The content of this evidence summary was up-to-date in March 2014. See summaries of product characteristics (SPCs), British national formulary (BNF) or the MHRA or NICE websites for up-to-date information.
One small randomised controlled trial (RCT) and 2 small non-comparative observational studies provide limited evidence that rifaximin alone or in combination with ciprofloxacin can improve symptoms or induce remission in people with pouchitis that is refractory to other antibiotics. One small non-comparative observational study provides limited evidence that rifaximin monotherapy can help maintain remission in people with chronic pouchitis that has responded to other antibiotics.
Regulatory status: off label.
The topic was prioritised because there was noted to be a high volume of requests from the NHS for information about this use of rifaximin, variation in clinical practice and uncertainty about the balance of risks and benefits when rifaximin is used for pouchitis.
Rifaximin is an oral rifamycin antibiotic that is poorly absorbed by the gastrointestinal system. It has wide antibacterial action against most Gram-negative and Gram-positive aerobic and anaerobic bacteria associated with gastrointestinal infection.
Rifaximin is available as 2 licensed products, both of which are licensed for use in people aged 18 years and older:
Rifaximin is not licensed for treating refractory pouchitis or maintaining remission in people with chronic pouchitis and its use for these indications is off-label.
Pouchitis is defined in the European Crohn's and Colitis Organisation (ECCO) publication European evidence-based consensus on the management of ulcerative colitis: special situations as non-specific inflammation of the ileal reservoir (pouch). It affects up to 50% of people 10 years after ileal pouch-anal anastomosis (IPAA) for ulcerative colitis, although the cumulative incidence of pouchitis in people with an IPAA for familial adenomatous polyposis is much lower. Symptoms of pouchitis include pelvic discomfort, abdominal cramps and urgency, tenesmus, increased stool frequency and liquidity, and faecal incontinence. There may also be rectal bleeding, fever or other systemic symptoms. The Pouchitis Disease Activity Index (PDAI) incorporates symptoms, endoscopy and histological findings. The range of possible scores is 0–18, with a score of 7 or more indicating pouchitis and higher scores indicating worse disease.
The ECCO consensus document states that single antibiotic treatment with a 2-week course of either metronidazole or ciprofloxacin is the first-line treatment of choice for acute pouchitis, and combination therapy may also be used. Up to 10% of people develop chronic pouchitis with symptoms lasting longer than 4 weeks. Chronic pouchitis is often treated with combined antibiotic treatment, and other possible treatments include oral or topical budesonide or infliximab. None of these drugs is licensed specifically for treating pouchitis. The consensus document states that a probiotic food supplement can be effective for maintaining antibiotic-induced remission and for preventing pouchitis within the first year after surgery. Surgery can be considered as a last resort for people whose pouchitis does not respond to other treatment options.
Limited research has examined rifaximin for the treatment of pouchitis. Isaacs et al. (2007) reported a double-blind placebo-controlled RCT examining 4 weeks' treatment with rifaximin (400 mg 3 times daily) for acute or chronic active pouchitis (n=18). Among the 17 participants in the study who had at least 1 post-baseline efficacy evaluation, all of those in the rifaximin group (8/8) and nearly all of those in the placebo group (8/9) had received previous antibiotic treatment. Of these 17 people, 2 of the 8 people in the rifaximin group and no one in the placebo group obtained clinical remission at the end of the 4 weeks' treatment (PDAI score of less than 7 points and a decrease from baseline PDAI score of 3 points). This was not statistically significant (p=0.211) but the study was underpowered. No one in the study obtained complete remission (PDAI score of 0).
Two small, non-comparative observational studies reported rates of remission (PDAI score of 0) or improvement (PDAI score reduction of at least 3 points) after treatment with rifaximin 1 g twice daily in combination with ciprofloxacin 500 mg twice daily for 2 weeks for chronic pouchitis that was not responsive to at least 4 weeks' treatment with other antibiotics (usually metronidazole or ciprofloxacillin monotherapy). The study by Gionchetti et al. (1999) included 18 adults, of whom 6 obtained remission with treatment and 10 had an improvement in their condition. The study by Abdelrazeq et al. (2005) included 8 adults: after treatment, 5 of them remained in remission for at least 6 months and a further 2 had an improvement in their condition.
Shen et al. (2008) reported experience with rifaximin for maintenance treatment after antibiotic-induced remission in 51 people with antibiotic-dependent pouchitis, at a daily dose of 200 mg up to a maximum 1800 mg for up to 24 months. At 3 months, 33 were still in remission. Four of these people later relapsed at between 3 and 12 months. Antibiotic induction regimen, symptom score after induction and rifaximin dose were not predictive of maintaining remission.
In the RCT by Isaacs et al. (2007), adverse events were experienced by 6 of the 8 people in the rifaximin group and 5 of the 10 people in the placebo group (statistical significance not reported). One case of each of the following adverse events was experienced by people in the rifaximin group: flatulence, frequent bowel movements, proctalgia, rectal haemorrhage, thirst, candida, upper respiratory tract infection, cluster headache and headache. In the study by Shen et al. (2008), 1 person discontinued rifaximin because of a transient facial rash. No adverse events were reported in the 2 other non-comparative observational studies.
Rifaximin is contraindicated in people with intestinal obstruction. The summaries of product characteristics for Targaxan and Xifaxanta state that Clostridium difficile-associated diarrhoea has been reported with the use of rifaximin. The potential association of rifaximin treatment with Clostridium difficile-associated diarrhoea and pseudomembranous colitis cannot be ruled out. The effects on gut flora may also lead to reduced effectiveness of oral contraceptives, and additional contraceptive precautions are recommended. Despite limited systemic absorption, there may also be reddish discolouration of the urine.
Common adverse events associated with rifaximin (occurring in more than 1 in 100 people) include dizziness and headaches, pruritus and rashes, and abdominal symptoms of pain, distension, nausea and vomiting, diarrhoea or constipation. Other adverse events affecting most systems of the body have been observed less frequently.
The 4 published studies provide limited evidence about rifaximin in the care of people with pouchitis. Large, double-blind RCTs are needed to better assess the safety and efficacy of rifaximin for the treatment of acute or chronic pouchitis and pouchitis refractory to other antibiotics, or for maintenance of antibiotic-induced remission.
About this evidence summary
'Evidence summaries: unlicensed or off-label medicines' summarise the published evidence for selected unlicensed or off-label medicines that are considered to be of significance to the NHS, where there are no clinically appropriate licensed alternatives. The summaries provide information for clinicians and patients to inform their decision-making and support the construction and updating of local formularies.
The summaries support decision-making on the use of an unlicensed or off-label medicine for an individual patient, where there are good clinical reasons for its use, usually when there is no licensed medicine for the condition requiring treatment, or the licensed medicine is not appropriate for that individual.
The strengths and weaknesses of the relevant evidence are critically reviewed within this summary, but this summary is not NICE guidance.