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), 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.

Mutagenesis

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).

14 CLINICAL STUDIES

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

The effects of fenofibrate at a dose equivalent to 130 mg 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 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

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 mg/dL
All FEN (n=361) -18.7% * -20.6% * +11% * -28.9% *
Placebo (n=285) -0.4% -2.2% +0.7% +7.7%
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% *
Placebo (n=141) +0.2% -2.2% +2.6% +11.7%
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% *
Placebo (n=116) -3% -6.6% +2.3% +0.9%

Duration of study treatment was 3 to 6 months.

* p=<0.05 vs. placebo

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 499 mg/dL. In patients with hypertriglyceridemia and normal cholesterolemia with or without hyperchylomicronemia, treatment with fenofibrate at dosages equivalent to 130 mg fenofibrate 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).

Table 5 Effects of Fenofibrate in Patients with Hypertriglyceridemia

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 1.2 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 48 30 36 22.9 *
LDL Cholesterol 42 100 90 -4.2 45 103 131 45 *
VLDL Cholesterol 42 137 142 11 45 126 54 -49.4*

* p < 0.05 vs. placebo

The effect of fenofibrate 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 fenofibrate equivalent to 130 mg taken once daily with meals, fenofibrate equivalent to 130 mg taken once daily between meals, or placebo. Fenofibrate equivalent to 130 mg, whether taken with meals or between meals, had comparable effects on TG and all lipid parameters (See Table 6).

Table 6 Fenofibrate Treatment in Patients with Hypertriglyceridemia

Placebo (n =50) Fenofibrate with meals (n=54) Fenofibrate 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)
Triglycerides 479 +0.7 475 -36.7 * 487 -36.6 *
Total Cholesterol 237 -0.8 248 -5.1 241 -3.4
HDL Cholesterol 35 +0.8 36 +13.7 * 36 +14.3 *
Non-HDL Cholesterol 202 -1.1 212 -8.2 ** 205 -6.6 **
LDL Cholesterol 115 +3.2 120 +15.4 * 122 +14.5
VLDL Cholesterol 87 -1.6 92 -34.4 * 83 -30.4 *

* p ≤ 0.05 vs placebo

** p ≤ 0.05 vs placebo (log transformed data)

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

16 HOW SUPPLIED/STORAGE AND HANDLING

Fenofibrate capsules, USP (micronized) are available in two strengths.

Fenofibrate Capsules, USP 43 mg are hard gelatin capsules with off-white opaque body and light green opaque cap, imprinted “APO F43” in black ink, filled with white to off-white granules/slugs. They are supplied as follows:

Bottles of 30s (NDC 60505-3120-3)

Fenofibrate Capsules, USP 130 mg are hard gelatin capsules with white, opaque body and dark green opaque cap, imprinted “APO F130” in black ink, filled with white to off-white granules/slugs. They are supplied as follows:

Bottles of 30s (NDC 60505-3121-3)

Bottles of 90s (NDC 60505-3121-9)

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

17 PATIENT COUNSELING INFORMATION

Patients should be advised:

  • of the potential benefits and risks of fenofibrate capsules.
  • not to use fenofibrate capsules if there is a known hypersensitivity to fenofibrate or fenofibric acid.
  • that if they are taking coumarin anticoagulants, fenofibrate capsules may increase their anticoagulant effect, and increased monitoring may be necessary.
  • of medications that should not be taken in combination with fenofibrate capsules.
  • to continue to follow an appropriate lipid-modifying diet while taking fenofibrate capsules.
  • to take fenofibrate capsules once daily, without regard to food, at the prescribed dose swallowing each capsule whole.
  • to inform their physician of all medications, supplements, and herbal preparations they are taking and any change to their medical condition. Patients should also be advised to inform their physicians prescribing a new medication that they are taking fenofibrate capsules.
  • to inform their physician of symptoms of liver injury (e.g., jaundice, abnormal pain, nausea, malaise, dark urine, abnormal stool, pruritus); any muscle pain, tenderness, or weakness; onset of abdominal pain; or any other new symptoms.
  • to return to their physician’s office for routine monitoring.

APOTEX INC.

FENOFIBRATE CAPSULES, USP

43 mg and 130 mg

Manufactured by: Manufactured for:
Apotex Inc. Apotex Corp.
Toronto, ON Weston, Florida
Canada, M9L 1T9 33326

Revised: November 2021

Rev. 12

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