Fibrates

Nervous system

Nervous system adverse reactions are rare, constituting 0.5% of all adverse reactions [ ]. Gemfibrozil-induced headache has been reported [ ] and occurred in one patient who had taken bezafibrate for 24 hours [ ]. Peripheral neuropathy has been observed with bezafibrate [ ].

Metabolism

Of 70 patients with cutaneous T cell lymphomas, three who were taking gemfibrozil had to have it withdrawn because of increases in serum triglycerides [ ].

• A 76-year-old woman with type 2 diabetes taking gemfibrozil for pronounced hypertriglyceridemia had recurrent episodes of hypoglycemia; her insulin requirements fell by 65% and her HbA1c concentration fell from 9% to 6.5% over 5 months [ ].

In patients taking fenofibrate and atorvastatin, increased concentrations of plasma homocysteine were attributed to an action of the fibrates themselves and not indirectly via their lipid-lowering effect [ ]. Concomitant administration of folic acid, at least in part, offset this adverse effect [ ]. The degree of rise in homocysteine differs among the various fibrates. It has been reported with fenofibrate and bezafibrate, and a study of fenofibrate and gemfibrozil substantiated a difference between the drugs [ ]. Because the concentration of plasma homocysteine depends on renal function, increased plasma homocysteine concentrations could result from renal function impairment caused by fenofibrate. In contrast, gemfibrozil does not affect renal function. This was tested in a crossover study in 22 patients who had hypertriglyceridemia, by giving them gemfibrozil 900 mg/day or fenofibrate 200 mg/day for 6 weeks [ ]. Lipids were altered similarly, but homocysteine, creatinine, and cystatin C were raised by fenofibrate but not by gemfibrozil. In another report, there was a 57% increase in homocysteine in 26 individuals who took ciprofibrate and a 17% reduction in homocysteine in 12 patients who took bezafibrate.

The authors of a review suggested using gemfibrozil instead of fenofibrate and bezafibrate or adding vitamin B ₁₂ and folic acid [ ].

Fluid balance

Clofibrate has a mild antidiuretic effect [ ], and animal studies suggest that this is due to release of antidiuretic hormone (ADH) [ ]. This effect has been used in the treatment of cranial diabetes insipidus [ ].

Hematologic

Leukopenia has been reported with bezafibrate [ ], clofibrate [ ], and fenofibrate [ ].

Gastrointestinal

Abdominal discomfort occurs in 5–10% of all patients taking fibrates. Epigastric fullness, nausea, meteorism, and mild diarrhea have been repeatedly described, and stomatitis has been incidentally mentioned. There are wide discrepancies in the figures given for such complications, ranging as they do from 2% (2) to 20%; the truth appears to be that during the first few days and weeks of treatment, mild discomfort of one sort or another is quite common, although some of it is due to a placebo effect; serious symptoms are most unusual. Bezafibrate is better tolerated than gemfibrozil [ ]. In a double-blind trial with fenofibrate, the incidence of gastrointestinal adverse reactions was not different from that seen with placebo [ ]. Five of 1213 individuals taking beclobrate complained of diarrhea [ ].

Liver

Assurance of good renal and hepatic function is mandatory before beginning treatment with the fibrates [ ]. Serum aminotransferase changes are regularly seen and hepatitis occurs [ ]. Several cases of hepatitis due to fenofibrate have been reviewed [ ] and it has also been observed with etofibrate [ ]. One case of liver failure, probably due to beclobrate, has been reported [ ]. Liver biopsies showed a lymphoplasmacytic infiltrate in all of five cases of chronic hepatitis associated with fibrates [ ].

Cirrhosis has been attributed to fenofibrate [ ].

• A 62-year-old Indian man developed abnormal liver function tests after taking fenofibrate for 11 months. Liver biopsy confirmed the presence of cirrhosis; there was no steatosis or cholestasis.

Possible mechanisms of fenofibrate-induced liver injury include activation of peroxisome proliferation-activator receptors, a hypersensitivity reaction, and immune-mediated injury from cross-reactivity of the drug with autoantigens. The authors referred to six reported cases of hepatic fibrosis attributed to fenofibrate. Raised aminotransferase activities occur commonly with fenofibrate but are generally transient, reverse on withdrawal, and do not result in long-term injury. Fenofibrate should be withdrawn if higher than normal enzyme activities persist, and a liver biopsy should be considered if liver enzymes do not normalize after withdrawal.

Biliary tract

Fibrates produce bile that is supersaturated with cholesterol. Although gallstones are common with clofibrate, no excess frequency has been observed with fenofibrate [ ]. In the WHO study, 59 patients taking clofibrate had to be operated on for gallstones, compared with 24 and 25 respectively in the two placebo groups [ ].

Pancreas

Pancreatitis has been attributed to bezafibrate.

• A 75-year-old white woman had fever and raised amylase on three consecutive occasions after taking a tablet of bezafibrate [ ]. After stopping taking the drug, she remained free of symptoms.