When are rifaximin and lactulose used in the treatment of hepatic encephalopathy?

Treatment of Hepatic Encephalopathy with Lactulose and Rifaximin

Lactulose is the first-line treatment for all forms of hepatic encephalopathy (both overt and covert), while rifaximin is added as adjunctive therapy when lactulose alone fails to prevent recurrence or is used in combination for prevention of recurrent episodes. 1, 2

Acute Overt Hepatic Encephalopathy

For acute episodes of overt hepatic encephalopathy, initiate lactulose immediately as monotherapy after addressing precipitating factors. 1

Lactulose Dosing for Acute Episodes

• Start lactulose 25-45 mL (20-30 g) orally every 1-2 hours until the patient produces at least 2 soft or loose bowel movements per day 1, 2
• Once bowel movements are established, titrate to maintenance dosing of 25 mL every 12 hours to maintain 2-3 soft stools daily 1
• For patients unable to take oral medications (severe encephalopathy, aspiration risk), use lactulose enemas: 300 mL lactulose mixed with 700 mL water 2

Rifaximin in Acute Episodes

Rifaximin should NOT be used as monotherapy for acute overt hepatic encephalopathy. 1, 2 While rifaximin shows beneficial effects on HE resolution and mortality, analysis of potential biases in supporting trials indicates it cannot be recommended alone for acute treatment 1. The FDA label for rifaximin (XIFAXAN) indicates it is approved for reduction in risk of recurrence, not acute treatment 3.

Prevention of Recurrent Hepatic Encephalopathy

For patients with at least two prior episodes of resolved overt hepatic encephalopathy, use lactulose as first-line prevention, and add rifaximin 550 mg twice daily if lactulose alone fails to prevent recurrence. 1, 2

Evidence for Combination Therapy

• Rifaximin 550 mg twice daily added to lactulose reduces recurrence risk by 58% compared to placebo (hazard ratio 0.42) 4, 2
• In the pivotal trial, 91% of patients were using lactulose concomitantly with rifaximin 1, 3
• Combination therapy reduces HE-related hospitalizations by 50% (hazard ratio 0.50) compared to lactulose alone 4, 2
• Long-term continuation of rifaximin for over 24 months maintains prevention of recurrence with good safety profile 1, 5

When to Add Rifaximin

Add rifaximin 550 mg twice daily when: 1, 2

• Patient experiences breakthrough episodes despite adequate lactulose therapy (2-3 soft stools daily)
• Patient has had ≥2 prior episodes of overt HE within 6 months
• Lactulose alone fails to maintain remission

Rifaximin as Monotherapy

Rifaximin monotherapy (550 mg twice daily) may only be considered when lactulose is poorly tolerated, though this recommendation is based on expert opinion rather than robust clinical evidence 1, 2. No solid data support the use of rifaximin alone 1.

Covert (Minimal) Hepatic Encephalopathy

For covert hepatic encephalopathy, either lactulose or rifaximin can be used to improve quality of life and reduce progression to overt HE. 1

• Both lactulose and rifaximin improve neuropsychiatric performance and cognitive functions in covert HE 1
• Treatment reduces the risk of progression from covert to overt HE 1
• Meta-analysis shows lactulose reduces incidence of overt HE from 28% to 7% (p<0.01) in patients with covert HE 1

Critical Dosing Details

Lactulose Maintenance Dosing

• Target: 2-3 soft bowel movements per day 1, 2
• Typical maintenance: 25 mL (15-30 g) twice daily, adjusted as needed 1
• Avoid excessive dosing: Overuse leads to dehydration, hypernatremia, aspiration risk, and can paradoxically precipitate HE 1

Rifaximin Dosing

• Standard dose: 550 mg orally twice daily for prevention of recurrence 1, 2, 3
• Alternative dosing of 400 mg three times daily has been used in some settings 2
• Maximum dose: 1,200 mg/day 2
• Can be taken with or without food 3

Important Clinical Pitfalls

Do not use rifaximin monotherapy for acute overt HE episodes - this is the most common error, as lactulose remains the cornerstone of acute treatment 1, 2

Do not overdose lactulose - the misconception that larger doses work better when smaller doses fail is dangerous and can cause dehydration, electrolyte abnormalities, and worsen encephalopathy 1

Do not stop lactulose when adding rifaximin - the evidence for rifaximin is primarily in combination with lactulose (91% of trial patients used both), not as replacement therapy 1, 3

Rifaximin has not been studied in patients with MELD scores >25, and only 8.6% of trial patients had MELD scores over 19, so use caution in severe liver disease 3

Safety Considerations

• Rifaximin does not increase risk of bacterial resistance or Clostridium difficile infection based on 13 randomized controlled trials 1, 2
• Lactulose is associated with non-severe side effects including diarrhea, bloating, and nausea, but reduces risk of serious adverse events including GI bleeding, bacterial infections, and hepatorenal syndrome 1
• Both medications demonstrate good long-term safety profiles with adverse events similar to placebo 1, 5, 4