Because of the potential hepatotoxicity of chenodiol, poor response rate in some subgroups of chenodiol treated patients, and an increased rate of a need of cholecystectomy in other chenodiol treated subgroups, chenodiol is not an appropriate treatment for many patients with gallstones. Chenodiol should be reserved for carefully selected patients and treatment must be accompanied by systematic monitoring for liver function alterations. Aspects of patient selection, response rates and risks versus benefits are given in the insert.
Cerebrotendinous xanthomatosis (off-label use): Oral: 250 mg 3 times daily for at least 1 year (Berginer 1984; Duell 2018).
Gallstone dissolution (monotherapy): Oral: Initial: 250 mg twice daily for 2 weeks, then increase dose by 250 mg/day each week until the recommended maintenance dose 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. 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.
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).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer’s labeling.
Preexisting hepatic impairment: There are no dosage adjustments provided in the manufacturer’s labeling; avoid use in patients with preexisting hepatic impairment. Contraindicated for use in presence of known hepatocyte dysfunction or bile duct abnormalities.
Hepatotoxicity during treatment:
Aminotransferase level 1.5 to 3 times ULN persisting for >3 to 6 months: Temporarily withhold treatment; resume when aminotransferases levels return to normal.
Aminotransferase level >3 times ULN: Discontinue treatment immediately.
(For additional information see "Chenodeoxycholic acid (chenodiol): Pediatric drug information")
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).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in manufacturer's labeling.
Infants, Children, and Adolescents: Use extreme caution; contraindicated for use in presence of known hepatocyte dysfunction or bile duct abnormalities. A case report describes an infant who developed hepatoxicity during therapy (jaundice, hepatomegaly) at 15 mg/kg/day dose; chenodiol was discontinued until clinical parameters normalized, then restarted at a reduced dose (5 mg/kg/day) without recurrence of hepatotoxicity (Huidekoper 2016).
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
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Chenodal: 250 mg
No
Prescriptions are only dispensed by Dohmen Life Science Services Chenodal Total Care Program which may be contacted at 866-758-7068.
Oral: May be taken without regard to meals.
Gallstone dissolution: Dissolution of radiolucent cholesterol gallstones in select patients as an alternative to surgery.
Limitations of use: Will not dissolve calcified (radiopaque) or radiolucent bile pigment stones.
Cerebrotendinous xanthomatosis
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drugs that have a heightened risk of causing significant patient harm when used in error.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%:
Gastrointestinal: Diarrhea (dose-related; 30% to 40%)
Hepatic: Increased serum transaminases (dose-related; transient: ≥30%)
1% to 10%: Hepatic: Increased serum aspartate aminotransferase (>3 x ULN: 2% to 3%)
Frequency not defined:
Endocrine & metabolic: Decreased serum triglycerides (females), increased LDL cholesterol, increased serum cholesterol (total)
Gastrointestinal: Abdominal cramps, abdominal pain, anorexia, biliary colic, bowel urgency, constipation, dyspepsia, epigastric discomfort, flatulence, heartburn, nausea, vomiting
Hematologic & oncologic: Decreased white blood cell count
Hepatic: Hepatotoxicity
Postmarketing: Hepatic: Chronic active hepatitis
Known hepatocyte dysfunction or bile ductal abnormalities (eg, intrahepatic cholestasis, primary biliary cirrhosis, sclerosing cholangitis); 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 patients who can become pregnant.
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.
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.
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Aluminum Hydroxide: May decrease the serum concentration of Chenodiol. Risk C: Monitor therapy
Bile Acid Sequestrants: May decrease the serum concentration of Chenodiol. Management: Administration of chenodiol 5 hours or more after bile acid sequestrants may reduce the magnitude of this interaction. Monitor for decreased therapeutic effects of chenodiol in patients receiving bile acid sequestrants. Risk D: Consider therapy modification
Estrogen Derivatives: May diminish the therapeutic effect of Chenodiol. Risk C: Monitor therapy
Vitamin K Antagonists (eg, warfarin): Chenodiol may enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy
Use is contraindicated in women who may become pregnant.
Use is contraindicated in women who are pregnant. Adverse events were observed in some animal reproduction studies.
It is not known if chenodiol is excreted in breast milk. The manufacturer recommends that caution be exercised when administering chenodiol to breastfeeding women.
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
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.
Absorption: Rapid, almost completely absorbed in proximal small intestine (Crosignani 1996)
Distribution: Vd: ~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
Half-life: ~45 hours (Crosignani 1996)
Excretion: Feces (~80%, as lithocholate)
Tablets (Chenodal Oral)
250 mg (per each): $567.60
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