Chenodiol (Page 2 of 4)

PATIENT SELECTION

Evaluation of Surgical Risk: Surgery offers the advantage of immediate and permanent stone removal, but carries a fairly high risk in some patients. About 5% of cholecystectomized patients have residual symptoms or retained common duct stones. The spectrum to surgical risk varies as a function of age and the presence of disease other than cholelithiasis. Selected tabulation of results from the National Halothane Study (JAMA, 1968, 197:775-778) is shown below: the study included 27,600 cholecystectomies.

Mortality per Operation

(Smoothed rates with denominators adjusted to one death)

Low Risk Patients* Cholecystectomy Cholecystectomy & Common Duct Exploration
Women 0-49 yrs 1/1851 1/469
50-69 yrs 1/357 1/99
Men 0-49 yrs 1/981 1/243
50-69 yrs 1/185 1/52
High Risk Patients**
Women 0-49 yrs 1/79 1/21
50-69 yrs 1/56 1/17
Men 0-49 yrs 1/41 1/11
50-69 yrs 1/30 1/9
* Includes those with good health or moderate systemic disease, with or without emergency surgery. ** Severe or extreme systemic disease, with or without emergency surgery.

Women in good health, or having only moderate systemic disease, under 49 years of age have the lowest rate (0.054%); men in all categories have a surgical mortality rate twice that of women; common duct exploration quadruples the rates in all categories; the rates rise with each decade of life and increase tenfold or more in all categories with severe or extreme systemic disease.

Relatively young patients requiring treatment might be better treated by surgery than with Chenodiol, because treatment with Chenodiol, even if successful, is associated with a high rate of recurrence, The long-term consequences of repeated courses of Chenodiol in terms of liver toxicity, neoplasia and elevated cholesterol levels are not know.

Watchful waiting has the advantage that no therapy may ever be required. For patients with silent or minimally symptomatic stones, the rate of moderate to severe symptoms or gallstone complications is estimated to be between 2% and 6% per year, leading to a cumulative rate of 7% and 27% in five years. Presumably the rate is higher for patients already having symptoms.

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 from 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.

CONTRAINDICATIONS

Chenodiol is contraindicated in the presence of known hepatocyte dysfunction or bile ductal abnormalities such as intrahepatic cholestasis, primary biliary cirrhosis or sclerosing cholangitis (see Warnings); a gallbladder confirmed as nonvisualizing after two consecutive single doses of dye; radiopaque stones; or gallstone complications or compelling reasons for gallbladder surgery including unremitting acute cholecystitis, cholangitis, biliary obstruction, gallstone pancreatitis, or biliary gastrointestinal fistula.

Pregnancy Category X:

Chenodiol may cause fetal harm when administered to a pregnant woman. Serious hepatic, renal and adrenal lesions occurred in fetuses of female Rhesus monkeys given 60 to 90 mg/kg/day (4 to 6 times the maximum recommended human dose, MRHD) from day 21 to day 45 of pregnancy. Hepatic lesions also occurred in neonatal baboons whose mothers had received 18 to 38 mg/kg (1 to 2 times the MRHD), all during pregnancy. Fetal malformations were not observed. Neither fetal liver damage nor fetal abnormalities occurred in reproduction studies in rats and hamsters. No human data are available at this time. Chenodiol is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

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 times. Chenodiol was discontinued at seven weeks, when the patient was hospitalized with advanced hepatic failure and E. coli peritonitis; death ensued at the eighth 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 known carcinogens. The possibility that Chenodiol therapy might contribute to colon cancer in otherwise susceptible individuals cannot be ruled out.

PRECAUTIONS

Information for patients

Patients should be counseled on the importance of periodic visits for liver function tests and oral cholecystograms (or ultrasonograms) for monitoring stone dissolution; they should be made aware of the symptoms of gallstone complications and be warned to report immediately such symptoms to the physician. Patients should be instructed on ways to facilitate faithful compliance with the dosage regimen throughout the usual long term of therapy, and on temporary doses reduction if episodes of diarrhea occur.

Drug interactions

Bile acid sequestering agents, such as cholestyramine and colestipol, may interfere with the action of Chenodiol by reducing its absorption. Aluminum-based antacids have been shown to absorb bile acids in vitro and may be expected to interfere with Chenodiol in the same manner as the sequestering agents. Estrogen, oral contraceptive and clofibrate (and perhaps other lipid-lowering drugs) increase biliary cholesterol secretion, and the incidence of cholesterol gallstones hence may counteract the effectiveness of Chenodiol.

Due to its hepatotoxicity, chenodiol can affect the pharmacodynamics of coumarin and its derivatives, causing unexpected prolongation of the prothrombin time and hemorrhages. Patients on concomitant therapy with chenodiol and coumarin or its derivatives should be monitored carefully. If prolongation of prothrombin time is observed, the coumarin dosage should be readjusted to give a prothrombin time 1½ to 2 times normal. If necessary chenodiol should be discontinued.

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