Rifaximin in Hepatic Encephalopathy
Rifaximin 550 mg twice daily should be added to lactulose therapy after a patient experiences a second episode of overt hepatic encephalopathy to prevent recurrent episodes. 1
Treatment Algorithm for Patients with History of Hepatic Encephalopathy
After First Episode of Overt HE
- Start lactulose as monotherapy for prevention of recurrent episodes (GRADE II-1, A, 1). 1
- Titrate lactulose to achieve 2-3 soft bowel movements daily. 2
- Do not add rifaximin at this stage—lactulose alone is sufficient after the first episode. 1
After Second Episode of Overt HE
- Add rifaximin 550 mg twice daily to ongoing lactulose therapy (GRADE I, A, 1). 1
- This combination is the best-documented regimen to maintain remission in patients who have already experienced one or more bouts of overt HE while on lactulose treatment. 1
- Continue both medications indefinitely unless precipitating factors are controlled or liver function improves substantially. 1
Evidence Supporting Rifaximin as Add-On Therapy
Rifaximin significantly reduces breakthrough episodes when added to lactulose. The landmark trial demonstrated that rifaximin reduced the risk of hepatic encephalopathy episodes by 58% compared to placebo (hazard ratio 0.42; 95% CI 0.28-0.64; P<0.001), with breakthrough episodes occurring in 22.1% of rifaximin patients versus 45.9% of placebo patients over 6 months. 3
- Rifaximin also reduced hospitalizations involving hepatic encephalopathy by 50% (hazard ratio 0.50; 95% CI 0.29-0.87; P=0.01), with 13.6% of rifaximin patients hospitalized versus 22.6% of placebo patients. 3
- Over 90% of patients in this pivotal trial received concomitant lactulose therapy, establishing rifaximin's role as add-on rather than monotherapy. 3
- A 2023 meta-analysis of 999 patients confirmed rifaximin reduces recurrence rates (RR 0.61; 95% CI 0.50-0.73; P=0.001) with no increase in adverse events or mortality. 4
Important Clinical Caveats
Rifaximin Should NOT Be Used Alone
No solid data support the use of rifaximin as monotherapy—it must be combined with lactulose. 1 The evidence base for rifaximin was established in patients already receiving lactulose (91% in the pivotal trial). 3
Post-TIPS Hepatic Encephalopathy Exception
Do not use routine prophylactic rifaximin or lactulose to prevent post-TIPS hepatic encephalopathy (GRADE III, B, 1). 1 Studies show neither agent prevents post-TIPS HE better than placebo. 1 If severe HE develops post-TIPS, shunt diameter reduction is the primary intervention. 1
Dosing Considerations
- The FDA-approved dose is rifaximin 550 mg twice daily. 5
- One study suggested once-daily dosing (550 mg) may be non-inferior to twice-daily dosing, though this requires further validation and is not guideline-recommended. 6
- Systemic absorption is minimal in healthy subjects but increases 10-21 fold in patients with hepatic impairment (Child-Pugh A-C), though no dose adjustment is recommended since rifaximin acts locally. 5
When to Consider Discontinuing Therapy
Prophylactic therapy may be discontinued if: 1
- Precipitating factors (infections, variceal bleeding) are well controlled
- Liver function or nutritional status has significantly improved
- However, this decision carries risk and should be made cautiously (GRADE III, C, 2). 1
Alternative Agents for Refractory Cases
If patients remain symptomatic despite lactulose plus rifaximin: 1
- Oral BCAAs can be added (GRADE I, B, 2)
- IV L-ornithine L-aspartate (LOLA) can be used (GRADE I, B, 2)—note that oral LOLA is ineffective 1
- Neomycin is an alternative but has long-term ototoxicity, nephrotoxicity, and neurotoxicity concerns (GRADE II-1, B, 2) 1
Safety Profile
Rifaximin is well-tolerated with adverse events similar to placebo. 3, 4 The incidence of serious adverse events and mortality rates are comparable between rifaximin and control groups. 3, 4 Rifaximin was better tolerated than lactulose alone in comparative studies. 7