Chenodiol

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Chenodal: 250 mg

Pharmacology

Mechanism of Action

Chenodiol (chenodeoxycholic acid) is a naturally occurring human bile acid, normally constituting one-third of the total bile acid pool. In patients with cholesterol gallstones, chenodiol is believed to suppress hepatic synthesis of cholesterol and cholic acid, and inhibit biliary cholesterol secretion, which leads to increased production of cholesterol unsaturated bile thereby allowing for dissolution of gallstones.

Pharmacokinetics/Pharmacodynamics

Absorption

Rapid, almost completely absorbed in proximal small intestine (Crosignani 1996)

Distribution

V_d: ~1600 L (Crosignani 1996)

Metabolism

Converted hepatically to taurine and glycine conjugates and secreted in bile; extensive first-pass hepatic clearance; undergoes enterohepatic circulation; further metabolized in colon by bacteria to lithocholic acid; small portion of lithocholate is absorbed and converted to sulfolithocholyl conjugates in the liver

Excretion

Feces (~80%, as lithocholate)

Half-Life Elimination

~45 hours (Crosignani 1996)

Use: Labeled Indications

Gallstone dissolution: Dissolution of radiolucent cholesterol gallstones in selected patients as an alternative to surgery

Limitations of use: Will not dissolve calcified (radiopaque) or radiolucent bile pigment stones.

Use: Off Label

Cerebrotendinous xanthomatosis (CTX)c

Data from a limited number of patients studied (case reports) suggest that chenodiol may be beneficial for the treatment of cerebrotendinous xanthomatosis Bel 2001, Berginer 2009, Bonnot 2010. Additional data may be necessary to further define the role of chenodiol in this condition.

Contraindications

Known hepatocyte dysfunction or bile ductal abnormalities (eg, intrahepatic cholestasis, primary biliary cirrhosis, sclerosing cholangitis); use in a patient with a gallbladder confirmed as nonvisualizing after two consecutive single doses of dye; radiopaque stones; gallstone complications or compelling reasons for gallbladder surgery (eg, unremitting acute cholecystitis, cholangitis, biliary obstruction, gallstone pancreatitis, biliary gastrointestinal fistula); use in pregnancy or in women who can become pregnant.

Dosage and Administration

Dosing: Adult

Gallstone dissolution (monotherapy): Oral: Initial: 250 mg twice daily for the first 2 weeks and increasing by 250 mg daily each week thereafter until the recommended or maximum tolerated dose is achieved; maintenance: 13 to 16 mg/kg/day in 2 divided doses. Note: Dosages <10 mg/kg are usually ineffective and may increase the risk of cholecystectomy.

Gallstone dissolution (combination therapy; off-label dose): Oral: 5 to 7.5 mg/kg/day once daily at bedtime, in combination with ursodeoxycholic acid, with or without adjuvant lithotripsy (Jazrawi 1992; Pereira 1997; Petroni 2001)

Cerebrotendinous xanthomatosis (off-label use): Oral: 750 mg/day in 3 divided doses for at least 1 year (Berginer 1984)

Dosing: Pediatric

Cerebrotendinous xanthomatosis: Limited data available: Infants, Children, and Adolescents: Oral: Usual dose: 10 to 15 mg/kg/day divided 1 to 3 times daily; maximum daily dose: 750 mg/day; in infants and young children, a lower dose of 5 mg/kg/day in 3 divided doses has been suggested by some experts (Berginer 2009; European Medicines Agency [chenodeoxycholic acid 2017]; Huidekoper 2016; Kaufman 2012; Salen 2017; Setchell 2006; van Heijst 1998)

Gallstone dissolution: Limited data available; not routinely used for cholelithiasis in pediatric patients; use has been replaced by other treatments (Salen 2017): Children ≥12 years and Adolescents: Oral: 15 mg/kg/day divided 3 times daily with meals; dosing based on reported experience in three obese pediatric patients (age range: 12 to 13 years); Note: Not first-line therapy due to frequent side effects (eg, increased LFT, diarrhea) and other therapeutic options available (Podda 1982)

Inborn errors of bile acid biosynthesis; steroid dehydrogenase or reductase deficiencies (susceptible): Very limited data available: Note: Due to the rarity of the disease states, data is limited to small case series and case reports. Adjust dose based upon targeted bile acid or biosynthesis intermediate compound concentrations. Combination therapy with ursodeoxycholic acid (ursodiol) dependent on specific deficiency, and phenotypic presentation of syndrome. Infants, Children, and Adolescents: Oral: Usual initial range: 5 to 10 mg/kg/day divided once or twice daily; higher initial doses of 11 to 18 mg/kg/day have also been reported; a maintenance dose of 5 mg/kg/day was the most frequently reported and initiated once targeted bile acid normalized or stabilized (depending upon the syndrome) (Clayton 1996; Clayton 2011; Dai 2014; Ichimiya 1990; Riello 2010).

Dosing: Adjustment for Toxicity

Diarrhea: Temporarily decrease dose; resume previous dose when diarrhea resolves. Discontinuation of therapy may be required for persistent diarrhea.

Increased cholesterol: Discontinue treatment if cholesterol increases above acceptable age-adjusted limit

Storage

Store at 20°C to 20°C (68°F to 77°F).

Drug Interactions

Aluminum Hydroxide: May decrease the serum concentration of Chenodiol. Management: Consider administration of chenodiol 2 hours before or 6 hours after aluminum-containing antacid products to prevent adsorption in the gastrointestinal tract. Consider therapy modification

Bile Acid Sequestrants: May decrease the serum concentration of Chenodiol. Management: Administration of chenodiol 5 hours or more after bile acid sequestrants may reduce chenodiol adsorption in the gastrointestinal tract. Monitor for decreased therapeutic effects of chenodiol in patients receiving bile acid sequestrants. Consider therapy modification

Estrogen Derivatives: May diminish the therapeutic effect of Chenodiol. Management: Monitor clinical response to chenodiol closely when used together with any estrogen derivative. Monitor therapy

Fibric Acid Derivatives: May diminish the therapeutic effect of Chenodiol. Management: Monitor clinical response to chenodiol closely when used together with any fibric acid derivative. Monitor therapy

Vitamin K Antagonists (eg, warfarin): Chenodiol may enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Adverse Reactions

Frequency not always defined. *Incidence not specifically defined, but reported in the range of >10%.

Endocrine & metabolic: Increased LDL cholesterol, increased serum cholesterol (total)

Gastrointestinal: Diarrhea (30% to 40%; severe diarrhea that requires dose reduction: 10% to 15%), biliary colic,* abdominal cramps, abdominal pain, anorexia, constipation, dyspepsia, flatulence, heartburn, nausea, vomiting

Hematologic & oncologic: Leukopenia

Hepatic: Increased serum transaminases (≥30%; >3 x ULN: 2% to 3%)

Warnings/Precautions

Concerns related to adverse effects:

• Diarrhea: Dose-related diarrhea commonly occurs (up to 40% of patients); may occur at any time, but is most common during treatment initiation. Diarrhea is usually mild and does not interfere with therapy; however, diarrhea may be severe and a temporary dosage reduction or discontinuation may be required. Antidiarrheal agents may be of benefit in some patients.
• Hepatotoxicity: Drug-induced liver toxicity may occur (dose-related); close monitoring of serum aminotransferase levels recommended during therapy. Aminotransferase elevations >3 times ULN have been reported; prompt discontinuation of therapy recommended. Transaminase levels usually return to normal after chenodiol is withheld. Temporarily withhold therapy for transient transaminase elevations of 1.5 to 3 times ULN. Biochemical and histologic chronic active hepatitis has been reported (rare case reports), although a causal relationship to chenodiol could not be determined.

Disease-related concerns:

• Colon cancer: Epidemiologic studies have suggested that bile acids may increase the risk of colon cancer. Evidence is weak and conflicting; however, a potential link between bile acids and colon cancer cannot be ruled out.
• Hepatic impairment: Avoid use in patients with preexisting hepatic impairment or elevated liver enzymes; use contraindicated in patients with known hepatocyte dysfunction or bile ductal abnormalities.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Appropriate use: [US Boxed Warning]: Due to the hepatotoxicity potential, poor response rate in certain subgroups, and an increased rate of cholecystectomy necessary in other subgroups, chenodiol is not an appropriate treatment for many patients with gallstones. Use should be reserved to carefully selected patients; treatment must be accompanied with liver function monitoring. Studies have shown dissolution rates are higher in patients with small (<15 mm in diameter), radiolucent, and/or floatable stones. Radiopaque (calcified or partially calcified) stones and bile pigment stones do not respond to bile acid dissolution therapy.
• Duration of therapy: Response to therapy should be monitored with oral cholecystograms or ultrasonograms at 6- to 9-month intervals. Complete dissolution should then be confirmed by a repeat test 1 to 3 months after continued therapy. If partial dissolution is not observed by 9 to 12 months, complete dissolution is unlikely. If no response is observed by 18 months, therapy should be discontinued; safety beyond 24 months of use has not been established.
• Gallstone recurrence: May occur within 5 years in approximately 50% of patients; serial cholecystograms or ultrasonograms are recommended to monitor for recurrence. Prophylactic doses have not been established and reduced doses cannot be recommended. Long-term consequences of repeated courses or chenodiol are not known.

Monitoring Parameters

Serum aminotransferase levels (monthly for first 3 months, then every 3 months thereafter during therapy); serum cholesterol (every 6 months); oral cholecystograms and/or ultrasonograms (at 6- to 9-month intervals for response to therapy); dissolutions of stones should be confirmed 1 to 3 months later

Pregnancy

Pregnancy Risk Factor

X

Pregnancy Considerations

Use is contraindicated in women who are or can become pregnant. Adverse events were observed in some animal reproduction studies.

Patient Education

What is this drug used for?

• It is used to treat gallstones.
• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Nausea
• Vomiting
• Abdominal cramps
• Abdominal pain
• Constipation
• Diarrhea
• Feeling of needing to have a bowel movement often
• Passing gas
• Heartburn
• Lack of appetite

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin
• Severe diarrhea
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.