18 GASTROENTEROLOGY A P R I L 1 5 , 2 0 1 0 • I N T E R N A L M E D I C I N E N E W S

Rifaximin Approved for Hepatic EncephalopathyB Y E L I Z A B E T H M E C H C AT I E

The Food and Drug Administrationhas approved the oral antibiotic ri-faximin as a treatment to reduce

the risk of developing episodes of overt he-patic encephalopathy in adults with chron-ic liver disease, making this the seconddrug approved for this indication.

Approved in 2004 for treating travelers’diarrhea caused by noninvasive strains of

Escherichia coli in people aged 12 andolder, rifaximin is a poorly absorbed oralantibiotic derived from rifamycin, andhas a broad spectrum of activity againstgram-positive and gram-negative, aero-bic and anaerobic enteric bacteria.

Rifaximin reduces levels of gut-derived neurotoxins such as ammonia,which is known to cause hepatic en-cephalopathy in patients with hepaticimpairment, according to the manufac-

turer, Salix Pharmaceuticals, which mar-kets the drug as Xifaxan.

The approval is for “reduction in riskof overt hepatic encephalopathy recur-rence” in patients aged 18 and older. Theapproved dosage is one 550-mg tablettaken orally twice a day, with or withoutfood.

Approval was based on a study com-paring treatment with rifaximin to place-bo in 299 patients with advanced liver

disease. The study was published onMarch 25, the same day that the FDA an-nounced the approval (N. Engl. J. Med.2010;362:1071-81).

During the 6-month study, 31 of 140patients (22%) on rifaximin and 73 of 159(46%) on placebo had a breakthroughepisode, a significant difference that rep-resented a nearly 60% reduction in risk.Secondary end points, including the riskof hepatic encephalopathy–related hos-pitalizations, also were significantly re-duced among those on rifaximin.

Based on the findings, the FDA’s Gas-trointestinal Drugs Advisory Committeevoted 14-4 in February that the risk-ben-efit profile of rifaximin supported its ap-proval for this indication. The panelistssupporting approval emphasized that thedrug’s labeling should clearly inform pre-scribers that most of the patients (91%)who participated in the study submittedfor approval were also being treated withlactulose, a drug approved in the 1970sfor the indication, and that most hadChild-Pugh class A or B cirrhosis.

The safety of rifaximin was uncertainwhen used for more severe liver disease,as was its efficacy as a single agent.

During their meeting in Silver Spring,Md., panelists said that if the drug wasapproved, these questions would need tobe addressed in postmarketing studies,which should evaluate the safety of thedrug in patients with more severe dis-ease, those with Child-Pugh class C cir-rhosis or a model for end-stage liver dis-ease (MELD) score above 25.

The safety of chronic treatment, in-cluding the effects of long-term use onthe gut flora, also was unclear, andshould be studied further if the drug wasapproved, panelists said. Also, the clini-cal trial conducted by the manufacturerfor this indication was for 6 months, buttreatment is expected to continue untilthe patient undergoes a liver transplantor dies. The longest follow-up that Salixhas done is an average of 1 year in pa-tients followed in an extension study.

These concerns were reflected in therevised label, which states in the warn-ing and precautions section that thedrug should be used “with caution” inpatients with severe (Child-Pugh C) he-patic impairment. The label also saysthat Clostridium difficile–associated diar-rhea should be considered if a patientdevelops diarrhea during treatment andit does not improve or gets worse.

In the randomized, controlled study of299 patients with advanced liver disease,treatment with rifaximin at a dose of 550mg twice a day was compared withplacebo. In the study, conducted by Dr.Nathan M. Bass of the University of Cal-ifornia, San Francisco, and his associ-ates, most of the patients were white,and the average age was 56 years. Pa-tients were treated at 70 medical centersin the United States, Russia, and Canadastarting in 2005.

Participants had Conn scores of 0(two-thirds of the patients) or 1. Theyhad had at least two episodes of hepatic

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encephalopathy, defined as a Conn scoreof at least 2, in the previous 6 months.

The 5-point Conn grading system isbased on a clinician’s subjective assess-ment, a concern raised by FDA re-viewers. A score of 0 indicates that noabnormality was detected, whereas ascore of 1 indicates trivial lack ofawareness, shortened attention span,impaired addition or subtraction, eu-phoria, or anxiety. A score of 2 is usedto indicate lethargy or apathy, disori-entation to time, obvious personalitychange, and/or inappropriate behavior,and a score of 4 indicates coma (unableto test mental state).

Neurologic impairment was also eval-uated with the Asterixis score, whichranges from grade 0 (no tremors) andgrade 1 (rare flapping motions) to grade2 (occasional, irregular flaps), grade 3(frequent flaps), and grade 4 (almostcontinuous flapping motions).

The primary end point was the time

Continued from previous page to first breakthrough overt hepatic en-cephalopathy episode, defined as an in-crease of the Conn score to a 2 or high-er, or an increase in the Conn score andAsterixis grade of 1 each among thosewith a baseline Conn score of 0.

The active drug also reduced the rela-tive risk for hospitalization by 50%. Hos-pitalization involving hepatic en-cephalopathy was reported for 13.6% ofpatients on rifaximin and 22.6% of thoseon placebo.

Mortality was 6% (9 of 140) with ri-faximin and 7% (11 of 159) with place-bo; deaths were due mostly to worsen-

ing hepatic function and progression ofthe underlying disease.

Since the drug was approved morethan 5 years ago for traveler’s diarrhea,there have been five postmarketing re-ports of C. difficile colitis associated withrifaximin treatment, including onedeath, according to the FDA.

In addition, anaphylaxis has been iden-tified as a notable adverse effect in post-marketing reports, and this risk is nowincluded in the drug’s label.

“These data suggest that four patientswould need to be treated with rifaximinfor 6 months to prevent one episode of

overt hepatic encephalopathy,” Dr. Bassand his colleagues said. First approved inItaly in 1985, rifaximin is now approvedin 33 countries for various GI uses, in-cluding hepatic encephalopathy and ad-junctive treatment of hyperammone-mia, according to the manufacturer. ■

Disclosures: The study was supported bySalix Pharmaceuticals. Dr. Bass reportedreceiving consulting, advisory, and lecturefees from Salix. Members of FDA advisorypanels have been cleared for potentialconflicts of interest related to the topicunder review prior to the meeting.

Try Lactulose,Then Rifaximin

Hepatic encephalopathy, afrequent complication for

patients with cirrhosis, resultsin disability that is generally recognizedas episodesof overtconfusion.M i n i m a lhepatic en-cephalopa-thy fromc i r r h o s i smay bemore diffi-cult to recognize, because it pro-duces less-overt complicationssuch as impaired driving and au-tomobile accidents.

Lactulose, a nonabsorbabledisaccharide that alters colonicpH and bowel frequency, hasbeen the mainstay of therapyfor hepatic encephalopathy, al-though the laxative effect of lac-tulose can be a problem for somepatients. Rifaximin, an antibiot-ic with limited absorption, re-duces the frequency of episodesof hepatic encephalopathy in pa-tients with cirrhosis and thus of-fers another therapeutic option.

Given the associated cost sav-ings, I typically use lactulose asfirst-line therapy for most pa-tients with hepatic encephalopa-thy, and reserve rifaximin forthose who are poorly controlledor who develop significant GIside effects from lactulose.

ROWEN K. ZETTERMAN, M.D.,a gastroenterologist, is dean of theschool of medicine at CreightonUniversity, Omaha, Neb. Hereported no relevant conflicts ofinterest.

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