58 % 50 % REDUCTION IN RISK OF OVERT HE RECURRENCE 1

Transcription

1 FOR ADULT PATIENTS WITH OVERT HEPATIC ENCEPHALOPATHY (HE) significntly reduced the risk of overt HE recurrence nd HE-relted hospitliztions 1 58 % 50 % REDUCTION IN RISK OF OVERT HE RECURRENCE 1 REDUCTION IN RISK OF HE-RELATED HOSPITALIZATIONS 1 Adding to lctulose therpy hs been proven to lower the risk of overt HE recurrences nd HE-relted hospitliztions. 1 Lctulose ws used concomitntly by 91% of ptients in both rms of the study. 1 Study Design 1 : In rndomized, plcebo-controlled, double-blind, multicenter, multintionl, 6-month study, the efficcy of 550 mg (tken orlly twice dy) ws evluted in 299 dult subjects. Inclusion criteri: currently in remission (Conn score of 0 or 1) from HE nd 2 episodes of HE ssocited with chronic liver disese in the previous 6 months. The primry endpoint ws the time to first brekthrough overt HE episode, defined s mrked deteriortion in neurologicl function (n increse of Conn score to grde 2 or n increse in Conn score nd sterixis grde of 1 ech if subject entered study t grde 0). Overt HE hospitliztion ws key secondry endpoint. IS ENDORSED BY AASLD GUIDELINES see bck for more informtion INDICATION (rifximin) 550 mg tblets re indicted for the reduction in risk of overt heptic encephlopthy (HE) recurrence in dults. IMPORTANT SAFETY INFORMATION is contrindicted in ptients with hypersensitivity to rifximin, rifmycin ntimicrobil gents, or ny of the components in. Hypersensitivity rections hve included exfolitive dermtitis, ngioneurotic edem, nd nphylxis. Clostridium difficile-ssocited dirrhe (CDAD) hs been reported with use of nerly ll ntibcteril gents, including, nd my rnge in severity from mild dirrhe to ftl colitis. If CDAD is suspected or confirmed, ongoing ntibiotic use not directed ginst C. difficile my need to be discontinued. There is n incresed systemic exposure in ptients with severe (Child-Pugh Clss C) heptic impirment. Cution should be exercised when dministering to these ptients. Cution should be exercised when concomitnt use of nd P-glycoprotein (P-gp) nd/or OATPs inhibitors is needed. Concomitnt dministrtion of cyclosporine, n inhibitor of P-gp nd OATPs, significntly incresed the systemic exposure of rifximin. In ptients with heptic impirment, potentil dditive effect of reduced metbolism nd concomitnt P-gp inhibitors my further increse the systemic exposure to rifximin. Plese see dditionl Importnt Sfety Informtion on the following pge nd ccompnying full Prescribing Informtion.

2 significntly reduced the risk of overt HE recurrence nd HE-relted hospitliztions 1 Despite tretment with lctulose, HE my recur 2 Subjects with recurrent overt heptic encephlopthy hve 40% cumultive risk of nother recurrence within 6 months, despite lctulose tretment. WAS GIVEN THE HIGHEST POSSIBLE RECOMMENDATION (GRADE I, A, 1) AS AN ADD-ON THERAPY TO LACTULOSE TO REDUCE THE RISK OF OVERT HE RECURRENCE 2 Rifximin dded to lctulose is the best-documented gent to mintin remission in ptients who hve lredy experienced one or more bouts of overt heptic encephlopthy while on lctulose tretment fter their initil episode of overt heptic encephlopthy. Postdischrge consulttions re recommended to ssess ongoing mngement nd ddress potentil side effects 2 Out-ptient postdischrge consulttions should be plnned to djust mngement nd prevent the reppernce of precipitting fctors. Close liison should be mde with the ptient s fmily, the generl prctitioner, nd other cregivers in the primry helth service, so tht ll prties involved understnd how to mnge HE in the specific ptient nd reduce the risk of HE-relted hospitliztions. Secondry prophylxis is recommended fter n episode of overt heptic encephlopthy (GRADE I, A, 1) 2 There is nerly uniform policy to continue tretment indefinitely fter it hs successfully reversed bout of overt heptic encephlopthy. The concept my be tht once the threshold for overt heptic encephlopthy is reched, then ptients re t high risk for recurrent episodes. This risk ppers to worsen s liver function deteriortes. * * The sfety nd efficcy of in HE hs not been studied beyond 6 months in rndomized, plcebo controlled clinicl trils. 1 If ptients recover significnt mount of liver function, they my discontinue HE therpy. 2 References: 1. [prescribing informtion]. Bridgewter, NJ: Slix Phrmceuticls. 2. Vilstrup H, Amodio P, Bjj J, et l. Heptic encephlopthy in chronic liver disese: 2014 prctice guideline by the Americn Assocition for the Study of Liver Diseses nd the Europen Assocition for the Study of the Liver. Heptology. 2014;60(2): IMPORTANT SAFETY INFORMATION (continued) In clinicl studies, the most common dverse rections for were: - HE ( 10%): Peripherl edem (15%), nuse (14%), dizziness (13%), ftigue (12%), nd scites (11%) -IBS-D ( 2%): Nuse (3%), ALT incresed (2%) INR chnges hve been reported in ptients receiving rifximin nd wrfrin concomitntly. Monitor INR nd prothrombin time. Dose djustment of wrfrin my be required. my cuse fetl hrm. Advise pregnnt women of the potentil risk to fetus. To report SUSPECTED ADVERSE REACTIONS, contct Slix Phrmceuticls t or FDA t FDA-1088 or Plese see ccompnying full Prescribing Informtion. Slix Phrmceuticls 400 Somerset Corporte Blvd., Bridgewter, NJ Tel SLXP (7597), Website: The 550 mg product nd the trdemrk re licensed by Alfsigm S.p.A. to Slix Phrmceuticls or its ffilites. XIF.0035.USA.18

3 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include ll the informtion needed to use sfely nd effectively. See full prescribing informtion for. (rifximin) tblets, for orl use Initil U.S. Approvl: 2004 To reduce the development of drug-resistnt bcteri nd mintin the effectiveness of nd other ntibcteril drugs, should be used only to tret or prevent infections tht re proven or strongly suspected to be cused by bcteri INDICATIONS AND USAGE is rifmycin ntibcteril indicted for: of trvelers dirrhe (TD) cused by noninvsive strins of Escherichi coli in dult nd peditric ptients 12 yers of ge nd older (1.1) Reduction in risk of overt heptic encephlopthy (HE) recurrence in dults (1.2) of irritble bowel syndrome with dirrhe (IBS-D) in dults (1.3) Limittions of Use TD: Do not use in ptients with dirrhe complicted by fever or blood in the stool or dirrhe due to pthogens other thn Escherichi coli (1.1, 5.1) DOSAGE AND ADMINISTRATION Condition Recommended Dosge Regimen TD (2.1) One 200 mg tblet 3 times dy for 3 dys HE (2.2) One 550 mg tblet 2 times dy IBS-D (2.3) One 550 mg tblet 3 times dy for 14 dys. Ptients who experience recurrence cn be retreted up to two times with the sme regimen. cn be tken with or without food. (2.4) DOSAGE FORMS AND STRENGTHS mg nd 550 mg tblets (3) FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Trvelers Dirrhe 1.2 Heptic Encephlopthy 1.3 Irritble Bowel Syndrome with Dirrhe 2 DOSAGE AND ADMINISTRATION 2.1 Dosge for Trvelers Dirrhe 2.2 Dosge for Heptic Encephlopthy 2.3 Dosge for Irritble Bowel Syndrome with Dirrhe 2.4 Administrtion 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Trvelers Dirrhe Not Cused by Escherichi coli 5.2 Clostridium difficile-associted Dirrhe 5.3 Development of Drug-Resistnt Bcteri 5.4 Severe (Child-Pugh Clss C) Heptic Impirment 5.5 Concomitnt Use with P-glycoprotein Inhibitors 6 ADVERSE REACTIONS 6.1 Clinicl Studies Experience 6.2 Postmrketing Experience 7 DRUG INTERACTIONS 7.1 P-glycoprotein Inhibitors 7.2 Wrfrin 7.3 CYP3A4 Substrtes FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE To reduce the development of drug-resistnt bcteri nd mintin the effectiveness of nd other ntibcteril drugs, when used to tret infection should be used only to tret or prevent infections tht re proven or strongly suspected to be cused by susceptible bcteri. When culture nd susceptibility informtion re vilble, they should be considered in selecting or modifying ntibcteril therpy. In the bsence of such dt, locl epidemiology nd susceptibility ptterns my contribute to the empiric selection of therpy. 1.1 Trvelers Dirrhe is indicted for the tretment of trvelers dirrhe (TD) cused by noninvsive strins of Escherichi coli in dults nd peditric ptients 12 yers of ge nd older. Limittions of Use should not be used in ptients with dirrhe complicted by fever or blood in the stool or dirrhe due to pthogens other thn Escherichi coli [see Wrnings nd Precutions (5.1), Clinicl Phrmcology (12.4), Clinicl Studies (14.1)]. 1.2 Heptic Encephlopthy is indicted for reduction in risk of overt heptic encephlopthy (HE) recurrence in dults. In the trils of for HE, 91% of the ptients were using lctulose concomitntly CONTRAINDICATIONS History of hypersensitivity to rifximin, rifmycin ntimicrobil gents, or ny of the components of (4) WARNINGS AND PRECAUTIONS Trvelers Dirrhe Not Cused by E. coli: ws not effective in dirrhe complicted by fever nd/or blood in the stool or dirrhe due to pthogens other thn E. coli. If dirrhe symptoms get worse or persist for more thn 24 to 48 hours, discontinue nd consider lterntive ntibiotics (5.1) Clostridium difficile-associted Dirrhe: Evlute if dirrhe occurs fter therpy or does not improve or worsens during therpy (5.2) Heptic Impirment: Use with cution in ptients with severe (Child-Pugh Clss C) heptic impirment (5.4, 8.7) Concomitnt P-glycoprotein (P-gp) inhibitors (e.g., cyclosporine): Cution should be exercised when concomitnt use of nd P-glycoprotein inhibitor is needed (5.5, 7.1) ADVERSE REACTIONS Most common dverse rections: TD ( 2%): Hedche (6.1) HE ( 10%): Peripherl edem, nuse, dizziness, ftigue, nd scites (6.1) IBS-D ( 2%): ALT incresed, nuse (6.1) To report SUSPECTED ADVERSE REACTIONS, contct Slix Phrmceuticls, division of Vlent Phrmceuticls North Americ LLC, t nd or FDA t FDA-1088 or DRUG INTERACTIONS Wrfrin: Monitor INR nd prothrombin time; dose djustment of wrfrin my be needed to mintin trget INR rnge. (7.2) USE IN SPECIFIC POPULATIONS Pregnncy: My cuse fetl hrm (8.1) See 17 for PATIENT COUNSELING INFORMATION. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnncy 8.2 Lcttion 8.4 Peditric Use 8.5 Geritric Use 8.6 Renl Impirment 8.7 Heptic Impirment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechnism of Action 12.3 Phrmcokinetics 12.4 Microbiology 13 NONCLINICAL TOXICOLOGY 13.1 Crcinogenesis, Mutgenesis, Impirment of Fertility 14 CLINICAL STUDIES 14.1 Trvelers Dirrhe 14.2 Heptic Encephlopthy 14.3 Irritble Bowel Syndrome with Dirrhe 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION Revised: 01/2018 *Sections or subsections omitted from the full prescribing informtion re not listed s in the tretment effect of those ptients not using lctulose concomitntly could not be ssessed. hs not been studied in ptients with MELD (Model for End-Stge Liver Disese) scores >25, nd only 8.6% of ptients in the controlled tril hd MELD scores over 19. There is incresed systemic exposure in ptients with more severe heptic dysfunction [see Wrnings nd Precutions (5.4), Use in Specific Popultions (8.7), Clinicl Phrmcology (12.3)]. 1.3 Irritble Bowel Syndrome with Dirrhe is indicted for the tretment of irritble bowel syndrome with dirrhe (IBS-D) in dults. 2 DOSAGE AND ADMINISTRATION 2.1 Dosge for Trvelers Dirrhe The recommended dose of is one 200 mg tblet tken orlly three times dy for 3 dys. 2.2 Dosge for Heptic Encephlopthy The recommended dose of is one 550 mg tblet tken orlly two times dy. 2.3 Dosge for Irritble Bowel Syndrome with Dirrhe The recommended dose of is one 550 mg tblet tken orlly three times dy for 14 dys. Ptients who experience recurrence of symptoms cn be retreted up to two times with the sme dosge regimen.

4 2.4 Administrtion cn be tken with or without food [see Clinicl Phrmcology (12.3)]. 3 DOSAGE FORMS AND STRENGTHS is pink-colored biconvex tblet nd is vilble in the following strengths: 200 mg round tblet debossed with Sx on one side nd plin on the other. 550 mg n ovl tblet debossed with rfx on one side nd plin on the other. 4 CONTRAINDICATIONS is contrindicted in ptients with hypersensitivity to rifximin, ny of the rifmycin ntimicrobil gents, or ny of the components in. Hypersensitivity rections hve included exfolitive dermtitis, ngioneurotic edem, nd nphylxis [see Adverse Rections (6.2)]. 5 WARNINGS AND PRECAUTIONS 5.1 Trvelers Dirrhe Not Cused by Escherichi coli ws not found to be effective in ptients with dirrhe complicted by fever nd/or blood in the stool or dirrhe due to pthogens other thn Escherichi coli. Discontinue if dirrhe symptoms get worse or persist more thn 24 to 48 hours nd lterntive ntibiotic therpy should be considered. is not effective in cses of trvelers dirrhe due to Cmpylobcter jejuni. The effectiveness of in trvelers dirrhe cused by Shigell spp. nd Slmonell spp. hs not been proven. should not be used in ptients where Cmpylobcter jejuni, Shigell spp., or Slmonell spp. my be suspected s custive pthogens [see Indictions nd Usge (1.1)]. 5.2 Clostridium difficile-associted Dirrhe Clostridium difficile-ssocited dirrhe (CDAD) hs been reported with use of nerly ll ntibcteril gents, including, nd my rnge in severity from mild dirrhe to ftl colitis. with ntibcteril gents lters the norml flor of the colon which my led to overgrowth of C. difficile. C. difficile produces toxins A nd B which contribute to the development of CDAD. Hypertoxin producing strins of C. difficile cuse incresed morbidity nd mortlity, s these infections cn be refrctory to ntimicrobil therpy nd my require colectomy. CDAD must be considered in ll ptients who present with dirrhe following ntibiotic use. Creful medicl history is necessry since CDAD hs been reported to occur over two months fter the dministrtion of ntibcteril gents. If CDAD is suspected or confirmed, ongoing ntibiotic use not directed ginst C. difficile my need to be discontinued. Approprite fluid nd electrolyte mngement, protein supplementtion, ntibiotic tretment of C. difficile, nd surgicl evlution should be instituted s cliniclly indicted. 5.3 Development of Drug-Resistnt Bcteri Prescribing for trvelers dirrhe in the bsence of proven or strongly suspected bcteril infection or prophylctic indiction is unlikely to provide benefit to the ptient nd increses the risk of the development of drug-resistnt bcteri. 5.4 Severe (Child-Pugh Clss C) Heptic Impirment There is incresed systemic exposure in ptients with severe heptic impirment. The clinicl trils were limited to ptients with MELD scores <25. Therefore, cution should be exercised when dministering to ptients with severe heptic impirment (Child-Pugh Clss C) [see Use in Specific Popultions (8.7), Clinicl Studies (14.2)]. 5.5 Concomitnt Use with P-glycoprotein Inhibitors Concomitnt dministrtion of drugs tht re P-glycoprotein (P-gp) inhibitors with cn substntilly increse the systemic exposure to rifximin. Cution should be exercised when concomitnt use of nd P-gp inhibitor such s cyclosporine is needed. In ptients with heptic impirment, potentil dditive effect of reduced metbolism nd concomitnt P-gp inhibitors my further increse the systemic exposure to rifximin [see Drug Interctions (7.1), Clinicl Phrmcology (12.3)]. 6 ADVERSE REACTIONS 6.1 Clinicl Studies Experience Becuse clinicl trils re conducted under widely vrying conditions, dverse rection rtes observed in the clinicl trils of drug cnnot be directly compred to rtes in the clinicl trils of nother drug nd my not reflect the rtes observed in prctice. Trvelers Dirrhe The sfety of 200 mg tken three times dy ws evluted in ptients with trvelers dirrhe consisting of 320 ptients in two plcebo-controlled clinicl trils with 95% of ptients receiving three or four dys of tretment with. The popultion studied hd men ge of 31.3 (18-79) yers of which pproximtely 3% were 65 yers old, 53% were mle nd 84% were White, 11% were Hispnic. Discontinutions due to dverse rections occurred in 0.4% of ptients. The dverse rections leding to discontinution were tste loss, dysentery, weight decrese, norexi, nuse nd nsl pssge irrittion. The dverse rection tht occurred t frequency 2% in -treted ptients (n=320) t higher rte thn plcebo (n=228) in the two plcebo-controlled trils of TD ws: hedche (10%, 9% plcebo) Heptic Encephlopthy The dt described below reflect exposure to in 348 ptients, including 265 exposed for 6 months nd 202 exposed for more thn yer (men exposure ws 364 dys). The sfety of 550 mg tken two times dy for reducing the risk of overt heptic encephlopthy recurrence in dult ptients ws evluted in 6-month plcebo-controlled clinicl tril (n=140) nd in long term follow-up study (n=280). The popultion studied hd men ge of 56 (rnge: 21 to 82) yers; pproximtely 20% of the ptients were 65 yers old, 61% were mle, 86% were White, nd 4% were Blck. Ninety-one percent of ptients in the tril were tking lctulose concomitntly. The most common dverse rections tht occurred t n incidence 5% nd t higher incidence in -treted subjects thn in the plcebo group in the 6-month tril re provided in Tble 1. Tble 1: Most Common Adverse Rections* in HE Tril Number (%) of Ptients Tblets MedDRA Preferred Term 550 mg TWICE DAILY n=140 n=159 Peripherl edem 21 (15%) 13 (8%) Nuse 20 (14%) 21 (13%) Dizziness 18 (13%) 13 (8%) Ftigue 17 (12%) 18 (11%) Ascites 16 (11%) 15 (9%) Muscle spsms 13 (9%) 11 (7%) Pruritus 13 (9%) 10 (6%) Abdominl pin 12 (9%) 13 (8%) Anemi 11 (8%) 6 (4%) Depression 10 (7%) 8 (5%) Nsophryngitis 10 (7%) 10 (6%) Abdominl pin upper 9 (6%) 8 (5%) Arthrlgi 9 (6%) 4 (3%) Dyspne 9 (6%) 7 (4%) Pyrexi 9 (6%) 5 (3%) Rsh 7 (5%) 6 (4%) * reported in 5% of Ptients Receiving nd t higher incidence thn plcebo Irritble Bowel Syndrome with Dirrhe The sfety of for the tretment of IBS-D ws evluted in 3 plcebo-controlled studies in which 952 ptients were rndomized to 550 mg three times dy for 14 dys. Across the 3 studies, 96% of ptients received t lest 14 dys of tretment with. In Trils 1 nd 2, 624 ptients received only one 14-dy tretment. Tril 3 evluted the sfety of in 328 ptients who received 1 open-lbel tretment nd 2 double-blind repet tretments of 14 dys ech over period of up to 46 weeks. The combined popultion studied hd men ge of 47 (rnge: 18 to 88) yers of whom pproximtely 11% of the ptients were 65 yers old, 72% were femle, 88% were White, 9% were Blck nd 12% were Hispnic. The dverse rection tht occurred t frequency 2% in -treted ptients t higher rte thn plcebo in Trils 1 nd 2 for IBS-D ws: nuse (3%, 2% plcebo) The dverse rections tht occurred t frequency 2% in -treted ptients (n=328) t higher rte thn plcebo (n=308) in Tril 3 for IBS-D during the doubleblind tretment phse were: ALT incresed ( 2%, plcebo 1%) nuse ( 2%, plcebo 1%) Less Common Adverse Rections The following dverse rections, presented by body system, were reported in less thn 2% of ptients in clinicl trils of TD nd IBS-D nd in less thn 5% of ptients in clinicl trils of HE: Heptobiliry disorders: Clostridium colitis Investigtions: Incresed blood cretine phosphokinse Musculoskeletl nd connective tissue disorders: mylgi 6.2 Postmrketing Experience The following dverse rections hve been identified during post-pprovl use of. Becuse these rections re reported voluntrily from popultion of unknown size, estimtes of frequency cnnot be mde. These rections hve been chosen for inclusion due to either their seriousness, frequency of reporting or cusl connection to. Infections nd Infesttions Cses of C. difficile-ssocited colitis hve been reported [see Wrnings nd Precutions (5.2)]. Generl Hypersensitivity rections, including exfolitive dermtitis, rsh, ngioneurotic edem (swelling of fce nd tongue nd difficulty swllowing), urticri, flushing, pruritus nd nphylxis hve been reported. These events occurred s erly s within 15 minutes of drug dministrtion.

5 7 DRUG INTERACTIONS 7.1 P-glycoprotein Inhibitors Concomitnt dministrtion of cyclosporine, n inhibitor of P-gp nd OATPs significntly incresed the systemic exposure of rifximin. In ptients with heptic impirment, potentil dditive effect of reduced metbolism nd concomitnt P-gp inhibitors my further increse the systemic exposure to rifximin. Cution should be exercised when concomitnt use of nd P-gp inhibitor such s cyclosporine is needed [see Wrnings nd Precutions (5.5), Clinicl Phrmcology (12.3)]. 7.2 Wrfrin Chnges in INR hve been reported postmrketing in ptients receiving rifximin nd wrfrin concomitntly. Monitor INR nd prothrombin time. Dose djustment of wrfrin my be needed to mintin trget INR rnge. See prescribing informtion for wrfrin. 7.3 CYP3A4 Substrtes An in vitro study hs suggested tht rifximin induces CYP3A4 [see Clinicl Phrmcology (12.3)]. However, in ptients with norml liver function, t the recommended dosing regimen is not expected to induce CYP3A4. It is unknown whether rifximin cn hve significnt effect on the phrmcokinetics of concomitnt CYP3A4 substrtes in ptients with reduced liver function who hve elevted rifximin concentrtions. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnncy Risk Summry There re no vilble dt on use in pregnnt women to inform ny drug ssocited risks. Tertogenic effects were observed in niml reproduction studies following dministrtion of rifximin to pregnnt rts nd rbbits during orgnogenesis t doses pproximtely 0.9 to 5 times nd 0.7 to 33 times, respectively of the recommended humn doses of 600 mg to 1650 mg per dy. In rbbits, oculr, orl nd mxillofcil, crdic, nd lumbr spine mlformtions were observed. Oculr mlformtions were observed in both rts nd rbbits t doses tht cused reduced mternl body weight gin [see Dt]. In the U.S. generl popultion, the estimted bckground risk of mjor birth defects nd miscrrige in cliniclly recognized pregnncies is 2 to 4% nd 15 to 20%, respectively. Advise pregnnt women of the potentil risk to fetus. Dt Animl Dt Rifximin ws tertogenic in rts t doses of 150 to 300 mg/kg (pproximtely 2.5 to 5 times the recommended dose for TD [600 mg per dy], nd pproximtely 1.3 to 2.6 times the recommended dose for HE [1100 mg per dy], nd pproximtely 0.9 to 1.8 times the recommended dose for IBS-D [1650 mg per dy] djusted for body surfce re). Rifximin ws tertogenic in rbbits t doses of 62.5 to 1000 mg/kg (pproximtely 2 to 33 times the recommended dose for TD [600 mg per dy], nd pproximtely 1.1 to 18 times the recommended dose for HE [1100 mg per dy], nd pproximtely 0.7 to 12 times the recommended dose for IBS-D [1650 mg per dy] djusted for body surfce re). These effects include cleft plte, gnthi, jw shortening, hemorrhge, eye prtilly open, smll eyes, brchygnthi, incomplete ossifiction, nd incresed thorcolumbr vertebre. A pre nd postntl development study in rts showed no evidence of ny dverse effect on pre nd postntl development t orl doses of rifximin up to 300 mg/kg per dy (pproximtely 5 times the recommended dose for TD [600 mg per dy], nd pproximtely 2.6 times the recommended dose for HE [1100 mg per dy], nd pproximtely 1.8 times the recommended dose for IBS-D [1650 mg per dy] djusted for body surfce re). 8.2 Lcttion Risk Summry There is no informtion regrding the presence of rifximin in humn milk, the effects of rifximin on the brestfed infnt, or the effects of rifximin on milk production. The development nd helth benefits of brestfeeding should be considered long with the mother s clinicl need for nd ny potentil dverse effects on the brestfed infnt from or from the underlying mternl condition. 8.4 Peditric Use The sfety nd effectiveness of hs not been estblished in peditric ptients less thn 12 yers of ge with TD or in ptients less thn 18 yers of ge for HE nd IBS-D. 8.5 Geritric Use Of the totl number of ptients in the clinicl study of for HE, 19% of ptients were 65 nd over, while 2% were 75 nd over. In the clinicl studies of IBS-D, 11% of ptients were 65 nd over, while 2% were 75 nd over. No overll differences in sfety or effectiveness were observed between these subjects nd younger subjects for either indiction. Clinicl studies with for TD did not include sufficient numbers of ptients ged 65 nd over to determine whether they respond differently thn younger subjects. Other reported clinicl experience hs not identified differences in responses between the elderly nd younger ptients, but greter sensitivity of some older individuls cnnot be ruled out. 8.6 Renl Impirment The phrmcokinetics of rifximin in ptients with impired renl function hs not been studied. 8.7 Heptic Impirment Following dministrtion of 550 mg twice dily to ptients with history of heptic encephlopthy, the systemic exposure (i.e., AUCτ) of rifximin ws bout 10-, 14-, nd 21-fold higher in those ptients with mild (Child-Pugh Clss A), moderte (Child-Pugh Clss B) nd severe (Child-Pugh Clss C) heptic impirment, respectively, compred to tht in helthy volunteers. No dosge djustment is recommended becuse rifximin is presumbly cting loclly. Nonetheless, cution should be exercised when is dministered to ptients with severe heptic impirment [see Wrnings nd Precutions (5.4), Clinicl Phrmcology (12.3), Clinicl Studies (14.2)]. 10 OVERDOSAGE No specific informtion is vilble on the tretment of overdosge with. In clinicl studies t doses higher thn the recommended dose (greter thn 600 mg per dy for TD, greter thn 1100 mg per dy for HE or greter thn 1650 mg per dy for IBS-D), dverse rections were similr in subjects who received doses higher thn the recommended dose nd plcebo. In the cse of overdosge, discontinue, tret symptomticlly, nd institute supportive mesures s required. 11 DESCRIPTION tblets contin rifximin, non-minoglycoside semi-synthetic, nonsystemic ntibiotic derived from rifmycin SV. Rifximin is structurl nlog of rifmpin. The chemicl nme for rifximin is (2S,16Z,18E,20S,21S,22R,23R,24R,25S,26S,27S,28E )- 5,6,21,23,25-penthydroxy-27-methoxy-2,4,11,16,20,22,24,26-octmethyl-2,7- (epoxypentdec-[1,11,13]trienimino)benzofuro[4,5-e]pyrido[1,2-á]-benzimidzole- 1,15(2H )-dione,25-cette. The empiricl formul is C 43 H 51 N 3 O 11 nd its moleculr weight is The chemicl structure is represented below: tblets for orl dministrtion re film-coted nd contin 200 mg or 550 mg of rifximin. Inctive ingredients: Ech 200 mg tblet contins colloidl silicon dioxide, disodium edette, glycerol plmitosterte, hypromellose, microcrystlline cellulose, propylene glycol, red iron oxide, sodium strch glycolte, tlc, nd titnium dioxide. Ech 550 mg tblet contins colloidl silicon dioxide, glycerol plmitosterte, microcrystlline cellulose, polyethylene glycol/mcrogol, polyvinyl lcohol, red iron oxide, sodium strch glycolte, tlc, nd titnium dioxide. 12 CLINICAL PHARMACOLOGY 12.1 Mechnism of Action Rifximin is n ntibcteril drug [see Clinicl Phrmcology (12.4)] Phrmcokinetics Absorption In helthy subjects, the men time to rech pek rifximin plsm concentrtions ws bout n hour nd the men C mx rnged 2.4 to 4 ng/ml fter single dose nd multiple doses of 550 mg. Trvelers Dirrhe Systemic bsorption of (200 mg three times dily) ws evluted in 13 subjects chllenged with shigellosis on Dys 1 nd 3 of three-dy course of tretment. Rifximin plsm concentrtions nd exposures were low nd vrible. There ws no evidence of ccumultion of rifximin following repeted dministrtion for 3 dys (9 doses). Pek plsm rifximin concentrtions fter 3 nd 9 consecutive doses rnged from 0.81 to 3.4 ng/ml on Dy 1 nd 0.68 to 2.26 ng/ml on Dy 3. Similrly, AUC 0-lst estimtes were 6.95 ± 5.15 ng h/ml on Dy 1 nd 7.83 ± 4.94 ng h/ml on Dy 3. is not suitble for treting systemic bcteril infections becuse of limited systemic exposure fter orl dministrtion [see Wrnings nd Precutions (5.1)]. Heptic Encephlopthy Men rifximin exposure (AUCτ) in ptients with history of HE ws pproximtely 12-fold higher thn tht observed in helthy subjects. Among ptients with history of HE, the men AUC in ptients with Child-Pugh Clss C heptic impirment ws 2-fold higher thn in ptients with Child-Pugh Clss A heptic impirment [see Wrnings nd Precutions (5.4) nd Use in Specific Popultions (8.7)]. Irritble Bowel Syndrome with Dirrhe In ptients with irritble bowel syndrome with dirrhe (IBS-D) treted with 550 mg three times dy for 14 dys, the medin T mx ws 1 hour nd men C mx nd AUC were generlly comprble with those in helthy subjects. After multiple doses, AUC tu ws 1.65-fold higher thn tht on Dy 1 in IBS-D ptients (Tble 2).

6 Tble 2. Men (± SD) Phrmcokinetic Prmeters of Rifximin Following 550 mg Three Times Dy in IBS-D Ptients nd Helthy Subjects C mx (ng/ml) Single-Dose (Dy 1) n= (1.51) T mx 0.75 (h) ( ) AUC tu (ng h/ml) Hlf-life (h) Medin (rnge) 10.4 (3.47) 1.83 (1.38) Helthy Subjects Multiple-Dose (Dy 14) n= (1.28) 1.00 ( ) 9.30 (2.7) 5.63 (5.27) Single-Dose (Dy 1) n= (1.36) 0.78 (0-2) 9.69 (4.16) 3.14 (1.71) IBS-D Ptients Multiple-Dose (Dy 14) n= (2.66) 1.00 (0.5-2) 16.0 (9.59) 6.08 (1.68) Food Effect in Helthy Subjects A high-ft mel consumed 30 minutes prior to dosing in helthy subjects delyed the men time to pek plsm concentrtion from 0.75 to 1.5 hours nd incresed the systemic exposure (AUC) of rifximin by 2-fold but did not significntly ffect C mx. Distribution Rifximin is modertely bound to humn plsm proteins. In vivo, the men protein binding rtio ws 67.5% in helthy subjects nd 62% in ptients with heptic impirment when ws dministered. Elimintion The men hlf-life of rifximin in helthy subjects t stedy-stte ws 5.6 hours nd ws 6 hours in IBS-D ptients. Metbolism In n in vitro study rifximin ws metbolized minly by CYP3A4. Rifximin ccounted for 18% of rdioctivity in plsm suggesting tht the bsorbed rifximin undergoes extensive metbolism. Excretion In mss blnce study, fter dministrtion of 400 mg 14 C-rifximin orlly to helthy volunteers, of the 96.94% totl recovery, 96.62% of the dministered rdioctivity ws recovered in feces mostly s the unchnged drug nd 0.32% ws recovered in urine mostly s metbolites with 0.03% s the unchnged drug. Biliry excretion of rifximin ws suggested by seprte study in which rifximin ws detected in the bile fter cholecystectomy in ptients with intct gstrointestinl mucos. Specific Popultions Heptic Impirment The systemic exposure of rifximin ws mrkedly elevted in ptients with heptic impirment compred to helthy subjects. The phrmcokinetics of rifximin in ptients with history of HE ws evluted fter dministrtion of 550 mg twice dy. The phrmcokinetic prmeters were ssocited with high vribility nd men rifximin exposure (AUCτ) in ptients with history of HE ws higher compred to those in helthy subjects. The men AUCτ in ptients with heptic impirment of Child-Pugh Clss A, B, nd C ws 10-, 14-, nd 21-fold higher, respectively, compred to tht in helthy subjects (Tble 3). Tble 3. Men (± SD) Phrmcokinetic Prmeters of Rifximin t Stedy-Stte in Ptients with History of Heptic Encephlopthy by Child-Pugh Clss 1 AUC tu (ng h/ml) C mx (ng/ml) T mx 2 (h) Helthy Subjects (n=14) Child-Pugh Clss A (n=18) B (n=15) C (n=6) 12.3 ± ± ± ± ± ± ± ± (0.5, 4.0) 1 (0.9, 10) 1 (1.0, 4.2) 1 (0, 2) 1 Cross-study comprison with phrmcokinetic prmeters in helthy subjects 2 Medin (rnge) Renl Impirment The phrmcokinetics of rifximin in ptients with impired renl function hs not been studied. Drug Interction Studies Effect of other drugs on rifximin An in vitro study suggests tht rifximin is substrte of CYP3A4. In vitro rifximin is substrte of P-glycoprotein, OATP1A2, OATP1B1, nd OATP1B3. Rifximin is not substrte of OATP2B1. Cyclosporine In vitro in the presence of P-glycoprotein inhibitor, verpmil, the efflux rtio of rifximin ws reduced greter thn 50%. In clinicl drug interction study, men C mx for rifximin ws incresed 83-fold, from 0.48 to 40.0 ng/ml; men AUC ws incresed 124-fold, from 2.54 to 314 ng h/ml following co-dministrtion of single dose of 550 mg with single 600 mg dose of cyclosporine, n inhibitor of P-glycoprotein [see Drug Interctions (7.1)]. Cyclosporine is lso n inhibitor of OATP, brest cncer resistnce protein (BCRP) nd wek inhibitor of CYP3A4. The reltive contribution of inhibition of ech trnsporter by cyclosporine to the increse in rifximin exposure is unknown. Effect of rifximin on other drugs In in vitro drug interction studies the IC 50 vlues for rifximin ws >50 micromolr (~60 mcg) for CYP isoforms 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, nd 2E1. In vitro IC 50 vlue of rifximin for CYP3A4 ws 25 micromolr. Bsed on in vitro studies, cliniclly significnt drug interction vi inhibition of 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1 nd 3A4 by rifximin is not expected. The inhibitory effect of rifximin on P-glycoprotein trnsport ws observed in n in vitro study. The effect of rifximin on P-gp trnsporter ws not evluted in vivo. In in vitro studies, rifximin t 3 micromolr inhibited the uptke of estrdiol glucuronide vi OATP1B1 by 64% nd vi OATP1B3 by 70% while the uptke of estrone sulfte vi OATP1A2 ws inhibited by 40%. The inhibitory potentil of rifximin on these trnsporters t the cliniclly relevnt concentrtions is unknown. Midzolm In n in vitro study, rifximin ws shown to induce CYP3A4 t the concentrtion of 0.2 micromolr. No significnt induction of CYP3A4 enzyme using midzolm s substrte ws observed when rifximin ws dministered three times dy for 7 dys t 200 mg nd 550 mg doses in two clinicl drug interction studies in helthy subjects. The effect of 200 mg dministered orlly every 8 hours for 3 dys nd for 7 dys on the phrmcokinetics of single dose of either 2 mg intrvenous midzolm or 6 mg orl midzolm ws evluted in helthy subjects. No significnt difference ws observed in the systemic exposure or elimintion of intrvenous or orl midzolm or its mjor metbolite, 1 -hydroxymidzolm, between midzolm lone or together with. Therefore, ws not shown to significntly ffect intestinl or heptic CYP3A4 ctivity for the 200 mg three times dy dosing regimen. When single dose of 2 mg midzolm ws orlly dministered fter dministrtion of 550 mg three times dy for 7 dys nd 14 dys to helthy subjects, the men AUC of midzolm ws 3.8% nd 8.8% lower, respectively, thn when midzolm ws dministered lone. The men C mx of midzolm ws lower by 4 to 5% when ws dministered for 7-14 dys prior to midzolm dministrtion. This degree of interction is not considered cliniclly meningful. Orl Contrceptives Contining Ethinyl Estrdiol nd Norgestimte The orl contrceptive study utilized n open-lbel, crossover design in 28 helthy femle subjects to determine if 200 mg orlly dministered three times dy for 3 dys (the dosing regimen for trvelers dirrhe) ltered the phrmcokinetics of single dose of n orl contrceptive contining 0.07 mg ethinyl estrdiol nd 0.5 mg norgestimte. Results showed tht the phrmcokinetics of single doses of ethinyl estrdiol nd norgestimte were not ltered by. An open-lbel orl contrceptive study ws conducted in 39 helthy femle subjects to determine if 550 mg orlly dministered three times dy for 7 dys ltered the phrmcokinetics of single dose of n orl contrceptive contining mg of ethinyl estrdiol (EE) nd 0.25 mg norgestimte (NGM). Men C mx of EE nd NGM ws lower by 25% nd 13%, fter the 7-dy regimen thn when the orl contrceptive ws given lone. The men AUC vlues of NGM ctive metbolites were lower by 7% to pproximtely 11%, while AUC of EE ws not ltered in presence of rifximin. The clinicl relevnce of the C mx nd AUC reductions in the presence of rifximin is not known Microbiology Mechnism of Action Rifximin is semi-synthetic derivtive of rifmpin nd cts by binding to the betsubunit of bcteril DNA-dependent RNA polymerse blocking one of the steps in trnscription. This results in inhibition of bcteril protein synthesis nd consequently inhibits the growth of bcteri. Drug Resistnce nd Cross-Resistnce Resistnce to rifximin is cused primrily by muttions in the rpob gene. This chnges the binding site on DNA dependent RNA polymerse nd decreses rifximin binding ffinity, thereby reducing efficcy. Cross-resistnce between rifximin nd other clsses of ntimicrobils hs not been observed. Antibcteril Activity Rifximin hs been shown to be ctive ginst the following pthogens both in vitro nd in clinicl studies of infectious dirrhe s described in the Indictions nd Usge (1.1) section: Escherichi coli (enterotoxigenic nd enteroggregtive strins). Susceptibility Tests In vitro susceptibility testing ws performed ccording to the Clinicl nd Lbortory Stndrds Institute (CLSI). 1,2,3 However, the correltion between susceptibility testing nd clinicl outcome hs not been determined.

7 13 NONCLINICAL TOXICOLOGY 13.1 Crcinogenesis, Mutgenesis, Impirment of Fertility Mlignnt schwnnoms in the hert were significntly incresed in mle Crl:CD (SD) rts tht received rifximin by orl gvge for two yers t 150 to 250 mg/kg per dy (doses equivlent to 2.4 to 4 times the recommended dose of 200 mg three times dily for TD, nd equivlent to 1.3 to 2.2 times the recommended dose of 550 mg twice dily for HE, bsed on reltive body surfce re comprisons). There ws no increse in tumors in Tg.rsH2 mice dosed orlly with rifximin for 26 weeks t 150 to 2000 mg/kg per dy (doses equivlent to 1.2 to 16 times the recommended dily dose for TD nd equivlent to 0.7 to 9 times the recommended dily dose for HE, bsed on reltive body surfce re comprisons). Rifximin ws not genotoxic in the bcteril reverse muttion ssy, chromosoml berrtion ssy, rt bone mrrow micronucleus ssy, rt heptocyte unscheduled DNA synthesis ssy, or the CHO/HGPRT muttion ssy. There ws no effect on fertility in mle or femle rts following the dministrtion of rifximin t doses up to 300 mg/kg (pproximtely 5 times the clinicl dose of 600 mg per dy for TD, nd pproximtely 2.6 times the clinicl dose of 1100 mg per dy for HE, djusted for body surfce re). 14 CLINICAL STUDIES 14.1 Trvelers Dirrhe The efficcy of given s 200 mg orlly tken three times dy for 3 dys ws evluted in 2 rndomized, multi-center, double-blind, plcebo-controlled studies in dult subjects with trvelers dirrhe. One study ws conducted t clinicl sites in Mexico, Guteml, nd Keny (Study 1). The other study ws conducted in Mexico, Guteml, Peru, nd Indi (Study 2). Stool specimens were collected before tretment nd 1 to 3 dys following the end of tretment to identify enteric pthogens. The predominnt pthogen in both studies ws Escherichi coli. The clinicl efficcy of ws ssessed by the time to return to norml, formed stools nd resolution of symptoms. The primry efficcy endpoint ws time to lst unformed stool (TLUS) which ws defined s the time to the lst unformed stool pssed, fter which clinicl cure ws declred. Tble 4 displys the medin TLUS nd the number of ptients who chieved clinicl cure for the intent to tret (ITT) popultion of Study 1. The durtion of dirrhe ws significntly shorter in ptients treted with thn in the plcebo group. More ptients treted with were clssified s clinicl cures thn were those in the plcebo group. Tble 4. Clinicl Response in Study 1 (ITT popultion) (n=125) (n=129) Medin TLUS (hours) Clinicl cure, 99 (79) 78 (60) Estimte (97.5% CI) 2 (1.26, 2.50) 19 b (5.3, 32.1) In n unrelted open-lbel, phrmcokinetic study of orl 200 mg tken every 8 hours for 3 dys, 15 dult subjects were chllenged with Shigell flexneri 2, of whom 13 developed dirrhe or dysentery nd were treted with. Although this open-lbel chllenge tril ws not dequte to ssess the effectiveness of in the tretment of shigellosis, the following observtions were noted: eight subjects received rescue tretment with ciprofloxcin either becuse of lck of response to tretment within 24 hours (2), or becuse they developed severe dysentery (5), or becuse of recurrence of Shigell flexneri in the stool (1); five of the 13 subjects received ciprofloxcin lthough they did not hve evidence of severe disese or relpse Heptic Encephlopthy The efficcy of 550 mg tken orlly two times dy ws evluted in rndomized, plcebo-controlled, double-blind, multi-center 6-month tril of dult subjects from the U.S., Cnd nd Russi who were defined s being in remission (Conn score of 0 or 1) from heptic encephlopthy (HE). Eligible subjects hd 2 episodes of HE ssocited with chronic liver disese in the previous 6 months. A totl of 299 subjects were rndomized to receive either (n=140) or plcebo (n=159) in this study. Ptients hd men ge of 56 yers (rnge, yers), 81% <65 yers of ge, 61% were mle nd 86% White. At bseline, 67% of ptients hd Conn score of 0 nd 68% hd n sterixis grde of 0. Ptients hd MELD scores of either 10 (27%) or 11 to 18 (64%) t bseline. No ptients were enrolled with MELD score of >25. Nine percent of the ptients were Child-Pugh Clss C. Lctulose ws concomitntly used by 91% of the ptients in ech tretment rm of the study. Per the study protocol, ptients were withdrwn from the study fter experiencing brekthrough HE episode. Other resons for erly study discontinution included: dverse rections ( 6%; plcebo 4%), ptient request to withdrw ( 4%; plcebo 6%) nd other ( 7%; plcebo 5%). The primry endpoint ws the time to first brekthrough overt HE episode. A brekthrough overt HE episode ws defined s mrked deteriortion in neurologicl function nd n increse of Conn score to Grde 2. In ptients with bseline Conn score of 0, brekthrough overt HE episode ws defined s n increse in Conn score of 1 nd sterixis grde of 1. Brekthrough overt HE episodes were experienced by 31 of 140 subjects (22%) in the group nd by 73 of 159 subjects (46%) in the plcebo group during the 6-month tretment period. Comprison of Kpln-Meier estimtes of event-free curves showed significntly reduced the risk of HE brekthrough by 58% during the 6-month tretment period. Presented below in Figure 1 is the Kpln-Meier event-free curve for ll subjects (n=299) in the study. Figure 1: Kpln-Meier Event-Free Curves 1 in HE Study (Time to First Brekthrough-HE Episode up to 6 Months of, Dy 170) (ITT Popultion) Hzrd Rtio (p-vlue <0.001) b in rtes (p-vlue <0.01) Microbiologicl erdiction (defined s the bsence of bseline pthogen in culture of stool fter 72 hours of therpy) rtes for Study 1 re presented in Tble 5 for ptients with ny pthogen t bseline nd for the subset of ptients with Escherichi coli t bseline. Escherichi coli ws the only pthogen with sufficient numbers to llow comprisons between tretment groups. Even though hd microbiologic ctivity similr to plcebo, it demonstrted cliniclly significnt reduction in durtion of dirrhe nd higher clinicl cure rte thn plcebo. Therefore, ptients should be mnged bsed on clinicl response to therpy rther thn microbiologic response. Tble 5. Microbiologic Erdiction Rtes in Study 1 Subjects with Bseline Pthogen Overll E. coli 48/70 (69) 38/53 (72) 41/61 (67) 40/54 (74) The results of Study 2 supported the results presented for Study 1. In ddition, this study provided evidence tht subjects treted with with fever nd/or blood in the stool t bseline hd prolonged TLUS. These subjects hd lower clinicl cure rtes thn those without fever or blood in the stool t bseline. Mny of the ptients with fever nd/or blood in the stool (dysentery-like dirrhel syndromes) hd invsive pthogens, primrily Cmpylobcter jejuni, isolted in the bseline stool. Also in this study, the mjority of the subjects treted with who hd Cmpylobcter jejuni isolted s sole pthogen t bseline filed tretment nd the resulting clinicl cure rte for these ptients ws 23.5% (4/17). In ddition to not being different from plcebo, the microbiologic erdiction rtes for subjects with Cmpylobcter jejuni isolted t bseline were much lower thn the erdiction rtes seen for Escherichi coli. Note: Open dimonds nd open tringles represent censored subjects. 1 Event-free refers to non-occurrence of brekthrough HE. When the results were evluted by the following demogrphic nd bseline chrcteristics, the tretment effect of 550 mg in reducing the risk of brekthrough overt HE recurrence ws consistent for: sex, bseline Conn score, durtion of current remission nd dibetes. The differences in tretment effect could not be ssessed in the following subpopultions due to smll smple size: non-white (n=42), bseline MELD >19 (n=26), Child-Pugh Clss C (n=31), nd those without concomitnt lctulose use (n=26). HE-relted hospitliztions (hospitliztions directly resulting from HE, or hospitliztions complicted by HE) were reported for 19 of 140 subjects (14%) nd 36 of 159 subjects (23%) in the (rifximin) nd plcebo groups respectively. Comprison of Kpln-Meier estimtes of event-free curves showed significntly reduced the risk of HE-relted hospitliztions by 50% during the 6-month tretment period. Comprison of Kpln-Meier estimtes of event-free curves is shown in Figure 2.

8 Figure 2: Kpln-Meier Event-Free Curves 1 in Pivotl HE Study (Time to First HE-Relted Hospitliztion in HE Study up to 6 Months of, Dy 170) (ITT Popultion) Note: Open dimonds nd open tringles represent censored subjects. 1 Event-free refers to non-occurrence of HE-relted hospitliztion Irritble Bowel Syndrome with Dirrhe The efficcy of for the tretment of IBS-D ws estblished in 3 rndomized, multi-center, double-blind, plcebo-controlled trils in dult ptients. Trils 1 nd 2 - Design The first two trils, Trils 1 nd 2 were of identicl design. In these trils, totl of 1258 ptients meeting Rome II criteri for IBS* were rndomized to receive 550 mg three times dy (n=624) or plcebo (n=634) for 14 dys nd then followed for 10-week tretment-free period. The Rome II criteri further ctegorizes IBS ptients into 3 subtypes: dirrhe-predominnt IBS (IBS-D), constiption-predominnt IBS (IBS-C), or lternting IBS (bowel hbits lternting between dirrhe nd constiption). Ptients with both IBS-D nd lternting IBS were included in Trils 1 nd 2. is recommended for use in ptients with IBS-D. *Rome II Criteri: At lest 12 weeks, which need not be consecutive, in the preceding 12 months of bdominl discomfort or pin tht hs two out of three fetures: 1. Relieved with defection; nd/or 2. Onset ssocited with chnge in frequency of stool; nd/or 3. Onset ssocited with chnge in form (ppernce) of stool. Symptoms tht Cumultively Support the Dignosis of Irritble Bowel Syndrome: Abnorml stool frequency (for reserch purposes bnorml my be defined s greter thn 3 bowel movements per dy nd less thn 3 bowel movements per week); Abnorml stool form (lumpy/hrd or loose/wtery stool); Abnorml stool pssge (strining, urgency, or feeling of incomplete evcution); Pssge of mucus; Bloting or feeling of bdominl distension. Tril 3 - Design Tril 3 evluted repet tretment in dults with IBS-D meeting Rome III criteri** for up to 46 weeks. A totl of 2579 were enrolled to receive open-lbel for 14 dys. Of 2438 evluble ptients, 1074 (44%) responded to initil tretment nd were evluted over 22 weeks for continued response or recurrence of IBS-symptoms. A totl of 636 ptients hd symptom recurrence nd were rndomized into the double-blind phse of the study. These ptients were scheduled to receive 550 mg three times dy (n=328) or plcebo (n=308) for two dditionl 14-dy repet tretment courses seprted by 10 weeks. See Figure 3. Figure 3: Tril 3 Study Design Trils 1 nd 2 - Results Trils 1 nd 2 included 1258 IBS-D ptients (309, 314 plcebo); (315, 320 plcebo). The primry endpoint for both trils ws the proportion of ptients who chieved dequte relief of IBS signs nd symptoms for t lest 2 of 4 weeks during the month following 14 dys of tretment. Adequte relief ws defined s response of yes to the following weekly Subject Globl Assessment (SGA) question: In regrds to your IBS symptoms, compred to the wy you felt before you strted study mediction, hve you, in the pst 7 dys, hd dequte relief of your IBS symptoms? [Yes/No]. Adequte relief of IBS symptoms ws experienced by more ptients receiving thn those receiving plcebo during the month following 2 weeks of tretment (SGA-IBS Weekly Results: 41% vs. 31%, p=0.0125; 41% vs. 32%, p= (See Tble 6). Tble 6. Adequte Relief of IBS Symptoms During the Month Following Two Weeks of Endpoint n=309 Adequte Relief of 126 IBS Symptoms b (41) Endpoint n=315 Adequte Relief of 128 IBS Symptoms b (41) Tril 1 n= (31) Tril 2 n=320 n (%) 103 (32) Confidence Intervl b The p-vlue for the primry endpoint for Tril 1 nd for Tril 2 ws <0.05. (95% CI ) 10% (2.1%, 17.1%) (95% CI ) 8% (1.0%, 15.9%) The trils exmined composite endpoint which defined responders by IBS-relted bdominl pin nd stool consistency mesures. Ptients were monthly responders if they met both of the following criteri: experienced 30% decrese from bseline in bdominl pin for 2 weeks during the month following 2 weeks of tretment hd weekly men stool consistency score <4 (loose stool) for 2 weeks during the month following 2 weeks of tretment More ptients receiving were monthly responders for bdominl pin nd stool consistency in Trils 1 nd 2 (see Tble 7). Tble 7. Efficcy Responder Rtes in Tril 1 nd 2 During the Month Following Two Weeks of Endpoint n=309 Abdominl Pin nd Stool 144 Consistency Responders b (47) Abdominl Pin Responders Stool Consistency Responders 159 (51) 244 (79) Tril 1 n= (39) 132 (42) 212 (68) (95% CI ) 8% (0.3%, 15.9%) 9% (1.8%, 17.5%) 11% (4.4%, 18.2%) Endpoint n=315 Abdominl Pin nd Stool Consistency Responders b 147 (47) Tril 2 n= (36) (95% CI ) 11% (2.7%, 18.0%) Abdominl Pin Responders 165 (52) 138 (43) 9% (1.5%, 17.0%) The IBS-D popultion from the three studies hd men ge of 47 (rnge: 18 to 88) yers of which pproximtely 11% of ptients were 65 yers old, 72% were femle nd 88% were White. **Rome III Criteri: Recurrent bdominl pin or discomfort (uncomfortble senstion not described s pin) t lest 3 dys/month in lst 3 months ssocited with two or more of the following: 1. Improvement with defection; 2. Onset ssocited with chnge in frequency of stool; 3. Onset ssocited with chnge in form (ppernce) of stool. Stool Consistency Responders 233 (74) 206 (64) Confidence Intervl b The p-vlue for the composite endpoint for Tril 1 nd 2 ws <0.05 nd <0.01, respectively. 10% (2.3%, 16.7%)