1½ to 2 times normal. If necessary chenodiol should be discontinued
Carcinogenesis, Mutagenesis, Impairment of Fertility
A two-year oral study of chenodiol in rats failed to show a carcinogenic potential at the tested levels of 15 to 60 mg/kg/day (1 to 4 times the maximum recommended human dose, MRHD). It has been reported that chenodiol given in long-term studies at oral doses up to 600 mg/kg/day (40 times the MRHD) to rats and 1000 mg/kg/day (65 times the MRHD) to mice induced benign and malignant liver cell tumors in female rats and cholangiomata in female rats and male mice. Two-year studies of lithocholic acid ( a major metabolite of chenodiol) in mice (125 to 250 mg/kg/day) and rats (250 and 500 mg/kg/day) found it not to be carcinogenic. The dietary administration of Lithocholic acid to chickens is reported to cause hepatic adenomatous hyperplasia.
Pregnancy
Pregnancy Category X: See CONTRAINDICATIONS.
Nursing Mothers
It is not known whether chenodiol is excreted in human mild. Because many drugs are excreted in human milk, caution should be exercised when chenodiol is administered to a nursing mother.
Pediatric Use
The safety and effectiveness of chenodiol in children have not been established.
ADVERSE REACTIONS
Hepatobiliary: Dose-related serum aminotransferase (mainly SGPT) elevations, usually not accompanied by rises in alkaline phosphatase or bilirubin, occurred in 30% or more of patients treated with the recommended dose of Chenodiol. In most cases, these elevations were minor (1 ½ to 3 times the upper limit of laboratory normal) and transient, returning to within the normal range within six months despite continued administration of the drug. In 2% to 3% of patients, SGPT levels rose to over three times the upper limit of laboratory normal, recurred on rechallenge with the drug, and required discontinuation of chenodiol treatment. Enzyme levels have returned to normal following withdrawal of chenodiol (see WARNINGS).
Morphologic studies of liver biopsies taken before and after 9 and 24 months of treatment with chenodiol have shown that 63% of the patients prior to chenodiol treatment had evidence of intrahepatic cholestasis. Almost all pretreatment patients had electron microscopic abnormalities. By the ninth month of treatment, reexamination of two-thirds of the patients showed an 89% incidence of the signs of intrahepatic cholestasis. Two of 89 patients at the ninth month had lithocholate-like lesions in the canalicular membrane, although there were not clinical enzyme abnormalities in the face of continued treatment and no change in Type 2 light microscopic parameters.
Increased Cholecystectomy Rate: NCGS patients with a history of biliary pain prior to treatment had higher cholecystectomy rates during the study if assigned to low dosage chenodiol (375 mg/day) than if assigned to either placebo or high dosage chenodiol (750 mg/day). The association with low dosage chenodiol though not clearly a causal one, suggests that patients unable to take higher doses of chenodiol may be at greater risk of cholecystectomy.
Gastrointestinal: Dose-related diarrhea has been encountered in 30% to 40% of chenodiol-treated patients and may occur at any time during treatment, but is most commonly encountered when treatment is initiated. Usually, the diarrhea is mild, translucent, well-tolerated and does not interfere with therapy. Dose reduction has been required in 10% to 15% of patients, and in a controlled trial about half of these req |
