Rifaximin and Lactulose in Hepatic Encephalopathy
Yes, patients on rifaximin should continue lactulose—rifaximin is recommended as an add-on therapy to lactulose, not as a replacement, particularly after a second breakthrough episode of hepatic encephalopathy. 1, 2
Evidence-Based Treatment Algorithm
First Episode of Overt Hepatic Encephalopathy
- Start with lactulose monotherapy as the first-line treatment, dosed at 20-30g (30-45 mL) orally 3-4 times daily, titrated to achieve 2-3 soft bowel movements per day 1, 2, 3
- Lactulose alone reduces 14-month recurrence risk to 20% versus 47% without treatment 2
- Continue lactulose indefinitely after the initial episode to prevent recurrence 1, 3
Second Episode (Breakthrough on Lactulose)
- Add rifaximin 550 mg twice daily to ongoing lactulose therapy—do not discontinue lactulose 1, 2, 3
- This combination reduces recurrence risk from 45.9% to 22.1% (hazard ratio 0.42; 95% CI 0.28-0.64; p<0.001) 2, 4
- The combination also reduces hospitalization risk by 50% (hazard ratio 0.50; 95% CI 0.29-0.87) 2, 4
Critical Evidence Supporting Combination Therapy
The landmark rifaximin trial demonstrates why lactulose must be continued: In the pivotal randomized controlled trial, 91% of patients were on concomitant lactulose therapy when rifaximin was studied 5, 4. The FDA label explicitly states this, noting that "differences in the treatment effect of those patients not using lactulose concomitantly could not be assessed" 5. This means rifaximin's efficacy as monotherapy is not well-established 2.
Additional Benefits of Combination Therapy
- Better recovery from hepatic encephalopathy within 10 days (76% vs. 44%, p=0.004) compared to lactulose alone 2
- Shorter hospital stays (5.8 vs. 8.2 days, p=0.001) 2
- Reduced mortality (RR 0.50; 95% CI 0.31-0.82) in meta-analysis 2, 6
- Decreased ammonia levels significantly at 8,12, and 24 weeks (p=0.005, p=0.01, p=0.01) 7
When Rifaximin Monotherapy May Be Considered
Rifaximin alone should only be used when lactulose is poorly tolerated, and this recommendation is based on expert opinion rather than robust evidence 2, 3. The European Association for the Study of the Liver emphasizes that rifaximin's efficacy as monotherapy is not well established 2.
Common Pitfalls to Avoid
- Never discontinue lactulose when starting rifaximin—lactulose remains the cornerstone of therapy and must be continued 8, 3
- Do not use rifaximin as monotherapy for initial treatment of overt hepatic encephalopathy—evidence supports lactulose as first-line 3
- Failing to titrate lactulose properly to achieve 2-3 bowel movements daily leads to treatment failure 2, 3
- Not recognizing that rifaximin is for secondary prophylaxis—it should be added after the second episode, not the first 1, 2
Special Considerations
Post-TIPS Hepatic Encephalopathy
- Neither rifaximin nor lactulose prevents post-TIPS hepatic encephalopathy better than placebo 1, 3
- Routine prophylactic therapy is not recommended in this specific situation 1
Severe Liver Disease
- Rifaximin has not been studied in patients with MELD scores >25, and only 8.6% of trial patients had MELD scores over 19 5
- There is increased systemic exposure in patients with more severe hepatic dysfunction 5
Long-Term Safety
- Rifaximin can be used safely for long-term continuous therapy (>24 months) with no increased risk of adverse events 2
- Common adverse events (10-15%) include peripheral edema, nausea, dizziness, fatigue, and ascites, with rates similar to placebo 2
Cost Considerations
The high cost of rifaximin (approximately $1,500-2,000 per month) may be a barrier, though benefits in reducing hospitalizations may offset costs through reduced hospital admissions 2. This economic reality reinforces the importance of using rifaximin appropriately—as add-on therapy after lactulose failure, not as first-line monotherapy.