Chenodiol is the oral formulation of chenodeoxycholic acid, a naturally occurring human bile acid. It is indicated for adult 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. Chenodiol therapy is most effective in patients whose gallstones are floatable or small. For patients with non-floatable stones, the risk of unsuccessful medical treatment should be weighed against the risks associated with postponed surgical intervention. Efficacy and many of the safety concerns are dose-dependant. In the National Cooperative Gallstone 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. Uncontrolled clinical trials using higher doses than those used in the NCGS have shown complete dissolution rates of 28% to 38% of enrolled patients who received weight-based doses of 13-16 mg/kg/day for up to 24 months. The safety of chenodiol use beyond 24 months has not be established. It is estimated that half of chenodiol-treated patients will experience stone recurrence within 5 years. Retreatment with chenodiol has proven successful in dissolving some newly formed stones; however, the safety of retreatment has not been established. Dose-dependant adverse events such as serum aminotransferase elevations and diarrhea have been observed in all clinical trials. Furthermore, chenodiol therapy has been associated with hepatotoxicity. Chenodiol should be reserved for carefully selected patients, and treated individuals must be counseled on the importance of diligent monitoring including systematic liver function test as well as periodic oral cholecystograms or ultrasonograms and cholesterol tests. Chenix (chenodeoxycholic acid) tablets 250 mg were originally FDA approved in 1983 and became the reference listed drug with the FDA. Chenix brand tablets are no longer marketed in the US, but Chenodal (chenodiol tablets) were determined to be bioequivalent and therefore, therapeutically equivalent to the reference listed drug. Accordingly, Chenodal (chenodiol) tablets were FDA approved in October 2009.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
Oral Solid Formulations:
-Administer orally with or without food.
National Cooperative Gallstone Study (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.
Although direct evidence is lacking, epidemiologic studies suggest that bile acids might contribute to human colon cancer. 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 a new primary malignancy of colon cancer in otherwise susceptible individuals cannot be ruled out.
Chenodiol administration has been associated with elevated hepatic enzymes. During clinical evaluation, dose-related serum aminotransferase (mainly SGPT) elevations occurred in >= 30% of patients receiving recommended doses. Elevations were transient and minor (1.5-3 times the upper limit of laboratory normal, xULN) and returned to normal within 6 months despite continued therapy. Generally, serum aminotransferase elevations were not accompanied by elevations in alkaline phosphatase or bilirubin. In a small number of patients (2-3%) SGPT concentrations were over 3xULN, recurred upon rechallenge, and required discontinuation of chenodiol therapy. After discontinuation, hepatic enzyme concentrations returned to normal. The manufacturer recommends routine monitoring of liver function tests during treatment.
Although clinical and biopsy studies have not shown fulminant lesions, the possibility remains that a patient may develop serious hepatic disease while receiving chenodiol. Chronic active hepatitis was reported in 3 patients while on chenodiol therapy (375 mg/day or 750 mg/day). In 2 of the 3 patients, biochemical abnormalities returned to normal within 13 and 17 months. After 17 months and treatment with prednisone, the third patient also achieved normal biochemical markers. In addition, chenodiol therapy was discontinued in another biopsied patient due to elevated aminotransferase levels. The liver biopsy on the patient was interpreted as showing active drug hepatitis. A separate patient with sclerosing cholangitis, biliary cirrhosis, and history of jaundice died during chenodiol treatment for hepatic duct stones. Before treatment was initiated, serum aminotransferase and alkaline phosphate levels were over twice the upper limit of normal and rose to over 10 times the upper limit within one month. At week 7 of treatment, chenodiol was discontinued and the patient was hospitalized with advanced hepatic failure and E. coli peritonitis; the patient died at week 8. A contribution of chenodiol to the death of the patient could not be ruled out. The manufacturer recommends routine monitoring of liver function tests during chenodiol therapy.
In a clinical study of patients set to receive chenodiol, morphologic studies of liver biopsies were taken before initiation of therapy. These tests showed that 63% of patients had previous evidence of intrahepatic cholestasis and almost all pretreatment patients had electron microscopic abnormalities. Reexamination after 9 months of therapy, showed that two-third of treated patients had an 89% incidence of the signs of intrahepatic cholestasis. Two out of 89 patients had lithocholate-like lesions in the canalicular membrane, with no hepatic enzyme abnormalities and no change in Type 2 light microscopic parameters.
During clinical evaluation of chenodiol, gastrointestinal effects were among the most commonly reported adverse events. Dose-related diarrhea was reported in 30-40% of patients. Diarrhea was most often reported at the onset of treatment or during dosage buildup, but can occur at any time during treatment. The diarrhea was generally mild, well-tolerated, and did not interfere with therapy. However, a temporary dosage reduction was required in 10-15% of patients, and about half of those patients required a permanent reduction. Anti-diarrheal agents proved useful in some patients. Discontinuation of chenodiol therapy due to failure to control diarrhea is to be expected in approximately 3% of patients treated. Other less frequent, gastrointestinal side effects reported include fecal urgency, abdominal cramps, pyrosis (heartburn), constipation, nausea, vomiting, anorexia, epigastric distress, dyspepsia, flatulence, and nonspecific abdominal pain.
Closely monitor patients with preexisting hypercholesterolemia during chenodiol treatment. Serum total cholesterol and low-density lipoprotein (LDL) cholesterol may rise 10% or more. No change has been seen in the high-density lipoprotein (HDL) fraction; small decreases in serum triglyceride concentrations for females have been reported.
Leukopenia was reported as a hematological adverse event observed in a few patients (exact number not defined) during chenodiol therapy. In the treated patients, leucocyte counts never fell below 3000 white blood cells per microliter; chenodiol therapy was continued in all patients without incident.
Because of the potential hepatotoxicity associated with chenodiol treatment, poor response rates in some chenodiol-treated subgroups, and the increased rate of cholecystectomy needed in some chenodiol-treated subgroups, chenodiol is not an appropriate treatment for many patients with gallstones.
During chenodiol therapy, oral cholesystograms or ultrasonograms are recommended at 6-9 month intervals to monitor response. Complete dissolution of stones should be confirmed by a repeat test after 1-3 months of continued therapy. If at the first test stones show partial dissolution, then it is likely that complete dissolution will occur with continued therapy. Treatment success is greatly reduced if at least partial dissolution is not evident within 12 months of continuous therapy. Therapy should be discontinued if no response is evident by 18 months.
After confirmed dissolution, therapy should generally be discontinued. Stone recurrence can be expected within five years in 50% of cases. Low cholesterol or carbohydrate diets, and dietary bran, have been reported to reduce biliary cholesterol; maintenance of reduced weight is recommended to forestall stone recurrence. Serial cholesystograms or ultrasonograms are recommended to monitor for recurrence. Gallbladder function and radiolucency of stones should be established before starting another course of chenodiol. The prophylactic use of chenodiol has not be established.
Chenodiol is contraindicated for use in patients hypersensitive to chenodiol or any component of the formulation. Chenodiol also should not be used in patients who have experienced bile acid agents hypersensitivity.
Chenodiol has been associated with an increased rate of need for surgery for gallbladder removal (cholecystectomy) in certain chenodiol-treated patients. In the National Cooperative Gallstone Study (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 between the rate of cholecystectomy and low dosage chenodiol is not clearly a causal one; however, data suggest that patients unable to take higher doses of chenodiol may be at an increased risk of cholecystectomy. Accordingly, chenodiol should be reserved for carefully selected patients and added weight should be given to the risk that more emergent surgery might result from a delay due to unsuccessful chenodiol-treatment.
Chenodiol is contraindicated in patients with biliary tract disease including bile ductal abnormalities such as intrahepatic cholestasis, primary biliary cirrhosis, or sclerosing cholangitis. Administration of chenodiol is also contraindicated in patients whose gallbladder is confirmed as non-visualizing after two consecutive single doses of dye. Chenodiol is contraindicated for use in patients with calcified radiopaque stones, as chenodiol will not dissolve these or radiolucent bile pigment stones. Patients with gallstone complications or gallbladder disease necessitating surgery due to unremitting acute cholecystitis, cholangitis, biliary obstruction, gallstone pancreatitis, or biliary-GI fistula are not candidates for chenodiol therapy. Patients carefully selected for chenodiol therapy should be counseled on the importance of periodic oral cholecystograms (or ultrasonograms) for monitoring stone dissolution. In addition, clinicians should counsel patients to recognize and immediately report symptoms of gallstone complications such as severe abdominal pain, jaundice, icteric sclera, and/or high fever.
Chenodiol is contraindicated in the presence of known hepatic disease. Although clinical and biopsy studies have not shown fulminant lesions, the possibility remains that a patient may develop serious hepatic disease while receiving chenodiol. Because of the potential for hepatotoxicity associated with chenodiol administration, the cautious selection of patients without pre-existing hepatocyte dysfunction is essential. In addition, patients must be counseled on the importance of systematic monitoring of serum aminotransferase concentrations to detect drug-induced liver toxicity. The optimal frequency of performing liver function tests (LFTs) is not known. The manufacturer recommends monitoring serum aminotransferase concentrations every month for the first 3 months of treatment and then at 3-month intervals thereafter. According to the National Cooperative Gallstone Study (NCGS) guidelines, serum aminotransferase elevations (1/2 to 3 times the upper limit of normal) persisting longer than 3 to 6 months would warrant an interruption of therapy until the concentrations return to normal. However, according to the manufacturer, allowing elevations to persist over such an interval is not known to be safe. Elevations greater that 3 times the upper limit of normal require immediate discontinuation and usually reoccur upon rechallenge.
Dose-related diarrhea has been reported in chenodiol-treated patients. Diarrhea is most often reported at the onset of treatment or during dosage buildup, but can occur at any time during treatment. Usually, the diarrhea is mild, well-tolerated, and does not interfere with therapy; however, if symptoms persist, a temporary reduction of the chenodiol dose may be necessary. If symptoms do not resolve, a permanent reduction in dose may be required. Anti-diarrhea agents have proven useful in some patients. Discontinuation of chenodiol therapy due to failure to control diarrhea is to be expected in approximately 3% of patients treated. Patients should be instructed on ways to facilitate compliance with the dosage regimen throughout long term therapy and on temporary dose reduction if episodes of diarrhea occur.
Although direct evidence is lacking, epidemiologic studies suggest that bile acids might contribute to human colon cancer. 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 a new primary malignancy of colon cancer in otherwise susceptible individuals cannot be ruled out.
Patients with preexisting hypercholesterolemia should be closely monitored during chenodiol treatment. Serum total cholesterol and low-density lipoprotein (LDL) cholesterol may rise 10% or more during chenodiol administration. No change has been seen in the high-density lipoprotein (HDL) fraction and small decreases in serum triglyceride concentrations for females have been reported. Serum cholesterol should be monitored at 6-month intervals. According to the manufacturer, it may be advisable to discontinue therapy if cholesterol rises above the acceptable age-adjusted limit for a given patient.
The safety and effectiveness of chenodiol for cholelithiasis in children have not been established.
Chenodiol is classified in FDA pregnancy risk category X. Chenodiol may cause fetal harm when administered to a pregnant woman; however, no human data are available at this time. In sub-human primate studies, serious hepatic, renal, and adrenal lesions have occurred. Chenodiol is therefore 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 informed of the potential hazards to the developing fetus.
According to the manufacturer, because many drugs are excreted into breast milk, caution should be used when chenodiol is administered to a breast-feeding mother. It is not known whether chenodiol is excreted in human milk. Possible effects on a nursing infant are not defined. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.
For treatment of cholelithiasis via the dissolution of radiolucent cholesterol gallstones:
NOTE: Chenodiol is indicated for use in patients with radiolucent stones who are ineligible for surgery because of systemic disease or age. Successful dissolution of stones is more likely in patients presenting with small or floatable stones; for patients with non-floatable stones, the risk of unsuccessful medical treatment should be weighed against the risk of postponed surgical intervention.
NOTE: Chenodiol will not dissolve calcified (radiopaque) or radiolucent bile pigment stones.
Oral dosage:
Adults: Initially, 250 mg PO twice daily for 2 weeks, then increase the dose by 250 mg/day each week until the recommended or maximum tolerated dose is achieved. The recommended dosage range is 13 to 16 mg/kg/day PO given in 2 divided doses. Dosages less than 10 mg/kg/day are not recommend as they are usually ineffective and may increase the risk of cholecystectomy. If diarrhea occurs, temporarily decrease dose; once symptoms resolve, attempt to reinstate the previous dose. Discontinue treatment if there is no response by 18 months; safe use beyond 24 months has not been established.
Adolescents: Safety and efficacy have not been established.
Children: Safety and efficacy have not been established.
Maximum Dosage Limits:
-Adults
Maximum dosage information is not available.
-Elderly
Maximum dosage information is not available.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Chenodiol is contraindicated in the presence of known hepatocyte dysfunction. Safe use of chenodiol depends upon selection of patients without pre-existing hepatic disease and upon careful monitoring of serum aminotransferase concentrations to detect drug-induced liver toxicity.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
Aluminum Hydroxide: (Moderate) Aluminum hydroxide based antacids have been shown to adsorb bile acids in vitro and are expected to interfere with the efficacy of chenodiol. To minimize drug interactions, administer chenodiol at least 1 hour before or at least 2 hours after the aluminum-based antacid.
Aluminum Hydroxide; Magnesium Carbonate: (Moderate) Aluminum hydroxide based antacids have been shown to adsorb bile acids in vitro and are expected to interfere with the efficacy of chenodiol. To minimize drug interactions, administer chenodiol at least 1 hour before or at least 2 hours after the aluminum-based antacid.
Aluminum Hydroxide; Magnesium Hydroxide: (Moderate) Aluminum hydroxide based antacids have been shown to adsorb bile acids in vitro and are expected to interfere with the efficacy of chenodiol. To minimize drug interactions, administer chenodiol at least 1 hour before or at least 2 hours after the aluminum-based antacid.
Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Moderate) Aluminum hydroxide based antacids have been shown to adsorb bile acids in vitro and are expected to interfere with the efficacy of chenodiol. To minimize drug interactions, administer chenodiol at least 1 hour before or at least 2 hours after the aluminum-based antacid.
Aluminum Hydroxide; Magnesium Trisilicate: (Moderate) Aluminum hydroxide based antacids have been shown to adsorb bile acids in vitro and are expected to interfere with the efficacy of chenodiol. To minimize drug interactions, administer chenodiol at least 1 hour before or at least 2 hours after the aluminum-based antacid.
Charcoal: (Major) Activated charcoal, which is available in some dietary supplements, has been shown to adsorb bile acids in vitro and is expected to interfere with the efficacy of chenodiol. Concurrent use is not recommended.
Cholestyramine: (Moderate) Bile acid sequestrants, such as cholestyramine, may interfere with the action of chenodiol by reducing its absorption. To minimize drug interactions, administer chenodiol at least 1 hour before or at least 4 hours after cholestyramine.
Colesevelam: (Moderate) Bile acid sequestrants, such as colesevelam, may interfere with the action of chenodiol by reducing its absorption. To minimize drug interactions, administer chenodiol at least 1 hour before or at least 4 hours after colesevelam.
Colestipol: (Major) Bile acid sequestrants, such as colestipol, may interfere with the action of chenodiol by reducing its absorption. To minimize drug interactions, administer chenodiol at least 1 hour before or at least 4 hours after colestipol.
Conjugated Estrogens: (Minor) Estrogens and combination hormonal oral contraceptives increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may theoretically counteract the effectiveness of chenodiol.
Conjugated Estrogens; Bazedoxifene: (Minor) Estrogens and combination hormonal oral contraceptives increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may theoretically counteract the effectiveness of chenodiol.
Conjugated Estrogens; Medroxyprogesterone: (Minor) Estrogens and combination hormonal oral contraceptives increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may theoretically counteract the effectiveness of chenodiol.
Desogestrel; Ethinyl Estradiol: (Minor) Estrogens and combination hormonal oral contraceptives increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may theoretically counteract the effectiveness of chenodiol.
Dienogest; Estradiol valerate: (Minor) Estrogens and combination hormonal oral contraceptives increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may theoretically counteract the effectiveness of chenodiol.
Drospirenone: (Minor) Estrogens and combination hormonal oral contraceptives increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may theoretically counteract the effectiveness of chenodiol.
Drospirenone; Estetrol: (Minor) Estrogens and combination hormonal oral contraceptives increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may theoretically counteract the effectiveness of chenodiol.
Drospirenone; Estradiol: (Minor) Estrogens and combination hormonal oral contraceptives increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may theoretically counteract the effectiveness of chenodiol.
Drospirenone; Ethinyl Estradiol: (Minor) Estrogens and combination hormonal oral contraceptives increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may theoretically counteract the effectiveness of chenodiol.
Drospirenone; Ethinyl Estradiol; Levomefolate: (Minor) Estrogens and combination hormonal oral contraceptives increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may theoretically counteract the effectiveness of chenodiol.
Elagolix; Estradiol; Norethindrone acetate: (Minor) Estrogens and combination hormonal oral contraceptives increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may theoretically counteract the effectiveness of chenodiol.
Esterified Estrogens: (Minor) Estrogens and combination hormonal oral contraceptives increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may theoretically counteract the effectiveness of chenodiol.
Esterified Estrogens; Methyltestosterone: (Minor) Estrogens and combination hormonal oral contraceptives increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may theoretically counteract the effectiveness of chenodiol.
Estradiol: (Minor) Estrogens and combination hormonal oral contraceptives increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may theoretically counteract the effectiveness of chenodiol.
Estradiol; Levonorgestrel: (Minor) Estrogens and combination hormonal oral contraceptives increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may theoretically counteract the effectiveness of chenodiol.
Estradiol; Norethindrone: (Minor) Estrogens and combination hormonal oral contraceptives increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may theoretically counteract the effectiveness of chenodiol.
Estradiol; Norgestimate: (Minor) Estrogens and combination hormonal oral contraceptives increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may theoretically counteract the effectiveness of chenodiol.
Estradiol; Progesterone: (Minor) Estrogens and combination hormonal oral contraceptives increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may theoretically counteract the effectiveness of chenodiol.
Estrogens: (Minor) Estrogens and combination hormonal oral contraceptives increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may theoretically counteract the effectiveness of chenodiol.
Estropipate: (Minor) Estrogens and combination hormonal oral contraceptives increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may theoretically counteract the effectiveness of chenodiol.
Ethinyl Estradiol; Norelgestromin: (Minor) Estrogens and combination hormonal oral contraceptives increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may theoretically counteract the effectiveness of chenodiol.
Ethinyl Estradiol; Norethindrone Acetate: (Minor) Estrogens and combination hormonal oral contraceptives increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may theoretically counteract the effectiveness of chenodiol.
Ethinyl Estradiol; Norgestrel: (Minor) Estrogens and combination hormonal oral contraceptives increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may theoretically counteract the effectiveness of chenodiol.
Ethynodiol Diacetate; Ethinyl Estradiol: (Minor) Estrogens and combination hormonal oral contraceptives increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may theoretically counteract the effectiveness of chenodiol.
Etonogestrel; Ethinyl Estradiol: (Minor) Estrogens and combination hormonal oral contraceptives increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may theoretically counteract the effectiveness of chenodiol.
Fenofibrate: (Major) Fibric acid derivatives (i.e., clofibrate and perhaps other lipid-lowering fibrate drugs) increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may counteract the effectiveness of chenodiol.
Fenofibric Acid: (Major) Fibric acid derivatives (i.e., clofibrate and perhaps other lipid-lowering fibrate drugs) increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may counteract the effectiveness of chenodiol.
Fibric acid derivatives: (Major) Fibric acid derivatives (i.e., clofibrate and perhaps other lipid-lowering fibrate drugs) increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may counteract the effectiveness of chenodiol.
Gemfibrozil: (Major) Fibric acid derivatives (i.e., clofibrate and perhaps other lipid-lowering fibrate drugs) increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may counteract the effectiveness of chenodiol.
Leuprolide; Norethindrone: (Minor) Estrogens and combination hormonal oral contraceptives increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may theoretically counteract the effectiveness of chenodiol.
Levonorgestrel: (Minor) Estrogens and combination hormonal oral contraceptives increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may theoretically counteract the effectiveness of chenodiol.
Levonorgestrel; Ethinyl Estradiol: (Minor) Estrogens and combination hormonal oral contraceptives increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may theoretically counteract the effectiveness of chenodiol.
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Minor) Estrogens and combination hormonal oral contraceptives increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may theoretically counteract the effectiveness of chenodiol.
Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate: (Minor) Estrogens and combination hormonal oral contraceptives increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may theoretically counteract the effectiveness of chenodiol.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Minor) Estrogens and combination hormonal oral contraceptives increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may theoretically counteract the effectiveness of chenodiol.
Norethindrone: (Minor) Estrogens and combination hormonal oral contraceptives increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may theoretically counteract the effectiveness of chenodiol.
Norethindrone; Ethinyl Estradiol: (Minor) Estrogens and combination hormonal oral contraceptives increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may theoretically counteract the effectiveness of chenodiol.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Minor) Estrogens and combination hormonal oral contraceptives increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may theoretically counteract the effectiveness of chenodiol.
Norgestimate; Ethinyl Estradiol: (Minor) Estrogens and combination hormonal oral contraceptives increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may theoretically counteract the effectiveness of chenodiol.
Norgestrel: (Minor) Estrogens and combination hormonal oral contraceptives increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may theoretically counteract the effectiveness of chenodiol.
Relugolix; Estradiol; Norethindrone acetate: (Minor) Estrogens and combination hormonal oral contraceptives increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may theoretically counteract the effectiveness of chenodiol.
Segesterone Acetate; Ethinyl Estradiol: (Minor) Estrogens and combination hormonal oral contraceptives increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may theoretically counteract the effectiveness of chenodiol.
Warfarin: (Moderate) Due to its potential for hepatotoxicity, chenodiol may affect the pharmacodynamics of warfarin. Patients with hepatic impairment may require a lower dosage of warfarin due to decreased warfarin metabolism and decreased production of coagulation factors. Coadministration with chenodiol can cause prolongation of the prothrombin time and increase the risk of bleeding. Monitor patients on concomitant therapy carefully. If prolongation of prothrombin time is observed, the warfarin dosage should be adjusted as needed to produce a prothrombin time 1.5 to 2 times normal. If necessary, discontinue chenodiol therapy.
The sites of action of chenodiol are the liver, bile, and the colon. At therapeutic doses, chenodiol suppresses the hepatic synthesis of both cholesterol and cholic acid, gradually replacing the latter and its metabolite, deoxycholic acid. These actions contribute to biliary cholesterol desaturation and gradual dissolution of radiolucent cholesterol gallstones. Chenodiol has no effect on radiopaque (calcified) gallstones or on radiolucent bile pigment stones. The large majority of the chenodiol in the body is found in the enterohepatic circulation; serum and urinary bile acid concentrations are not significantly affected during chenodiol therapy.
Although chenodiol therapy has been linked to hepatotoxicity, the mechanism by which this occurs is unclear. Lithocholic acid, a major metabolite of chenodiol and an established hepatotoxin, may be the cause of chenodiol-related hepatotoxicity; however, since humans possess an efficient mechanism for sulfating and eliminating this substance, there is some evidence that the demonstrated hepatotoxicity could be due, at least in part, to chenodiol itself. Moreover, the possible variations that may exist between individual patient's capacity to sulfate and eliminate lithocholic acid has not been clearly established. Published literature suggests that patients who develop chenodiol-induced serum aminotransferase elevations may be poor sulfators of lithocholic acid.
Chenodiol is administered orally.
During chenodiol therapy, serum and urinary bile acid concentrations are not significantly affected. Once steady-state is achieved, an amount of chenodiol that approximates the daily dose escapes to the colon. In the colon, chenodiol is converted by bacterial action to lithocholic acid, a major metabolite of chenodiol. Approximately 80% of the lithocholate is excreted in the feces with the remainder being absorbed and converted in the liver to its poorly absorbed sulfolithocholyl conjugates. Fecal bile acids are increased 3- to 4-fold, while biliary lithocholate is only increased slightly.
-Route-Specific Pharmacokinetics
Oral Route
After oral administration, chenodiol is well absorbed from the small intestine and taken up by the liver where it is converted to its taurine and glycine conjugates and secreted in bile. Between 60% and 80% of chenodiol undergoes first-pass hepatic clearance; therefore, the body pool of chenodiol resides mainly in the enterohepatic circulation.