Ursodiol

Pronunciation

Class: Cholelitholytic Agents
VA Class: GA900
Chemical Name: 3α,7β-dihydroxy-5β-cholan-24-oic acid
Molecular Formula: C24H40O4
CAS Number: 128-13-2
Brands: Actigall, Urso 250, Urso Forte

Introduction

Ursodiol, a naturally occurring bile acid, is used for its cholelitholytic or anticholestatic action.1 3 4 6 18

Uses for Ursodiol

Gallstone Dissolution (Ursodiol Capsules)

Dissolution of gallstones in patients with radiolucent, noncalcified gallbladder stones <20 mm in greatest diameter who are not candidates for cholecystectomy because of systemic disease, advanced age, idiosyncratic reaction to general anesthesia, or refusal of surgery;1 4 5 6 considered pharmacologic treatment of choice in these patients.3 6

Dissolution of gallstones usually requires several months of ursodiol therapy.1 3 Complete dissolution of gallstones does not occur in all patients, and recurrence, which may occur within 5 years, is reported in up to 50% of patients who have achieved dissolution of the stones with the drug.1 3 Monitor for recurrence of stones.1 (See Adequate Patient Monitoring under Cautions.)

Successful dissolution of gallstones with ursodiol occurs rarely in patients with calcified gallstones prior to treatment, those who develop stone calcification or gallbladder nonvisualization during treatment, and those with gallstones >20 mm in greatest diameter.1

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Successful dissolution is more likely in patients with floating or floatable stones (i.e., those with high cholesterol content) and dissolution is inversely related to stone size for stones <20 mm in greatest diameter.1 3 4 5

Gallbladder nonvisualization prior to treatment is not a contraindication to ursodiol therapy; however, discontinue treatment in patients who develop gallbladder nonvisualization during therapy since this is predictive of failure for complete dissolution.1

Prevention of Gallstones (Ursodiol Capsules)

Prevention of gallstone formation in obese patients undergoing rapid weight loss.1 7 8

Reduces incidence of gallstone formation in obese patients experiencing rapid weight loss secondary to a very low calorie diet or following gastric bypass surgery.1 7 8

Primary Biliary Cirrhosis (Ursodiol Tablets)

Treatment of primary biliary cirrhosis.2 9 10 11 12

Although optimal treatment for primary biliary cirrhosis remains to be established,9 many clinicians consider ursodiol the preferred initial treatment.9 10

Substantial improvement in total bilirubin, AST, ALT, alkaline phosphatase, IgM concentrations, and histologic signs of disease has been reported.2 9 10 11 12 14 17

In controlled studies, improved biochemical markers (e.g., reduction in serum bilirubin) often not accompanied by symptomatic improvement or prevention of complications of liver disease (e.g., ascites, GI bleeding).11 14 In addition, the impact of favorable changes in bilirubin concentrations on survival and need for liver transplantation has not been elucidated.11 12 14

Reduces the incidence of and delays time to treatment failure (defined as death; need for liver transplantation; histologic progression by 2 stages or to cirrhosis; development of varices, ascites, or encephalopathy; marked worsening of fatigue or pruritus; inability to tolerate the drug; a doubling of or an increase to 1.5 mg/dL or higher of serum bilirubin concentrations; voluntary withdrawal from study or discontinuance of study for any reason).2 9 10 11 12 14

May delay progression of hepatic fibrosis in patients with early-stage disease;9 13 17 however, in majority of studies no improvement in fibrosis reported.10 14

May delay development of esophageal varices9 15 and may improve pruritus.14 15

Ursodiol Dosage and Administration

General

  • Carefully select patients for ursodiol therapy; consider alternative therapies (e.g., watchful waiting, cholecystectomy).1 3

Administration

Oral Administration

Capsules: Administer orally.1

Tablets: Administer orally with food.2

Dosage

Adults

Gallstone Dissolution (Ursodiol Capsules)
Oral

8–10 mg/kg per day in 2–3 divided doses.1

Safety of use beyond 24 months of therapy has not been established.1

Prevention of Gallstones (Ursodiol Capsules)
Oral

300 mg twice daily.1

Primary Biliary Cirrhosis (Ursodiol Tablets)

Adjust dosage regimen according to patient’s response and tolerance.2

Oral

Tablets: 13–15 mg/kg daily in 2–4 divided doses.2

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time.1 2

Renal Impairment

No specific dosage recommendations at this time.1 2

Geriatric Patients

Select dosage with caution.1

Cautions for Ursodiol

Contraindications

  • Hypersensitivity or intolerance to ursodiol, bile acids, or any component of the formulation.1 2

  • Do not use for dissolution of calcified cholesterol stones, radiopaque stones, or radiolucent bile pigment stones.1

  • Do not use in patients with compelling reasons for cholecystectomy, including unremitting cholecystitis, cholangitis, biliary obstruction, gallstone pancreatitis, or biliary-gastrointestinal fistula.1

Warnings/Precautions

General Precautions

Hepatic Effects

Institute appropriate specific treatment in patients with primary biliary cirrhosis who have variceal bleeding, hepatic encephalopathy, ascites, or require an urgent liver transplant.2

Lithocholic acid, a known hepatotoxin, is formed in the GI tract from ursodiol (to a lesser extent than with chenodiol).1 2 3 Humans are able to sulfate (and thus detoxify) lithocholic acid efficiently;1 2 3 however, it is possible that a rare congenital or acquired deficiency in sulfation could lead to a risk for lithocholate-induced hepatic damage.1 2

Ursodiol has not been associated with liver damage;1 2 3 however, measure AST and ALT at initiation of and during therapy as indicated by particular clinical circumstances.1

Adequate Patient Monitoring

Perform ultrasound images of gallbladder at 6-month intervals for first year of therapy to monitor gallstone response.1

Most patients who eventually achieve complete stone dissolution will show partial or complete dissolution at first on-treatment evaluation.1

If partial stone dissolution is not seen by 12 months of therapy, likelihood of success is greatly reduced.1

Continue ursodiol therapy in patients experiencing stone dissolution; reconfirm dissolution by repeat ultrasound within 1–3 months.1

Obtain serial ultrasonographic examinations to monitor for recurrence of stones since stone recurrence has been observed in up to 50% of patients within 5 years of complete stone dissolution on ursodiol therapy.1

Establish radiolucency of stones before starting another course of ursodiol.1

In patients receiving ursodiol tablets for the treatment of primary biliary cirrhosis, monitor liver function tests (γ-glutamyltransferase [GGT, γ-glutamyltranspeptidase, GGTP], AST, ALT) and bilirubin concentrations every month for the first 3 months of therapy and then every 6 months.18 Rapid decreases in these parameters demonstrate efficacy of treatment.18 Discontinue ursodiol therapy in patients who experience increases in these parameters.18

Specific Populations

Pregnancy

Category B.1 2

Lactation

Not known whether ursodiol is distributed into human milk.1 2 Use caution.1 2

Pediatric Use

Safety and efficacy not established.1 2

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity and small differences in efficacy cannot be ruled out.1

Common Adverse Effects

Capsules (gallstone dissolution): Abdominal pain,1 diarrhea,1 4 5 6 viral infection,1 headache,1 dyspepsia,1 upper respiratory tract infection,1 nausea,1 sinusitis,1 constipation,1 vomiting,1 pharyngitis,1 arthralgia,1 flatulence,1 back pain,1 cough,1 bronchitis,1 urinary tract infection,1 arthritis,1 myalgia,1 allergy,1 cholecystitis,1 rhinitis,1 fatigue.

Capsules (prevention of gallstone formation): Constipation,1 7 diarrhea,1 7 headache,1 7 nausea,1 dizziness,1 vomiting,1 upper respiratory tract infection,1 7 back pain,1 viral infection,1 fatigue,1 influenza-like symptoms,1 abdominal pain,1 musculoskeletal pain,1 dysmenorrhea,1 alopecia,1 sinusitis,1 flatulence.1

Tablets (primary biliary cirrhosis): Asthenia,2 dyspepsia,2 peripheral edema,2 hypertension,2 nausea,2 GI disorders,2 chest pain,2 pruritus.2 10

Interactions for Ursodiol

Specific Drugs

Drug

Interaction

Comments

Antacids (aluminum-containing)

Decreased absorption of ursodiol 1 2

Bile acid sequestrants (cholestyramine, colestipol)

Decreased absorption of ursodiol1 2

Administer bile acid sequestrants at least 2 hours before or after ursodiol12 16

Clofibrate

Possible reduced efficacy of ursodiol because of increased hepatic cholesterol secretion caused by clofibrate (and possibly other antilipemic drugs)1 2

Estrogens

Possible reduced efficacy of ursodiol because of increased hepatic cholesterol secretion caused by estrogens1 2

Hormonal contraceptives, oral

Possible reduced efficacy of ursodiol because of increased hepatic cholesterol secretion caused by oral contraceptives1 2

Ursodiol Pharmacokinetics

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

Stability

Storage

Oral

Capsules

Tight containers at 25°C (may be exposed to 15–30°C).1

Tablets

Tight containers at 20–25°C.2

Actions

  • Ursodiol, the 7β-hydroxyepimer of chenodeoxycholic acid (chenodiol),3 15 is a naturally occurring, hydrophilic bile acid found in small quantities in normal human bile (normally about 5% of total bile acids) and in the bile of certain animals.1 2 15

  • The exact mechanism of action(s) of ursodiol in the dissolution of gallstones has not been fully elucidated, but it has been suggested that the drug suppresses hepatic synthesis and secretion of cholesterol and inhibits intestinal absorption of cholesterol.1 7

  • Despite aqueous insolubility of cholesterol, in the presence of dihydroxy bile acids cholesterol can be solubilized in aqueous media through the dispersion of cholesterol as liquid crystals or in micelles.1 3

  • Increases the concentration at which saturation of cholesterol occurs.1 7

  • Ursodiol may affect the nucleation of cholesterol from bile by altering nucleation factors.7

  • Appears to have small inhibitory effect on synthesis and secretion of endogenous bile acids into bile; does not appear to affect secretion of phospholipids into bile.1

  • Sites of therapeutic action include the liver, bile, and gut lumen.1

  • In patients with gallstones, combined actions of ursodiol change the bile from cholesterol-precipitating to cholesterol-solubilizing, which results in dissolution of cholesterol stones.1

  • Has hepatoprotective effects, which are thought to be principally related to displacement of more hydrophobic and toxic bile acids (e.g., lithocholic acid) that accumulate in the setting of cholestasis.15

  • Reduction in serum bilirubin in patients with primary biliary cirrhosis may be related to improved biliary transport.15

  • Immunomodulatory effects, including reduction in expression of class I antigens on hepatocytes, also may play a role in beneficial effects in patients with primary biliary cirrhosis.15

Advice to Patients

  • Importance of instructing patients to take ursodiol tablets with food.2

  • Importance of instructing patients not to chew ursodiol tablets or segments of ursodiol 500 mg tablets (Urso Forte).2 Importance of instructing patients not to take tablet segments if they are broken incorrectly (i.e., not evenly in half).2 Importance of advising patients to store tablet segments separately from whole tablets due to bitter taste.2

  • Importance of informing clinicians of existing or contemplated therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1 2

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 2

  • Importance of informing patients of other important precautionary information.1 2 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Ursodiol

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

300 mg*

Actigall Capsules

Watson

Tablets, film-coated

250 mg

Urso 250 (with povidone)

Axcan Pharma US

500 mg

Urso Forte (with povidone; scored)

Axcan Pharma US

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Actigall 300MG Capsules (WATSON LABS): 30/$198.98 or 90/$551.00

Urso 250 250MG Tablets (AXCAN PHARMA US): 30/$106.46 or 90/$297.01

Urso Forte 500MG Tablets (AXCAN PHARMA US): 30/$185.99 or 90/$526.00

Ursodiol 250MG Tablets (TEVA PHARMACEUTICALS USA): 100/$214.00 or 300/$541.98

Ursodiol 300MG Capsules (TEVA PHARMACEUTICALS USA): 30/$71.99 or 90/$201.98

Ursodiol 500MG Tablets (TEVA PHARMACEUTICALS USA): 100/$404.99 or 300/$1,114.01

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions August 1, 2008. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Watson. Ursodiol capsules prescribing information. Corona, CA; 2007 Jul.

2. Axcan Pharma US. Urso 250/Urso Forte (ursodiol tablets) prescribing information. Birmingham, AL; 2008 Mar 10.

3. Ward A, Brogden RN, Heel RC et al. Ursodeoxycholic acid: a review of its pharmacological properties and therapeutic efficacy. Drugs. 1984; 27:95-131. [PubMed 6365507]

4. Tokyo Cooperative Gallstone Study Group. Efficacy and indications of ursodeoxycholic acid treatment for dissolving gallstones: a multicenter double-blind trial. Gastroenterology. 1980; 78:542-8. [PubMed 6985882]

5. Erlinger S, Le Go A, Husson JM et al. Franco-Belgian cooperative study of ursodeoxycholic acid in the medical dissolution of gallstones: a double-blind, randomized, dose-response study, and comparison with chenodeoxycholic acid. Hepatology. 1984; 4:308-14. [PubMed 6706305]

6. Roda E, Bazzoli F, Morselli Labate AM et al. Ursodeoxycholic acid vs. chenodeoxycholic acid as cholesterol gallstone-dissolving agents: a comparative randomized study. Hepatology. 1982; 2:804-10. [PubMed 7141392]

7. Shiffman ML, Kaplan GD, Brinkman-Kaplan V et al. Prophylaxis against gallstone formation with ursodeoxycholic acid in patients participating in a very-low-calorie diet program. Ann Intern Med. 1995; 122:899-905. [PubMed 7755224]

8. Sugerman HJ, Brewer WH, Shiffman ML et al. A multicenter, placebo-controlled, randomized, double-blind, prospective trial of prophylactic ursodiol for the prevention of gallstone formation following gastric-bypass-induced rapid weight loss. Am J Surg. 1995; 169:91-7. [PubMed 7818005]

9. Kaplan MM, Gershwin ME. Primary biliary cirrhosis. N Engl J Med. 2005; 353:1261-73. [PubMed 16177252]

10. Poupon RE, Balkau B, Eschwège E et al. A multicenter, controlled trial of ursodiol for the treatment of primary biliary cirrhosis. N Engl J Med. 1991; 324:1548-54. [PubMed 1674105]

11. Heathcote EJ, Cauch-Dudek K, Walker V et al. The Canadian multicenter double-blind randomized controlled trial of ursodeoxycholic acid in primary biliary cirrhosis. Hepatology. 1994; 19:1149-56. [PubMed 8175136]

12. Lindor KD, Dickson ER, Baldus WP et al. Ursodeoxycholic acid in the treatment of primary biliary cirrhosis. Gastroenterology. 1994; 106:1284-90. [PubMed 8174890]

13. Poupon RE, Lindor KD, Parés A et al. Combined analysis of the effect of treatment with ursodeoxycholic acid on histologic progression in primary biliary cirrhosis. J Hepatol. 2003; 39:12-6. [PubMed 12821038]

14. Goulis J, Leandro G, Burroughs AK. Randomised controlled trials of ursodeoxycholic-acid therapy for primary biliary cirrhosis: a meta-analysis. Lancet. 1999; 354:1053-60. [PubMed 10509495]

15. Kowdley KV. Ursodeoxycholic acid therapy in hepatobiliary disease. Am J Med. 2000; 108:481-6. [PubMed 10781781]

16. Poupon RE, Lindor KD, Cauch-Dudek K et al. Combined analysis of randomized controlled trials of ursodeoxycholic acid in primary biliary cirrhosis. Gastroenterology. 1997; 113:884-90. [PubMed 9287980]

17. Corpechot C, Carrat F, Bonnand AM et al. The effect of ursodeoxycholic acid therapy on liver fibrosis progression in primary biliary cirrhosis. Hepatology. 2000; 32:1196-9. [PubMed 11093724]

18. Axcan Pharma US, Birmingham, AL: Personal communication.

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