Urso - Drug Monograph

Introduction

Ursodiol (Urso), also known as ursodeoxycholic acid, is a naturally occurring bile acid used therapeutically for various hepatobiliary disorders. It represents a significant advancement in the management of cholestatic liver diseases, offering both symptomatic relief and potential disease-modifying effects.

Mechanism of Action

Ursodiol exerts multiple pharmacological effects:

• Hydrophobicity reduction: Replaces endogenous, more hydrophobic bile acids that contribute to hepatotoxicity
• Choleretic action: Stimulates bile flow and bicarbonate-rich biliary secretion
• Cytoprotective effects: Stabilizes hepatocyte membranes against bile acid-induced injury
• Immunomodulatory properties: Reduces expression of HLA class I antigens on hepatocytes
• Antiapoptotic effects: Inhibits mitochondrial membrane permeability transition

Indications

• Primary biliary cholangitis (PBC)
• Gallstone dissolution in selected patients with radiolucent, non-calcified gallstones <20 mm in diameter
• Prevention of gallstone formation in obese patients undergoing rapid weight loss

• Primary sclerosing cholangitis
• Intrahepatic cholestasis of pregnancy
• Chronic hepatitis C with cholestasis
• Cystic fibrosis-related liver disease
• Drug-induced hepatotoxicity

Dosage and Administration

• Initial: 13-15 mg/kg/day divided BID-TID
• Maintenance: May increase to 20-30 mg/kg/day based on response

• 8-10 mg/kg/day divided BID-TID
• Therapy duration: Typically 6-24 months

• Oral administration with food to enhance absorption
• Tablets should be swallowed whole, not crushed or chewed
• Dosage adjustment required in hepatic impairment

• Renal impairment: No dosage adjustment typically needed
• Elderly: Use with caution; consider reduced dosing
• Pediatric: Safety and efficacy not established

Pharmacokinetics

• Approximately 90% absorbed from small intestine
• Tmax: 30-150 minutes
• Food enhances bioavailability

• Volume of distribution: Limited to extracellular space
• Protein binding: High (96-98%) primarily to albumin

• Extensive hepatic metabolism via conjugation and 7-dehydroxylation
• Enterohepatic recirculation: Significant (60-80%)

• Primarily fecal excretion (as metabolites)
• Half-life: 3.5-5.8 days
• Clearance: Hepatic and biliary

Contraindications

• Hypersensitivity to ursodiol or bile acids
• Acute cholecystitis, cholangitis
• Biliary obstruction (non-functioning gallbladder)
• Radio-opaque calcified gallstones
• Chronic liver disease with hepatic decompensation
• Inflammatory bowel disease affecting small intestine

Warnings and Precautions

• Monitor for paradoxical worsening of PBC (occurs in 5-10% of patients)
• Discontinue if liver enzymes significantly increase
• Use caution in patients with advanced cirrhosis

• Regular ultrasound monitoring required during dissolution therapy
• High failure rate in obese patients and those with large stones

• Category B: Generally considered safe but requires careful risk-benefit assessment
• Effective for intrahepatic cholestasis of pregnancy

• May cause dose-related diarrhea
• Use caution in patients with peptic ulcer disease

Drug Interactions

• Decreased ursodiol absorption (separate administration by 2 hours)

• Cholestyramine, colestipol: Reduced efficacy (avoid concurrent use)

• Possible reduced cyclosporine absorption

• May counteract ursodiol's effects on bile cholesterol saturation

• May increase cholesterol saturation of bile

• Reduced ursodiol absorption

Adverse Effects

• Diarrhea (10-20%)
• Constipation (5-10%)
• Nausea/vomiting (5-8%)
• Dyspepsia (5-7%)
• Abdominal pain (5-6%)

• Headache
• Fatigue
• Rash
• Pruritus
• Back pain

• Hepatic dysfunction (paradoxical worsening)
• Gallstone complications (impaction, pancreatitis)
• Severe allergic reactions
• Stevens-Johnson syndrome (rare)

Monitoring Parameters

• Complete liver function tests (ALT, AST, ALP, GGT, bilirubin)
• Abdominal ultrasound
• Lipid profile
• Complete blood count

• Liver enzymes monthly for first 3 months, then every 3-6 months
• Bilirubin levels regularly
• Ultrasound every 6 months during gallstone therapy
• Symptom assessment for pruritus and fatigue

• Annual liver function tests in stable PBC patients
• Bone density assessment in chronic cholestasis
• Vitamin levels (A, D, E, K) in advanced disease

Patient Education

• Take with meals to improve absorption
• Do not crush or chew tablets
• Maintain consistent dosing schedule

• Maintain low-fat diet if prescribed for gallstone disease
• Report any worsening itching, yellowing of skin/eyes, or dark urine
• Inform all healthcare providers about ursodiol use

• Expect possible mild diarrhea initially (usually resolves)
• Report severe or persistent gastrointestinal symptoms
• Seek immediate care for signs of allergic reaction

• Understand that PBC treatment is typically lifelong
• Gallstone therapy requires regular monitoring and may take months to years
• Do not discontinue without medical advice

• Women of childbearing age should discuss pregnancy planning
• Elderly patients should report any falls or dizziness

References

1. Lindor KD, Bowlus CL, Boyer J, et al. Primary Biliary Cholangitis: 2018 Practice Guidance from the American Association for the Study of Liver Diseases. Hepatology. 2019;69(1):394-419.

2. European Association for the Study of the Liver. EASL Clinical Practice Guidelines: The diagnosis and management of patients with primary biliary cholangitis. J Hepatol. 2017;67(1):145-172.

3. Paumgartner G, Pauletzki J, Sackmann M. Ursodeoxycholic acid treatment of cholesterol gallstone disease. Scand J Gastroenterol Suppl. 1994;204:27-31.

4. 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(22):1548-1554.

5. FDA Prescribing Information: Urso (ursodiol). Revised 2021.

6. Hofmann AF. Pharmacology of ursodeoxycholic acid, an enterohepatic drug. Scand J Gastroenterol Suppl. 1994;204:1-15.

7. Beuers U, Trauner M, Jansen P, et al. New paradigms in the treatment of hepatic cholestasis: From UDCA to FXR, PXR and beyond. J Hepatol. 2015;62(1 Suppl):S25-S37.