Chenodiol

Description

DESCRIPTION Chenodiol is the non-proprietary name for chenodeoxycholic acid, a naturally occurring human bile acid. It is a bitter-tasting white powder consisting of crystalline and amorphous particles freely soluble in methanol, acetone and acetic acid and practically insoluble in water. Its chemical name is 3α, 7α-dihydroxy-5β-cholan-24-oic acid (C 24 H 40 O 4 ), it has a molecular weight of 392.58, and its structure is shown below; Chenodiol film-coated tablets for oral administration contain 250 mg of chenodiol. Inactive ingredients: pregelatinized starch; silicon dioxide; microcrystalline cellulose, sodium starch glycollate; and magnesium stearate; the thin-film coating contains: opadry YS-2-7035 [consisting of methylcellulose and glycerin] and sodium lauryl sulfate Its chemical name is 3α, 7α-dihydroxy-5β-cholan-24-oic acid (C24H40O4), it has a molecular weight of 392.58, and its structure is shown below;

What Is Chenodiol Used For?

INDICATIONS AND USAGE Chenodiol is indicated 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. The likelihood of successful dissolution is far greater if the stones are floatable or small. For patients with nonfloatable stones, dissolution is less likely and added weight should be given to the risk that more emergent surgery might result form a delay due to unsuccessful treatment. Safety of use beyond 24 months is not established. Chenodiol will not dissolve calcified (radiopaque) or radiolucent bile pigment stones.

Dosage and Administration

DOSAGE AND ADMINISTRATION 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. Body Weight Recommended Tablets/Day Dose Range mg/kg lb kg 100-130 45-58 3 17-13 131-185 59-75 4 17-13 186-200 76-90 5 18-14 201-235 91-107 6 18-14 236-275 108-125 7 18-14 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.

Side Effects (Adverse Reactions)

ADVERSE REACTIONS Hepatobiliary: Dose-related serum aminotransferase (mainly SGPT) elevations, usually not accompanied by rises in alkaline phosphatase or bilirubin, occurred in 30% or more of patients treated with the recommended dose of Chenodiol. In most cases, these elevations were minor (1 ½ to 3 times the upper limit of laboratory normal) and transient, returning to within the normal range within six months despite continued administration of the drug. In 2% to 3% of patients, SGPT levels rose to over three times the upper limit of laboratory normal, recurred on rechallenge with the drug, and required discontinuation of chenodiol treatment. Enzyme levels have returned to normal following withdrawal of chenodiol ( see WARNINGS ). Morphologic studies of liver biopsies taken before and after 9 and 24 months of treatment with chenodiol have shown that 63% of the patients prior to chenodiol treatment had evidence of intrahepatic cholestasis. Almost all pretreatment patients had electron microscopic abnormalities. By the ninth month of treatment, reexamination of two-thirds of the patients showed an 89% incidence of the signs of intrahepatic cholestasis. Two of 89 patients at the ninth month had lithocholate-like lesions in the canalicular membrane, although there were not clinical enzyme abnormalities in the face of continued treatment and no change in Type 2 light microscopic parameters. Increased Cholecystectomy Rate : 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. Gastrointestinal: Dose-related diarrhea has been encountered in 30% to 40% of chenodiol-treated patients and may occur at any time during treatment, but is most commonly encountered when treatment is initiated. Usually, the diarrhea is mild, translucent, well-tolerated and does not interfere with therapy. Dose reduction has been required in 10% to 15% of patients, and in a controlled trial about half of these required a permanent reduction in dose. Anti-diarrhea agents have proven useful in some patients. Discontinuation of chenodiol because of failure to control diarrhea is to be expected in approximately 3% of patients treated. Steady epigastric pain with nausea typical of lithiasis (biliary colic) usually is easily distinguishable from the crampy abdominal pain of drug-induced diarrhea. Other less frequent, gastrointestinal side effects reported include urgency, cramps, heartburn, constipation, nausea, and vomiting, anorexic, epigastric distress, dyspepsis, flatulence and nonspecific abdominal pain. Serum Lipids: Serum total cholesterol and low-density lipoprotein (LDL) cholesterol may rise 10% or more during administration of chenodiol: no change has been seen in the high-density lipoprotein (HDL) fraction; small decreases in serum triglyceride levels for females have been reported. Hematologic: Decreases in white cell count, never below 3000, have been noted in a few patients treated with chenodiol; the drug was continued in all patients without incident.

Drug Interactions

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

Contraindications

CONTRAINDICATIONS Chenodiol is contraindicated in the presence of know hepatocyte dysfunction or bile ductal abnormalities such as intrahepatic cholestasis, primary biliary cirrhosis or sclerosing cholangitits (see Warnings); a gallbladder confirmed as nonvisualizing after two consecutive single doses of dye; radiopaque stones; or gallstone complications or compelling reasons for gallbladder surgery including unremitting acute cholecystitis, cholangitis, biliary obstruction, gallstone pancreatitis, or biliary gastrointestinal fistula. Pregnancy Category X: Chenodiol may cause fetal harm when administered to a pregnant woman. Serious hepatic, renal and adrenal lesions occurred in fetuses of female Rhesus monkeys given 60 to 90 mg/kg/day (4 to 6 times the maximum recommended human dose, MRHD) from day 21 to day 45 of pregnancy. Hepatic lesions also occurred in neonatal baboons whose mothers had received 18 to 38 mg/kg ( 1 to 2 times the MRHD), all during pregnancy. Fetal malformations were not observed. Neither fetal liver damage nor fetal abnormalities occurred in reproduction studies in rats and hamsters. No human data are available at this time. Chenodiol is 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 apprised of the potential hazard to the fetus.

Pregnancy and Breastfeeding

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.

Overdosage

O verdosage Accidental or intentional overdoses of chenodiol have not been reported. One patient tolerated 4 gm/day (58 mg/kg/day) for six months without incident.

How Supplied

HOW SUPPLIED Chenodal® (chenodiol tablets) is available as white film-coated 250 mg tablets imprinted “MP” on one side and "250" on the other in bottles of 100, NDC 68974-876-40. Store at 20 o C to 25 o C (68 o F to 77 o F) [see USP Controlled Room Temperature]. Dispense in a tight container. Manufactured for: Retrophin, Inc. San Diego, CA 92130 866-758-7068 Rev. 06/15