70% of patients had hypertension and 32% had diabetes. Patients were treated for eight weeks with either Antara equivalent to 90 mg taken once daily with meals, Antara equivalent to 90 mg taken once daily between meals, or placebo. Antara equivalent to 90 mg, whether taken with meals or between meals, had comparable effects on TG and all lipid parameters (See Table 6).
|Placebo ( n = 50 )||Antara with meals ( n = 54 )||Antara between meals ( n = 42 )|
|Baseline mg/dL (mean)||% Change at endpoint (mean)||Baseline mg/dL (mean)||% Change at endpoint (mean)||Baseline mg/dL (mean)||% Change at endpoint (mean)|
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