Gemfibrozil - Warnings and Precautions

Because of chemical, pharmacological, and clinical similarities between gemfibrozil and clofibrate, the adverse findings with clofibrate in two large clinical studies may also apply to gemfibrozil.

In the first of those studies, the Coronary Drug Project, 1000 subjects with previous myocardial infarction were treated for five years with clofibrate.

There was no difference in mortality between the clofibrate-treated subjects and 3000 placebo-treated subjects, but twice as many clofibrate-treated subjects developed cholelithiasis and cholecystitis requiring surgery.

In the other study, conducted by the World Health Organization (WHO), 5000 subjects without known coronary heart disease were treated with clofibrate for five years and followed one year beyond.

There was a statistically significant (44%) higher age-adjusted total mortality in the clofibrate-treated group than in a comparable placebo-treated control group during the trial period.

The excess mortality was due to a 33% increase in non-cardiovascular causes, including malignancy, post-cholecystectomy complications, and pancreatitis.

The higher risk of clofibrate-treated subjects for gallbladder disease was confirmed.

Because of the more limited size of the Helsinki Heart Study, the observed difference in mortality from any cause between the gemfibrozil and placebo groups is not statistically significantly different from the 29% excess mortality reported in the clofibrate group in the separate WHO study at the nine year follow-up (see CLINICAL PHARMACOLOGY).

Noncoronary heart disease related mortality showed an excess in the group originally randomized to gemfibrozil primarily due to cancer deaths observed during the open-label extension.

During the five year primary prevention component of the During the five year primary prevention component of the Helsinki Heart Study, mortality from any cause was 44 (2.2%) in the gemfibrozil group and 43 (2.1%) in the placebo group; including the 3.5 year follow-up period since the trial was completed, cumulative mortality from any cause was 101 (4.9%) in the gemfibrozil group and 83 (4.1%) in the group originally randomized to placebo (hazard ratio 1:20 in favor of placebo).

Because of the more limited size of the Helsinki Heart Study, the observed difference in mortality from any cause between the gemfibrozil and placebo groups at Year-5 or at Year-8.5 is not statistically significantly different from the 29% excess mortality reported in the clofibrate group in the separate WHO study at the nine year follow-up.

Noncoronary heart disease related mortality showed an excess in the group originally randomized to gemfibrozil at the 8.5 year follow-up (65 gemfibrozil versus 45 placebo noncoronary deaths).

The incidence of cancer (excluding basal cell carcinoma) discovered during the trial and in the 3.5 years after the trial was completed was 51 (2.5%) in both originally randomized groups.

In addition, there were 16 basal cell carcinomas in the group originally randomized to gemfibrozil and 9 in the group originally randomized to placebo (p=0.22).

There were 30 (1.5%) deaths attributed to cancer in the group originally randomized to gemfibrozil and 18 (0.9%) in the group originally randomized to placebo (p=0.11).

Adverse outcomes, including coronary events, were higher in gemfibrozil patients in a corresponding study in men with a history of known or suspected coronary heart disease in the secondary prevention component of the Helsinki Heart Study (see CLINICAL PHARMACOLOGY ).

A comparative carcinogenicity study was also done in rats comparing three drugs in this class: fenofibrate (10 and 60 mg/kg; 0.3 and 1.6 times the human dose, respectively), clofibrate (400 mg/kg; 1.6 times the human dose), and gemfibrozil (250 mg/kg; 1.7 times the human dose).

Pancreatic acinar adenomas were increased in males and females on fenofibrate; hepatocellular carcinoma and pancreatic acinar adenomas were increased in males and hepatic neoplastic nodules in females treated with clofibrate; hepatic neoplastic nodules were increased in males and females treated with clofibrate; hepatic neoplastic nodules were increased in males and females treated with gemfibrozil while testicular interstitial cell (Leydig cell) tumors were increased in males on all three drugs.

A gallstone prevalence substudy of 450 Helsinki Heart Study participants showed a trend toward a greater prevalence of gallstones during the study within the gemfibrozil treatment group (7.5% versus 4.9% for the placebo group, a 55% excess for the gemfibrozil group).

A trend toward a greater incidence of gallbladder surgery was observed for the gemfibrozil group (17 versus 11 subjects, a 54% excess).

This result did not differ statistically from the increased incidence of cholecystectomy observed in the WHO study in the group treated with clofibrate.

Both clofibrate and gemfibrozil may increase cholesterol excretion into the bile, leading to cholelithiasis.

If cholelithiasis is suspected, gallbladder studies are indicated.

Gemfibrozil therapy should be discontinued if gallstones are found.

Cases of cholelithiasis have been reported with gemfibrozil therapy.