Background and aims: Rifaximin, a minimally absorbed gut-selective antibiotic, significantly reduced the risk of breakthrough hepatic encephalopathy (HE) in patients with HE by 58% (hazard ratio, 0.421; p< 0.0001) versus placebo in a large multinational trial. This analysis evaluated the safety of rifaximin in the study population.

Methods: Rifaximin (550 mg twice daily) was compared with placebo in a randomized, double-blind, placebo-controlled trial for 6 months in patients with a history of HE. Continued therapy with lactulose was permitted. Patients with cirrhosis and documented episodic HE (Conn score ≥2) were enrolled while in remission (Conn score = 0 or 1). The primary endpoint was time to first breakthrough HE episode. Safety evaluations, including physical examination, laboratory values, and adverse events, were assessed at study visits.

Results: The safety population included 299 patients who received ≥1 dose of either rifaximin (n=140) or placebo (n=159). Mean exposure was greater for rifaximin (130 d) versus placebo (106 d), primarily due to breakthrough HE in the placebo group resulting in early discontinuation. Overall, 80% of patients experienced at least one treatment-emergent adverse event (TEAE), the majority being mild to moderate in intensity. The most common TEAEs (≥10%) that occurred more frequently for rifaximin than placebo were ascites (11% vs 9%), dizziness (13% vs 8%), fatigue (12% vs 11%), and peripheral edema (15% vs 8%) for rifaximin versus placebo, respectively. Severe TEAEs (26% vs 31%) and drug-related TEAEs (19% vs 21%) were similar in rifaximin versus placebo groups, respectively. A similar percentage of patients reported infection in the rifaximin and placebo groups (33% vs 31%, respectively), with the most common being urinary tract infections (6% vs 9%, respectively). The percentage of patients who experienced serious adverse events was similar in the rifaximin (36%) versus placebo group (40%). Additionally, 7% of patients died in each group. No significant differences were noted between groups in other safety assessments

Conclusions: These findings indicate that rifaximin 550 mg taken twice daily has a favorable safety profile, comparable to placebo in patients with HE treated for up to 6 months.