Label: CHENODAL- chenodiol tablet, film coated


Drug Label Information

Updated January 7, 2010

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    NDC 45043-876-40

    Chenodal 250 mg

    (Chenodiol Tablets)

    100 Tablets

    Manchester Pharmaceuticals, Inc.

    Each Film-Coated Tablet Contains: Chenodiol 250 mg


    Usual Adult Dosage: Please see package insert for detailed prescribing information.


    Store and Dispense: Store at 200 to 250C (680 to 770F). [see USP Controlled Room Temperature].  Dispense in a tight container as defined in the USP.




    Manufactured for: Manchester Pharmaceuticals, Inc.

                                        Fort Collins, CO 80525


    Bar code

    45043 87640

    Lot No.:

    Exp. Date:


    Because of the potential hepatoxicity of Chenodal, poor response rate in
    some subgroups of Chenodal treated patients, and an increased rate of a need
    for cholecystectomy in other Chenodal treated subgroups, Chenodal is not an
    appropriate treatment for many patients with gallstones. Chenodal 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.

    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 (C24H40O4), it has a molecular weight of
    392.58, and its structure is shown below;

    chenodiol structural formula

    Chenodiol film-coated tablets for oral administration contain 250 mg of

    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


    At therapeutic doses, chenodiol suppresses hepatic synthesis of
    both cholesterol and cholic acid, gradually replacing the latter and its
    metabolite, deoxycholic acid in an expanded bile acid pool. These actions
    contribute to biliary cholesterol desaturation and gradual dissolution of
    radiolucent cholesterol gallstones in the presence of a gall-bladder visualized
    by oral cholecystography. Chenodiol has no effect on radiopaque (calcified)
    gallstones or on radiolucent bile pigment stones.

    Chenodiol is well absorbed from the small intestine and taken up by the liver
    where it is converted to its taurine and glycine conjugates and secreted in
    bile. Owing to 60 % to 80% first-pass hepatic clearance, the body pool of
    chenodiol resides mainly in the enterohepatic circulation; serum and urinary
    bile acid levels are not significantly affected during chenodiol therapy.

    At steady-state, an amount of chenodiol near the daily dose escapes to the
    colon and is converted by bacterial action to lithocholic acid. About 80% of the
    lithocholate is excreted in the feces; the remainder is absorbed and converted
    in the liver to its poorly absorbed sulfolithocholyl conjugates. During
    chenodiol therapy there is only a minor increase in biliary lithocholate, while
    fecal bile acids are increased three- to fourfold.

    Chenodiol is unequivocally hepatotoxic in many animal species, including
    sub-human primates at doses close to the human dose. Although the theoretical
    cause is the metabolite, lithocholic acid, an established hepatotoxin, and man
    has an efficient mechanism for sulfating and eliminating this substance, there
    is some evidence that the demonstrated hepatotoxicity is partly due to chenodiol
    per se. The hepatotoxicity of
    lithocholic acid is characterized biochemically and morphologically as

    Man has the capacity to form sulfate conjugates of lithocholic acid.
    Variation in this capacity among individuals has not been well established and a
    recent published report suggests that patients who develop chenodiol-induced
    serum aminotransferase elevations are poor sulfators of lithocholic acid (see   ADVERSE

    General Clinical Results

     Both the desaturation of bile and the clinical dissolution of cholesterol gallstones are dose-related. In
    the National Cooperative Gallstone Study (NCGS) involving 305 patients in each
    treatment group, placebo and chenodiol dosages of 375 mg and 750 mg per day were
    associated with complete stone dissolution in 0.8%, 5.2% and 13.5%,
    respectively, of enrolled subjects over 24 months of treatment. Uncontrolled
    clinical trials using higher doses than those used in the NCGS have shown
    complete dissolution rates of 28 to 38% of enrolled patients receiving body
    weight doses of from 13 to 16 mg/kg/day for up to 24 months. In a prospective
    trial using 15 mg/kg/day, 31% enrolled surgical-risk patients treated more than
    six months (n = 86) achieved complete confirmed dissolutions.

    Observed stone dissolution rates achieved with chenodiol treatment are higher
    in subgroups having certain pretreatment characteristics. In the NCGS, patients
    with small {less than 15 mm in diameter} radiolucent stones, the observed rate
    of complete dissolution was approximately 20% on 750 mg/day. In the uncontrolled
    trails using 13 to 16 mg/kg/day doses of chenodiol, the rates of complete
    dissolution for small radiolucent stones ranged from 42% to 60%. Even higher
    dissolution rates have been observed in patients with small floatable stones.
    (See Floatable versus Nonfloatable Stones, below). Some
    obese patients and occasional normal weight patients fail to achieve bile
    desaturation even with doses of chenodiol up to 19 mg/kg/day for unknown
    reasons. Although dissolution is generally higher with increased dosage of
    chenodiol, doses that are too low are associated with increased cholecystectomy
    rates (see    ADVERSE REACTIONS).

    Stones have recurred within five years in about 50% of patients following
    complete confirmed dissolutions. Although retreatment with chenodiol has proven
    successful in dissolving some newly formed stones, the indications for and
    safety of retreatment are not well defined. Serum aminotransferase elevations
    and diarrhea have been notable in all clinical trials and are dose-related
    (refer to    ADVERSE REACTIONS and WARNINGSsections
    for full information).

    Floatable versus Nonfloatable Stones

    A major finding in clinical trials was a difference between floatable and nonfloatable stones,
    with respect to both natural history and response to chenodiol. Over the
    two-year course of the National Cooperative Gallstone Study (NCGS), placebo –
    treated patients with floatable stones (n = 47) had significantly higher rates
    of biliary pain and cholecystectomy than patients with nonfloatable stones (n =
    258) (47% versus 27% and 19%versus 4%, respectively). Chenodiol treatment (750
    mg/day) compared to placebo was associated with a significant reduction in both
    biliary pain and the cholecystectomy rates in the group with floatable stones
    (27% versus 47% and 1.5% versus 19%, respectively). In an uncontrolled clinical
    trial using 15 mg/kg/day, 70% of the patients with small (less than 15 mm)
    floatable stones (n = 10) had complete confirmed dissolution.

    In the NCGS in patients with nonfloatable stones, chenodiol produced no
    reduction in biliary pain and showed a tendency to increase the cholecystectomy
    rate (8% versus 4%). This finding was more pronounced with doses of chenodiol
    below 10 mg/kg. The subgroup of patients with nonfloatable stones and a history
    of biliary pain had the highest rates of cholecystectomy and aminotransferase
    elevations during chenodiol treatment. Except for the NCGS subgroup with
    pretreatment biliary pain, dose-related aminotransferase elevations and diarrhea
    have occurred with equal frequency in patients with floatable or nonfloatable
    stones. In the uncontrolled clinical trial mentioned above, 27% of the patients
    with nonfloatable stones (n = 59) had complete confirmed dissolutions, including
    35% with small (less than 15 mm)(n= 40) and only 11% with large, nonfloatable
    stones (n= 19).

    Of 916 patients enrolled NCGS, 17.6% had stones seen in upright form
    (horizontal X-ray beam) to float in the dye-laden bile during oral
    cholecystography using iopanoic acid. Other investigators report similar
    findings. Floatable stones are not detected by ultrasonography in the absence
    for dye. Chemical analysis has shown floatable stones to be essentially pure

    Other Radiographic and Laboratory Features

    Radiolucent stones may have rims or centers of opacity representing
    calcification. Pigment stones and partially calcified radiolucent stones do not
    respond to chenodiol. Subtle calcification can sometimes be detected in flat
    film X-rays, if not obvious in the oral cholecystogram. Among nonfloatable
    stones, cholesterol stones are more apt than pigment stones to be smooth
    surfaced, less than 0.5 cm in diameter, and to occur in numbers less than 10. As
    stone size number and volume increase, the probability of dissolution within 24
    months decreases. Hemolytic disorders, chronic alcoholism, biliary cirrhosis and
    bacterial invasion of the biliary system predispose to pigment gallstone
    formation. Pigment stones of primary biliary cirrhosis should be suspected in
    patients with elevated alkaline phosphates, especially if positive
    anti-mitochondrial antibodies are present. The presence of microscopic
    cholesterol crystals in aspirated gallbladder bile, and demonstration of
    cholesterol super saturation by bile lipid analysis increase the likelihood that
    the stones are cholesterol stones.


  • Evaluation of Surgical Risk

    Surgery offers the advantage of immediate and permanent stone removal, but carries a fairly high risk. In some patients, about 5% of cholecystectomized patients have residual symptoms or retained common duct stones. The spectrum to surgical risk varies as a function of age and the presence of disease other than cholelithiasis. Selected tabulation of results from the National Halothane Study (JAMA, 1968, 197:775-778) is shown below: the study included 27,600 cholecystectomies.

    Mortality per Operation Table

    Women in good health, or having only moderate systemic disease, under 49 years of age have the lowest rate (0.054%); men in all categories have a surgical mortality rate twice that of women; common duct exploration quadruples the rates in all categories; the rates rise with each decade of life and increase tenfold or more in all categories with severe or extreme systemic disease.
    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. The long-term consequences of repeated courses of chenodiol in terms of liver toxicity, neoplasia and elevated cholesterol levels are not known. Watchful waiting has the advantage that no therapy may ever be required. For patients with silent or minimally symptomatic stones, the rate of moderate to severe symptoms or gallstone complications is estimated to be between 2% and 6% per year, leading to a cumulative rate of 7% and 27% in five years. Presumably the rate is higher for patients already having symptoms.

    Chenodal (chenodiol tablets) 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.


    Chenodal (chenodiol tablets) 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

    Pregnancy Category X

    Chenodal (chenodiol tablets) 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. Chenodal (chenodiol tablets) 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.

    Safe use of chenodiol depends upon selection of patients without
    pre-existing liver disease and upon faithful monitoring of serum
    aminotransferase levels to detect drug-induced liver toxicity. Aminotransferase
    elevations over three times the upper limit of normal have required
    discontinuation of chenodiol in 2% to 3% of patients. Although clinical and
    biopsy studies have not shown fulminant lesions, the possibility remains that an
    occasional patient may develop serious hepatic disease. Three patients with
    biochemical and histologic pictures of chronic active hepatitis while on
    chenodiol, 375 mg/day or 750 mg/day, have been reported. The biochemical
    abnormalities returned spontaneously to normal in two of the patients within 13
    and 17 months; and after 17 months’ treatment with prednisone in the third.
    Follow-up biopsies were not done; and the causal relationship of the drug could
    not be determined. Another biopsied patient was terminated from therapy because
    of elevated aminotransferase levels and a liver biopsy was interpreted as
    showing active drug hepatitis.

    One patient with sclerosing cholangitis, biliary cirrhosis and history of
    jaundice died during chenodiol treatment for hepatic duct stones. Before
    treatment, serum aminotransferase and alkaline phosphate levels were over twice
    the upper limit of normal; within one month they rose to over 10 time normal.
    Chenodiol was discontinued at seven weeks, when the patient was hospitalized
    with advanced hepatic failure and E. coli peritonitis; death ensued at the eight
    week. A contribution of chenodiol to the fatal outcome could not be ruled

    Epidemiologic studies suggest that bile acids might contribute to human colon
    cancer, but direct evidence is lacking. Bile acids, including chenodiol and
    lithocholic acid, have no carcinogenic potential in animal models, but have been
    shown to increase the number of tumors when administered with certain know
    carcinogens. The possibility that chenodiol therapy might contribute to colon
    cancer in otherwise susceptible individuals cannot be ruled out.

    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

    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 Chenodal (chenodiol tablets) should be

    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 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
    Chenodal (chenodiol tablets) is administered to a nursing mother.

    Pediatric use

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



    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


    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 Chenodal (chenodiol tablets) 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


    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.


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

    The recommended dose range for Chenodal (chenodiol tablets) 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.

    Weight-Dosage Guide

    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 Chenodal (chenodiol tablets) 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 Chenodal (chenodiol tablets) and usually reoccur on challenge.

    Serum cholesterol should be monitored at six months intervals. It may be advisable to discontinue Chenodal (chenodiol tablets) 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 Chenodal (chenodiol tablets) 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; Chenodal (chenodiol tablets) 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 Chenodal (chenodiol tablets). 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.

    Chenodal™ 250 mg (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 45043-876-40.
    Store at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature].
    Dispense in a tight container.
    Manufactured for:
    Manchester Pharmaceuticals, Inc.™
    Fort Collins, CO 80525
    866-758-7068 7121
    Rev. 9/09
    chenodiol tablet, film coated
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:45043-876(NDC:0722-7121)
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    Chenodiol (UNII: 0GEI24LG0J) (Chenodiol - UNII:0GEI24LG0J) Chenodiol250 mg
    Product Characteristics
    Colorwhite (White to Off-White) Scoreno score
    FlavorImprint Code MP;250
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC:45043-876-40100 in 1 BOTTLE, PLASTIC
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    Labeler - Manchester Pharmaceuticals Inc. (832417641)
    Registrant - Manchester Pharmaceuticals Inc. (832417641)
    NameAddressID/FEIBusiness Operations
    Manchester Pharmaceuticals Inc.832417641relabel