Rifaximin has a Favorable Long-Term Safety Profile for Maintenance of Remission from Overt Hepatic Encephalopathy (2009)

Purpose: The minimally absorbed, gut-selective antibiotic rifaximin (550 mg twice daily [BID]) was effective in maintaining remission from overt hepatic encephalopathy (HE) in a randomized, double-blind, placebo-controlled, 6-month trial (RCT). This protective effect was sustained in a longterm, ongoing, open-label maintenance study (OLM). The safety profile of rifaximin as demonstrated in the RCT and OLM is described here. Methods: Patients (n=299) with cirrhosis and a history of ≥2 overt HE episodes (Conn score [CS] ≥2) within 6 months before screening and in remission (CS ≤ 1) were enrolled in the RCT. Patients who completed the RCT were permitted to rollover into the OLM. New patients who met eligibility requirements and had ≥1 HE episodes of CS ≥2 within the previous 12 months were also enrolled in the OLM. All patients had a CS ≤2 at enrollment. Results: A total of 336 patients were treated with rifaximin (550 mg BID) in the RCT and OLM for up to 840 days (mean: 274 days). Of these, 257 patients were on rifaximin for ≥ 6 months and 114 patients for ≥1 year. Most patients in the RCT and OLM received concomitant lactulose therapy. During treatment with rifaximin, the overall profile of adverse events (AEs) was consistent with expectations for patients with liver cirrhosis and a history of overt HE. In the RCT, the pattern of AEs was similar between the rifaximin (N=140) and placebo (N=159) groups, with AEs experienced by 80% of patients in each group. Fewer patients in the rifaximin group than the placebo group experienced severe AEs (26% vs. 31%), drugrelated AEs (19% vs. 21%), serious AEs (36% vs. 40%), and AEs leading to discontinuation (21% vs. 28%). Rifaximin did not adversely affect mortality, which occurred in 7% of patients in each group. The safety profile of rifaximin during long-term treatment (N=336) was similar to that in the RCT. When normalized for exposure duration, long-term treatment and increased exposure did not adversely impact the safety profile. Adverse event rates, including discontinuation rates and deaths were all lower during long term rifaximin therapy compared with the RCT rifaximin group. Clinical laboratory results were consistent with the cirrhotic population under study. Laboratory findings did not show hepatotoxic or nephrotoxic drug effects. Conclusion: The rates and spectrum of AEs were similar in patients on rifaximin therapy (plus lactulose) when compared with patients who received placebo (i.e., lactulose alone). The favorable long-term safety profile of rifaximin together with its previously demonstrated long-term efficacy in the maintenance of remission of HE support its preventive role in this potentially disabling complication of cirrhosis. Disclosure: Sheikh - Salix, grant; Bass - Salix: consultant, speaker bureau; Sanyal - Salix: consultant, research support; Poordad - Salix: grant/research, speaker bureau, advisory board; Mullen - Salix: grant, consultant, speaker bureau; Sigal - Salix: consultant, research support; Frederick - Salix: consultant, advisory board; Bhandari - Salix: consultant; Vemuru - Salix: consultant; Huang - Salix: employee; Merchant - Salix: employee; Shaw - Salix: employee; Bortey - Salix: employee; Forbes - Salix: employee. This research was supported by an industry grant from Salix Pharmaceuticals, Inc.