Rif Pres 2 Slides Per Page Plus Notes

8/2/2019 Rif Pres 2 Slides Per Page Plus Notes

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B ackgroun d: D ru g In fo Rifaximin (Xifaxan, Salix Pharmaceuticals)

o Oral drug, not systemically absorbedo Approved for use in preventing hepaticencephalopathyo Approved for non-invasive traveler's diarrhea

Comes in two strengths: 200 mg and 550 mg tabletso Cost:.200 mg tablets: $17 per tablet.550 mg tablets: $23 per tablet

May be easily confused - rifaMPIN and rifaXIMIN, andothers .

Rifaximin was initially approved in 1998 for the use in preventing hepaticencephalopathy, which can flare and subside depending on the patients'health. Itwas later approved for use in non-invasive traveler's diarrhea. Ithas been studied in several gastrointestinal problems, including clostridiumdifficile associated diarrhea and pseudomembranous colitis, irritable bowelsyndrome, and diverticulitis. I'll talk about those a little bit later.The cost l is ted here isan approximation. I tg ives you an idea what acourse of this will cost, when taking it two to three times per day, on a long-term basis for most cases.I also wanted to point out that i t may be one of the drugs that shows up ona list of look-alike, sound-alike drugs, since most of the rifamycinderivatives start with "RIFA", although they are mainly used fortuberculosis.


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Mechanism & Spectrum Dosing and Admin ist ration Semi-synthetic antibacterial drug

o Derived from rifamycin Inhibits bacterial replication Similar_spectrum of activity to rifampin

o structural analogso demonstrate cross-resistance

Susceptible organisms:o Escherichia colio some gut flora

To reduce recurrence of hepatic encephalopathy0550 mg BID for persons> 12 yearso Long-term treatment, >6 months For treatment of overt HE (off-label)0400 mg Q8H for 5-10 days

For treatment of traveler's diarrheao 200 mg TID for 3 days

Clostridium difficile-associated diarrhea (off-label)o 200-400 mg BID-TID for 14 days

Rifaximin is a non-aminoglycoside antibacterial rifamycin derivative drug. Itbinds to the beta subunit of bacterial DNA-dependent RNA polymerase,thereby inhibiting bacterial RNA synthesis.Since it is a structural analog of rifampin, it was expected to have similarspectrum of activity, which was shown to be true in vitro. Organisms thathave some resistance to rifaximin also demonstrate resistance to rifampin.Cross-resistance between other antimicrobial categories has not yet beenstudied.E. coli has been shown to develop resistance in vitro, but the clinicalsignificance of that effect has not yet been studied.Only some gut flora are affected, but compared to some traditional oralantibiotics, this spectrum is fairly narrow.

Dosing is fairly self-explanatory. The doses were determined from studiesthat were conducted before and after the drug was brought to market.Continuing studies are being done to assess efficacy in differentconditions, but some evidence exists that there is benefit in the listed off-label uses.Administration is simply, the drug is an oral only tablet that is swallowed.Food does not significantly affect the utility of the drug, as it is notabsorbed and stays in the gut.Itcan be formulated into an oral suspension if a patient is unable toswallow. The recipe is available online or in the extemporaneouscompounding section of Lexi-Complete.


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Warn ings and P recautions Adve rse Reac tions From the package insert:

oCDADo Non-E. coli traveler's diarrheao Severe hepatic dysfunction (Child-Pugh Class C)o Resistant bacteriao Pregnancy category Co Children less than 12o Renal impariment

Adverse reactionsleading todiscontinuation:o taste losso dysenteryo weight decreaseo anorexiao nauseao nasal passageirritation

Clostridium dif fici le associated diarrhea has been reported with the use of r ifaximin, as wel l asmost other antibacterial agents. The studies have shown that the severity of clostridiumdif fici le associated diarrhea ranges from mild tofatal, although i tdoes not mention whether thefatal case was associated with rifaximin or not. Since clostridium difficile produces toxins thatcan increase morbidi ty and mortali ty in pat ients who are aff licted, i t is recommended not touse antibiotics that are not targeted toward clostridium difficile.Similarly, with traveler's diarrhea - the only organism that was studied and shown to besusceptible to rifaximin was e. col i. Using rifaximin in a case of diarrhea that is not contr ibutedto e. col i could be dangerous i f the diarrhea issevere and hydration status iscompromised.

this isaccording to the package insert from the manufacturer, not the clinical trial iufo. ..The severe hepatic dysfunction can reduce clearance of the drug from the body, leading toincreased systemic exposure. In most cases, the drug is not absorbed into the body, so thismay be a source of additional toxicity.I t is possible that bacteria can become resistant to rifaximin. Inthis case, i t is recommended tonot use rifaximin without a proven bacterial infection, strongly suspected bacterial infection, orprophylactic indicat ion so as to avoid the risk of developing resistance inthe drug.For the last three l isted warnings, the main problem isthat they have not been studied. I tdidshow some teratogenicity in rats and rabbi ts, but they were studied at doses that causedmaternal toxicity anyway. It is recommended to avoid rifaximin in pregnancy unless the benefitisgreater than the risk.

Others:lymphocytosis, monocytosis,neutropenia, ear pain, motion sickness,tinnitus, abdominal distention, drythroat, fecal abnormality, gingivaldisorder, inguinal hernia, dry l ips,stomach discomfort, chest pain,fatigue, malaise, weakness, URI,sunburn, blood in stool/urine, arthralgia,muscle spasms, myalgia, neck pain,syncope, choluria, dysuria, hematuria,etc ...


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Clinical Studies: Hepatic Encephalopathy

,NumberXJFAXANTablets,600 mg/day Placebo

N=320 N=22836 (11%) 45(20%)31 (10%) 21 (9%)23 (7%) 23(10%)23 (7%) 2t) (9%)9 (6%) 21 (9%7 (5%) 19 (8%)2 (4%) (4%)

(3%) 4%)%

Bucci L, Palmieri CG. Double-blind, double-dummy comparison between treat-mentwith rifaximin and lactulose in patients with medium to severe degree hepaticencephalopathy. Curr Med Res Opin 1993;13:109-18. MassaR,ValierinoE,DoderoM.Treatmentofhepaticencephalopathywithrifaximin: double-blind, double-dummy studyversus lactulose. Eur J Clin Res 1993;4:4-18. Pedretti G, Calzetti C, Missale G, et al. Rifaximin versus neomycin on hyperam-monemia in chronic portal systemic encephalopathy of cirrhosis: a double-blind,randomized trial. Ital J Gastroenterol 1991 ;23:175-8. Festi D, Mazzella G, Orsini M,et al. Rifaximin inthe treatment ofchronichepatic encephalopathy: results of a multicenter study of efficacy and safety. CurrTher Res Clin Exp 1993;54:598-609. Alcorn J. Review: rifaximin is equally or more effective than other antibioticsand lactulose for hepatic encephalopathy. ACP J Club 2008;149(5):11.

This table shows the incidence of adverse reactions that occurred in atleast two percent of the population. The studied dose was 600 mg/day,which is the traveler's diarrhea dosing, and is about half of the hepaticencephalopathy prevention total daily dosing.Notice that 6 categories have higher incidence (percentage-wise) of sideeffects with placebo, two categories have the same percent incidence, andonly two categories show a greater percent of incidence of side effects forrifaximin versus placebo.

Hepatic encephalopathy occurs when the liver cannot remove toxicsubstances, like ammonia, from the body in an efficient manner, due tocirrhosis, hepatitis, liver disease, or other reasons. 'Encephalopathy'describes the neurologic nature of the symptoms of hepaticencephalopathy, which include changes in sleep, changes in thinking, mildconfusion, forgetfulness, mental 'fogginess', personality changes, moodchanges, poor concentration or judgment, loss of small hand movements,abnormal shaking of hands or arms, agitation, excitement, seizures (rare),disorientation, slurred speech, etc. The patient who has hepaticencephalopathy can become unconscious, unresponsive, or potentiallycomatose.Inclinical trials, rifaximin has been shown to be as effective or even moreeffective than lactulose. However, some trials did not optimize the lactulosedose. Since lactulose binds to ammonia and rifaximin prevents formation ofammonia by killing the bacteria that make it, this might make the resultslook more positive than is realistic.The trials have shown efficacy, but considering cost makes peoplereluctant to consider rifaximin a first-line therapy. There is also a possibilityof resistance, and antibiotic associated diarrhea.


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Clinical Studies: Traveler's Diarrhea Clinical Studies: C . difficile-associated diarrhea

DuPont, H; Jiang, Z; Ericsson, C; Adachi, J; Mathewson,J; DuPont, M; Palazzini, E; Riopel, L; Ashley, D; Mart inez-Sandoval, F. Rifaximin versus Ciprofloxacin for theTreatment of Traveler's Diarrhea: A Randomized,Double-Blind Clinical Trial. Clin Inf Dis 2001; 22:1807-15

Dhara Shah, Minh-Duc Dang, Rodrigo Hasbun, Hoonmo Koo,Zhi-Dong Jiang,Herbert DuPont, Kevin Garey. Clostridium dif fici le infection: update onemergingantibiotic treatment opt ions and antibiotic resistance. Pub: Expert Review ofAnti-Infect ive Therapy 2010.

DuPont, H; Jiang, Z; Okhuysen, P; Ericsson, C; de laCabada, J; Ke, 5; DuPont, M; Martinez-Sandoval, F.Antibacterial Chemoprophylaxis in the Prevention ofTraveler's Diarrhea: Evaluation of Poorly Absorbed OralRifaximin. Cl in Inf Dis 2005; 41:5571-6

Kevin Garey, Miguel Salazar, Dhara Shah, Richard Rodrigue, Herbert DuPont.Rifamycin Antibiotics for Treatment of Clostridium difficile-associated Diarrhea.The Annals of Pharmacotherapy. 2008, Vol 42:827-835

Jenni fer O'Connor, Minerva Galang, Susan Sambol, David Hecht, GayatriVedantam, Dale Gerding, Stuart Johnson. Rifampin and Rifaximin Resistance inClinical Isolates of Clostridium difficile. Antimicrobial Agents and Chemotherapy.2008; 52:2813-2817

Inthis f irst trial , 187 students in Mexico or Jamaica, all f rom the United States, were studiedfor efficacy of rifaximin in traveler's diarrhea, compared to the already established efficacy ofciprofloxacin. The overall results were that there were no significant differences in clinicalimprovement for one drug or the other, over the f irst 24 hours. There were also no signi ficantdifference infailure to respond to antibiotics, and in achievement of a microbiological cure.Adverse effect incidence was low in both groups. Some of the bacteria that were isolated frompatients in the trial included shigella, enterotoxigenic e. coli, salmonella, shigella,cryptosporidium, campylobacter jejuni, entamoeba, and some combinations of the above. Theenterotoxigenic strains of e. col i had the highest l ikel ihood offailure to cure in both groups. Iwould say that one of the l imitat ions of this trial isthat i twas not placebo control led, so we donot know how much of the data to contr ibute to sel f- limi ting infection and how much toattribute to the drugs themselves.

Clostridium difficile infection (COl) is the most common cause of ident if iable d iarrhea in hospita lized pat ients. COl isanevo lv ing pathogen with h igh incidence and severi ty . In vitro resistance to ant ib io tics used for the t reatment o fCOl continues tobe low; however, resistance among certa in strains has been ident if ied . Unfortunate ly, up to 50% of pat ients experienceref ractory or recurrent COAD, which has been att ribu ted to the emergence of a new hypervirulen t strain and an increasinglycomplex and older patient population.Rifaximin, a nonabsorbab le rifamycin, a lso d isplays potent act ivi ty aga inst C. difficile strains. Rifaximin ach ieves h ighconcentrat ions with in the bacteria, and may spare enteric f lora making i ta potential ly usefu l agent for a recurrence prevent ionstrategy. They a lso investiga ted the uti li ty o fa course of r ifax imin after a course of vancomycin for c lost ridium dif fic ileinfection . These were main ly case studies, however, and there fore cannot be used to general ize t reatment data.The study comparing ri famycin deriva tive ant ib io tics was mainly looking at the minimum inh ib itory concent rat ions of therifamycin ant ib io tic to those of metron idazole and vancomycin. Rifaximin showed a much lower MIC-50 than e ithervancomycin or metronidazo le , but the MIC-90 was signi ficant ly h igher.The las t s tu dy loo ked a t how res is ta nce i sdeve loped in c los tr id ia species . The RpoB gene isma in ly respons ib le f orresistance, and they authors postu la ted that i tdeve lops independent ly rather than becoming d isseminated f rom otherresistant c lones. They a lso confirmed that resistance to ri fampin general ly confers resistance to ri faximin .

The second study isdone bythe same group of people. Th is t ime it was not compared head-to-head with any other drugs, but they did show eff icacy in the prevention of traveler'sdiarrhea. However, without a head-to-head trial , we do not know ifthis isvery applicable.They did mention use of r ifaximin in place of ciprofloxacin, in areas where there is resistanceto ciprofloxacin, specifically the campylobacter strains in Thailand. At this time, rifaximin is nota f irst-l ine therapy for traveler's diarrhea, and due to cost is unl ikely to become one inthe nearfuture. I believe itwill be reserved for places like Thailand which are harboring ciprofloxacin-resistant strains of bacteria, or for patients with allergic reacnons to other antibiotics.


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Clinical Studies: Diverticulitis Clinical Studies: Others PapiC,CiacoA, KochM, et al.Efficacy of rifaximin onsymptomsof uncompli-cated diverticular diseaseof the colon.A pilot multicentre opentrial.Diverticular DiseaseStudy Group.Ital JGastroenterol1992; 24: 452-6.

Ir ri table Bowel Syndromeo Kimberly Low, Laura Hwang, Johnson Hua, Amy Zhu, WalterMorales, Mark Pimentel. A Combination of Rifaximin and NeomycinisMost Effec tive inTreating I rr itable Bowel Syndrome Pat ientswith Methane onLactu lose Breath Test . J Cl in Gastroenterol 2010;44:547-550

PapiC,CiacoA, KochM, et al. Efficacy of rifaximin inthe treatment of symp-tomatic diverticular diseaseof the colon.A multicenter double-blindplacebo-con-trolled trial. Aliment PharmacolTher 1995;9: 33-9.

Latella G,PimpoMT,Sottili S,et al.Rif- aximinimprovessymptomsof acquireduncomplicateddiverticular diseaseof the colon.Int J Colorectal Dis2003; 18:55-62. Small Intestinal Bacterial Overgrowth

o Patrizio Petrone, Grand Sarkisyan, Maura Fernandez, EileenColome, Gabriel Akopian, Adrian Ortega, Howard Kaufman. SmallIntest inal Bacterial Overgrowth inPatients wi th LowerGastrointestinal Symptoms and a History of Previous AbdominalSurgery. Arch Surg. 2011; 146(4):444-447

ColecchiaA, Vestito A,PasquiF, et al.Efficacy of longterm administrration ofthe poorlyabsorbedantibiotic rifaximin in symptomatic, uncomplicatedcolonicdiverticular disease.World J Gastroenterol 2007; 13:264-9.

These four trials were combined into a meta-analysis that concludedrifaximin (plus fiber supp lements) is an effective treatment to providesymptom relief and prevent complications from diverticulitis for a year.However, earlier this year an application was submitted to the FDA to adddiverticulitis to the possible indications for rifaximin, but was rejected forlack of follow-up. Diverticulitis tends to be a long-term disease, and thosewho complain of symptoms often have significantly long periods of timebetween bouts of active problems. The results were determined to bestatistica lly relevant, but not c linically relevant.

Diagnosing SIBO is a very dif ficult and controversial issue; there is no goldstandard. This is partly due to the fact that the etiology sti ll remains unknown. SIBOmay be diagnosed by a noninvasive breath test. The condition of SIBO has beenassociated with irr itable bowel syndrome (IBS) and a variety of autonomicsymptoms.

The meta-analysis that concluded that these four trials showed a benefitstated right in the discussion that their accuracy is limited by the quality ofthe trials that are included, implying that at least one of the trials is poorlydesigned. They state that this can lead to overestimation of the effect ofrifaximin.

The overall IBS improvement (clinical response) of the neomycin and rifaximincombination group was compared individually with the rifaximin only group and theneomycin only group. The measurement was whether the methane breath test wasposit ive after treatment. Subjects who had a fai led initial response to rifaximin andsubsequently received rifaximin and neomycin combination treatment were alsoanalyzed to evaluate their breath test normalization. There was no significantdif ference between rifaximin alone and neomycin alone, but itdid show astatistically significant improvement when the two were used in combination.


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MUE: Me thods Retrospective Chart Review (data gathered):

o patient informationo date of admissiono date of dischargeo original order (date, start time, stop time)o medication (route, frequency, strength)o chargeo indicationo physician ordering physician specialty

o number of doses administered

Since rifaximin had been inthe top 10 non-formulary drug for thepharmacy spend over the past 4 months, it was suggested that we addthe drug to formulary. At the time of the recommendation, rifaximin has two FDA-approvedindications: prevention of recurrence of Traveler's diarrhea and hepaticencephalopathy. However, it has been used for other indications such as: IBS,diverticulitis, and C. Diff. resistant to metronidazole although clinicalevidence has not shown significant efficacy in these indications. The drug isone with high cost and supposedly l imited use, so itwasthought that we might ultimately restrict the use of rifaximin to certainspecialties and physicians. The final recommendation in June was to hold off on formulary additionunti l i t is clear what we are using the medication at this point

I was able to gather most of this information from the combined medicalrecord and some from centricity and sentri7. The physician specialty Iusually looked up, some on the ministry website and some on MarshfieldClinic's websites.Itwas difficult to determine a few of the pieces of information that I needed,like the indication, number of doses given, and original ordering physician,due to limitations of documentation that was available to me at the time.


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MUE: Methods MUE: Results Research questions:

o Is the prescribing physician a gastroenterology orhepatology specialist?o At what point intherapy was rifaximin introduced?

o Is the dosing appropriate for the intended use?o What was the duration of therapy?o What monitoring parameters were employed?o Were drug interactions assessed?

15 total patientsprescribed 14 courses 1 ID physician 3 differentgastroenterologyspecialists (pediatric;gastroenterology &hepatology specialist)

I asked the questions for specific reasons. The question about specialtiesapplies because the more common condition for which rifaximin is used(hepatic encephalopathy) should be addressed by a specialist, who couldbe either a gastroenterology specialist, or a liver specialist.The point in therapy that rifaximin is usually intended to be used would besecond line for hepatic encephalopathy, but depending on the severity ofthe traveler's diarrhea it could be first line.Appropriate dosing and duration I am sure we all understand as a part ofantibiotic stewardship.Monitoring and drug interactions were more difficult to find answers forthose questions, because rarely does a chart explicitly detail those.

Indications: GI bleeding cryptogenic l iver cirrhosis &

V R E hyperammonemia small bowel bacterialovergrowth

abdominal distention hepatic encephalopathy hepatitis C cirrhosis "obtunded state,decompensated liver disease"

. not defined

A total of 15 patients were prescribed a total of 14 courses ofrifaximin by physicians at Ministry St. Joseph's Hospital betweenJanuary 1st, 2011 and June 27th, 2011. One patient did not receiveany doses of rifaximin; one patient was prescribed rifaximin beforetransfer from another facility (transferred for unrelated reasons); andone patient received two courses of rifaximin, about one monthapart.


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MUE: C ost-Benefit Analysis MUE: Analysis & Discussion Bil ling for FDA-approved indication

035 doseso approximately $370

Bil ling for non-FDA-approved indication0172 doses0$5186

Total spendo 80% was used in unapproved or unproven treatment

Reason for MUE:o to ensure appropriate prescribingo address potential cost savingso maximize patient benefit from drug

6 patient charts had FDA-approved indications Place in therapy not clear Lactulose common prior/concomitant therapy

Almost 90% of the dollar amount bi lled was due to a use that is either notapproved or not known to be an effective treatment. Eighty percent or moreof the dollar amount spent by pharmacy was for rifaximin that wasprescribed for an unapproved or unproven treatment.

The drug use evaluation was employed in this situation to ensure appropriateprescribing of rifaximin, as well as address potential cost savings, all withoutminimizing patient benefit from use of the drug.FDAapproved indications specify use in prevention ofhepaticencephalopathy and non-invasive travelers diarrhea caused by E.coli. Ofthefifteen patients and sixteen admissions for the study period, only six patientcharts had an indication for which rifaximin could be used (hepaticencephalopathy, hyperammonemia), accounting for 35 doses.There were two patients who appear to have used rifaximin for a known, off-label use where the efficacy of rifaximin in those disease states has not beenproven (diverticulitis, clostridium difficile infection). Over 80% ofthe drugcost that was dispensed to patients was accounted for by patients takingrifaximin for reasons that are currently not approved uses.The place in therapy is not clearly indicated for many patients, althoughseveral patients who had a long-term prescription for rifaximin had had othertreatments for the same disease state in the past. The most common previoustherapy for hepatic encephalopathy and hyperammonemia patients waslactulose, which inhibits diffusion of ammonia into the blood from the gut andenhances removal ofammonia from the blood to the gut. Itwas often usedconcurrently with rifaximin.


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Establish a protocol (preprinted orders) for use of rifaximin, which statesspecifically that rifaximin is FDA-approved and has shown efficacy ONLYinthe prevention ofhepatic encephalopathy and treatment of noninvasivetravelers' diarrhea.All physicians shall retain the ability to prescribe rifaximin for hepaticencephalopathy and (noninvasive, E.coli) travelers' diarrhea.Gastroenterology specialists and hepatology specialists will have the ability touse rifaximin for expanded indications as appropriate. However, ifthe drug isprescribed "off-label", the prescribing physician must document thespecific indication and/or rationale for prescribing.

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