Reduction of Risk of Recurrence
Rifaximin is used for reduction of risk of recurrence of overt hepatic encephalopathy in adults.
The comparative efficacy of rifaximin used alone or in conjunction with lactulose for prevention of overt hepatic encephalopathy recurrence has not been established. Some experts recommend that rifaximin be used as an adjunct to lactulose for prevention of hepatic encephalopathy recurrence in patients who have had at least 1 episode of overt hepatic encephalopathy while receiving lactulose alone. Rifaximin has not been studied for reduction of risk of recurrence of overt hepatic encephalopathy in patients with scores exceeding 25 on the model for end-stage liver disease (MELD).
Efficacy and safety of rifaximin for reduction of risk of recurrence of overt hepatic encephalopathy were evaluated in a randomized, placebo-controlled, double-blind study in adults who were in remission from hepatic encephalopathy (Conn score of 0 or 1) after having 2 or more episodes of hepatic encephalopathy associated with chronic liver disease during the previous 6 months. A total of 299 adults (mean age 56 years [81% younger than 65 years of age], 61% male, 86% white, 67% with Conn score of 0, 68% with asterixis grade 0, 27% with MELD score 10 or less, 64% with MELD score 11-18, 9% Child-Pugh class C) were randomized to receive rifaximin 550 mg or placebo twice daily for 6 months or until the drug was discontinued because of a breakthrough episode of hepatic encephalopathy or another reason (e.g., adverse effects, request to withdraw). Concomitant use of lactulose was permitted (91.4% of those receiving rifaximin and 91.2% of those receiving placebo also received lactulose). The primary end point was time to first breakthrough episode of overt hepatic encephalopathy (defined as a marked deterioration in neurologic function and an increase from a baseline Conn score of 0 or 1 to a score of 2 or more or an increase from a baseline Conn score of 0 to a score of 1 plus a 1-unit increase in asterixis grade). Comparison of Kaplan-Meier estimates of event-free curves showed that rifaximin reduced the risk of hepatic encephalopathy episodes by 58% compared with placebo during the 6-month treatment period; 22% of patients in the rifaximin treatment group and 46% of patients in the placebo group experienced breakthrough episodes of overt hepatic encephalopathy. Efficacy of rifaximin was consistent regardless of gender, baseline Conn score, duration of current remission, and presence or absence of diabetes mellitus. During the 6-month treatment period, rifaximin also reduced the risk of hepatic encephalopathy-associated hospitalizations by 50% compared with placebo; hepatic encephalopathy-associated hospitalizations were reported in 14 and 23% of patients in the rifaximin and placebo groups, respectively.
Although safety and efficacy have not been established, rifaximin also has been used for the treatment of hepatic encephalopathy and is designated an orphan drug by FDA for treatment of this condition.
Efficacy of rifaximin for the treatment of hepatic encephalopathy has been evaluated in several controlled studies and adjunctive use of the drug appears to be effective in reducing blood ammonia concentrations and decreasing the severity of neurologic manifestations. In one double-blind, dose-ranging study, 54 adults with cirrhosis and mild to moderate hepatic encephalopathy were randomized to receive 600, 1200, or 2400 mg of rifaximin daily in 3 divided doses for 7 days. Rifaximin treatment at the 2 higher dosages (1200 or 2400 mg daily) was associated with an improvement in the portal-systemic encephalopathy index (based on mental state, asterixis, number connection test time, EEG mean cycle frequency, and blood ammonia concentrations). In another double-blind study, 58 adults with cirrhosis and portosystemic encephalopathy were randomized to receive 1200 mg of rifaximin daily for 15 days or 30 g of lactulose daily for 15 days. Although clinical improvement in manifestations of portosystemic encephalopathy was reported for both drugs and correlated with reductions in serum ammonia concentrations, data suggested that rifaximin may be better tolerated than lactulose. Clinical improvement was also reported in a case series of 55 adults with cirrhosis and grade 1, 2, and 3 portosystemic encephalopathy treated with rifaximin (1200 mg daily in 3 divided doses) in conjunction with lactulose therapy at a dosage sufficient to induce 2 or 3 evacuations daily.
A meta-analysis of 12 randomized, controlled trials comparing rifaximin to nonabsorbable disaccharides (e.g., lactulose, lactitol) or to other oral anti-infectives (e.g., neomycin, paromomycin) was conducted to assess the efficacy and safety of rifaximin for the treatment of hepatic encephalopathy in adults. Results from an analysis of the 7 studies that compared rifaximin to nonabsorbable disaccharides indicated that resolution or clinical improvement of hepatic encephalopathy occurred with both types of treatment; analysis of the 5 studies that compared rifaximin to other anti-infectives indicated that efficacy of rifaximin was similar to that of neomycin or paromomycin. A combined analysis of all 12 studies indicated that rifaximin was associated with fewer adverse effects than the other treatments.
Information from the American Association for the Study of Liver Diseases (AASLD) and European Association for the Study of the Liver (EASL) regarding the management of hepatic encephalopathy, including recommendations for treatment and prevention of recurrence, is available at http://www.aasld.org.
Irritable Bowel Syndrome with Diarrhea
Rifaximin is used for the treatment of irritable bowel syndrome (IBS) with diarrhea in adults.
Efficacy and safety of rifaximin for the treatment of IBS with diarrhea have been evaluated in 3 randomized, double-blind, placebo-controlled, phase 3 studies.
TARGET 1 (NCT00731679) and TARGET 2 (NCT00724126) were identically designed studies that included a total of 1258 adults who met Rome II criteria for diarrhea-predominant IBS (mean age 46 years, 24-30% male, 89-94% white, 4-10% black); patients with constipation-predominant IBS (according to Rome II criteria) were excluded. After a screening phase of 7-13 days, patients were randomized in a 1:1 ratio to receive rifaximin 550 mg or placebo 3 times daily for 14 days followed by a 10-week treatment-free evaluation period. The primary end point was the proportion of patients who had adequate relief of global IBS symptoms for at least 2 of the 4 weeks during the first month of the treatment-free evaluation period (primary evaluation period). This end point (adequate relief) was defined as a ''yes'' by the patient to a once-weekly subject global assessment question: ''In regard to all your symptoms of IBS, as compared with the way you felt before you started the study medication, have you, in the past 7 days, had adequate relief of your IBS symptoms?''. During the primary evaluation period, adequate relief was experienced by 41% of patients treated with rifaximin and 31-32% of patients treated with placebo. Substantially more patients in the rifaximin group experienced continued relief through 3 months compared with those in the placebo group. In addition, an exploratory, composite end point (defined as at least 30% improvement from baseline in abdominal pain and weekly mean stool consistency score less than 4 for at least 2 of the 4 weeks during the primary evaluation period) was achieved in 47% of patients treated with rifaximin compared with 36-39% of those treated with placebo.
TARGET 3 evaluated efficacy and safety of repeat courses of rifaximin for the treatment of diarrhea-predominant IBS. A total of 2579 adults received open-label rifaximin for 14 days followed by a 4-week treatment-free evaluation period. Of the 2438 evaluable patients, 1074 (44%) responded to initial rifaximin treatment (defined as the composite end point of at least a 30% improvement from baseline in abdominal pain and at least a 50% reduction in the number of days per week with a daily stool consistency of Bristol Stool Scale type 6 or 7). These responders were then followed for recurrence for up to an additional 20-week treatment-free period. A total of 636 initial responders subsequently had recurrence of IBS symptoms (return of abdominal pain or lack of stool consistency for at least 3 weeks during a 4-week follow-up period); the median time to recurrence was 10 weeks (range 6-24 weeks). Patients who experienced recurrence were then enrolled in a double-blind, placebo-controlled, repeat treatment phase and randomized in a 1:1 ratio to receive rifaximin 550 mg or placebo 3 times daily for 2 additional 14-day repeat treatment courses separated by 10 weeks. The primary end point of this randomized portion of the study was the proportion of patients who were responders to repeat treatment in the composite outcome of at least a 30% improvement from baseline in IBS-related abdominal pain and at least a 50% reduction in the number of days per week with a daily stool consistency of Bristol Stool Scale type 6 or 7 during the 4 weeks following the first 14-day repeat treatment course. Response at 4 weeks after completion of the first repeat treatment course was achieved by 38% of patients treated with rifaximin and 31% of those treated with placebo. During the 10-week treatment free follow up period, 17.1 or 11.7% of patients treated with rifaximin or placebo, respectively, had no recurrence of signs and symptoms of IBS.
Rifaximin is used for the treatment of travelers' diarrhea caused by noninvasive strains of Escherichia coli in adults and adolescents 12 years of age and older.
Rifaximin is not effective in and should not be used for the treatment of diarrhea complicated by fever or bloody stools or for the treatment of diarrhea caused by pathogens other than E. coli. Rifaximin is not effective in and should not be used for the treatment of travelers' diarrhea caused by Campylobacter jejuni. In addition, efficacy of the drug has not been established for the treatment of travelers' diarrhea caused by Shigella or Salmonella.
(See Precautions Related to Treatment of Travelers' Diarrhea under Cautions: Warnings/Precautions.)
In a multicenter, randomized, double-blind, placebo-controlled study in 380 adults with travelers' diarrhea, including 43 cases caused by enteroaggregative E. coli, treatment with rifaximin (200 mg 3 times daily for 3 days) was associated with a more rapid resolution of diarrhea and an increased rate of clinical cure (defined as 48 hours without unformed stools and without fever or 24 hours without watery stools, no more than 2 soft stools, and absence of other clinical symptoms) compared with placebo. The primary study end point was the median elapsed time after initiating therapy to the passage of the last unformed stool (time to the last unformed stool [TLUS]) and was 32.5 hours in patients treated with rifaximin and 59-60 hours in those treated with placebo. The rate of clinical cure within 5 days (120 hours) of initiating therapy was 79% in those treated with rifaximin and 60-61% in those treated with placebo. Treatment with a higher rifaximin dosage (400 mg 3 times daily) did not provide additional clinical benefit. In this study, the overall rate of microbiological cure (i.e., the absence of E. coli or other pathogen in stool cultured after 72 hours of therapy) in those treated with rifaximin (69%) was similar to the microbiologic cure rate in those treated with placebo (67%).
The most common cause of travelers' diarrhea worldwide is noninvasive enterotoxigenic strains of E. coli, but travelers' diarrhea may be caused by various other bacteria, including enteroadherent and other E. coli pathotypes, C. jejuni, Shigella, Salmonella, Aeromonas, or Plesiomonas. In some cases, travelers' diarrhea is caused by parasitic enteric pathogens (e.g., Giardia duodenalis [also known as G. lamblia or G. intestinalis], Cryptosporidium, Cyclospora, Entamoeba histolytica, Dientamoeba fragilis) or viral enteric pathogens (e.g., norovirus, rotavirus, astrovirus).
Travelers' diarrhea caused by bacteria may be self-limited and often resolves within 3-7 days without anti-infective treatment. If diarrhea is moderate or severe, associated with fever or bloody stools, persisting longer than 3 days, or extremely disruptive to travel plans, short-term (1-3 days) treatment with an anti-infective usually is recommended. Since bacteria are the most common cause of travelers' diarrhea (80-90% of cases), an anti-infective directed against enteric bacterial pathogens is used for empiric treatment. The US Centers for Disease Control and Prevention (CDC) and other experts state that a fluoroquinolone (e.g., ciprofloxacin, levofloxacin) generally is considered the anti-infective of choice for empiric treatment, including self-treatment, of travelers' diarrhea in adults. Azithromycin can be used as a treatment alternative for individuals who should not receive fluoroquinolones (e.g., children, pregnant women) and is a drug of choice for travelers in areas with a high prevalence of fluoroquinolone-resistant Campylobacter (e.g., South and Southeast Asia) or those who have not responded after 48 hours of fluoroquinolone treatment. Rifaximin can be considered an alternative when the causative organism is enterotoxigenic E. coli; however, since it may be difficult for travelers to distinguish between invasive and noninvasive diarrhea and since travelers would have to carry a back-up anti-infective, the overall usefulness of rifaximin for empiric self-treatment of travelers' diarrhea remains to be determined.
Although safety and efficacy have not been established, rifaximin has been used in some adults for prevention of travelers' diarrhea. Because travelers' diarrhea is a relatively nonthreatening illness that usually is mild and self-limiting and can be effectively treated and because of the risks of widespread use of prophylactic anti-infectives (i.e., potential adverse drug reactions, selection of resistant organisms, increased susceptibility to infections caused by these or other organisms), CDC and other experts state that anti-infective prophylaxis for prevention of travelers' diarrhea is not recommended for most travelers.
For additional information on treatment and prevention of travelers' diarrhea, .