Prescription Drug Information: FENOFIBRATE (Page 4 of 5)

Oral Anticoagulants

CAUTION SHOULD BE EXERCISED WHEN COUMARIN ANTICOAGULANTS ARE GIVEN IN CONJUNCTION WITH FENOFIBRATE TABLETS. 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

The combined use of fenofibrate tablets 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 fenofibrate tablets at least 1 hour before or 4 to 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 fenofibrate tablets, there is a risk that an interaction will lead to deterioration.

The benefits and risks of using fenofibrate tablets 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 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, 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 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.

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 adverse effect on fertility at doses up to 300 mg/kg/day (~10 times the MRHD, based on mg/m2 surface area comparisons).

Pregnancy

Teratogenic Effects

Pregnancy Category C

Safety in pregnant women has not been established. There are no adequate and well controlled studies of fenofibrate in pregnant women. Fenofibrate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In female rats given oral dietary doses of 15, 75, and 300 mg/kg/day of fenofibrate from 15 days prior to mating through weaning, maternal toxicity was observed at 0.3 times the MRHD, based on body surface area comparisons; mg/m2.

In pregnant rats given oral dietary doses of 14, 127, and 361 mg/kg/day from gestation day 6-15 during the period of organogenesis, adverse developmental findings were not observed at 14 mg/kg/day (less than 1 times the MRHD, based on body surface area comparisons; mg/m2). At higher multiples of human doses evidence of maternal toxicity was observed.

In pregnant rabbits given oral gavage doses of 15, 150, and 300 mg/kg/day from gestation day 6-18 during the period of organogenesis and allowed to deliver, aborted litters were observed at 150 mg/kg/day (10 times the MRHD, based on body surface area comparisons: mg/m2). No developmental findings were observed at 15 mg/kg/day (at less than 1 times the MRHD, based on body surface area comparisons; mg/m2).

In pregnant rats given oral dietary doses of 15, 75, and 300 mg/kg/day from gestation day 15 through lactation day 21 (weaning), maternal toxicity was observed at less than 1 times the MRHD, based on body surface area comparisons; mg/m2.

Nursing Mothers

It is not known whether fenofibrate is excreted into milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from fenofibrate, a decision should be made whether to discontinue nursing or administration of fenofibrate taking into account the importance of the drug to the lactating woman.

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. Fenofibric acid exposure is not influenced by age. However, elderly patients have a higher incidence of renal impairment, such that dose selection for the elderly should be made on the basis of renal function (see CLINICAL PHARMACOLOGY, Special Populations, Renal Insufficiency). Elderly patients with normal renal function should require no dose modifications.

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.

BODY SYSTEM Fenofibrate * Placebo
Adverse Event (N=439) (N=365)
*
Dosage equivalent to 145 mg fenofibrate tablets.
Significantly different from Placebo.
BODY AS A WHOLE
Abdominal Pain 4.6% 4.4%
Back Pain 3.4% 2.5%
Headache 3.2% 2.7%
Asthenia 2.1% 3.0%
Flu Syndrome 2.1% 2.7%
DIGESTIVE
Liver Function Test Abnormal 7.5% 1.4%
Diarrhea 2.3% 4.1%
Nausea 2.3% 1.9%
Constipation 2.1% 1.4%
METABOLIC AND NUTRITIONAL DISORDERS
SGPT Increased 3.0% 1.6%
Creatine Phophokinase Increased 3.0% 1.4%
SGOT Increased 3.4% 0.5%
RESPIRATORY
Respiratory Disorder 6.2% 5.5%
Rhinitis 2.3% 1.1%

Additional adverse events reported during post-marketing surveillance or 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: Accidental injury, allergic reaction, chest pain, cyst, fever, hernia, infection, malaise and pain (unspecified).

CARDIOVASCULAR SYSTEM: Angina pectoris, arrhythmia, atrial fibrillation, cardiovascular disorder, coronary artery disorder, electrocardiogram abnormal, extrasystoles, hypertension, hypotension, migraine, myocardial infarct, palpitation, peripheral vascular disorder, phlebitis, tachycardia, varicose vein, vascular disorder, vasodilatation, venous thromboembolic events (deep vein thrombosis, pulmonary embolus) and ventricular extrasystoles.

DIGESTIVE SYSTEM: Anorexia, cholecystitis, cholelithiasis, colitis, diarrhea, duodenal ulcer, dyspepsia, eructation, esophagitis, flatulence, gastritis, gastroenteritis, gastrointestinal disorder, increased appetite, jaundice, liver fatty deposit, nausea, pancreatitis, peptic ulcer, rectal disorder, rectal hemorrhage, tooth disorder and vomiting.

ENDOCRINE SYSTEM: Diabetes mellitus.

HEMIC AND LYMPHATIC SYSTEM: Anemia, ecchymosis, eosinophilia, leukopenia, lymphadenopathy, and thrombocytopenia.

LABORATORY INVESTIGATIONS: Alkaline phosphatase increased, bilirubin increased, blood urea nitrogen increased, serum creatinine increased, gamma glutamyl transpeptidase increased, lactate dehydrogenase increased, SGOT and SGPT increased.

METABOLIC AND NUTRITIONAL DISORDERS: Edema, gout, hyperuricemia, hypoglycemia, peripheral edema, weight gain, and weight loss.

MUSCULOSKELETAL SYSTEM: Arthralgia, arthritis, arthrosis, bursitis, joint disorder, leg cramps, myalgia, myasthenia, myositis, rhabdomyolysis and tenosynovitis.

NERVOUS SYSTEM: Anxiety or nervousness, depression, dizziness, dry mouth, hypertonia, insomnia, libido decreased, neuralgia, paresthesia, somnolence and vertigo.

RESPIRATORY SYSTEM: Allergic pulmonary alveolitis, asthma, bronchitis, cough increased, dyspnea, laryngitis, pharyngitis, pneumonia and sinusitis.

SKIN AND APPENDAGES: Acne, alopecia, contact dermatitis, eczema, fungal dermatitis, herpes simplex, herpes zoster, maculopapular rash, nail disorder, photosensitivity reaction, pruritus, rash, sweating, skin disorder, skin ulcer and urticaria.

SPECIAL SENSES: Abnormal vision, amblyopia, cataract specified, conjunctivitis, ear pain, eye disorder, otitis media and refraction disorder.

UROGENITAL SYSTEM: Abnormal kidney function, cystitis, dysuria, gynecomastia, prostatic disorder, unintended pregnancy, urinary frequency, urolithiasis and vaginal moniliasis.

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