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CHENODIOL AND RELATED AGENTS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Chenodiol (chenodeoxycholic acid) and ursodiol (ursodeoxycholic acid) are naturally occurring bile acid. Chenodiol and ursodiol are used for the dissolution of gallstones.

Specific Substances

    A) CHENODIOL
    1) 3alpha, 7alpha-dihydroxy-5beta-cholan-24-oic acid
    2) CDCA
    3) Chenic acid
    4) Chenodeoxycholic acid
    5) Molecular Formula: C24-H40-O4
    6) CAS 474-25-9
    URSODIOL
    1) 3alpha,7beta-dihydroxy-5beta-cholan-24-oic acid
    2) Molecular Formula: C24-H40-O4
    3) Ursodeoxycholic acid
    4) CAS 128-13-2

Available Forms Sources

    A) USES
    1) Chenodiol is indicated in high surgical-risk adults (due to disease or age) with radiolucent stones in well-opacifying gallbladders (Prod Info CHENODAL(TM) oral tablets, 2009).
    2) Ursodiol is used for radiolucent, noncalcified gallstones less than 20 mm in diameter in whom elective cholecystectomy is refused by patient or not elected due to presence of increased surgical risk. It is also used for the prevention of gallstone formation in obese patients experiencing rapid weight loss (Prod Info ACTIGALL(R) oral capsules, 2009).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Chenodiol (chenodeoxycholic acid) and ursodiol (ursodeoxycholic acid) are used for the dissolution of gallstones. Ursodiol is also used for the prevention of gallstone formation in obese patients experiencing rapid weight loss.
    B) PHARMACOLOGY: Chenodiol (chenodeoxycholic acid) and ursodiol (ursodeoxycholic acid) are naturally occurring bile acid. Hepatic synthesis of cholesterol and cholic acid is suppressed by chenodiol. Suppression of cholic acid and the metabolite, deoxycholic acid lead to desaturation of biliary cholesterol, which leads to gradual dissolution of radiolucent cholesterol gallstones in the gall bladder. Chenodiol has no effects on radiopaque (calcified) gallstones or radiolucent bile pigment stones.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) CHENODIOL: Dose-related diarrhea is the most common adverse effect of chenodiol. Nausea, vomiting, constipation, abdominal pain, flatulence, heartburn, anorexia, dyspepsia, and elevated liver enzymes are less frequently reported side effects associated with chenodiol therapy. Serious hepatic disease may occasionally occur in patients treated with chenodiol. URSODIOL: Diarrhea, nausea, vomiting, constipation, dyspepsia, itching, hypersensitivity reaction, backache, dizziness, cough, and pharyngitis have been reported. Chenodiol has the pregnancy category X.
    E) WITH POISONING/EXPOSURE
    1) At the time of this review, there is no acute overdose data available. Overdose effects are anticipated to be an extension of adverse effects (eg, diarrhea) observed following therapeutic doses.
    0.2.20) REPRODUCTIVE
    A) Chenodiol is classified as FDA pregnancy category X and ursodiol as category B. Chenodiol may cause fetal harm and is contraindicated in pregnant women. Serious hepatic, renal, and adrenal lesions have occurred in animals following maternal administration of chenodiol. Limited human data in the treatment of intrahepatic cholestasis of pregnancy indicated ursodiol was safe for the fetus. No fetal harm was noted with ursodiol in animal studies. It is unknown whether chenodiol or ursodiol are excreted in human milk, and no human data are available on fertility effects. Animal data indicate no adverse effects on fertility for ursodiol.

Laboratory Monitoring

    A) Monitor liver enzymes in symptomatic patients.
    B) Monitor serum electrolytes in patients with severe vomiting and/or diarrhea.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Significant toxicity is not expected after an overdose.
    C) DECONTAMINATION
    1) PREHOSPITAL: Prehospital decontamination is generally NOT required.
    2) HOSPITAL: Severe toxicity is not expected after an overdose. Gastrointestinal decontamination is generally not necessary. Consider activated charcoal only if coingestants with significant toxicity are involved.
    D) AIRWAY MANAGEMENT
    1) Should not be required in these cases.
    E) ANTIDOTE
    1) None.
    F) ENHANCED ELIMINATION
    1) Hemodialysis is not recommended given the low toxicity of these drugs.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are more than mildly symptomatic, need to be monitored for several hours to assess electrolyte and fluid balance. Patients that remain asymptomatic can be discharged.
    3) ADMISSION CRITERIA: Patients should be admitted for severe vomiting, profuse diarrhea, severe abdominal pain, dehydration, and electrolyte abnormalities.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    H) PITFALLS
    1) When managing a suspected overdose, the possibility of multidrug involvement should be considered. If severe toxicity develops the diagnosis should be considered.
    I) PHARMACOKINETICS
    1) CHENODIOL: Bioavailability, Oral: 81% to 100%; protein binding, extent unknown. After absorption, chenodiol is conjugated with either glycine or taurine in the liver and rapidly located in the bile. First pass hepatic clearance is 60% to 80%. Excretion: fecal: extensive, 80% as lithocholate. URSODIOL: Bioavailability, Oral: 90%; protein binding: 70%. Excretion: Ursodiol is eliminated primarily in the feces as lithocholic acid.
    J) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause hepatotoxicity.

Range Of Toxicity

    A) TOXICITY: CHENODIOL: Four grams daily (58 mg/kg/day) for 6 months was well tolerated without adverse sequelae in one patient. URSODIOL: A 39-day-old preterm infant received an inadvertent dosage of 360 mg/day (148 mg/kg/day) of ursodiol for 6 days, which was approximately 6 times the intended dose of 25 mg/kg/day and developed no adverse events.
    B) THERAPEUTIC DOSES: Initial, 250 mg orally twice daily for the first 2 weeks; increase the dose by 250 mg/day each week until a range of 13 to 16 mg/kg/day in 2 divided doses or until the maximum tolerated dose is reached. Doses varies by weight (body weight 100 to 275 pounds): 750 mg (17 to 13 mg/kg) to 1750 mg (18 to 14 mg/kg) orally once a day in 2 divided doses. URSODIOL: Chemodissolution of bile duct stone: 8 to 10 mg/kg/day orally divided into 2 to 3 doses. Prophylaxis of gallstone during rapid weight loss: 300 mg orally twice daily.

Clinical Effects

Summary Of Exposure

    A) USES: Chenodiol (chenodeoxycholic acid) and ursodiol (ursodeoxycholic acid) are used for the dissolution of gallstones. Ursodiol is also used for the prevention of gallstone formation in obese patients experiencing rapid weight loss.
    B) PHARMACOLOGY: Chenodiol (chenodeoxycholic acid) and ursodiol (ursodeoxycholic acid) are naturally occurring bile acid. Hepatic synthesis of cholesterol and cholic acid is suppressed by chenodiol. Suppression of cholic acid and the metabolite, deoxycholic acid lead to desaturation of biliary cholesterol, which leads to gradual dissolution of radiolucent cholesterol gallstones in the gall bladder. Chenodiol has no effects on radiopaque (calcified) gallstones or radiolucent bile pigment stones.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) CHENODIOL: Dose-related diarrhea is the most common adverse effect of chenodiol. Nausea, vomiting, constipation, abdominal pain, flatulence, heartburn, anorexia, dyspepsia, and elevated liver enzymes are less frequently reported side effects associated with chenodiol therapy. Serious hepatic disease may occasionally occur in patients treated with chenodiol. URSODIOL: Diarrhea, nausea, vomiting, constipation, dyspepsia, itching, hypersensitivity reaction, backache, dizziness, cough, and pharyngitis have been reported. Chenodiol has the pregnancy category X.
    E) WITH POISONING/EXPOSURE
    1) At the time of this review, there is no acute overdose data available. Overdose effects are anticipated to be an extension of adverse effects (eg, diarrhea) observed following therapeutic doses.

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) COUGH
    1) WITH THERAPEUTIC USE
    a) URSODIOL: Coughing was reported in 7.1% of patients who received ursodiol 8 to 10 mg/kg/day (n=155) compared with 4.4% of patients who received placebo (n=159) in a study for gallstone dissolution (Prod Info ACTIGALL(R) oral capsule, 2007).
    B) PHARYNGITIS
    1) WITH THERAPEUTIC USE
    a) URSODIOL: Pharyngitis was reported in 8.4% of patients who received ursodiol 8 to 10 mg/kg/day (n=155) compared with 3.1% of patients who received placebo (n=159) in a study for gallstone dissolution (Prod Info ACTIGALL(R) oral capsule, 2007).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) URSODIOL: Dizziness was reported in 16.5% of patients who received ursodiol 600 mg (n=322) compared with 12.9% of patients who received placebo (n=325) in a study for gallstone prevention (Prod Info ACTIGALL(R) oral capsule, 2007).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) CHENODIOL
    1) Dose-related diarrhea is the most common adverse effect of chenodiol, with a reported incidence of 30% to 50% (Prod Info CHENODAL(TM) oral tablets, 2009; Dowling, 1977; Iser et al, 1975; Mok et al, 1974; Schoenfield et al, 1983; Maton et al, 1982).
    2) Chenodiol-induced diarrhea appears to be dose-related, and is usually mild and transient; diarrhea generally occurs during the first few weeks of treatment. No cases of diarrhea were reported in patients receiving less than 500 mg daily (Mok et al, 1974). Another report described diarrhea in all patients receiving 3 g orally daily (Gerolami et al, 1977). Chenodiol probably causes diarrhea by inducing colonic secretion of fluids or morphologic damage, or both (Zak et al, 1983).
    b) URSODIOL
    1) Diarrhea was reported in 27.1% of patients who received ursodiol 8 to 10 mg/kg/day (n=155) compared with 21.4% of patients who received placebo (n=159) in a study for gallstone dissolution (Prod Info ACTIGALL(R) oral capsule, 2007).
    2) In one study, only 4% of patients treated with ursodiol developed diarrhea (Rosenbaum & Cluxton, 1988).
    3) Ursodiol did not produce significant diarrhea at doses up to 15 mg/kg/day (Bachrach & Hofmann, 1982a).
    B) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) CHENODIOL: Nausea and vomiting is a less frequently reported gastrointestinal side effect associated with chenodiol therapy (Prod Info CHENODAL(TM) oral tablets, 2009).
    b) URSODIOL: Nausea was reported in 17.4% of patients who received ursodiol 600 mg (n=322) compared with 13.2% of patients who received placebo (n=325) in a study for gallstone prevention (Prod Info ACTIGALL(R) oral capsule, 2007).
    c) URSODIOL: Vomiting was reported in 9.7% of patients who received ursodiol 8 to 10 mg/kg/day (n=155) compared with 6.9% of patients who received placebo (n=159) in a study for gallstone dissolution (Prod Info ACTIGALL(R) oral capsule, 2007).
    C) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) CHENODIOL: Constipation is a less frequently reported gastrointestinal side effect associated with chenodiol therapy (Prod Info CHENODAL(TM) oral tablets, 2009).
    b) URSODIOL: Constipation was reported in 26.4% of patients who received ursodiol 600 mg (n=322) compared with 22.2% of patients who received placebo (n=325) in a study for gallstone prevention (Prod Info ACTIGALL(R) oral capsule, 2007).
    D) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) CHENODIOL: Nonspecific abdominal pain is a less frequently reported gastrointestinal side effect associated with chenodiol therapy (Prod Info CHENODAL(TM) oral tablets, 2009).
    E) FLATULENCE/WIND
    1) WITH THERAPEUTIC USE
    a) CHENODIOL: Flatulence is a less frequently reported gastrointestinal side effect associated with chenodiol therapy (Prod Info CHENODAL(TM) oral tablets, 2009).
    F) HEARTBURN
    1) WITH THERAPEUTIC USE
    a) CHENODIOL: Heartburn is a less frequently reported gastrointestinal side effect associated with chenodiol therapy (Prod Info CHENODAL(TM) oral tablets, 2009).
    G) LOSS OF APPETITE
    1) WITH THERAPEUTIC USE
    a) CHENODIOL: Anorexia is a less frequently reported gastrointestinal side effect associated with chenodiol therapy (Prod Info CHENODAL(TM) oral tablets, 2009).
    H) INDIGESTION
    1) WITH THERAPEUTIC USE
    a) CHENODIOL: Dyspepsia is a less frequently reported gastrointestinal side effect associated with chenodiol therapy (Prod Info CHENODAL(TM) oral tablets, 2009).
    b) URSODIOL: Dyspepsia was reported in 16.8% of patients who received ursodiol 8 to 10 mg/kg/day (n=155) compared with 11.3% of patients who received placebo (n=159) in a study for gallstone dissolution (Prod Info ACTIGALL(R) oral capsule, 2007).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) CHENODIOL: The incidence of serum aminotransferase elevations (1.5 to 3 times the ULN and transient) have been reported in 30% or more patients treated with recommended doses of chenodiol. These elevations were primarily with SGPT, they were dose-related, and they lacked concurrent elevation in alkaline phosphatase or bilirubin. Additionally, the elevations returned to normal ranges within 6 months during continued therapy. In 2% to 3% of patients SGPT rose to over 3 times the ULN, recurred on rechallenge and required discontinuation of chenodiol (Prod Info CHENODAL(TM) oral tablets, 2009).
    b) CHENODIOL: A reversible 2 to 3-fold rise in liver function tests (hypertransaminasemia) has been reported in up to 50% of patients treated with chenodiol, possibly due to a hepatotoxic metabolite, lithocholic acid (Schoenfield & Lachin, 1981).
    c) URSODIOL: Hypertransaminemia has not been reported to occur after therapeutic doses (Bachrach & Hofmann, 1982a).
    B) LIVER DAMAGE
    1) WITH THERAPEUTIC USE
    a) CHENODIOL: Serious hepatic disease may occasionally occur in patients treated with chenodiol (Prod Info CHENODAL(TM) oral tablets, 2009). Clinically significant hepatotoxicity was reported in 3% of patients in the National Cooperative Gallstone Study (Schoenfield & Lachin, 1981).
    b) CHENODIOL: Biochemical and histologic evidence of chronic active hepatitis has been described in 3 patients treated with chenodiol 375 mg/day and 750 mg/day. Spontaneous resolution of the biochemical abnormalities occurred in 2 patients within 13 to 17 months. The third patient had resolution of biochemical abnormalities after 17 months of treatment with prednisone. Causality was not determined (Prod Info CHENODAL(TM) oral tablets, 2009).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) CHENODIOL: Decreases in WBC count (never below 3000) have been reported in patients receiving chenodiol treatment (Prod Info CHENODAL(TM) oral tablets, 2009).
    b) CHENODIOL: Isolated reports of leukopenia have occurred; however, a cause-effect relationship was not established and the drug was continued in all patients without adverse sequelae (Schoenfield & Lachin, 1981).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ITCHING
    1) WITH THERAPEUTIC USE
    a) URSODIOL: Pruritus was reported during post-marketing use of ursodiol (Prod Info URSO 250(R) / URSO Forte(R) oral tablets, 2009).
    B) ERUPTION
    1) WITH THERAPEUTIC USE
    a) CHENODIOL: A reaction that was similar to atopic dermatitis was reported in a 30-year-old woman with cerebrotendinous xanthomatosis following 2 weeks of chenodiol therapy. The patient presented with a pruritic eruption consisting of erythematous lichenoid patches in the antecubital and popliteal spaces, the neck, forehead, and around the eyes. Elevated IgE levels were observed. The eruption was unresponsive to topical steroids; withdrawal of chenodiol resulted in disappearance of skin lesions and pruritus within 3 weeks; IgE levels returned to baseline (Wolf & Kahane, 1987).
    C) LICHENOID DERMATITIS
    1) WITH THERAPEUTIC USE
    a) URSODIOL: Lichenoid eruptions occurred in a 61-year-old man due to the use of ursodiol 600 mg/day for gallstones. The patient presented with prurigo lesions. He stopped taking ursodiol and his lesions improved. Several weeks later, he resumed use of ursodiol and the lesions reappeared. The lesions were erythematous, the size of soybeans, and covered his entire body surface with thick scaly, coalescing plaque. Biopsy revealed a lichenoid reaction showing degeneration of basal layer keratinocytes with lymphocytic cell infiltrates and lymphocytic mononuclear cells infiltrating the upper dermis. Discontinuation of ursodiol brought prompt subsidence of the lesions. In provocation testing, ursodiol produced itching and erythematous eruptions (Horiuchi, 2001).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) BACKACHE
    1) WITH THERAPEUTIC USE
    a) URSODIOL: Back pain was reported in 11.8% of patients who received ursodiol 600 mg (n=322) compared with 6.5% of patients who received placebo (n=325) in a study for gallstone prevention (Prod Info ACTIGALL(R) oral capsule, 2007).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) HYPERSENSITIVITY REACTION
    1) WITH THERAPEUTIC USE
    a) URSODIOL: Drug hypersensitivity, including facial edema, urticaria, angioedema, and laryngeal edema, was reported during post-marketing use of ursodiol (Prod Info URSO 250(R) / URSO Forte(R) oral tablets, 2009).

Reproductive

    3.20.1) SUMMARY
    A) Chenodiol is classified as FDA pregnancy category X and ursodiol as category B. Chenodiol may cause fetal harm and is contraindicated in pregnant women. Serious hepatic, renal, and adrenal lesions have occurred in animals following maternal administration of chenodiol. Limited human data in the treatment of intrahepatic cholestasis of pregnancy indicated ursodiol was safe for the fetus. No fetal harm was noted with ursodiol in animal studies. It is unknown whether chenodiol or ursodiol are excreted in human milk, and no human data are available on fertility effects. Animal data indicate no adverse effects on fertility for ursodiol.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) CHENODIOL
    a) BABOONS: Hepatic lesions occurred in neonatal baboons following maternal administration of chenodiol 18 to 38 mg/kg (1 to 2 times the maximum recommended human dose) throughout pregnancy. No fetal malformations were observed (Prod Info CHENODAL(TM) oral tablets, 2009).
    b) MONKEYS: Serious hepatic, renal, and adrenal lesions occurred in the offspring of female Rhesus monkeys who were given chenodiol 60 to 90 mg/kg/day (4 to 6 times the maximum recommended human dose) from days 21 to 45 of pregnancy. No fetal malformations were observed (Prod Info CHENODAL(TM) oral tablets, 2009).
    c) PRIMATES: The administration of chenodiol at doses several times the maximum recommended human dose have caused fetal hepatic, renal, and adrenal lesions in primates (Heywood et al, 1973; McSherry et al, 1976). The less efficient sulfation in the baboon may exaggerate the toxicity of chenodiol compared to humans (McSherry et al, 1976).
    d) RATS: Embryolethality was observed in rats after administration of 120 mg/kg/day of chenodiol (Celle et al, 1980).
    2) URSODIOL
    a) RABBITS: No harm to the fetus was noted after pregnant rabbits were given oral ursodiol in doses up to 7 times the maximum recommended human dose (based on body surface area) (Prod Info URSO 250(R) / URSO Forte(R) oral tablets, 2009).
    b) RATS: No harm to the fetus was noted after pregnant rats were given oral ursodiol in doses up to 22 times the maximum recommended human dose (based on body surface area) (Prod Info URSO 250(R) / URSO Forte(R) oral tablets, 2009).
    c) RATS: Ursodiol produced embryolethality in rats at a dose of 700 mg/kg/day (Celle et al, 1980).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) CHENODIOL is classified as FDA pregnancy category X (Prod Info CHENODAL(TM) oral tablets, 2009).
    2) URSODIOL is classified as FDA pregnancy category B (Prod Info URSO 250(R) / URSO Forte(R) oral tablets, 2009).
    B) LACK OF EFFECT
    1) URSODIOL
    a) The use of ursodeoxycholic acid (UDCA) for treatment of intrahepatic cholestasis of pregnancy provided beneficial maternal benefits with no fetal and mild gastrointestinal maternal adverse effects according to a metaanalysis. In 9 randomized, controlled trials, 207 patients received UDCA alone, 70 received placebo, and 177 received an active control. A total resolution of pruritus occurred in 41.6% of patients administered UDCA compared with 6.1% and 8.6% of patients administered active controls and placebo, respectively. Pruritus improved in 61.3% of UDCA patients compared with 26.8% and 25.7% of active control and placebo patients, respectively. In terms of fetal outcomes, the rate of total prematurity was 15.9%, 33.6%, and 40% for UDCA, active control, and placebo patients, respectively. A weight-adjusted pooled analysis showed the rate of prematurity to be lower in the UDCA group compared with all control groups (odds ratio (OR), 0.44; 95% CI, 0.24 to 0.79). There was no difference in the total incidence rates of prematurity between UDCA and placebo patients (OR, 0.59; 95% CI, 0.19 to 1.77). The Incidence of fetal distress were lower in UDCA patients compared with active control and placebo patients (18.6%, 33.3%, and 35.7%, respectively). A weight-adjusted pooled analysis revealed a lower rate in UDCA patients compared with all controls groups (OR, 0.46; 95% CI, 0.25 and 0.86). However, no differences were noted between the UDCA and placebo groups (OR, 0.63; 95% CI, 0.23 to 1.72). The incidence rate of respiratory distress syndrome was 3.3%, 16.3%, and 9.1% in UDCA, active control, and placebo patients, respectively. These rates were lower in the UDCA groups compared with the active control groups (OR, 0.3; 95% CI, 0.12 to 0.74) based on a weight-adjusted analysis. There was no difference in rates between the UDCA and placebo group (OR, 0.66; 95% CI, 0.11 to 3.91). There was also a lower rate of neonatal intensive care admissions for UDCA compared to all control patients (9.1% (12/132); 18.1% (24/133), respectively); however rates were similar to the placebo group (9.1% (2/22) (Bacq et al, 2012).
    b) High-dose ursodiol (ursodeoxycholic acid) for treatment of intrahepatic cholestasis of pregnancy (ICP) produced beneficial effects (maternal) related to pruritus and serum levels of bile acids and hepatic enzymes, while proving completely safe for the fetus. Of 30 women affected with ICP (appearance at week 18 to 34 of gestation), 20 were given ursodiol 1.5 to 2 g/day (20 to 25 mg/kg/day) divided in 3 doses; the other 10 patients (controls) were treated only with a low-fat diet and bed rest. In the ursodiol treatment group, maternal serum conjugated cholic (CCA) and chenodeoxycholic (CCDCA) acid concentrations decreased significantly (both p less than 0.01). Serum conjugated ursodeoxycholic acid concentrations rose significantly in the active treatment group (p less than 0.001). AST, ALT, and bilirubin values dropped significantly with ursodiol treatment (all, p less than 0.01). Concentrations of CCA and CCDCA in amniotic fluid were significantly higher in untreated patients (p=0.027 and p=0.001, respectively); also, both CCA and CCDCA were significantly higher in cord blood in the control group (both p=0.0001). Early delivery was not found to be necessary in the ursodiol group (delivery week 36 versus week 33 for controls (mean); p less than 0.05), and postpartum maternal clinical status was improved by the use of ursodiol (Mazzella et al, 2001).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) CHENODIOL: It is not known whether chenodiol is excreted in human breast milk (Prod Info CHENODAL(TM) oral tablets, 2009).
    2) URSODIOL: It is not known whether ursodiol is excreted in human breast milk (Prod Info URSO 250(R) / URSO Forte(R) oral tablets, 2009). However, since small amounts of ursodiol appear in the serum after oral doses (Bachrach & Hofmann, 1982), only trace amounts, if any, would appear in breast milk.
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) URSODIOL
    a) RABBITS: No effect on fertility was noted after pregnant rabbits were given oral ursodiol in doses up to 7 times the maximum recommended human dose (based on body surface area) (Prod Info URSO 250(R) / URSO Forte(R) oral tablets, 2009).
    b) RATS: No effect on fertility and reproductive performance was noted after male and female rats were given oral ursodiol in doses up to 2700 mg/kg/day (16,200 mg/m(2)/day; 29 times the maximum recommended human dose based on body surface area) (Prod Info URSO 250(R) / URSO Forte(R) oral tablets, 2009).

Carcinogenicity

    3.21.3) HUMAN STUDIES
    A) ANIMAL STUDIES
    1) Animal studies have not demonstrated carcinogenic effects of chenodiol at 1 to 4 times the maximum recommended dose (MRD) in humans.
    B) HEPATIC CARCINOMA
    1) Doses 40 to 60 times the MRD have produced malignant liver cell tumors and cholangiomata (USPDI, 1991).
    C) CARCINOMA
    1) One study has reported the occurrence of adenocarcinoma of the gallbladder during long-term (5 years) chenodiol treatment for gallstone dissolution (Irving, 1981). However, this may have been an incidental finding during treatment.
    2) BILE ACIDS: Some epidemiologic reports indicate that bile acids may contribute to the occurrence of colon cancer; however, direct evidence is lacking (Prod Info, 1983).
    a) Quantitative and qualitative changes in fecal bile acids occur with chenodiol treatment; however, whether this promotes carcinogenesis is unknown (Zak et al, 1983).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor liver enzymes in symptomatic patients.
    B) Monitor serum electrolytes in patients with severe vomiting and/or diarrhea.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Serum/blood concentrations of chenodiol and ursodiol are considered to be minimal and not clinically relevant since therapy depends on biliary concentrations (Rosenbaum & Cluxton, 1988).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients should be admitted for severe vomiting, profuse diarrhea, severe abdominal pain, dehydration, and electrolyte abnormalities.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, and those who are more than mildly symptomatic, need to be monitored for several hours to assess electrolyte and fluid balance. Patients that remain asymptomatic can be discharged.

Monitoring

    A) Monitor liver enzymes in symptomatic patients.
    B) Monitor serum electrolytes in patients with severe vomiting and/or diarrhea.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital decontamination is generally NOT required.
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY: Severe toxicity is not expected after an overdose. Gastrointestinal decontamination is generally not necessary. Consider activated charcoal only if coingestants with significant toxicity are involved.
    B) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Monitor liver enzymes in symptomatic patients.
    2) Monitor serum electrolytes in patients with severe vomiting and/or diarrhea.
    B) DIARRHEA
    1) Diarrhea usually responds to a reduction in dosage. Diphenoxylate 7.5 mg/day was effective in controlling diarrhea in 4 patients (Corazzini et al, 1978).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Hemodialysis is not recommended given the low toxicity of these drugs.

Range Of Toxicity

Summary

    A) TOXICITY: CHENODIOL: Four grams daily (58 mg/kg/day) for 6 months was well tolerated without adverse sequelae in one patient. URSODIOL: A 39-day-old preterm infant received an inadvertent dosage of 360 mg/day (148 mg/kg/day) of ursodiol for 6 days, which was approximately 6 times the intended dose of 25 mg/kg/day and developed no adverse events.
    B) THERAPEUTIC DOSES: Initial, 250 mg orally twice daily for the first 2 weeks; increase the dose by 250 mg/day each week until a range of 13 to 16 mg/kg/day in 2 divided doses or until the maximum tolerated dose is reached. Doses varies by weight (body weight 100 to 275 pounds): 750 mg (17 to 13 mg/kg) to 1750 mg (18 to 14 mg/kg) orally once a day in 2 divided doses. URSODIOL: Chemodissolution of bile duct stone: 8 to 10 mg/kg/day orally divided into 2 to 3 doses. Prophylaxis of gallstone during rapid weight loss: 300 mg orally twice daily.

Therapeutic Dose

    7.2.1) ADULT
    A) CHENODIOL
    1) Initial, 250 mg orally twice daily for the first 2 weeks; increase the dose by 250 mg/day each week until a range of 13 to 16 mg/kg/day in 2 divided doses or until the maximum tolerated dose is reached (Prod Info CHENODAL(TM) oral tablets, 2009)
    2) Doses varies by weight (body weight 45 to 125 kg): 750 mg (17 to 13 mg/kg) to 1750 mg (18 to 14 mg/kg) orally once a day in 2 divided doses (Prod Info CHENODAL(TM) oral tablets, 2009).
    B) URSODIOL
    1) Chemodissolution of bile duct stone: 8 to 10 mg/kg/day orally divided into 2 to 3 doses (Prod Info ACTIGALL(R) oral capsule, 2007)
    2) Prophylaxis of gallstone during rapid weight loss: 300 mg orally twice daily (Prod Info ACTIGALL(R) oral capsule, 2007)

Minimum Lethal Exposure

    A) No fatal exposures from chenodiol or ursodiol have been reported.

Maximum Tolerated Exposure

    A) CHENODIOL: No reports of overdoses in humans have been reported to date. One patient tolerated 4 grams daily (58 mg/kg/day) for 6 months without adverse sequelae (Prod Info CHENODAL(TM) oral tablets, 2009).
    B) URSODIOL: A 39-day-old preterm infant received an inadvertent dosage of 360 mg/day (148 mg/kg/day) of ursodiol for 6 days, which was approximately 6 times the intended dose of 25 mg/kg/day due to a change in compounding and developed no adverse events (Goodwin et al, 2006).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) GENERAL
    a) Toxic serum/blood levels have not been established.

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (INTRAMUSCULAR)MOUSE:
    1) >1 gm/kg ((RTECS, 2000))
    B) LD50- (INTRAPERITONEAL)MOUSE:
    1) 86 mg/kg ((RTECS, 2000))
    C) LD50- (ORAL)MOUSE:
    1) >2 gm/kg ((RTECS, 2000))
    D) LD50- (INTRAMUSCULAR)RAT:
    1) >500 mg/kg ((RTECS, 2000))
    E) LD50- (INTRAPERITONEAL)RAT:
    1) 105 mg/kg ((RTECS, 2000))
    F) LD50- (ORAL)RAT:
    1) 4 gm/kg ((RTECS, 2000))

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Chenodeoxycholic acid reduces the ratio of cholesterol to bile salts plus phospholipids in bile and so causes desaturation of cholesterol-saturated bile associated with gallstones (Prod Info, 1983).

Toxicologic Mechanism

    A) There is compelling evidence to suggest that the cause of hepatotoxicity secondary to chenodiol is related to its conversion to lithocholic acid, which is formed from metabolism of chenodiol by intestinal bacteria via 7-alpha-dehydroxylation (Fedorowski et al, 1979; Fisher et al, 1982).
    B) Lithocholic acid is a known hepatotoxin in animals, such as the Rhesus monkey and rabbit (Fisher et al, 1982). Animals fed high doses of chenodiol have developed hepatic abnormalities similar to those induced by lithocholic acid (Dryszka et al, 1976; Fischer et al, 1974).
    C) LITHOCHOLIC ACID SULFATION
    1) It has been demonstrated that the livers in Rhesus monkey and rabbit do not sulfate lithocholic acid (Palmer & Carey, 1982; Fisher et al, 1982).
    2) Sulfation diminishes the toxicity of lithocholic acid, since lithocholic acid sulfate is not absorbed from the intestine but rather is excreted in the stool.
    3) Humans and other animals, such as the chimpanzee and guinea pig, have the necessary hepatic enzymes to sulfate lithocolic acid, subsequently maintaining low circulating levels of the acid and reducing the chances of hepatic damage (Fisher et al, 1982).
    D) There are data to indicate a wide variation among individuals with regard to the percentage of sulfated lithocholic acid in the bile.
    1) It is postulated that individuals who sulfate lithocholic acid less efficiently might be more prone to developing hepatic abnormalities during chenodiol treatment (Zak et al, 1983).
    E) LITHOCHOLIC ACID FORMATION
    1) Both chenodiol and ursodiol are hydroxylated to yield lithocholic acid; however, studies have indicated that the 7beta-hydroxy group of ursodiol is more resistant to dehydroxylation than the 7alpha-hydroxy group of chenodiol (Fedorowski et al, 1979).
    2) It is presumed that lithocholic acid is liberated much more slowly from ursodiol than chenodiol, resulting in less lithocholic acid in the bile of ursodiol treated patients and a much lower incidence of hypertransaminasemia (Fedorowski et al, 1979; Rosenbaum & Cluxton, 1988).

Physicochemical

Physical Characteristics

    A) A white powder consisting of crystalline and amorphous particles (USPDI, 1991; JEF Reynolds , 2000)

Molecular Weight

    A) 392.6 (JEF Reynolds , 2000)

References

General Bibliography

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    2) Bachrach WH & Hofmann AF: Ursodeoxycholic acid in the treatment of cholesterol cholelithiasis (Part I). Dig Dis Sci 1982a; 27:737-761.
    3) Bacq Y, Sentilhes L, Reyes HB, et al: Efficacy of ursodeoxycholic acid in treating intrahepatic cholestasis of pregnancy: a meta-analysis. Gastroenterology 2012; 143(6):1492-1501.
    4) Celle G, Cavanna M, & Bocchini R: Chenodeoxycholic acid (CDCA) versus ursodeoxycholic acid (UDCA): a comparison of their effects in pregnant rats. Arch Int Pharmacodyn 1980; 246:149-158.
    5) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    6) Cowen AE, Korman MG, & Hofmann AF: Metabolism of lithocholate in healthy man. Gastroenterology 1975; 69:59-66.
    7) Dowling RH: Chenodeoxycholic acid therapy of gallstones. Clin Gastroenterol 1977; 6:141-163.
    8) Dryszka H, Salen G, & Zaki FG: Hepatic toxicity in the rhesus monkey treated with chenodeoxycholic acid for six months. Biochemical and ultrastructural studies. Gastroenterology 1976; 70:93-104.
    9) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    10) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
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    12) Fischer DC, Cooper NS, & Rothschild MA: Effect of dietary chenodeoxycholic acid and lithocholic acid in the rabbit. Am J Dig Dis 1974; 19:877-886.
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    14) Gerolami A, Sarles H, & Brette R: Controlled trial of chenodeoxycholic therapy for radiolucent gallstones. A multicenter study. Digestion 1977; 16:299-307.
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    23) Iser JH, Dowling RH, Mok HYI, et al: Chenodeoxycholic acid treatment of gallstones. A follow-up report and analysis of factors influencing response to therapy. N Engl J Med 1975; 293:378-383.
    24) JEF Reynolds : Martindale: The Extra Pharmacopoeia (CD-ROM version). The Pharmaceutical Press. London, UK (Internet Version). Edition expires 2000; provided by Truven Health Analytics Inc., Greenwood Village, CO.
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    29) Mok HYI, Bell GD, & Dowling RH: Effect of different doses of chenodeoxycholic acid on bile lipid composition and on frequency of side effects in patients with gallstones. Lancet 1974; 2:253-257.
    30) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
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    34) Product Information: ACTIGALL(R) oral capsule, ursodiol oral capsule. Watson Pharmaceutical, Inc., Corona, CA, 2007.
    35) Product Information: ACTIGALL(R) oral capsules, ursodiol oral capsules. Watson Pharma, Inc. (per DailyMed), Corona, CA, 2009.
    36) Product Information: CHENODAL(TM) oral tablets, chenodiol oral tablets. Manchester Pharmaceuticals, Inc. (per manufacturer), Fort Collins, CO, 2009.
    37) Product Information: URSO 250(R) / URSO Forte(R) oral tablets, ursodiol oral tablets. Axcan Pharma US, Inc., Birmingham, AL, 2009.
    38) RTECS : Registry of Toxic Effects of Chemical Substances. National Institute for Occupational Safety and Health. Cincinnati, OH (Internet Version). Edition expires 2000; provided by Truven Health Analytics Inc., Greenwood Village, CO.
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