Xifaxan (rifaximin)

Xifaxan (rifaximin) is a rifamycin antibiotic that is gut selective with negligible systemic absorption and broad-spectrum activity in vitro against both gram-positive and gram-negative pathogens. The drug is minimally absorbed and concentrates in the gastrointestinal tract.

Rifaximin was recently approved for reduction in risk of overt hepatic encephalopathy recurrence in patients ≥18 years of age. The product is also indicated for treatment of patients ≥12 years of age with travelers’ diarrhea caused by noninvasive strains of Escherichia coli.

Hepatic encephalopathy is a worsening of brain function that can occur in patients whose liver can no longer remove toxins from the blood. Increased levels of ammonia in the blood are thought to play a role in the development of hepatic encephalopathy, and rifaximin works by reducing these levels.

For hepatic encephalopathy, the recommended dosing regimen is one 550-mg tablet taken orally 2 times a day, with or without food. For travelers’ diarrhea, the recommended starting dose for rifaximin is one 200-mg tablet taken orally 3 times a day for 3 days, with or without food.

Xifaxan received a priority review under the US Food and Drug Administration’s new drug application process and was granted orphan designation status. The efficacy of rifaximin 550 mg taken orally 2 times a day was evaluated in a randomized, placebo-controlled, double-blind, multicenter, 6-month trial of adult subjects from the United States, Canada, and Russia who were defined as being in remission from hepatic encephalopathy.

This First Report – Managed Care Product Spotlight provides a summary of results from the pivotal study of rifaximin 550-mg tablets for the reduction in risk of recurrence of hepatic encephalopathy. At the time results were published, the study was the largest randomized trial of maintenance therapy in hepatic encephalopathy.

HEPATIC ENCEPHALOPATHY TRIAL
Below is a summary of a phase 3 trial that compared the efficacy and safety of rifaximin and placebo for reducing the risk of hepatic encephalopathy.

Reference: Bass NM, Mullen KD, Sanyal A, et al. Rifaximin treatment in hepatic encephalopathy. N Engl J Med. 2010;362(12):1071-1081.

Study Objectives: The trial was designed to evaluate the efficacy of rifaximin at a dose of 550 mg taken orally 2 times a day concomitantly with lactulose for maintenance of remission from hepatic encephalopathy in outpatients with recent history of the disease.

Method
The trial was randomized, double-blind, and placebo-controlled. Subjects were randomized to receive either 550 mg of rifaximin or placebo twice daily for 6 months. Patients could also receive concomitant administration of lactulose.

Patients visited the clinic on days 7 and 14 and every 2 weeks thereafter through day 168. There were also optional visits. Investigators determined Conn scores on a scale from 0 (no symptoms of hepatic encephalopathy) to 4 (coma). All patients who received at least 1 dose of study medication were included in the intention-to-treat population for evaluation of efficacy data.

Episodes of breakthrough hepatic encephalopathy were defined as an increase from a baseline Conn score of 0 or 1 to a score of ≥2 or from a baseline Conn score of 0 to a Conn score of 1 plus a 1-unit increase in the patient’s asterixis grade measured on a scale of 0 (no tremors) to 4 (almost continuous flapping motions).

Population
A total of 299 patients were randomized for the trial—140 in the rifaximin group and 159 in the placebo group. Mean age was 56 years (range, 21-82 years), 81% were <65 years of age, 61% were male, and 86% were white. At baseline, 67% of patients had a Conn score of 0 and 68% had an asterixis grade of 0.

Patients had model for end-stage liver disease (MELD) scores of either ≤10 (27%) or 11 to 18 (64%) at baseline. No patients were enrolled with a MELD score of >25. Nine percent of the patients were Child-Pugh Class C. Lactulose was concomitantly used by 91% of the patients in each treatment arm of the study. Per the study protocol, patients were withdrawn from the study after experiencing a breakthrough hepatic encephalopathy episode.

Patients were excluded if they were expecting a liver transplant within 1 month after the screening visit or if they had other conditions known to precipitate hepatic encephalopathy within 3 months of screening.

Investigators reported that baseline patient characteristics were similar in the rifaximin and placebo groups. At baseline, 91.4% of patients in the rifaximin group and 91.2% of patients in the placebo group were receiving lactulose.

Primary end point:
•    Risk of experiencing a breakthrough overt episode of hepatic encephalopathy

Secondary end point:
•    Time to hospitalization related to hepatic encephalopathy

Results
The study showed rifaximin 550-mg tablets significantly reduced the risk of overt hepatic encephalopathy recurrence over a 6-month period, maintaining remission more effectively than placebo. Additionally in this study, rifaximin 550-mg treatment significantly reduced the risk of hospitalization for hepatic encephalopathy.

Risk of experiencing a breakthrough overt episode of hepatic encephalopathy was reduced by 58% in subjects treated with rifaximin compared with subjects who received placebo (P<.0001). Breakthrough overt episodes of hepatic encephalopathy were experienced by 31 of 140 subjects (22%) in the rifaximin group and by 73 of 159 subjects (46%) in the placebo group during the 6-month treatment period.

Risk of experiencing hospitalizations related to hepatic encephalopathy was reduced by 50% in subjects treated with rifaximin compared with subjects who received placebo (P=.0129). Hospitalizations directly resulting from hepatic encephalopathy or hospitalizations complicated by hepatic encephalopathy were reported for 19 of 140 subjects (14%) in the rifaximin group and 36 of 159 subjects (23%) in the placebo group.

When the results were evaluated by the following demographic and baseline characteristics, the treatment effect of rifaximin in reducing the risk of breakthrough overt recurrence of hepatic encephalopathy was consistent for sex, baseline Conn score, duration of current remission, and diabetes.

The most common adverse reactions occurring in >8% of patients in the clinical study were peripheral edema (15%), nausea (14%), dizziness (13%), fatigue (12%), ascites (11%), muscle spasms (9%), pruritus (9%), and abdominal pain (9%).

Safety Notes
Rifaximin has a similar tolerability profile to that of placebo. The prescribing information states that to reduce the development of drug-resistant bacteria and maintain the effectiveness of Xifaxan and other antibacterial drugs, Xifaxan should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

Rifaximin is contraindicated in patients with a hypersensitivity to rifaximin, any of the rifamycin antimicrobial agents, or any of the components in Xifaxan. Hypersensitivity reactions have included exfoliative dermatitis, angioneurotic edema, and anaphylaxis.

Xifaxan Facts
•    Xifaxan was approved for prevention of hepatic encephalopathy on March 24, 2010
•    Xifaxan was approved for travelers’ diarrhea in May 2004
•    Salix Pharmaceuticals Inc manufactures Xifaxan
•    Rifaximin is approved in 33 countries