Prescription Drug Information: Gemfibrozil (Page 3 of 4)

Repaglinide

In healthy volunteers, coadministration with gemfibrozil increased the plasma concentration of repaglinide and prolonged its hypoglycemic effects. Coadministration of gemfibrozil and repaglinide increases the risk for severe hypoglycemia and is contraindicated (see CONTRAINDICATIONS).

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies have been conducted in rats at 0.2 and 1.3 times the human exposure (based on AUC). The incidence of benign liver nodules and liver carcinomas was significantly increased in high dose male rats. The incidence of liver carcinomas increased also in low dose males, but this increase was not statistically significant (p = 0.1). Male rats had a dose-related and statistically significant increase of benign Leydig cell tumors. The higher dose female rats had a significant increase in the combined incidence of benign and malignant liver neoplasms.

Long-term studies have been conducted in mice at 0.1 and 0.7 times the human exposure (based on AUC). There were no statistically significant differences from controls in the incidence of liver tumors, but the doses tested were lower than those shown to be carcinogenic with other fibrates.

Electron microscopy studies have demonstrated a florid hepatic peroxisome proliferation following gemfibrozil administration to the male rat. An adequate study to test for peroxisome proliferation has not been done in humans but changes in peroxisome morphology have been observed. Peroxisome proliferation has been shown to occur in humans with either of two other drugs of the fibrate class when liver biopsies were compared before and after treatment in the same individual.

Administration of approximately 2 times the human dose (based on surface area) to male rats for 10 weeks resulted in a dose-related decrease of fertility. Subsequent studies demonstrated that this effect was reversed after a drug-free period of about eight weeks, and it was not transmitted to the offspring.

Pregnancy

Teratogenic Effects

Pregnancy category C

Gemfibrozil has been shown to produce adverse effects in rats and rabbits at doses between 0.5 and 3 times the human dose (based on surface area). There are no adequate and well-controlled studies in pregnant women. Gemfibrozil should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Administration of gemfibrozil to female rats at 2 times the human dose (based on surface area) before and throughout gestation caused a dose-related decrease in conception rate and an increase in stillborns and a slight reduction in pup weight during lactation. There were also dose-related increased skeletal variations. Anophthalmia occurred, but rarely.

Administration of 0.6 and 2 times the human dose (based on surface area) of gemfibrozil to female rats from gestation day 15 through weaning caused dose-related decreases in birth weight and suppressions of pup growth during lactation.

Administration of 1 and 3 times the human dose (based on surface area) of gemfibrozil to female rabbits during organogenesis caused a dose-related decrease in litter size and, at the high dose, an increased incidence of parietal bone variations.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for tumorigenicity shown for gemfibrozil in animal studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Hematologic Changes

Mild hemoglobin, hematocrit and white blood cell decreases have been observed in occasional patients following initiation of gemfibrozil therapy. However, these levels stabilize during long-term administration. Rarely, severe anemia, leukopenia, thrombocytopenia, and bone marrow hypoplasia have been reported. Therefore, periodic blood counts are recommended during the first 12 months of gemfibrozil administration.

Liver Function

Abnormal liver function tests have been observed occasionally during gemfibrozil administration, including elevations of AST (SGOT), ALT (SGPT), LDH, bilirubin, and alkaline phosphatase. These are usually reversible when gemfibrozil is discontinued. Therefore, periodic liver function studies are recommended and gemfibrozil therapy should be terminated if abnormalities persist.

Kidney Function

There have been reports of worsening renal insufficiency upon the addition of gemfibrozil therapy in individuals with baseline plasma creatinine > 2.0 mg/dL. In such patients, the use of alternative therapy should be considered against the risks and benefits of a lower dose of gemfibrozil.

Pediatric Use

Safety and efficacy in pediatric patients have not been established.

ADVERSE REACTIONS

In the double-blind controlled phase of the primary prevention component of the Helsinki Heart Study, 2046 patients received gemfibrozil for up to five years. In that study, the following adverse reactions were statistically more frequent in subjects in the gemfibrozil group:

GEMFIBROZIL (N = 2046) PLACEBO (N = 2035)
Frequency in percent of subjects
Gastrointestinal reactions 34.2 23.8
Dyspepsia 19.6 11.9
Abdominal pain 9.8 5.6
Acute appendicitis (histologically confirmed in most cases where data were available) 1.2 0.6
Atrial fibrillation 0.7 0.1
Adverse events reported by more than 1% of subjects, but without a significant difference between groups:
Diarrhea 7.2 6.5
Fatigue 3.8 3.5
Nausea/Vomiting 2.5 2.1
Eczema 1.9 1.2
Rash 1.7 1.3
Vertigo 1.5 1.3
Constipation 1.4 1.3
Headache 1.2 1.1

Gallbladder surgery was performed in 0.9% of gemfibrozil and 0.5% of placebo subjects in the primary prevention component, a 64% excess, which is not statistically different from the excess of gallbladder surgery observed in the clofibrate compared to the placebo group of the WHO study. Gallbladder surgery was also performed more frequently in the gemfibrozil group compared to placebo (1.9% vs 0.3%, p = 0.07) in the secondary prevention component. A statistically significant increase in appendectomy in the gemfibrozil group was seen also in the secondary prevention component (6 on gemfibrozil vs 0 on placebo, p = 0.014).

Nervous system and special senses adverse reactions were more common in the gemfibrozil group. These included hypesthesia, paresthesias, and taste perversion. Other adverse reactions that were more common among gemfibrozil treatment group subjects but where a causal relationship was not established include cataracts, peripheral vascular disease, and intracerebral hemorrhage.

From other studies it seems probable that gemfibrozil is causally related to the occurrence of MUSCULOSKELETAL SYMPTOMS (see WARNINGS), and to ABNORMAL LIVER FUNCTION TESTS and HEMATOLOGIC CHANGES (see PRECAUTIONS).

Reports of viral and bacterial infections (common cold, cough, urinary tract infections) were more common in gemfibrozil treated patients in other controlled clinical trials of 805 patients. Additional adverse reactions that have been reported for gemfibrozil are listed below by system. These are categorized according to whether a causal relationship to treatment with gemfibrozil is probable or not established:

CAUSAL RELATIONSHIP PROBABLE CAUSAL RELATIONSHIP NOT ESTABLISHED
General: weight loss
Cardiac: extrasystoles
Gastrointestinal: cholestatic jaundice pancreatitis
hepatoma
colitis
Central Nervous System: dizziness confusion
somnolence convulsions
paresthesia syncope
peripheral neuritis
decreased libido
depression
headache
Eye: blurred vision retinal edema
Genitourinary: impotence decreased male fertility
renal dysfunction
Musculoskeletal: myopathy
myasthenia
myalgia
painful extremeties
arthralgia
synovitis
rhabdomyolysis (see WARNINGS and PRECAUTIONS , Drug Interactions)
Clinical Laboratory: increased creatine phosphokinase positive antinuclear antibody
increased bilirubin
increased liver transaminases (AST [SGOT], ALT [SGPT])
increased alkaline phosphatase
Hematopoietic: anemia thrombocytopenia
leukopenia
bone marrow hypoplasia
eosinophilia
Immunologic: angioedema anaphylaxis
laryngeal edema Lupus-like syndrome
urticaria vasculitis
Integumentary: exfoliative dermatitis alopecia
rash photosensitivity
dermatitis
pruritus

Additional adverse reactions that have been reported include cholecystitis and cholelithiasis (see WARNINGS ).

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