When to choose rifaximin (Xifaxan) versus lactulose for hepatic encephalopathy?

Treatment Selection for Hepatic Encephalopathy: Lactulose vs. Rifaximin

Lactulose should be used as first-line therapy for initial episodes of overt hepatic encephalopathy (OHE), while rifaximin should be added to lactulose for prevention of recurrence after a second episode of OHE. 1

Initial Treatment Algorithm

First Episode of OHE

• Lactulose is the first choice for treatment of episodic OHE (Grade II-1, B, 1) 1
• Initial dosing: 25 mL lactulose syrup every 1-2 hours until at least two soft bowel movements per day are produced 1
• Maintenance dosing: Titrate to maintain 2-3 bowel movements daily 1
• Lactulose works by acidifying the gastrointestinal tract, which inhibits ammonia production by coliform bacteria 2

After First Recurrence

• Continue lactulose for prevention of recurrent episodes of HE (Grade II-1, A, 1) 1
• Lactulose alone has been shown to reduce recurrence of HE in patients with cirrhosis 1

After Second Recurrence

• Add rifaximin to lactulose therapy (Grade I, A, 1) 1
• Rifaximin dosing: 550 mg tablet taken orally twice daily 3
• Rifaximin plus lactulose is superior to lactulose alone for preventing OHE recurrence 1
• In clinical trials, 91% of patients were using lactulose concomitantly with rifaximin 3

Evidence Supporting This Approach

Efficacy of Lactulose as First-Line Therapy

• Lactulose is FDA-approved for the prevention and treatment of portal-systemic encephalopathy 4
• Lactulose therapy reduces blood ammonia levels by 25-50%, which generally correlates with improvement in mental status 4
• Clinical response has been observed in approximately 75% of patients 4
• Despite limited placebo-controlled trials, lactulose is widely recommended and practiced as first-line therapy 1

Benefits of Adding Rifaximin After Recurrence

• Rifaximin is FDA-approved for reduction in risk of OHE recurrence in adults 3
• Rifaximin added to lactulose is the best-documented agent to maintain remission in patients who have experienced one or more bouts of OHE while on lactulose 1
• The combination of rifaximin plus lactulose significantly reduces the risk of OHE recurrence and HE-related hospitalization compared to lactulose alone 5
• A randomized controlled trial showed that patients receiving rifaximin plus lactulose had:
  • Higher rates of complete reversal of HE (76% vs 50.8%, p<0.004) 6
  • Lower mortality (23.8% vs 49.1%, p<0.05) 6
  • Shorter hospital stays (5.8 vs 8.2 days, p=0.001) 6

Special Considerations

Dosing Considerations

• Avoid overuse of lactulose as it can lead to complications including aspiration, dehydration, hypernatremia, severe perianal skin irritation, and can even precipitate HE 1
• Rifaximin can be taken with or without food 3

Post-TIPS Hepatic Encephalopathy

• Routine prophylactic therapy (lactulose or rifaximin) is not recommended for prevention of post-TIPS HE (Grade III, B, 1) 1
• If HE occurs after TIPS, standard treatment approaches should be used 1

Alternative Agents for Non-Responders

• For patients not responsive to conventional therapy, consider:
  • Oral branched-chain amino acids (BCAAs) (Grade I, B, 2) 1
  • IV L-ornithine L-aspartate (LOLA) (Grade I, B, 2) 1
  • Neomycin (Grade II-1, B, 2) - limited by long-term toxicity 1
  • Metronidazole (Grade II-3, B, 2) - limited by long-term toxicity 1

Common Pitfalls to Avoid

• Using rifaximin alone without lactulose - no solid data support this approach 1
• Failing to identify and treat precipitating factors for HE (Grade II-2, A, 1) 1
• Excessive lactulose dosing leading to complications 1
• Not considering rifaximin add-on therapy after multiple recurrences despite lactulose treatment 1, 5
• Long-term use of neomycin or metronidazole due to ototoxicity, nephrotoxicity, and neurotoxicity 1