What are the alternatives to Ursodeoxycholic acid (UDCA) for patients who do not respond or tolerate it?

Alternatives to UDCA for Primary Biliary Cholangitis

For patients with PBC who do not respond to or cannot tolerate UDCA, obeticholic acid (OCA) is the FDA-approved second-line therapy, starting at 5 mg daily with titration to 10 mg based on tolerability and biochemical response. 1

First-Line Approach: Obeticholic Acid (OCA)

OCA is the only FDA-approved alternative for UDCA non-responders or intolerant patients. 1

Dosing Strategy

• Start at 5 mg orally once daily for 3 months (not 10 mg, due to increased pruritus risk) 1
• Titrate to 10 mg once daily if tolerated and inadequate biochemical response after 3 months 1
• Can be used as monotherapy in UDCA-intolerant patients or combination therapy with UDCA in non-responders 1

Efficacy Data

• In the pivotal trial, 47% of patients on OCA 10 mg achieved the composite endpoint (ALP <1.67× ULN, total bilirubin ≤ULN, and ≥15% ALP reduction) versus 10% on placebo 1
• Among patients who started at 5 mg and titrated to 10 mg, 39% achieved the primary endpoint 1

Critical Contraindications

• Absolutely contraindicated in decompensated cirrhosis (Child-Pugh B or C) due to risk of hepatic decompensation and failure 1
• Avoid in patients with MELD score ≥15 1

Common Adverse Effects

• Pruritus occurs in 56-70% of patients (higher with 10 mg starting dose) 1
• Dose-dependent HDL-C reduction (19% reduction at 12 months with 10 mg dose) 1
• Manage pruritus with bile acid binding resins, antihistamines, dose reduction, or temporary interruption 1

Second-Line Approach: Fibrates (Off-Label)

For patients who cannot access or tolerate OCA, fibrates combined with UDCA show significant biochemical improvement and may reduce progression to cirrhosis. 2

Bezafibrate

• All 12 patients with pruritus achieved complete or partial resolution in one study 2
• 20-24 UDCA non-responders achieved >40% ALP reduction within 6-12 months 2
• Typical dosing not specified in guidelines but used in clinical practice 2

Fenofibrate

• 69% pooled complete biochemical response rate in systematic review 2
• Improved transplant-free survival in retrospective study of 120 UDCA non-responders (P<0.001) 2
• Associated with lower risk of cirrhosis development (0% vs 44.1% in UDCA alone, HR=0.12, P=0.04) 3
• No hepatic deterioration in fibrate-treated group versus 23.9% in UDCA-alone group (HR=0.12, P=0.04) 3

Important Caveats About Fibrates

• Biochemical improvements have not been shown to sufficiently alter long-term mortality when stratified by UK-PBC risk score 2
• Possible negative impact on renal function requires monitoring 2
• Some patients experienced rising bilirubin values despite ALP improvement 2
• Not FDA-approved for PBC; used off-label based on observational data 2

Third-Line Options for Specific Scenarios

For UDCA-Intolerant Patients

1. OCA monotherapy (5 mg daily, titrate to 10 mg) 1
2. Consider clinical trial enrollment for novel therapies 2

For Persistent Pruritus Despite Treatment

Stepwise management algorithm: 2

1. First-line: Cholestyramine 4-16 g/day

   • Must be given 2-4 hours before/after UDCA 2
   • Main side effect: constipation 2

2. Second-line: Rifampicin 300-600 mg/day

   • Start at 150 mg once-twice daily, titrate based on LFTs 2
   • Risk of hepatotoxicity requires regular monitoring 2
   • Check LFTs in 2-4 weeks; use caution in advanced liver disease 2

3. Third-line options (based on clinician experience):

   • Naltrexone 50 mg/day (start at 12.5 mg, titrate slowly to avoid withdrawal symptoms) 2
   • Gabapentin (dose titrate to effect) 2
   • Sertraline 100 mg/day 2

For PBC-AIH Overlap Syndrome

Combined UDCA and immunosuppression is mandatory. 2

• Start UDCA plus corticosteroids (prednisone 0.5 mg/kg/day, tapered based on ALT response) 2
• Alternative: Start UDCA alone, add corticosteroids if inadequate response at 3 months 2
• Azathioprine for long-term steroid-sparing maintenance 2
• Fibrosis progression occurred more frequently with UDCA monotherapy (4/8 patients) versus combination therapy (0/6 patients, p=0.04) 2

Clinical Trial Consideration

Patients meeting any of these criteria should be offered clinical trial enrollment: 2

• UDCA non-responders (inadequate response after 1 year at 13-15 mg/kg/day) 2
• UDCA-intolerant patients 2
• Resistant pruritus despite first and second-line therapy 2
• Severe fatigue (after excluding confounding causes) 2

Monitoring Strategy

• Assess biochemical response at 3-6 months after initiating alternative therapy 1
• For OCA non-responders at 1 year on maximum tolerated dose with HDL-C reduction, weigh risks versus benefits of continuing 1
• Regular LFT monitoring essential, especially with rifampicin or OCA 2, 1
• Renal function monitoring when using fibrates 2