Ursodiol - Drug Monograph

Introduction

Ursodiol (ursodeoxycholic acid) is a naturally occurring bile acid that has been developed as a pharmaceutical agent for the treatment of various hepatobiliary disorders. It is a hydrophilic bile acid that differs from the more hydrophobic endogenous bile acids, which contributes to its therapeutic effects and favorable safety profile.

Mechanism of Action

Ursodiol exerts multiple pharmacological effects:

• Hepato-protective action: Replaces toxic hydrophobic bile acids (chenodeoxycholic acid, deoxycholic acid) with non-toxic hydrophilic bile acids
• Choleretic effect: Stimulates bile flow and bicarbonate-rich biliary secretion
• Immunomodulatory effects: Reduces expression of HLA antigens on hepatocytes and modulates cytokine production
• Cytoprotective action: Stabilizes hepatocyte membranes against bile acid-induced damage
• Cholesterol dissolution: Reduces cholesterol saturation of bile by decreasing cholesterol secretion and dissolving cholesterol stones

Indications

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

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

Dosage and Administration

• 13-15 mg/kg/day administered in 2-4 divided doses
• Typical dose: 300 mg twice daily or 200 mg three times daily

• 8-10 mg/kg/day administered in 2-3 divided doses
• Therapy typically continues for up to 24 months

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

• Renal impairment: No specific dosage adjustment recommended
• Hepatic impairment: Use with caution; monitor closely
• Elderly: No specific dosage adjustment recommended
• Pediatric: Safety and effectiveness not established

Pharmacokinetics

• Incomplete absorption (variable, approximately 30-60%)
• Food enhances bioavailability
• Peak plasma concentrations reached within 30-150 minutes

• Highly protein-bound (96-98%)
• Volume of distribution: approximately 0.24 L/kg
• Crosses placenta and enters breast milk

• Undergoes extensive enterohepatic recirculation
• Metabolized in liver by conjugation with glycine or taurine
• Undergoes 7α-dehydroxylation by gut bacteria to lithocholic acid

• Primarily fecal elimination (≥90%)
• Renal elimination minimal (<1%)
• Half-life: 3.5-5.8 days

Contraindications

• Hypersensitivity to ursodiol or any component of the formulation
• Patients with calcified cholesterol stones, radiopaque stones, or radiolucent bile pigment stones
• Acute cholecystitis, cholangitis, biliary obstruction, or biliary-gastrointestinal fistula
• Patients requiring urgent surgical intervention

Warnings and Precautions

• Use with caution in patients with severe hepatic dysfunction
• Monitor liver function tests regularly

• Regular ultrasound monitoring required to assess stone dissolution
• Discontinue if partial dissolution not observed after 12 months

• May experience worsening pruritus initially
• Monitor for treatment response and disease progression

• Category B: No evidence of risk in humans
• Used off-label for intrahepatic cholestasis of pregnancy

Drug Interactions

• May decrease ursodiol absorption
• Separate administration by at least 2 hours

• Reduce ursodiol absorption and efficacy
• Administer ursodiol at least 1 hour before or 4-6 hours after

• May decrease cyclosporine absorption
• Monitor cyclosporine levels closely

• May counteract ursodiol's effect on cholesterol saturation

• May increase cholesterol saturation of bile

Adverse Effects

• Diarrhea (5-9%)
• Constipation (2-5%)
• Nausea (1-3%)
• Vomiting (1-2%)
• Dyspepsia (1-2%)
• Headache (1-2%)
• Back pain (1-2%)

• Pruritus (may worsen initially in PBC patients)
• Rash
• Dizziness
• Fatigue
• Metallic taste

• Hepatotoxicity (rare)
• Gallstone calcification
• Recurrent cholelithiasis

Monitoring Parameters

• Complete medical history and physical examination
• Liver function tests (ALT, AST, ALP, GGT, bilirubin)
• Abdominal ultrasound for gallstone patients
• Lipid profile

• Liver function tests every 3-6 months for PBC patients
• Abdominal ultrasound every 6 months for gallstone dissolution
• Symptom assessment for pruritus, gastrointestinal effects
• Assessment of treatment response in PBC (bilirubin normalization)

• Continued liver function monitoring
• Assessment for disease progression in PBC
• Monitoring for gallstone recurrence

Patient Education

• Take with food to improve absorption
• Swallow tablets whole; do not crush or chew
• If taking bile acid binders, separate administration by several hours

• Emphasize importance of consistent dosing
• Do not discontinue without consulting healthcare provider

• Keep all scheduled follow-up appointments
• Report any persistent gastrointestinal symptoms
• Report worsening itching or yellowing of skin/eyes

• Maintain healthy diet and weight
• Regular physical activity as tolerated
• Avoid alcohol consumption

• Discuss with healthcare provider before conception
• Medication is generally considered safe during pregnancy and breastfeeding

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. Poupon R. Ursodeoxycholic acid and bile acid mimetics as therapeutic agents for cholestatic liver diseases. Pharmacol Ther. 2012;136(1):35-44. 3. European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Management of cholestatic liver diseases. J Hepatol. 2009;51(2):237-267. 4. FDA Prescribing Information: Ursodiol Tablets. Revised 2021. 5. Broomé U, Olsson R, Lööf L, et al. Natural history and prognostic factors in 305 Swedish patients with primary sclerosing cholangitis. Gut. 1996;38(4):610-615. 6. 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. 7. Hofmann AF. Pharmacology of ursodeoxycholic acid, an enterohepatic drug. Scand J Gastroenterol Suppl. 1994;204:1-15.