Ursodiol

The recommended dose for dissolving gallstones in adults is 8-10 mg/kg/day split into two or three doses (every 8 or 12 hours). Each dose should not exceed 300 mg. The maintenance dose is 250 mg at bedtime for six months.

For treating primary biliary cirrhosis, the recommended dose is 13-15 mg/kg/day split into 2 to 4 doses. Ursodiol should be taken with meals.

Capsules: 300 mg. Tablets: 250 and 500 mg

Ursodiol should be stored at room temperature, 15 C - 30 C (59 F - 86 F).

URSO 250 (ursodiol, 250 mg) is available as a film-coated tablet for oral administration. URSO Forte (ursodiol, 500 mg) is available as a scored film-coated tablet for oral administration. Ursodiol (ursodeoxycholic acid, UDCA) is a naturally occurring bile acid found in small quantities in normal human bile and in larger quantities in the biles of certain species of bears. It is a bitter-tasting white powder consisting of crystalline particles freely soluble in ethanol and glacial acetic acid, slightly soluble in chloroform, sparingly soluble in ether, and practically insoluble in water. The chemical name of ursodiol is 3α,7ß-dihydroxy-5ß-cholan-24-oic (C24H40O4). Ursodiol has a molecular weight of 392.56. Its structure is shown below.

Inactive ingredients: microcrystalline cellulose, povidone, sodium starch glycolate, magnesium stearate, ethylcellulose, dibutyl sebacate, carnauba wax, hydroxypropyl methylcellulose, PEG 3350, PEG 8000, cetyl alcohol, sodium lauryl sulfate and hydrogen peroxide.

Common side effects include:

• diarrhea
• constipation
• upset stomach
• indigestion
• dizziness
• vomiting
• cough
• sore throat
• runny nose
• back pain
• muscle and joint pain
• hair loss

This is not a complete list of ursodiol side effects. Ask your doctor or pharmacist for more information.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X - are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

Ursodiol falls into category B. There are no well-done studies that have been done in humans with ursodiol. In animal studies, pregnant animals were given this medication and the babies did not show any medical issues related to this medication.

Tell your doctor if you are breastfeeding or plan to breastfeed.

It is not known if ursodiol crosses into human milk. Because many medications can cross into human milk, caution should be exercised when ursodiol is administered to a nursing mother.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Ask your doctor before using an antacid, and use only the type your doctor recommends. Some antacids can make it harder for your body to absorb ursodiol.

If you also take cholestyramine or colestipol, avoid taking ursodiol at the same time. Ask your doctor how many hours apart you should take your medicines.

Usual Adult Dose for Biliary Cirrhosis:

Tablets: 13 to 15 mg/kg/day orally in 2 to 4 divided doses with food

Comments:
-Dose should be adjusted according to patient's need at physician's discretion.

Approved indication: For treatment of patients with primary biliary cirrhosis

Usual Adult Dose for Gallbladder Disease:

Capsules:
Gallbladder stone dissolution: 8 to 10 mg/kg/day orally in 2 or 3 divided doses
Gallstone prevention: 300 mg orally twice a day

Comments:
-Ultrasound images of gallbladder recommended at 6-month intervals for first year of therapy to monitor gallstone response. If gallstones appear to have dissolved, therapy should be continued and dissolution confirmed on a repeat ultrasound examination within 1 to 3 months.
-Most patients who eventually achieve complete stone dissolution show partial or complete dissolution at the first on-treatment reevaluation.
-If partial stone dissolution is not seen by 12 months of therapy, likelihood of success is greatly reduced.
-Safety of use beyond 24 months is not established.

Approved indications:
-For dissolution of gallstones in patients with radiolucent, noncalcified gallbladder stones less than 20 mm in greatest diameter who are not candidates for cholecystectomy due to increased surgical risk (e.g., systemic disease, advanced age, idiosyncratic reaction to general anesthesia) or who refuse surgery
-For gallstone prevention in obese patients undergoing rapid weight loss

Usual Pediatric Dose for Gallbladder Disease:

(Not approved by FDA)

Some experts recommend:
Parenteral nutrition-induced cholestasis in neonates:
Treatment: 30 mg/kg/day orally in 3 divided doses; some centers divide in 2 daily doses

Prevention:
With initiation of parenteral nutrition: 5 mg/kg/day orally in 4 divided doses beginning on day of life 3
With initiation of enteral feeding: Increase dose to 10 mg/kg/day orally in 4 divided doses.
When full enteral feedings reached: Increase dose to 20 mg/kg/day orally in 4 divided doses.

Biliary atresia:
Infants: 10 to 15 mg/kg orally once a day

Treatment of TPN-induced cholestasis:
Infants and children: 30 mg/kg/day orally in 3 divided doses

Improvement in the hepatic metabolism of essential fatty acids in cystic fibrosis:
Children: 30 mg/kg/day orally in 2 divided doses

Other drugs may interact with ursodiol, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.

Absorption

Bioavailability

Tablets: Absorption from GI tract is incomplete, occurring mainly by passive diffusion.2

Capsules: About 90% of an oral dose absorbed in small intestine.1

Only small amounts of ursodiol appear in the systemic circulation.1

Distribution

Extent

Following absorption from the GI tract, ursodiol distributes to the portal vein and undergoes hepatic extraction (about 50% in the absence of liver disease; extent of extraction decreases as severity of liver disease increases) from portal blood by the liver (i.e., there is a large first-pass effect). 1 2 3

After drug is conjugated in liver, it is distributed into bile.1 2 (See Metabolism under Pharmacokinetics.)

Ursodiol in bile is concentrated in the gallbladder and distributed into the duodenum in gallbladder bile via the cystic and common ducts by gallbladder contractions stimulated by physiologic responses to eating.1

During chronic administration (13–15 mg/kg daily), ursodiol becomes a major biliary and plasma bile acid, comprising 30–50% of biliary and plasma bile acids.2 3 Following discontinuance of the drug, the concentration of ursodiol in bile falls exponentially.1

It is not known whether ursodiol is distributed into milk.1 2

Plasma Protein Binding

Healthy individuals: ≥70% (as unconjugated ursodiol).2

Healthy individuals or patients with primary biliary cirrhosis: extent of protein binding of conjugated ursodiol is not known.2

Special Populations

The extent of hepatic extraction of ursodiol from portal blood decreases with increasing severity of liver disease.2 3

Elimination

Metabolism

Ursodiol is conjugated with glycine or taurine in the liver and distributed into bile.1 2

Ursodiol conjugates are absorbed into small intestine by passive and active mechanisms.2 These conjugates may be deconjugated in the ileum by intestinal enzymes (or by bacteria in the small intestine), creating free ursodiol that can be reabsorbed and reconjugated in the liver.1 2 3

Unabsorbed ursodiol reaches the colon unchanged, where it is primarily 7-dehydroxylated to form lithocholic acid.2 Some ursodiol may be epimerized to form chenodiol, which also undergoes 7-dehydroxylation to form lithocholic acid.2 A small portion of lithocholic acid is reabsorbed and conjugated in the liver with glycine or taurine, and sulfated at the 3 position.2

Ursodiol also can be oxidized at the 7-carbon, producing 7-keto-lithocholic acid.1 Absorbed 7-keto-lithocholic acid is stereospecifically reduced in the liver to chenodiol.1

A small portion of orally administered ursodiol undergoes bacterial degradation with each cycle of enterohepatic circulation.1 3

Elimination Route

Ursodiol is excreted principally in the feces.2 3 Urinary excretion increases with treatment but remains below 1% except in patients with severe cholestatic liver disease.2

Lithocholic acid formed in the small intestine is primarily (80%) excreted in the feces; the 20% that is absorbed is sulfated at the 3-hydroxyl group in the liver to relatively insoluble lithocholyl conjugates, which are then excreted into bile and eliminated in the feces.1 2

Half-life

About 4–6 days.3

Special Populations

In patients with severe cholestatic liver disease, urinary excretion may increase to over 1% with chronic treatment.2

Ursodiol, 250 mg is available as a film-coated tablet for oral administration. Ursodiol, 500 mg is available as a scored film-coated tablet for oral administration. Ursodiol (ursodeoxycholic acid, UDCA) is a naturally occurring bile acid found in small quantities in normal human bile and in larger quantities in the biles of certain species of bears. It is a bitter-tasting white powder consisting of crystalline particles freely soluble in ethanol and glacial acetic acid, slightly soluble in chloroform, sparingly soluble in ether, and practically insoluble in water. The chemical name of Ursodiol is 3α,7β-dihydroxy-5β-cholan-24-oic (C24H40O4). Ursodiol has a molecular weight of 392.56. Its structure is shown below.

Inactive ingredients: microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide, povidone, magnesium stearate, lactose monohydrate, hypromellose, titanium dioxide, and macrogol/polyethylene glycol.

Carcinogenicity, Mutagenicity and Impairment of Fertility

In two 24-month oral carcinogenicity studies in mice, Ursodiol at doses up to 1,000 mg/kg/day (3,000 mg/m2/day) was not tumorigenic. Based on body surface area, for a 50 kg person of average height (1.46 m2 body surface area), this dose represents 5.4 times the recommended maximum clinical dose of 15 mg/kg/day (555 mg/m2/day).

In a two-year oral carcinogenicity study in Fischer 344 rats, Ursodiol at doses up to 300 mg/kg/day (1,800 mg/m2/day, 3.2 times the recommended maximum human dose based on body surface area) was not tumorigenic.

In a life-span (126-138 weeks) oral carcinogenicity study, Sprague-Dawley rats were treated with doses of 33 to 300 mg/kg/day, 0.4 to 3.2 times the recommended maximum human dose based on body surface area. Ursodiol produced a significantly (p<0.5, Fisher's exact test) increased incidence of pheochromocytomas of the adrenal medulla in females of the highest dose group.

In 103-week oral carcinogenicity studies of lithocholic acid, a metabolite of Ursodiol, doses up to 250 mg/kg/day in mice and 500 mg/kg/day in rats did not produce any tumors. In a 78-week rat study, intrarectal instillation of lithocholic acid (1 mg/kg/day) for 13 months did not produce colorectal tumors. A tumor-promoting effect was observed when it was administered after a single intrarectal dose of a known carcinogen N-methyl-N'-nitro-N-nitrosoguanidine. On the other hand, in a 32-week rat study, Ursodiol at a daily dose of 240 mg/kg (1,440 mg/m2, 2.6 times the maximum recommended human dose based on body surface area) suppressed the colonic carcinogenic effect of another known carcinogen azoxymethane.

Ursodiol was not genotoxic in the Ames test, the mouse lymphoma cell (L5178Y, TK+/-) forward mutation test, the human lymphocyte sister chromatid exchange test, the mouse spermatogonia chromosome aberration test, the Chinese hamster micronucleus test and the Chinese hamster bone marrow cell chromosome aberration test.

Ursodiol at oral doses of up to 2,700 mg/kg/day (16,200 mg/m2/day, 29 times the recommended maximum human dose based on body surface area) was found to have no effect on fertility and reproductive performance of male and female rats.

Ursodiol Tablets USP, 250 mg

Each 250 mg tablet - white, film coated, oval shaped beveled edged, biconvex tablet debossed with "2368" on one side, contains 250 mg of Ursodiol. Available in bottles of 100 tablets (NDC 0115-1524-01).

Ursodiol Tablets USP, 500 mg

Each 500 mg tablet - white, film coated, oval shaped beveled edged, biconvex tablet debossed with "2369" on one side and scored on the other side, contains 500 mg of Ursodiol. Available in bottles of 100 tablets (NDC 0115-1525-01).

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Dispense in a tight container.

Half-tablets (scored Ursodiol 500 mg tablets broken in half) maintain acceptable quality for up to 28 days when stored in the current packaging (bottles) at 20° to 25°C (68° to 77°F). Due to the bitter taste, the halved segments should be stored separately from the whole tablets [see Dosage and Administration (2.2)].

• Gallstone Dissolution Agent

Concerns related to adverse effects:

• Biliary obstruction: Maintain bile flow during therapy to prevent biliary obstruction.

Disease-related concerns:

• Hepatic effects: Use with caution in patients with chronic liver disease; monitor liver function tests monthly for the first 3 months, and every 6 months thereafter or as clinically necessary. Discontinuation of therapy may be necessary with significant elevations in liver function tests.

Other warnings/precautions:

• Appropriate use: Gallbladder stone dissolution may take several months of therapy; complete dissolution may not occur and recurrence of stones within 5 years has been observed in up to 50% of patients. Patients should be cautiously selected for therapy, consider alternative treatments. Specific treatments should be initiated in patients with ascites, hepatic encephalopathy, variceal bleeding, or if an urgent liver transplant is necessary.

• Nonvisualizing gallbladder: Use with caution in patients with a nonvisualizing gallbladder; therapy should be discontinued if gallbladder nonvisualization occurs during treatment.

Gallstone disease: ALT, AST, sonogram

Hepatic disease: Monitor liver function tests (GGT, AST, ALT, bilirubin, and alkaline phosphatase) monthly for the first 3 months and every 6 months thereafter or as clinically necessary.