INDICATIONS AND USAGE Chenodiol is indicated for patients with radiolucent stones in well-opacifying gallbladders, in whom selective surgery would be undertaken except for the presence of increased surgical risk due to systemic disease or age.

The likelihood of successful dissolution is far greater if the stones are floatable or small.

For patients with nonfloatable stones, dissolution is less likely and added weight should be given to the risk that more emergent surgery might result form a delay due to unsuccessful treatment.

Safety of use beyond 24 months is not established.

Chenodiol will not dissolve calcified (radiopaque) or radiolucent bile pigment stones.

WARNINGS Safe use of chenodiol depends upon selection of patients without pre-existing liver disease and upon faithful monitoring of serum aminotransferase levels to detect drug-induced liver toxicity.

Aminotransferase elevations over three times the upper limit of normal have required discontinuation of chenodiol in 2% to 3% of patients.

Although clinical and biopsy studies have not shown fulminant lesions, the possibility remains that an occasional patient may develop serious hepatic disease.

Three patients with biochemical and histologic pictures of chronic active hepatitis while on chenodiol, 375 mg/day or 750 mg/day, have been reported.

The biochemical abnormalities returned spontaneously to normal in two of the patients within 13 and 17 months; and after 17 months’ treatment with prednisone in the third.

Follow-up biopsies were not done; and the causal relationship of the drug could not be determined.

Another biopsied patient was terminated from therapy because of elevated aminotransferase levels and a liver biopsy was interpreted as showing active drug hepatitis.

One patient with sclerosing cholangitis, biliary cirrhosis and history of jaundice died during chenodiol treatment for hepatic duct stones.

Before treatment, serum aminotransferase and alkaline phosphate levels were over twice the upper limit of normal; within one month they rose to over 10 time normal.

Chenodiol was discontinued at seven weeks, when the patient was hospitalized with advanced hepatic failure and E.

coli peritonitis; death ensued at the eight week.

A contribution of chenodiol to the fatal outcome could not be ruled out.

Epidemiologic studies suggest that bile acids might contribute to human colon cancer, but direct evidence is lacking.

Bile acids, including chenodiol and lithocholic acid, have no carcinogenic potential in animal models, but have been shown to increase the number of tumors when administered with certain know carcinogens.

The possibility that chenodiol therapy might contribute to colon cancer in otherwise susceptible individuals cannot be ruled out.

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 required a permanent reduction in dose.

Anti-diarrhea agents have proven useful in some patients.

Discontinuation of chenodiol because of failure to control diarrhea is to be expected in approximately 3% of patients treated.

Steady epigastric pain with nausea typical of lithiasis (biliary colic) usually is easily distinguishable from the crampy abdominal pain of drug-induced diarrhea.

Other less frequent, gastrointestinal side effects reported include urgency, cramps, heartburn, constipation, nausea, and vomiting, anorexic, epigastric distress, dyspepsis, flatulence and nonspecific abdominal pain.

Serum Lipids: Serum total cholesterol and low-density lipoprotein (LDL) cholesterol may rise 10% or more during administration of chenodiol: no change has been seen in the high-density lipoprotein (HDL) fraction; small decreases in serum triglyceride levels for females have been reported.

Hematologic: Decreases in white cell count, never below 3000, have been noted in a few patients treated with chenodiol; the drug was continued in all patients without incident.