Prescription Drug Information: Fenofibrate (Page 4 of 5)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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) of 300 mg fenofibrate daily, equivalent to 150 mg fenofibrate daily, based on body surface area comparisons. 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, based on body surface area comparisons), 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, based on body surface area comparisons) 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.

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 body surface area comparisons).

14 CLINICAL STUDIES

Clinical trials have not been conducted with fenofibrate capsules.

14.1 Primary Hypercholesterolemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia

The effects of fenofibrate at a dose equivalent to 150 mg per day of fenofibrate was 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).

Table 4. Mean Percent Change in Lipid Parameters at End of Treatment+
+ Duration of study treatment was 3 to 6 months. * p = <0.05 vs. Placebo

Treatment Group

Total-C

LDL-C

HDL-C

TG

Pooled Cohort

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%*

Placebo (n=285)

-0.4%

-2.2%

+0.7%

+7.7%

Baseline LDL-C >160 mg/dLand TG <150 mg/dL

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%*

Placebo (n=141)

+0.2%

-2.2%

+2.6%

+11.7%

Baseline LDL-C >160 mg/dLand TG ≥150 mg/dL

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%*

Placebo (n=116)

-3.0%

-6.6%

+2.3%

+0.9%

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).

14.2 Severe Hypertriglyceridemia

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 500 mg/dL. In patients with hypertriglyceridemia and normal cholesterolemia with or without hyperchylomicronemia, treatment with fenofibrate at dosages equivalent to 150 mg fenofibrate per day decreased primarily very low density lipoprotein (VLDL), triglycerides and VLDL cholesterol. Treatment of some with elevated triglycerides often results in an increase of LDL-C (see Table 5).

Table 5. Effects in Patients With Severe Hypertriglyceridemia
* = P<0.05 vs. Placebo

Study 1

Placebo

Fenofibrate

Baseline TG Levels 350 to 499 mg/dL

N

Baseline (Mean)

Endpoint (Mean)

% Change (Mean)

N

Baseline (Mean)

Endpoint (Mean)

% Change (Mean)

Triglycerides

28

449

450

-0.5

27

432

223

-46.2*

VLDL Triglycerides

19

367

350

2.7

19

350

178

-44.1*

Total Cholesterol

28

255

261

2.8

27

252

227

-9.1*

HDL Cholesterol

28

35

36

4

27

34

40

19.6*

LDL Cholesterol

28

120

129

12

27

128

137

14.5

VLDL Cholesterol

27

99

99

5.8

27

92

46

-44.7*

Study 2

Placebo

Fenofibrate

Baseline TG Levels 500 to 1500 mg/dL

N

Baseline (Mean)

Endpoint (Mean)

% Change (Mean)

N

Baseline (Mean)

Endpoint (Mean)

% Change (Mean)

Triglycerides

44

710

750

7.2

48

726

308

-54.5*

VLDL Triglycerides

29

537

571

18.7

33

543

205

-50.6*

Total Cholesterol

44

272

271

0.4

48

261

223

-13.8*

HDL Cholesterol

44

27

28

5.0

48

30

36

22.9*

LDL Cholesterol

42

100

90

-4.2

45

103

131

45.0*

VLDL Cholesterol

42

137

142

11.0

45

126

54

-49.4*

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

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