Rifaximin reduced hepatic encephalopathy events in cirrhosis

Provided by Clinical Advisor

March 25, 2014

Patients assigned rifaximin experienced significantly fewer hepatic encephalopathy events compared with patients assigned placebo.

Rifaximin decreased hepatic encephalopathy episodes in patients with cirrhosis, new study findings show.

“[Rifaximin] is approved to treat urea cycle defects that prevent the removal of ammonia from the body,” Bruce F. Scharschmidt, MD, of Hyperion Therapeutics in San Francisco, said in a press release. “Our trial was the first to investigate the efficacy of a direct ammonia lowering agent in patients with cirrhosis and hepatic encephalopathy.”

The phase 2 study included 178 patients with cirrhosis, of which 59 were previously assigned rifaximin (XIFAXAN, Salix Pharmaceuticals). Researchers aimed to determine the proportion of patients with hepatic encephalopathy assigned twice-daily 6mL rifaximin vs. placebo.  

Patients assigned rifaximin experienced significantly fewer hepatic encephalopathy events when compared with patients assigned placebo (21% vs. 36%; P=0.02). The total number of hepatic encephalopathy events were lower in those assigned the medication (n=35) when compared with those assigned placebo (n=57).

Further, there were 13 total hospitalizations in the rifaximin arm vs. 25 hospitalizations in the placebo arm. Ammonia levels in the blood were lower in patients assigned rifaximin versus placebo.

Among those not previously treated with the drug before enrollment, rifaximin decreased the number of patients with a hepatic encephalopathy event (10% vs. 32%; P<0.01), the time to a first event (HR=0.29; P<0.01) and the total number of events (7 vs. 31; P<0.01).

“Our findings provide evidence that elevated blood ammonia plays an important role in the development of hepatic encephalopathy,” Scharschmidt said. “Rifaximin reduced the risk for hepatic encephalopathy in patients with cirrhosis and further investigation of its therapeutic potential for patients with hepatic encephalopathy is warranted.”

“The study shows that [rifaximin] improves the outcome among cirrhotic patients with highly recurrent hepatic encephalopathy,” Juan Cordoba, MD, and Meritxell Ventura-Cots, MD, both of the Hospital Vall Hebron in Barcelona, Spain wrote in an accompanying editorial. “The new drug avoids the risk for sodium overload, was well tolerated and had a good safety profile.”

References

1. Rockey DC et al. Hepatology. 2014;59(3):1073-1083.
2. Cordoba J. Hepatology. 2014;59(3):764-766.

Disclosure: See study for full list of disclosures.

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Salix Pharmaceuticals Outlines Data Presentations at American Association for the Study of Liver Diseases Annual Meeting

PRESS RELEASE

Nov. 1, 2013, 7:00 a.m. EDT

RALEIGH, N.C., Nov 01, 2013 (BUSINESS WIRE) -- Salix Pharmaceuticals, Ltd. /quotes/zigman/87125/delayed/quotes/nls/slxp SLXP -0.02% today announced that presentations related to the investigation of rifaximin are scheduled to take place during the 64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD). AASLD is being held in Washington, DC November 1-5 2013.

Rifaximin Presentations

Poster #1344: Flamm et al. "Impact of Liver Disease Status and Treatment with Rifaximin on Complications of Cirrhosis in a Randomized, Placebo-Controlled Trial"

Poster #374: Neff et al. "Hospital Costs, Length of Stay and Readmission Rates in a Cohort of Cirrhotic Patients Discharged with Hepatic Encephalopathy"

Important Safety Information about XIFAXAN 550 mg

XIFAXAN(R) (rifaximin) 550 mg tablets are 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.

Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including XIFAXAN, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon which may lead to overgrowth of C. difficile. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued.

There is increased systemic exposure in patients with more severe hepatic dysfunction. The clinical trials were limited to patients with MELD scores < 25. Therefore, caution should be exercised when administering XIFAXAN to patients with severe hepatic impairment (Child-Pugh C).

Based on animal data, XIFAXAN may cause fetal harm. Discontinue in nursing mothers after taking into account the importance of the drug to the mother.

The most common adverse reactions occurring in greater-than or equal to 10% of patients and at a higher incidence than placebo in the clinical study were edema peripheral (15%), nausea (14%), dizziness (13%), fatigue (12%), and ascites (11%).

Xifaxan 550 mg is licensed by Alfa Wassermann S.p.A. to Salix Pharmaceuticals, Inc.

Please see complete Prescribing Information for XIFAXAN.

About Salix

Salix Pharmaceuticals, Ltd., headquartered in Raleigh, North Carolina, develops and markets prescription pharmaceutical products and medical devices for the prevention and treatment of gastrointestinal diseases. Salix's strategy is to in-license late-stage or marketed proprietary therapeutic products, complete any required development and regulatory submission of these products, and market them through the Company's gastroenterology specialty sales and marketing team.

Salix markets XIFAXAN(R) (rifaximin) tablets 200 mg and 550 mg, MOVIPREP(R) (PEG 3350, Sodium Sulfate, Sodium Chloride, Potassium Chloride, Sodium Ascorbate and Ascorbic Acid for Oral Solution), OSMOPREP(R) (sodium phosphate monobasic monohydrate, USP and sodium phosphate dibasic anhydrous, USP) Tablets, APRISO(R) (mesalamine) extended-release capsules 0.375 g, GIAZO(TM) (balsalazide disodium) tablets, COLAZAL(R) (balsalazide disodium) Capsules, METOZOLV(R) ODT (metoclopramide HCl), RELISTOR(R) (methylnaltrexone bromide) Subcutaneous Injection, FULYZAQ(TM) (crofelemer) delayed-release tablets, SOLESTA(R), DEFLUX(R), PEPCID(R) (famotidine) for Oral Suspension, DIURIL(R) (Chlorothiazide) Oral Suspension, AZASAN(R) (Azathioprine) Tablets, USP, 75/100 mg, ANUSOL-HC(R) 2.5% (Hydrocortisone Cream, USP), ANUSOL-HC(R) 25 mg Suppository (Hydrocortisone Acetate), PROCTOCORT(R) Cream (Hydrocortisone Cream, USP) 1% and PROCTOCORT(R) Suppository (Hydrocortisone Acetate Rectal Suppositories) 30 mg. Budesonide foam, RELISTOR(R) , LUMACAN(TM) and rifaximin for additional indications are under development.

For full prescribing information and important safety information on Salix products, including BOXED WARNINGS for OSMOPREP, AZASAN and METOZOLV, please visit www.salix.com where the Company promptly posts press releases, SEC filings and other important information or contact the Company at 919 862-1000.

Salix trades on the NASDAQ Global Select Market under the ticker symbol "SLXP".

For more information, please visit our Website at www.salix.com or contact the Company at 919-862-1000. Follow us on Twitter (@SalixPharma) and Facebook (www.facebook.com/SalixPharma). Information on our Twitter feed, Facebook page and web site is not incorporated in our SEC filings.

Please Note: The materials provided herein that are not historical facts are or might constitute forward-looking statements under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Although we believe the expectations reflected in such forward-looking statements are based on reasonable assumptions, our expectations might not be attained. Forward-looking statements involve known and unknown risks that could cause actual results to differ materially from expected results. Factors that could cause actual results to differ materially from our expectations expressed in the report include, among others: the high cost and uncertainty of the research, clinical trials and other development activities involving pharmaceutical products; the unpredictability of the duration and results of regulatory review of New Drug Applications and Investigational New Drug Applications; the uncertainty of market acceptance of our products; intense competition, including from generics in an increasingly global market; the possible impairment of, or inability to obtain intellectual property rights and the costs of obtaining such rights from third parties in an increasingly global market; general economic conditions; our need to maintain profitability; the uncertainty of obtaining, and our dependence on, third parties to manufacture and sell our products; results of ongoing and any future litigation and investigations and other risk factors detailed from time to time in our other SEC filings.

SOURCE: Salix Pharmaceuticals, Ltd.

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A Randomized, Double-Blind, Controlled Trial Comparing Rifaximin Plus Lactulose With Lactulose Alone in Treatment of Overt Hepatic Encephalopathy

The American Journal of Gastroenterology , (23 July 2013) | doi:10.1038/ajg.2013.219

Barjesh Chander Sharma, Praveen Sharma, Manish Kumar Lunia, Siddharth Srivastava, Rohit Goyal and S K Sarin

Abstract

OBJECTIVES:

Hepatic encephalopathy (HE) is associated with poor prognosis in cirrhosis. Drugs used in the treatment of HE are primarily directed at the reduction of the blood ammonia levels. Rifaximin and lactulose have shown to be effective in HE. We evaluated the efficacy and safety of rifaximin plus lactulose vs. lactulose alone for treatment of overt HE.

METHODS:

In this prospective double-blind randomized controlled trial, 120 patients with overt HE were randomized into two groups: (group A lactulose plus rifaximin 1,200 mg/day; n=63) and group B (lactulose (n=57) plus placebo). The primary end point was complete reversal of HE and the secondary end points were mortality and hospital stay.

RESULTS:

A total of 120 patients (mean age 39.4±9.6 years; male/female ratio 89:31) were included in the study. 37 (30.8%) patients were in Child–Turcotte–Pugh (CTP) class B and 83 (69.2%) were in CTP class C. Mean CTP score was 9.7±2.8 and the MELD (model for end-stage liver disease) score was 24.6±4.2. At the time of admission, 22 patients (18.3%) had grade 2, 40 (33.3%) had grade 3, and 58 (48.3%) had grade 4 HE. Of the patients, 48 (76%) in group A compared with 29 (50.8%) in group B had complete reversal of HE (P<0.004). There was a significant decrease in mortality after treatment with lactulose plus rifaximin vs. lactulose and placebo (23.8% vs. 49.1%, P<0.05). There were significantly more deaths in group B because of sepsis (group A vs. group B: 7:17, P=0.01), whereas there were no differences because of gastrointestinal bleed (group A vs. group B: 4:4, P=nonsignificant (NS)) and hepatorenal syndrome (group A vs. group B: 4:7, P=NS). Patients in the lactulose plus rifaximin group had shorter hospital stay (5.8±3.4 vs. 8.2±4.6 days, P=0.001).

CONCLUSION:

Combination of lactulose plus rifaximin is more effective than lactulose alone in the treatment of overt HE.

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AASLD: Rifaximin is Safe and Beneficial in Addressing Hepatic Encephalopathy

Bob Roehr

November 8, 2010 (Boston, Massachusetts) — In March of this year, the US Food and Drug Administration granted a label indication to the antibiotic rifaximin (Xifaxan 550 mg) for the treatment of hepatic encephalopathy. One consequence is a trickle of studies presented here at The Liver Meeting 2010: American Association for the Study of Liver Diseases 61st Annual Meeting that confirm the efficacy of the drug.

Rifaximin is a potent broad-spectrum antibiotic that has virtually no systemic absorption and is well suited to control intestinal bacterial overgrowth without systemic exposure. Cirrhotic patients are predisposed to intestinal bacterial overgrowth. Deterioration of the gut barrier function can result in the translocation of bacteria and increased abdominal inflammation, which in turn can result in increased portal venous pressure.

Jiannis Vlachogiannakos, MD, and colleagues from the Evangelismos General Hospital in Athens, Greece, conducted a retrospective matched study of patients with alcohol-related decompensated cirrhosis (Child-Pugh score above 7) and ascites. Patients took rifaximin for a short course (4 weeks) and, if they responded with improved liver hemodynamics on hepatic venous pressure gradient testing, were continued on a daily dose of 1200 mg.

The analysis consisted of 23 patients (20 male, 3 female) who took rifaximin, each of whom were sex and age matched (±5 years) to 2 control patients with decompensated cirrhosis of the same etiology who did not take rifaximin. All patients had abstained from alcohol consumption for at least 6 months prior to entering the registry. They were followed for 5 years, death, or liver transplantation, whichever came first.

Dr. Vlachogiannakos said the active group "had a significantly lower risk of developing variceal bleeding (35% vs 59.5%; P = .011), hepatic encephalopathy (31.5% vs 47%; P = .034), spontaneous bacterial peritonitis (5.5% vs 46%; P = .027), and hepatorenal syndrome (4.5% vs 51%; P = .037) than controls."

Patients who did not take rifaximin died in disproportionate numbers (24/46 vs 7/23). He said that "the probability of 5-year survival was 61% in the rifaximin group and 13.5% in the control group (p = .012).

Michael D. Leise, MD, and colleagues from the Mayo Clinic in Rochester, Minnesota, examined medical records from the Mayo Clinic and identified 280 patients with hepatic encephalitis who were given rifaximin on a long-term open-label basis. They compared it with an algorithm of disease state and survival generated from data recorded in the Organ Procurement and Transplant Network.

They found that patients receiving rifaximin generally had better rates of survival, although the difference did not reach statistical significance except in the highest-risk patient group. The authors conclude that in addition to suggesting benefit, it provides assurance on the long-term safety of rifaximin.

Finally, a study from Virginia Commonwealth University in Richmond offered insights into improvement in brain function with rifaximin. Hepatic encephalopathy is associated with driving impairment.

Jasmohan Bajaj, MD, and colleagues used performance on a 15-minute driving-simulator test to evaluate driving and navigation skills (speeding tickets, collisions, and illegal turns) at baseline and 8 weeks after 42 hepatic encephalopathy patients were randomized in a 1:1 manner to receive rifaximin or placebo.

Comparing results from the 2 time points, he found that "76% of patients in the rifaximin group reduced their driving error, compared with only 33% in the placebo group, which is statistically significant." On the speeding ticket criteria, 81% and 33% of the respective groups reduced their errors. But there was no difference between them in terms of collisions, a fact that he attributed to the greater awareness of and learning from a simulated collision.

When asked what physicians might do if they believe a patient is suffering from hepatic-encephalopathy-related cognitive impairment, Dr. Bajaj said the findings are preliminary. More important, "if you have any questions about your patient's driving ability, you are not qualified as a doctor to make that decision. You should send those patients to your department of motor vehicles."

All of the studies were conducted as part of academic research. The researchers have disclosed no relevant financial relationships.

The Liver Meeting 2010: American Association for the Study of Liver Diseases (AASLD) 61st Annual Meeting: Abstracts 19, 24, and 22. Presented October 31, 2010.

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Also See: AASLD: Antibiotic Reverses Cognition Loss in MHE

AASLD: Antibiotic Reverses Cognition Loss in MHE

By Michael Smith, North American Correspondent, MedPage Today
Published: November 01, 2010
Reviewed by Zalman S. Agus, MD; Emeritus Professor
University of Pennsylvania School of Medicine.
 
BOSTON -- In patients with minimal hepatic encephalopathy, an antibiotic appears to reverse difficulties in driving a car associated with the condition, a researcher said here.

Rifaximin (Xifaxan) is most commonly used to treat travelers' diarrhea, but it is also approved for minimal hepatic encephalopathy, according to Jasmohan Bajaj, MD, of Virginia Commonwealth University Medical Center in Richmond, Va.

In a randomized, placebo-controlled, double-blind trial, patients taking the drug did better on simulated driving tasks than those given placebo, Bajaj reported at the annual meeting of the American Association for the Study of Liver Diseases.

Minimal encephalopathy does not lead to overt cognitive dysfunction, but can be shown to exist with neuropsychological tests. It impairs quality of life and has been shown to increase the risk of traffic accidents.

The importance of the study, Bajaj said, is that "it's the first time a cognitive change has resulted in a real-life outcome."

He and his colleagues enrolled 41 patients -- all current drivers -- with minimal hepatic encephalopathy confirmed by a battery of five cognitive tests.

At baseline, the patients were tested using a simulator for driving and navigation skills, with the outcomes being such things as collisions, speeding tickets, and illegal turns, Bajaj said. At the same time, they were given cognitive tests, quality of life was measured using the Sickness Impact Profile, venous ammonia levels were measured, and they were graded on the Model for End-Stage Liver Disease (MELD) score.

The patients were randomly assigned to get rifaximin (at 550 mg a day) or placebo for 30 days, at the end of which time they returned for adherence testing and were given another 30 days of study drug, Bajaj said.

At the end of the eight-week study period, the baseline tests were repeated, including those in the simulator. The primary outcomes were improvements in the driving measures -- speeding, illegal turns, and collisions. Changes in cognition and quality of life were secondary outcomes.

The researchers found:

• 76% of those getting the drug had fewer total driving errors, compared with 33% of those on placebo (P=0.013)

• 81% of those on the drug had fewer speeding tickets, compared with 33% of those on placebo (P=0.005)

• 62% of those on rifaximin had fewer illegal turns, compared with 19% of those on placebo (P=0.012)

• There was no significant difference in the number of collisions

Participants on rifaximin also had a significantly better increase in cognition and on the psychosocial elements of the Sickness Impact Profile, Bajaj reported.

He said the goal was to increase insight into driving errors, which was best measured by such subtle factors as illegal turns and speeding tickets. In the simulator, he said, a collision stopped the game, with a loud crash, which allowed patients in both groups to gain the same insight.

"Tickets and illegal turns do not come with anything, so the patients have to themselves realize they've gone off," he said.

The findings are important because they appear to demonstrate that some of the cognitive effects of minimal hepatic encephalopathy can be turned back by medication, according to Kevin Mullen, MD, of MetroHealth Medical Center in Cleveland, who moderated the session at which the data were presented.

"Up to now, no one had ever shown reversibility of those driving problems," he told MedPage Today.

Other papers presented at the session, he noted, suggested that the drug could improve survival and slow progression of the disease. But those effects -- as well as the possible cognitive benefits -- are "still up in the air" and need more study.

The study was supported by the NIH and Salix.

Bajaj reported financial links with Salix and Ocera Therapeutics.

Mullen reported financial links with Salix, Ocera, Hyperion, Hoffman LaRoche, and CLDG.

Primary source: American Association for the Study of Liver Diseases

Source reference:
Bajaj JS, et al "Rifaximin improves driving simulator performance in minimal hepatic encephalopathy: A double - blind, placebo - controlled, prospective randomized trial" AASLD 2010; Abstract 22.

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