What are alternative treatments to Xifaxan (rifaximin) for a patient with hepatic encephalopathy or irritable bowel syndrome with diarrhea?

Alternative Treatments to Xifaxan (Rifaximin)

Lactulose is the first-line alternative to rifaximin for hepatic encephalopathy, while eluxadoline or alosetron serve as alternatives for IBS-D. 1

For Hepatic Encephalopathy

Primary Alternative: Non-Absorbable Disaccharides

Lactulose (or lactitol) should be used as the primary alternative, as it is the first-choice treatment for episodic overt hepatic encephalopathy and remains the cornerstone of therapy. 1

• Dosing for acute episodes: Start lactulose 30-45 mL (20-30 g) every 1-2 hours until at least 2 soft bowel movements are produced daily 1
• Maintenance dosing: Lactulose 20-30 g (30-45 mL) 3-4 times daily, titrated to achieve 2-3 soft stools per day 1, 2
• For severe HE (West Haven grade ≥3) or inability to take oral medications: Use lactulose enemas (300 mL lactulose mixed with 700 mL water) rather than oral formulations 1, 2

Secondary Alternatives for Refractory Cases

When lactulose alone is insufficient or poorly tolerated, consider these evidence-based alternatives:

Oral Branched-Chain Amino Acids (BCAAs) can be used as an alternative or additional agent for patients nonresponsive to conventional therapy. 1 Meta-analysis of eight RCTs demonstrated that oral BCAA-enriched formulations improve manifestations of both overt and minimal hepatic encephalopathy. 1

Intravenous L-ornithine L-aspartate (LOLA) is an alternative or additional agent for patients nonresponsive to conventional therapy. 1 RCTs demonstrated improvement in psychometric testing and postprandial venous ammonia levels in patients with persistent HE. 1 Note that oral LOLA supplementation is ineffective—only IV formulation works. 1

Neomycin is an alternative choice for treatment of overt HE, though it is less preferred. 1 While historically used and shown to be as effective as lactulose, long-term use carries significant risks of ototoxicity, nephrotoxicity, and neurotoxicity, making it unattractive for continuous long-term therapy. 1, 3 If used long-term, annual auditory testing and continuous renal function monitoring are required. 3

Metronidazole is an alternative choice for short-term treatment of overt HE only. 1 It should be used for no more than 1-2 weeks due to risks of ototoxicity, nephrotoxicity, and peripheral neuropathy with prolonged use. 2 Long-term use has been associated with dose-dependent neurotoxicity in patients with cirrhosis. 3

Emerging and Adjunctive Therapies

Intravenous albumin showed no effect on resolution of HE in RCTs, but was associated with better post-discharge survival when added to rifaximin. 1 It can be used as an additional agent. 1

Probiotics showed similar efficacy to lactulose in an open-label study for preventing HE recurrence, with no difference in readmission rates between lactulose and probiotic arms. 1 However, evidence remains limited compared to established therapies.

Levo-carnitine or sodium benzoate might be effective in managing HE by lowering plasma ammonia concentrations, though evidence is less robust. 1

Flumazenil transiently improves mental status in overt HE without improving recovery or survival. 1 It is not recommended as first-line therapy but can be used specifically in patients with HE caused by benzodiazepine toxicity or in marginal situations to avoid assisted ventilation. 1

Critical Pitfalls to Avoid

• Never use simple laxatives alone as they lack the prebiotic properties of disaccharides and have no published evidence supporting their use in HE. 1
• Avoid long-term protein restriction, as it can induce protein catabolism, hepatic dysfunction, and sarcopenia—daily protein intake should be 1.2-1.5 g/kg. 1
• Do not use IV BCAAs for acute episodes, as they have no effect on episodic bouts of HE (only oral formulations are effective). 1
• Always identify and treat precipitating factors first (GI bleeding, infection, constipation, excessive protein intake, dehydration, renal dysfunction, electrolyte imbalance, psychoactive medications, acute hepatic injury). 1

For Irritable Bowel Syndrome with Diarrhea (IBS-D)

FDA-Approved Alternatives

Eluxadoline (Viberzi) is FDA-approved for treatment of IBS-D in adults. 4 In two large RCTs (n=1,281 and n=1,145), eluxadoline demonstrated statistically significant improvement over placebo in composite responder rates (simultaneous improvement in abdominal pain ≥30% and reduction in stool consistency). 4 The drug showed similar efficacy in both male and female patients. 4

Alosetron (Lotronex) is another FDA-approved option for women with severe diarrhea-predominant IBS. 5 However, it carries significant risks: constipation occurs in 29% of patients (vs 6% placebo), with 11% withdrawing due to constipation. 5 More concerning, ischemic colitis has been reported at a rate of 0.2% through 3 months and 0.3% through 6 months. 5 Alosetron must be discontinued immediately if signs of ischemic colitis develop (rectal bleeding, bloody diarrhea, new or worsening abdominal pain). 5

Important Considerations for IBS-D Alternatives

• Patients in rifaximin trials for IBS-D were allowed to use loperamide as rescue medication for acute uncontrolled diarrhea, but not other antidiarrheals, antispasmodics, or rifaximin during the study period. 4
• The long-term safety profile beyond 6 months is less well-established for both eluxadoline and alosetron compared to rifaximin. 4, 5