FDA Approves Chenodal for Rare Cholesterol Disorder

Because of the potential hepatoxicity of Chenodal, poor response rate in some subgroups of Chenodal-treated patients, and an increased rate of a need for cholecystectomy in other Chenodal-treated subgroups, Chenodal is not an appropriate treatment for many patients with gallstones. Chenodal should be reserved for carefully selected patients and treatment must be accompanied by systematic monitoring for liver function alterations. 

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.

Women in good health, or having only moderate systemic disease, under 49 years of age have the lowest rate (0.054%) of risk; men in al categories have a surgical mortality rate twice that of women; common duct exploration quadruples the rates in al categories; the rates rise with each decade of life and increase tenfold or more in al 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 known. Watchful waiting has the advantage that no therapy may ever be required. For patients with silent of minimaly 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 that rate is higher for patients already having symptoms.

General Clinical Results: Both the desaturation of bile and the clinical dissolution of cholesterol gallstones are dose-related. In the National Cooperative Galstone Study (NCGS), involving 305 patients in each treatment group, placebo and chenodiol dosages of 375 mg and 750 mg per day were associated with complete stone dissolution in 0.8%, 5.2%, and 13.5%, respectively, of enrolled subjects over 24 months of treatment. Uncontrolled clinical trails using higher doses than those used in the NCGS have shown complete dissolution rates of 28 to 38% of enrolled patients receiving body weight doses of from 13 to 16 mg/kg/day for up to 24 months. In a prospective trial using 15 mg/kg/day, 31% enrolled surgical-risk patients treated more than six months (n=86) achieved complete confirmed dissolutions. Observed stone dissolution rates achieved with chenodiol treatment are higher in subgroups having certain pretreatment characteristics. In the NCGS, patient with small {less than 15 mm in diameter} radiolucent stones, the observed rate of complete dissolution was approximately 20% on 750 mg/day. In the luncontroled trials using 13 to 16 mg/kg/day doses of chenodiol, the rates of complete dissolution for small radiolucent stones ranged from 42% to 60%. Even higher dissolution rates have been observed in patients with small floatable stones.. Some obese patients and occasional normal weight patients fail to achieve bile desaturation even with doses of chenodiol up to 19 mg/kg/day for unknown reasons. Although dissolution is generally higher with increased dosage of chenodiol, doses that are too low are associated with increased cholecystectomy rates.

Stones have recurred within five years in about 50% of patients following complete confirmed dissolutions. Although retreatment with chenodiol has proven successful in dissolving some newly formed stones, the indications for and safety of retreatment are not well defined. Serum aminotransferase elevations and diarrhea have been notable in al clinical trials and are dose-related