Chenodiol

You should not use chenodiol if you are allergic to it, or if:

• you are pregnant;

• you have a bile duct obstruction or other disorder;

• you have pancreatitis related to your gallstones;

• you have cirrhosis or other liver disease; or

• you have a blockage in your digestive tract (stomach or intestines).

To make sure chenodiol is safe for you, tell your doctor if you have a history of liver problems or jaundice.

Do not use chenodiol if you are pregnant. It could harm the unborn baby or cause birth defects. Use effective birth control to prevent pregnancy while you are using this medicine.

It is not known whether chenodiol passes into breast milk or if it could affect the nursing baby. Tell your doctor if you are breast-feeding.

Gallstone Dissolution

Dissolution of gallstones in patients with radiolucent stones in well-opacifying gallbladders who are not candidates for surgery because of systemic disease or advanced age.1 6 Likelihood of dissolution is far greater if the stones are floatable or small.1 Chenodiol does not dissolve calcified (radiopaque) or radiolucent bile pigment stones.1

Not an appropriate treatment for many patients with gallstones, because of potential hepatoxicity and poor response rate and/or increased need for cholecystectomy in certain groups of patients.1 Reserve chenodiol for carefully selected patients and monitor liver function.1

In patients with nonfloatable stones, chenodiol, particularly at dosages <10 mg/kg daily, produced no reduction in biliary pain and tended to increase the cholecystectomy rate.1 Consider the risk that patients with nonfloatable stones treated unsuccessfully with chenodiol might require more-emergent surgery because effective treatment is delayed.1

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.1

Following complete dissolution, stones have recurred within 5 years in about 50% of patients.1 Although retreatment with chenodiol has proven successful in dissolving some newly formed stones, the indications for and safety of retreatment are not well defined.1

Safety beyond 2 years of use not established.1 Long-term consequences of repeated courses of chenodiol (e.g., potential for liver toxicity, neoplasia, and elevated cholesterol levels) are not known.1

Specific Drugs

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Use this medicine as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• Keep taking chenodiol as you have been told by your doctor or other health care provider, even if you feel well.
• To gain the most benefit, do not miss doses.

What do I do if I miss a dose?

• Take a missed dose as soon as you think about it.
• If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
• Do not use 2 doses or extra doses.

• Store at room temperature.
• Store in a dry place. Do not store in a bathroom.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

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 collaborate (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 hemorrahages. Patients on concommitant 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.

Carcinogenesis, mutagenesis, impairment of fertility

A two-year oral study of Chenodiol in rats failed to show a carcinogenic potential at the tested levels of 15 to 60 mg/kg/day (1 to 4 times the maximum recommended human dose, MRHD). It has been reported that Chenodiol given in long-term studies at oral doses up to 600 mg/kg/day (40 times the MRHD) to rats and 1000 mg/kg/day (65 times the MRHD) to mice induced benign and malignant liver cell tumors in female rats and cholangiomata in female rats and male mice. Two-year studies of lithocholic acid ( a major metabolite of Chenodiol) in mice (125 to 250 mg/kg/day) and rats (250 and 500 mg/kg/day) found it not to be carcinogenic. The dietary administration of Lithocholic acid to chickens is reported to cause hepatic adenomatous hyperplasia.

Pregnancy

Pregnancy Category X: See CONTRAINDICATIONS.

Nursing mothers

It is not known whether Chenodiol is excreted in human mild. Because many drugs are excreted in human milk, caution should be exercised when Chenodiol is administered to a nursing mother.

Pediatric use

The safety and effectiveness of Chenodiol in children have not been established.

The recommended dose range for Chenodiol is 13 to 16 mg/kg/day in two divided doses, morning and night, starting with 250 mg b.i.d. the first two weeks and increasing by 250 mg/day each week thereafter until the recommended or maximum tolerated dose is reached. If diarrhea occurs during dosage buildup or later in treatment, it usually can be controlled by temporary dosage adjustment until symptoms abate, after which the previous dosage usually is tolerated. Dosage less than 10 mg/kg usually is ineffective and may be associated with increased risk of cholecystectomy, so is not recommended.

The optimal frequency of monitoring liver function tests is not known. It is suggested that serum aminotransferase levels should be monitored monthly for the first three months and every three months thereafter during Chenodiol administration. Under NCGS guidelines, if a minor, usually transient elevations (1 ½ to3 three times the upper limit of normal) persisted longer than three to six months. Chenodiol was discontinued and resumed only after the aminotransferase level returned to normal; however, allowing the elevations to persist over such an interval is not know to be safe. Elevations over three times the upper limit of normal require immediate discontinuation of Chenodiol and usually reoccur on challenge.

Serum cholesterol should be monitored at six months intervals. It may be advisable to discontinue Chenodiol if cholesterol rises above the acceptable age-adjusted limit for given patient.

Oral cholecystograms or ultrasonograms are recommend at six to nine month intervals to monitor response. Complete dissolutions should be confirmed by a repeat test after one to three months continued Chenodiol administration. Most patients who eventually achieve complete dissolution will show partial (or complete) dissolution at the first on-treatment test. If partial dissolution is not seen by nine to 12 months, the likelihood of success of treating loner is greatly reduced; Chenodiol should be discontinued if there is no response by 18 months. Safety of use beyond 24 months is not established.

Stone recurrence can be expected within five years in 50% of cases. After confirmed dissolution, treatment generally should be stopped. Serial cholecystograms or ultrasonograms are recommended to monitor for recurrence, keeping in mind that radiolucency and gallbladder function should be established before starting another course of Chenodiol. A prophylactic doses is not established; reduced doses cannot be recommended; stones have recurred on 500 mg/day. 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.

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)

Commonly reported side effects of chenodeoxycholic acid include: increased serum alanine aminotransferase. See below for a comprehensive list of adverse effects.

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:

13 to 16 mg/kg/day in two divided doses, morning and night, starting with 250 mg twice a day for the first two weeks and increasing by 250 mg/day each week thereafter until the recommended or maximum tolerated dose is reached. If diarrhea occurs during dosage buildup or later in treatment, it usually can be controlled by temporary dosage adjustment until symptoms abate, after which the previous dosage usually is tolerated. Dosage less than 10 mg/kg usually is ineffective and may be associated with increased risk of cholecystectomy, so is not recommended. Safety of use beyond 24 months is not established.

Safety and effectiveness have not been established in pediatric patients (less than 18 years of age).