WARNINGS

Liver function: Fenofibrate at doses equivalent to 107 mg to 160 mg fenofibrate per day has been associated with increase in serum transaminases [AST (SGOT) or ALT (SGPT)].

In a pooled analysis of 10 placebo-controlled trials, increases to > 3 times the upper limit of normal occurred in 5.3% of patients taking fenofibrate versus 1.1% of patients treated with placebo.

When transaminase determinations were followed either after discontinuation of treatment or during continued treatment, a return to normal limits was usually observed.

The incidence of increases in transaminases related to fenofibrate therapy appear to be dose related.

In an 8-week dose-ranging study, the incidence of ALT or AST elevations to at least three times the upper limit of normal was 13% in patients receiving dosages equivalent to 107 mg to 160 mg fenofibrate per day, and was 0% in those receiving dosages equivalent to 54 mg or less fenofibrate per day or placebo.

Hepatocellular, chronic active and cholestatic hepatitis associated with fenofibrate therapy have been reported after exposures of weeks to several years.

In extremely rare cases, cirrhosis has been reported in association with chronic active hepatitis.

Regular periodic monitoring of liver function, including serum ALT (SGPT) should be performed for the duration of therapy with fenofibrate, and therapy discontinued if enzyme levels persist above three times the normal limit.

Cholelithiasis: Fenofibrate, like clofibrate and gemfibrozil, may increase cholesterol excretion into the bile, leading to cholelithiasis.

If cholelithiasis is suspected, gallbladder studies are indicated.

Fenofibrate therapy should be discontinued if gallstones are found.

Concomitant Oral Anticoagulants: Caution should be exercised when anticoagulants are given in conjunction with fenofibrate because of the potentiation of coumarin-type anticoagulants in prolonging the prothrombin time/INR.

The dosage of the anticoagulant 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.

Concomitant HMG-CoA Reductase Inhibitors: The combined use of fenofibrate 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.

Concomitant administration of fenofibrate (160 mg) and pravastatin (40 mg) once daily for 10 days increased the mean Cmax and AUC values for pravastatin by 36% (range from 69% decrease to 321% increase) and 28% (range from 54% decrease to 128% increase), respectively, and for 3α-hydroxy-iso-pravastatin by 55% (range from 32% decrease to 314% increase) and 39% (range from 24% decrease to 261% increase), respectively.

(See also CLINICAL PHARMACOLOGY, Drug-drug interactions ).

The combined use of fibric acid derivatives and HMG-CoA reductase inhibitors has been associated, in the absence of a marked pharmacokinetic interaction, in numerous case reports, with rhabdomyolysis, markedly elevated creatine kinase (CK) levels and myoglobinuria, leading in a high proportion of cases to acute renal failure.

The use of fibrates alone, including fenofibrate, may occasionally be associated with myositis, myopathy, or rhabdomyolysis.

Patients receiving fenofibrate and complaining of muscle pain, tenderness, or weakness should have prompt medical evaluation for myopathy, including serum creatine kinase level determination.

If myopathy/myositis is suspected or diagnosed, fenofibrate therapy should be stopped.

Mortality: The effect of fenofibrate on coronary heart disease morbidity and mortality and non-cardiovascular mortality has not been established.

Other Considerations: In the Coronary Drug Project, a large study of post myocardial infarction of patients treated for 5 years with clofibrate, there was no difference in mortality seen between the clofibrate group and the placebo group.

There was however, a difference in the rate of cholelithiasis and cholecystitis requiring surgery between the two groups (3.0% vs 1.8%).

Because of chemical, pharmacological, and clinical similarities between fenofibrate tablets, Atromid-S (clofibrate), and Lopid (gemfibrozil), the adverse findings in 4 large randomized, placebo-controlled clinical studies with these other fibrate drugs may also apply to fenofibrate.

In a study conducted by the World Health Organization (WHO), 5000 subjects without known coronary artery disease were treated with placebo or clofibrate for 5 years and followed for an additional one year.

There was a statistically significant, higher age-adjusted all-cause mortality in the clofibrate group compared with the placebo group (5.70% vs 3.96%, p=<0.01).

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

This appeared to confirm the higher risk of gallbladder disease seen in clofibrate-treated patients studied in the Coronary Drug Project.

The Helsinki Heart Study was a large (n=4081) study of middle-aged men without a history of coronary artery disease.

Subjects received either placebo or gemfibrozil for 5 years, with a 3.5 year open extension afterward.

Total mortality was numerically higher in the gemfibrozil randomization group but did not achieve statistical significance (p=0.19, 95% confidence interval for relative risk G:P=.91-1.64).

Although cancer deaths trended higher in the gemfibrozil group (p=0.11), cancers (excluding basal cell carcinoma) were diagnosed with equal frequency in both study groups.

Due to the limited size of the study, the relative risk of death from any cause was not shown to be different than that seen in the 9-year follow-up data from World Health Organization study (RR=1.29).

Similarly, the numerical excess of gallbladder surgeries in the gemfibrozil group did not differ statistically from that observed in the WHO study.

A secondary prevention component of the Helsinki Heart Study enrolled middle-aged men excluded from the primary prevention study because of known or suspected coronary heart disease.

Subjects received gemfibrozil or placebo for 5 years.

Although cardiac deaths trended higher in the gemfibrozil group, this was not statistically significant (hazard ratio 2.2, 95% confidence interval: 0.94–5.05).

The rate of gallbladder surgery was not statistically significant between study groups, but did trend higher in the gemfibrozil group, (1.9% vs 0.3%, p=0.07).

There was a statistically significant difference in the number of appendectomies in the gemfibrozil group (6/311 vs 0/317, p=0.029).