What are the side effects of ursodeoxycholic acid?

Side Effects of Ursodeoxycholic Acid

Ursodeoxycholic acid is generally well tolerated with minimal adverse effects, most commonly causing mild gastrointestinal symptoms such as diarrhea (25-27%), nausea (14-17%), and abdominal pain (43-44%), with serious adverse events being rare when used at recommended doses of 13-15 mg/kg/day. 1, 2

Common Gastrointestinal Side Effects

The most frequently reported adverse effects involve the digestive system and are typically mild 1:

• Diarrhea occurs in 25-27% of patients 1
• Abdominal pain affects 43-44% of patients 1
• Nausea develops in 14-17% of patients 1
• Dyspepsia occurs in 11-17% of patients 1
• Flatulence affects approximately 7-8% of patients 1
• Constipation occurs in 9-26% of patients depending on indication 1
• Vomiting affects 9-14% of patients 1

These gastrointestinal symptoms rarely require discontinuation of therapy 2.

Neurological and General Symptoms

Non-specific systemic symptoms occur with moderate frequency 1:

• Headache affects 18-25% of patients 1
• Dizziness occurs in 13-17% of patients 1
• Fatigue develops in 5-10% of patients 1

Musculoskeletal Effects

Joint and muscle symptoms are reported but their causal relationship to ursodeoxycholic acid is uncertain 1:

• Arthralgia occurs in 8-15% of patients 1
• Back pain affects 7-12% of patients 1
• Myalgia occurs in approximately 6% of patients 1

Dermatological Reactions

• Alopecia occurs in approximately 5% of patients 1
• Rare skin reactions have been attributed to drug adjuvants rather than ursodeoxycholic acid itself 2

Serious and Rare Adverse Events

Dose-Dependent Toxicity

High-dose ursodeoxycholic acid (>20 mg/kg/day) is associated with significantly worse outcomes and should be strictly avoided 3, 4, 5:

• In primary sclerosing cholangitis, doses of 28 mg/kg/day resulted in more than double the number of deaths and liver transplantations compared to controls, necessitating trial termination 6
• The therapeutic window is narrow, with recommended doses of 13-15 mg/kg/day and toxic effects emerging at 28 mg/kg/day 6

Hepatic Complications (Rare)

• Decompensation of liver cirrhosis has been reported in isolated cases of end-stage primary biliary cirrhosis 2
• Hepatocellular carcinoma incidence increases in primary biliary cirrhosis patients who fail to achieve biochemical response (9% at 10 years, 20% at 15 years) 6
• Vanishing bile duct syndrome and liver cell failure have been reported rarely 6

Other Serious Adverse Events (Rare)

Uncommon but serious adverse effects include 6:

• Severe watery diarrhea (distinct from common mild diarrhea)
• Cholangitis and ascites
• Pneumonia
• Immune suppression
• Withdrawal syndrome upon abrupt discontinuation

Postmarketing Reports

• Enteroliths (bezoars) have been identified in postmarketing surveillance 1

Drug Interactions Affecting Safety

Several medications can interfere with ursodeoxycholic acid absorption or metabolism 1, 2:

• Bile acid sequestrants (cholestyramine, colestipol, colestimide) reduce ursodeoxycholic acid absorption 1, 2
• Aluminum-based antacids and smectite impair absorption 1, 2
• Estrogens, oral contraceptives, and clofibrate may counteract effectiveness by promoting cholesterol gallstone formation 1
• Cytochrome P450 3A substrates (ciclosporin, nitrendipine, dapsone) may have altered metabolism 2

Special Populations

Pregnancy and Lactation

• Ursodeoxycholic acid is considered safe during pregnancy and breastfeeding 4
• Four inadvertent first-trimester exposures showed no evidence of fetal harm 1
• However, formal recommendation is to avoid use during pregnancy due to insufficient controlled studies 1

Elderly Patients

• No significant age-related differences in safety or effectiveness have been identified 1
• Dosing should proceed with caution in elderly patients due to potential for greater sensitivity 1

Pediatric Patients

• Safety and effectiveness have not been established in pediatric populations 1

Important Clinical Caveats

Monitoring requirements 1:

• Liver enzymes (AST/ALT) should be measured at therapy initiation and periodically thereafter, though ursodeoxycholic acid typically decreases rather than increases liver enzymes 1
• Regular monitoring of liver biochemistry is essential to assess treatment response 4

Contraindications to consider 6:

• Patients with congenital or acquired sulfation deficiency may be predisposed to lithocholic acid-induced liver damage, as ursodeoxycholic acid is metabolized to lithocholic acid 1, 6

Discontinuation rates 7, 2:

• No patients discontinued therapy due to side effects or toxicity in controlled trials using recommended doses 7
• Treatment is well tolerated for extended periods (up to 12 years documented) 8