Ursodiol (Systemic)



INN:

Ursodeoxycholic acid {07}

BAN:
Ursodeoxycholic acid {07}


JAN:
Ursodesoxycholic acid {07}

VA CLASSIFICATION
Primary: GA900

Commonly used brand name(s): Actigall; Ursofalk.

Another commonly used name is UDCA.
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Anticholelithic—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Gallstone disease (treatment)—Orally administered ursodiol is indicated for dissolution of cholesterol gallstones {32} in selected patients with uncomplicated radiolucent gallstone disease. However, alternative therapies should be considered since gallstone dissolution with ursodiol may require many months of treatment, complete dissolution does not occur in all patients, and recurrence of stones occurs within 5 years in about 50% of patients who have had stones dissolved by use of bile acid therapy {01} {02} {04} {05} {06} {13} {18} {19} {52}.
—Ursodiol therapy is more likely to be effective if the stones are small (< 20 mm) and of the floatable type {01} {05} {06} {13}.
—Body weight and dietary factors may influence gallstone formation and/or dissolution rate {17}.

Gallstone formation (prophylaxis)1—Ursodiol is indicated for the prevention of gallstone formation in obese patients experiencing rapid weight loss {27} {28} {52} {53}.


[Atresia, biliary (treatment)]1
[Cholangitis, sclerosing (treatment)]1
[Cirrhosis, alcoholic (treatment)]1
[Cirrhosis, biliary (treatment)]1{54}
[Hepatic disease, cholestatic (treatment){54}]
[Hepatic disease, cystic fibrosis–associated (treatment)]1 and
[Hepatitis, chronic (treatment)]1—Ursodiol is used for the treatment of some chronic liver diseases, including primary biliary cirrhosis, primary sclerosing cholangitis, cystic fibrosis–associated liver disease, biliary atresia, chronic hepatitis, and alcoholic cirrhosis {20} {21} {22} {23} {24} {25} {26} {35} {36} {37} {38} {39} {40} {41} {42} {43} {44} {45} {46} {48} {52}.

[Transplant rejection, liver (prophylaxis)]1—Ursodiol is used as adjuvant therapy following orthotopic liver transplantation to prevent early graft rejection {20} {44} {45} {52}.

Unaccepted
Ursodiol is not indicated when there are calcified cholesterol stones, radiopaque stones (calcium-containing), or radiolucent bile pigment stones; when the gallbladder is not functioning {55}; or when surgery for gallstones is clearly indicated {01} {05} {53} {54} {55}.

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    392.58 {01} {05} {07}

Mechanism of action/Effect:

Anticholelithic—Although the exact mechanism of ursodiol's anticholelithic action is not completely understood, it is known that when administered orally ursodiol is concentrated in bile and decreases biliary cholesterol saturation by suppressing hepatic synthesis and secretion of cholesterol, and by inhibiting its intestinal absorption. The reduced cholesterol saturation permits the gradual solubilization of cholesterol from gallstones, resulting in their eventual dissolution. {01} {02} {04} {05} {06} {13} {20} {48} {52}


Other actions/effects:

Ursodiol increases bile flow {02}. In chronic cholestatic liver disease, ursodiol appears to reduce the detergent properties of the bile salts, thus reducing their cytotoxicity. Also, ursodiol may protect liver cells from the damaging activity of toxic bile acids (e.g., lithocholate, deoxycholate, and chenodeoxycholate), which increase in concentration in patients with chronic liver disease. {08} {16} {20} {30} {31} {48} {49} {50} {52}

Absorption:

Absorbed from the small bowel (about 90% of dose) {01} {04} {05} {20}.

Protein binding:

High {02}.

Biotransformation:

Hepatic (first-pass hepatic clearance). Exogenous ursodiol is metabolized in the liver to its taurine and glycine conjugates. The resulting conjugates are secreted into bile. {01} {02} {04} {20}

Time to peak concentration:

1 to 3 hours {20}.

Elimination:
    Primarily fecal; very small amounts are excreted into urine. Small amount of unabsorbed ursodiol passes into the colon where it undergoes bacterial degradation (7-dehydroxylation); the resulting lithocholic acid is partly absorbed from the colon but is sulfated in the liver and rapidly eliminated in the feces {02} {05} as the sulfolithocholyl glycine or sulfolithocholyl taurine conjugate. {01} {04} {20} {52}


Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to other bile acid products may be sensitive to ursodiol also {01} {13}.

Carcinogenicity/Tumorigenicity

Studies in rats with intrarectal instillation of lithocholic acid and other metabolites of ursodiol and chenodiol did not show evidence of tumorigenicity, except when these substances were administered in conjunction with a carcinogenic agent. Epidemiologic studies suggest that bile acids might be involved in the pathogenesis of human colon cancer in patients who have undergone a cholecystectomy; however, conclusive evidence is lacking. {01} {05}

Pregnancy/Reproduction

Pregnancy—
Adequate and well-controlled studies have not been done in humans {05}.

Studies in rats at doses 20 to 100 times the human dose, and in rabbits at doses 5 times the human dose, have not shown that ursodiol causes adverse effects in the fetus.

FDA Pregnancy Category B {05}.

Breast-feeding

It is not known whether ursodiol is distributed into breast milk {05} {13}. However, problems in humans have not been documented.

Pediatrics

Appropriate studies on the relationship of age to the effects of ursodiol when used as an anticholelithic have not been performed in the pediatric population. However, studies performed to date in children and infants with cholestatic liver disease and biliary atresia have not demonstrated pediatrics-specific problems that would limit the usefulness of ursodiol in children. {33} {34} {40}


Geriatrics


Appropriate studies on the relationship of age to the effects of ursodiol have not been performed in the geriatric population. However, geriatrics-specific problems that would limit the usefulness of this medication in the elderly are not expected. {13}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Antacids, aluminum-containing or
Cholestyramine or
Colestipol    (concurrent use may result in binding of ursodiol, thus decreasing its absorption {01} {02} {05} {13} {53})


Antihyperlipidemics, especially clofibrate {01} {02} {05} {13} {53} or
Estrogens {01} {02} {05} {13} {53} or
Neomycin {01} {02} {05} {13} or
Progestins {01} {02} {05} {13}    (concurrent use of these medications with ursodiol may decrease ursodiol's ability to dissolve cholesterol gallstones, since these medications tend to increase cholesterol saturation of bile {01} {02} {05} {13})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Transaminase (mainly serum alanine aminotransferase [ALT (SGPT)])     (although this effect has not been clearly demonstrated, serum concentrations of liver enzymes may be increased due to the inability of some patients to form sulfate conjugates of lithocholic acid; however, these concentrations may be decreased in patients with primary biliary cirrhosis, with other cholestatic conditions, and with chronic active hepatitis {01} {16} {47} {52})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
» Gallstone complications, such as:
Biliary gastrointestinal fistula {18}
Biliary obstruction {18}
Cholangitis {18}
Cholecystitis {18}
Pancreatitis {18}    (medical treatment with ursodiol would be too lengthy; surgery may be indicated {01} {05} {13} {18})


Hepatic function impairment, chronic    (bile acid metabolism may be further impaired {01}; however, in some studies ursodiol had a normalizing effect on previously abnormal liver test findings. Data suggest a possible therapeutic role for ursodiol in chronic cholestatic liver disease, in which cholestasis [impaired bile formation or flow] appears to play an important role {02} {03} {08} {10} {12} {14} {15} {16} {20} {47})


Sensitivity to ursodiol or to other bile acids {05} {13}

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Alanine aminotransferase (ALT [SGPT]) {54} and
Alkaline phosphatase {54} and
Aspartate aminotransferase (AST [SGOT]) {54} and
Bilirubin {54} and
Gamma-glutamyltransferase (GGT) {54}    (monitoring of serum values is recommended upon initiation of treatment, every 1 to 3 months for the first 3 months of treatment [depending on the indication for use], and then every 6 months during treatment; ursodiol must be discontinued if increased values persist {01} {05} {13} {18} {54})


Cholecystogram {54}    (recommended prior to treatment for gallstones to determine whether the gallbladder is functional, and whether gallstones are translucent or radiopaque {54})


Ultrasonograms    (recommended prior to treatment to confirm the presence of gallstones, and at 6-month intervals during the first year of treatment to monitor stone dissolution; also recommended after gallstone dissolution to monitor for possible recurrence {01} {02} {04} {05} {06} {13} {53} {54})




Side/Adverse Effects

Note: Hepatotoxicity has not been associated with ursodiol therapy. However, in some individuals with a congenital or acquired reduction in ability to sulfate hepatotoxic lithocholic acid, the theoretical risk of lithocholate-induced liver damage may be increased. {01} {05} {08} {11} {13} {16} {18} {19} {53} {56}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Back pain{53}
    
diarrhea{01}{04}{05}{06}{09}{53} —may be dose-related{09}

Incidence less frequent or rare
    
Alopecia{53} (hair loss)
    
constipation{53}
    
dizziness{53}
    
dyspepsia{53} (heartburn)
    
nausea{53}
    
psoriasis, exacerbation of pre-existing{09}{54}
    
vomiting{53}





Overdose
No cases of ursodiol overdose have been reported {53}.

For information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Ursodiol (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to ursodiol or to other bile acids
Other medical problems, especially gallstone complications

Proper use of this medication
Taking with meals for optimal therapeutic effect

» Compliance with full course of therapy

» Proper dosing
Missed dose: Taking as soon as possible or doubling the next dose {19} {20} {52}

» Proper storage

Precautions while using this medication
» Regular visits to physician to check progress; laboratory tests may be required during therapy

Avoiding aluminum-containing antacids; may interfere with absorption of ursodiol

» Notifying physician immediately if symptoms of acute cholecystitis develop


General Dosing Information
Ursodiol should be taken with meals or a snack since it dissolves more rapidly when bile and pancreatic juice are present in the intestinal chyme. {02} {52}

Gallstone dissolution may require 6 months to 2 years of continuous dosing depending on the size and composition of the stone(s). Response should be monitored by ultrasonograms performed at 6-month intervals during the first year of therapy. {01} {02} After complete dissolution, it is recommended that ursodiol be continued for at least 3 months to promote dissolution of particles that are too small to image {02} {05}.

Ursodiol therapy is unlikely to be effective if partial dissolution has not occurred after 6 {55} to 12 months of treatment {05} {13}.

Gallbladder nonvisualization that develops during therapy is an indication that complete stone dissolution will not occur and therapy should be discontinued {01}.


Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

URSODIOL CAPSULES USP

Usual adult and adolescent dose
Gallstone disease (treatment)
Oral, 8 to 10 mg per kg of body weight a day, divided into two or three doses {01} {02} {04} {05} {13}, usually taken with meals {01} {04} {13}.

Gallstone formation (prophylaxis)1
Oral, 300 mg two times a day {53}. Alternatively, some clinicians continue the dissolution dose of 8 to 10 mg per kg of body weight a day {55}. Bedtime dosing has been reported to enhance dissolution {55}.

[Hepatic disease, cholestatic (treatment)]
Oral, 13 to 15 mg per kg of body weight a day, given in two divided doses (morning and bedtime) with food {54}.


Usual pediatric dose
Anticholelithic
Dosage has not been established.


Note: In children with cholestatic liver disease and extrahepatic biliary atresia, total daily doses have ranged from 10 to 18 mg per kg of body weight {19} {20}.


Usual geriatric dose
See Usual adult and adolescent dose .

Strength(s) usually available
U.S.—


300 mg (Rx) [Actigall]

Canada—


250 mg (Rx) [Ursofalk]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a tight container, unless otherwise specified by manufacturer.

Auxiliary labeling:
   • Continue medication for full time of treatment.
   • Take with food.



Revised: 08/12/1997



References
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  1. Panel comment, 7/97.
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