HIGHLIGHTS F PRESCRIBING INFRMATIN These highlights do not include ll the informtion needed to use sfely nd effectively. See full prescriing informtion for. (rifximin) tlets, for orl use Initil U.S. Approvl: 2004 To reduce the development of drug-resistnt cteri nd mintin the effectiveness of nd other nticteril drugs, should e used only to tret or prevent infections tht re proven or strongly suspected to e cused y cteri. ----------------------------------- RECENT MAJR CHANGES --------------------------------- Indictions nd Usge, Irritle Bowel Syndrome with Dirrhe (1.3) 5/2015 Dosge nd Administrtion, Irritle Bowel Syndrome with Dirrhe (2.3) 5/2015 ------------------------------------INDICATINS AND USAGE --------------------------------- is rifmycin nticteril indicted for: Tretment of trvelers dirrhe (TD) cused y 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) Tretment of irritle owel syndrome with dirrhe (IBS-D) in dults (1.3) Limittions of Use TD: Do not use in ptients with dirrhe complicted y fever or lood in the stool or dirrhe due to pthogens other thn Escherichi coli (1.1, 5.1) -------------------------------- DSAGE AND ADMINISTRATIN ------------------------------ Condition TD (2.1) HE (2.2) IBS-D (2.3) Recommended Dosge Regimen ne 200 mg tlet 3 times dy for 3 dys ne 550 mg tlet 2 times dy ne 550 mg tlet 3 times dy for 14 dys. Ptients who experience recurrence cn e retreted up to two times with the sme regimen. cn e tken with or without food. (2.4) ------------------------------- DSAGE FRMS AND STRENGTHS ----------------------------- 200 mg nd 550 mg tlets (3) --------------------------------------CNTRAINDICATINS ------------------------------------ History of hypersensitivity to rifximin, rifmycin ntimicroil gents, or ny of the components of (4) ---------------------------------WARNINGS AND PRECAUTINS------------------------------- Trvelers Dirrhe Not Cused y E. coli: ws not effective in dirrhe complicted y fever nd/or lood 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 ntiiotics (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 inhiitor: Cution should e exercised when concomitnt use of nd P-glycoprotein inhiitor is needed (5.5, 7.2) --------------------------------------ADVERSE REACTINS ----------------------------------- 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 REACTINS, contct Slix Phrmceuticls t 1-800-508-0024 nd www.slix.com or FDA t 1-800-FDA-1088 or www.fd.gov/medwtch ---------------------------------USE IN SPECIFIC PPULATINS ------------------------------ Pregnncy: My cuse fetl hrm (8.1) See 17 for PATIENT CUNSELING INFRMATIN Revised: 11/2015 FULL PRESCRIBING INFRMATIN: CNTENTS* 1 INDICATINS AND USAGE 1.1 Trvelers Dirrhe 1.2 Heptic Encephlopthy 1.3 Irritle Bowel Syndrome with Dirrhe 2 DSAGE AND ADMINISTRATIN 2.1 Dosge for Trvelers Dirrhe 2.2 Dosge for Heptic Encephlopthy 2.3 Dosge for Irritle Bowel Syndrome with Dirrhe 2.4 Administrtion 3 DSAGE FRMS AND STRENGTHS 4 CNTRAINDICATINS 5 WARNINGS AND PRECAUTINS 5.1 Trvelers Dirrhe Not Cused y 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 Inhiitors 6 ADVERSE REACTINS 6.1 Clinicl Studies Experience 6.2 Postmrketing Experience 7 DRUG INTERACTINS 7.1 Effects of on ther Drugs 7.2 Effects of ther Drugs on 8 USE IN SPECIFIC PPULATINS 8.1 Pregnncy 8.2 Lcttion 8.4 Peditric Use 8.5 Geritric Use 8.6 Renl Impirment 8.7 Heptic Impirment 10 VERDSAGE 11 DESCRIPTIN 12 CLINICAL PHARMACLGY 12.1 Mechnism of Action 12.3 Phrmcokinetics 12.4 Microiology 13 NNCLINICAL TXICLGY 13.1 Crcinogenesis, Mutgenesis, Impirment of Fertility 14 CLINICAL STUDIES 14.1 Trvelers Dirrhe 14.2 Heptic Encephlopthy 14.3 Irritle Bowel Syndrome with Dirrhe 15 REFERENCES 16 HW SUPPLIED/STRAGE AND HANDLING 17 PATIENT CUNSELING INFRMATIN *Sections or susections omitted from the full prescriing informtion re not listed FULL PRESCRIBING INFRMATIN 1 INDICATINS AND USAGE To reduce the development of drug-resistnt cteri nd mintin the effectiveness of nd other nticteril drugs, when used to tret infection should e used only to tret or prevent infections tht re proven or strongly suspected to e cused y susceptile cteri. When culture nd susceptiility informtion re ville, they should e considered in selecting or modifying nticteril therpy. In the sence of such dt, locl epidemiology nd susceptiility ptterns my contriute to the empiric selection of therpy. 1.1 Trvelers Dirrhe is indicted for the tretment of trvelers dirrhe (TD) cused y noninvsive strins of Escherichi coli in dults nd peditric ptients 12 yers of ge nd older. Limittions of Use should not e used in ptients with dirrhe complicted y fever or lood 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. s in the tretment effect of those ptients not using lctulose concomitntly could not e ssessed. hs not een 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 Irritle Bowel Syndrome with Dirrhe is indicted for the tretment of irritle owel syndrome with dirrhe (IBS-D) in dults. 2 DSAGE AND ADMINISTRATIN 2.1 Dosge for Trvelers Dirrhe The recommended dose of is one 200 mg tlet tken orlly three times dy for 3 dys. 2.2 Dosge for Heptic Encephlopthy The recommended dose of is one 550 mg tlet tken orlly two times dy. 2.3 Dosge for Irritle Bowel Syndrome with Dirrhe The recommended dose of is one 550 mg tlet tken orlly three times dy for 14 dys. Ptients who experience recurrence of symptoms cn e retreted up to two times with the sme dosge regimen. 2.4 Administrtion cn e tken with or without food [see Clinicl Phrmcology (12.3)]. 3 DSAGE FRMS AND STRENGTHS is pink-colored iconvex tlet nd is ville in the following strengths: 200 mg round tlet deossed with Sx on one side. 550 mg n ovl tlet deossed with rfx on one side. 4 CNTRAINDICATINS is contrindicted in ptients with hypersensitivity to rifximin, ny of the rifmycin ntimicroil 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 PRECAUTINS 5.1 Trvelers Dirrhe Not Cused y Escherichi coli ws not found to e effective in ptients with dirrhe complicted y fever nd/or lood 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 ntiiotic therpy should e considered. is not effective in cses of trvelers dirrhe due to Cmpylocter jejuni. The effectiveness of in trvelers dirrhe cused y Shigell spp. nd Slmonell spp. hs not een proven. should not e used in ptients where Cmpylocter jejuni, Shigell spp., or Slmonell spp. my e suspected s custive pthogens [see Indictions nd Usge (1.1)].
5.2 Clostridium difficile-associted Dirrhe Clostridium difficile-ssocited dirrhe (CDAD) hs een reported with use of nerly ll nticteril gents, including, nd my rnge in severity from mild dirrhe to ftl colitis. Tretment with nticteril gents lters the norml flor of the colon which my led to overgrowth of C. difficile. C. difficile produces toxins A nd B which contriute to the development of CDAD. Hypertoxin producing strins of C. difficile cuse incresed moridity nd mortlity, s these infections cn e refrctory to ntimicroil therpy nd my require colectomy. CDAD must e considered in ll ptients who present with dirrhe following ntiiotic use. Creful medicl history is necessry since CDAD hs een reported to occur over two months fter the dministrtion of nticteril gents. If CDAD is suspected or confirmed, ongoing ntiiotic use not directed ginst C. difficile my need to e discontinued. Approprite fluid nd electrolyte mngement, protein supplementtion, ntiiotic tretment of C. difficile, nd surgicl evlution should e instituted s cliniclly indicted. 5.3 Development of Drug-Resistnt Bcteri Prescriing for trvelers dirrhe in the sence of proven or strongly suspected cteril infection or prophylctic indiction is unlikely to provide enefit to the ptient nd increses the risk of the development of drugresistnt cteri. 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 e 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 Inhiitors Concomitnt dministrtion of drugs tht re P-glycoprotein inhiitors with cn sustntilly increse the systemic exposure to rifximin. Cution should e exercised when concomitnt use of nd P-glycoprotein inhiitor such s cyclosporine is needed. In ptients with heptic impirment, potentil dditive effect of reduced metolism nd concomitnt P-glycoprotein inhiitors my further increse the systemic exposure to rifximin [see Drug Interctions (7.2), Phrmcokinetics (12.3)]. 6 ADVERSE REACTINS 6.1 Clinicl Studies Experience Becuse clinicl trils re conducted under widely vrying conditions, dverse rection rtes oserved in the clinicl trils of drug cnnot e directly compred to rtes in the clinicl trils of nother drug nd my not reflect the rtes oserved 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 plceo-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 plceo (n=228) in the two plceo-controlled trils of TD ws: hedche (10%, 9% plceo) Heptic Encephlopthy The dt descried elow 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 plceo-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 sujects thn in the plceo group in the 6-month tril re provided in Tle 1. Tle 1: Most Common Adverse Rections* in HE Tril MedDRA Preferred Term Numer (%) of Ptients Tlets 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%) pin 12 (9%) 13 (8%) Anemi 11 (8%) 6 (4%) Depression 10 (7%) 8 (5%) Nsophryngitis 10 (7%) 10 (6%) 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 plceo Irritle Bowel Syndrome with Dirrhe The sfety of for the tretment of IBS-D ws evluted in 3 plceo-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-lel tretment nd 2 doule-lind repet tretments of 14 dys ech over period of up to 46 weeks. The comined 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 plceo in Trils 1 nd 2 for IBS-D ws: nuse (3%, 2% plceo) The dverse rections tht occurred t frequency 2% in -treted ptients (n=328) t higher rte thn plceo (n=308) in Tril 3 for IBS-D during the doule-lind tretment phse were: ALT incresed ( 2%, plceo 1%) nuse ( 2%, plceo 1%) Less Common Adverse Rections The following dverse rections, presented y ody 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: Heptoiliry disorders: Clostridium colitis Investigtions: Incresed lood cretine phosphokinse Musculoskeletl nd connective tissue disorders: mylgi 6.2 Postmrketing Experience The following dverse rections hve een identified during post-pprovl use of. Becuse these rections re reported voluntrily from popultion of unknown size, estimtes of frequency cnnot e mde. These rections hve een 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 een 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 een reported. These events occurred s erly s within 15 minutes of drug dministrtion. 7 DRUG INTERACTINS 7.1 Effects of on ther Drugs Sustrtes of Cytochrome P450 enzymes Rifximin is not expected to inhiit cytochrome P450 isoenzymes 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1 nd CYP3A4 in clinicl use sed on in vitro studies [see Clinicl Phrmcology (12.3)]. 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 sustrtes in ptients with reduced liver function who hve elevted rifximin concentrtions. 7.2 Effects of ther Drugs on In vitro studies suggested tht rifximin is sustrte of P-glycoprotein, ATP1A2, ATP1B1 nd ATP1B3. Concomitnt cyclosporine, n inhiitor of P-glycoprotein nd ATPs, significntly incresed the systemic exposure to rifximin. Cyclosporine Co-dministrtion of cyclosporine, with resulted in 83-fold nd 124-fold increses in rifximin men C mx nd AUC in helthy sujects. The clinicl significnce of this increse in systemic exposure is unknown [see Wrnings nd Precutions (5.4), Clinicl Phrmcology (12.3)]. 8 USE IN SPECIFIC PPULATINS 8.1 Pregnncy Risk Summry There re no ville dt on use in pregnnt women to inform ny drug ssocited risks. Tertogenic effects were oserved in niml reproduction studies following dministrtion of rifximin to pregnnt rts nd rits 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 rits, oculr, orl nd mxillofcil, crdic, nd lumr spine mlformtions were oserved. culr mlformtions were oserved in oth rts nd rits t doses tht cused reduced mternl ody weight gin [see Dt]. In the U.S. generl popultion, the estimted ckground risk of mjor irth 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 ody surfce re). Rifximin ws tertogenic in rits 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 ody surfce re). These effects include cleft plte, gnthi, jw shortening, hemorrhge, eye prtilly open, smll eyes, rchygnthi, incomplete ossifiction, nd incresed thorcolumr vertere. 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 ody 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 restfed infnt, or the effects of rifximin on milk production. The development nd helth enefits of restfeeding should e considered long with the mother s clinicl need for nd ny potentil dverse effects on the restfed infnt from or from the underlying mternl condition. 8.4 Peditric Use The sfety nd effectiveness of hs not een estlished 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 f the totl numer 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 oserved
etween these sujects nd younger sujects for either indiction. Clinicl studies with for TD did not include sufficient numers of ptients ged 65 nd over to determine whether they respond differently thn younger sujects. ther reported clinicl experience hs not identified differences in responses etween the elderly nd younger ptients, ut greter sensitivity of some older individuls cnnot e ruled out. 8.6 Renl Impirment The phrmcokinetics of rifximin in ptients with impired renl function hs not een studied. 8.7 Heptic Impirment Following dministrtion of 550 mg twice dily to ptients with history of heptic encephlopthy, the systemic exposure (i.e., AUC τ ) of rifximin ws out 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 ecuse rifximin is presumly cting loclly. Nonetheless, cution should e 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 VERDSAGE No specific informtion is ville 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 sujects who received doses higher thn the recommended dose nd plceo. In the cse of overdosge, discontinue, tret symptomticlly, nd institute supportive mesures s required. 11 DESCRIPTIN tlets contin rifximin, nonminoglycoside semi-synthetic, nonsystemic ntiiotic 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)enzofuro[4,5-e] pyrido[1,2-á]-enzimidzole-1,15(2h)-dione,25-cette. The empiricl formul is C 43 H 51 N 3 11 nd its moleculr weight is 785.9. The chemicl structure is represented elow: H 3 C H 3 C H tlets for orl dministrtion re film-coted nd contin 200 mg or 550 mg of rifximin. Inctive ingredients: Ech 200 mg tlet 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 tlet 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 PHARMACLGY 12.1 Mechnism of Action Rifximin is n nticteril drug [see Clinicl Phrmcology (12.4)]. 12.3 Phrmcokinetics Asorption In helthy sujects, the men time to rech pek rifximin plsm concentrtions ws out 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 sorption of (200 mg three times dily) ws evluted in 13 sujects chllenged with shigellosis on Dys 1 nd 3 of three-dy course of tretment. Rifximin plsm concentrtions nd exposures were low nd vrile. 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 H H H N NH N 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 suitle for treting systemic cteril infections ecuse of limited systemic exposure fter orl dministrtion [see Wrnings nd Precutions (5.1)]. Heptic Encephlopthy Men rifximin exposure (AUC τ ) in ptients with history of HE ws pproximtely 12-fold higher thn tht oserved in helthy sujects. 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)]. Irritle Bowel Syndrome with Dirrhe In ptients with irritle owel 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 comprle with those in helthy sujects. After multiple doses, AUC tu ws 1.65-fold higher thn tht on Dy 1 in IBS-D ptients (Tle 2). Tle 2. Men (± SD) Phrmcokinetic Prmeters of Rifximin Following 550 mg Three Times Dy in IBS-D Ptients nd Helthy Sujects Helthy Sujects Single- (Dy 1) n=12 C mx (ng/ml) 4.04 (1.51) T mx (h) 0.75 (0.5-2.1) AUC tu (ng h/ml) 10.4 (3.47) Hlf-life (h) 1.83 (1.38) Medin (rnge) Multiple- (Dy 14) n=14 2.39 (1.28) 1.00 (0.5-2.0) 9.30 (2.7) 5.63 (5.27) IBS-D Ptients Single- (Dy 1) n=24 3.49 (1.36) 0.78 (0-2) 9.69 (4.16) 3.14 (1.71) Multiple- (Dy 14) n=24 4.22 (2.66) 1.00 (0.5-2) 16.0 (9.59) 6.08 (1.68) Food Effect in Helthy Sujects A high-ft mel consumed 30 minutes prior to dosing in helthy sujects delyed the men time to pek plsm concentrtion from 0.75 to 1.5 hours nd incresed the systemic exposure (AUC) of rifximin y 2-fold ut did not significntly ffect C mx. Distriution Rifximin is modertely ound to humn plsm proteins. In vivo, the men protein inding rtio ws 67.5% in helthy sujects nd 62% in ptients with heptic impirment when ws dministered. Elimintion The men hlf-life of rifximin in helthy sujects t stedy-stte ws 5.6 hours nd ws 6 hours in IBS-D ptients. Metolism: In n in vitro study rifximin ws metolized minly y CYP3A4. Rifximin ccounted for 18% of rdioctivity in plsm suggesting tht the sored rifximin undergoes extensive metolism. Excretion: In mss lnce 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 metolites with 0.03% s the unchnged drug. Biliry excretion of rifximin ws suggested y seprte study in which rifximin ws detected in the ile 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 sujects. 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 vriility nd men rifximin exposure (AUC τ ) in ptients with history of HE ws higher compred to those in helthy sujects. The men AUC τ 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 sujects (Tle 3). Tle 3. Men (± SD) Phrmcokinetic Prmeters of Rifximin t Stedy-Stte in Ptients with History of Heptic Encephlopthy y Child-Pugh Clss 1 AUC tu (ng h/ml) C mx (ng/ml) T mx 2 (h) Helthy Sujects (n=14) Child-Pugh Clss A (n=18) B (n=15) C (n=6) 12.3 ± 4.8 118 ± 67.8 169 ± 55.7 257 ± 100.2 3.4 ± 1.6 19.5 ± 11.4 25.4 ± 11.9 39.7 ± 13.4 0.8 (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 sujects 2 Medin (rnge) Renl Impirment The phrmcokinetics of rifximin in ptients with impired renl function hs not een studied. Drug Interction Studies Effect of other drugs on rifximin An in vitro study suggests tht rifximin is sustrte of CYP3A4. In vitro rifximin is sustrte of P-glycoprotein, ATP1A2, ATP1B1, nd ATP1B3. Rifximin is not sustrte of ATP2B1. Cyclosporine In vitro in the presence of P-glycoprotein inhiitor, 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 inhiitor of P-glycoprotein [see Drug Interctions (7.2)]. Cyclosporine is lso n inhiitor of ATP, rest cncer resistnce protein (BCRP) nd wek inhiitor of CYP3A4. The reltive contriution of inhiition of ech trnsporter y 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 inhiition of 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1 nd 3A4 y rifximin is not expected. The inhiitory effect of rifximin on P-glycoprotein trnsport ws oserved 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 inhiited the uptke of estrdiol glucuronide vi ATP1B1 y 64% nd vi ATP1B3 y 70% while the uptke of estrone sulfte vi ATP1A2 ws inhiited y 40%. The inhiitory 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 sustrte ws oserved 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 sujects. 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 sujects. No significnt difference ws oserved in the systemic exposure or elimintion of intrvenous or orl midzolm or its mjor metolite, 1 -hydroxymidzolm, etween 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 sujects, 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 y 4 to 5% when ws dministered for 7-14 dys prior to midzolm
dministrtion. This degree of interction is not considered cliniclly meningful. rl Contrceptives Contining Ethinyl Estrdiol nd Norgestimte The orl contrceptive study utilized n open-lel, crossover design in 28 helthy femle sujects 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 y. An open-lel orl contrceptive study ws conducted in 39 helthy femle sujects to determine if 550 mg orlly dministered three times dy for 7 dys ltered the phrmcokinetics of single dose of n orl contrceptive contining 0.025 mg of ethinyl estrdiol (EE) nd 0.25 mg norgestimte (NGM). Men C mx of EE nd NGM ws lower y 25% nd 13%, fter the 7-dy regimen thn when the orl contrceptive ws given lone. The men AUC vlues of NGM ctive metolites were lower y 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. 12.4 Microiology Mechnism of Action Rifximin is semi-synthetic derivtive of rifmpin nd cts y inding to the et-suunit of cteril DNA-dependent RNA polymerse locking one of the steps in trnscription. This results in inhiition of cteril protein synthesis nd consequently inhiits the growth of cteri. Drug Resistnce nd Cross-Resistnce Resistnce to rifximin is cused primrily y muttions in the rpob gene. This chnges the inding site on DNA dependent RNA polymerse nd decreses rifximin inding ffinity, therey reducing efficcy. Cross-resistnce etween rifximin nd other clsses of ntimicroils hs not een oserved. Anticteril Activity Rifximin hs een shown to e ctive ginst the following pthogens oth in vitro nd in clinicl studies of infectious dirrhe s descried in the Indictions nd Usge (1.1) section: Escherichi coli (enterotoxigenic nd enteroggregtive strins). Susceptiility Tests In vitro susceptiility testing ws performed ccording to the Clinicl nd Lortory Stndrds Institute (CLSI). 1,2,3 However, the correltion etween susceptiility testing nd clinicl outcome hs not een determined. 13 NNCLINICAL TXICLGY 13.1 Crcinogenesis, Mutgenesis, Impirment of Fertility Mlignnt schwnnoms in the hert were significntly incresed in mle Crl:CD (SD) rts tht received rifximin y 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, sed on reltive ody 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, sed on reltive ody surfce re comprisons). Rifximin ws not genotoxic in the cteril reverse muttion ssy, chromosoml errtion ssy, rt one mrrow micronucleus ssy, rt heptocyte unscheduled DNA synthesis ssy, or the CH/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 ody 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, doule-lind, plceo-controlled studies in dult sujects with trvelers dirrhe. ne 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). specimens were collected efore tretment nd 1 to 3 dys following the end of tretment to identify enteric pthogens. The predominnt pthogen in oth studies ws Escherichi coli. The clinicl efficcy of ws ssessed y 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. Tle 4 displys the medin TLUS nd the numer 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 plceo group. More ptients treted with were clssified s clinicl cures thn were those in the plceo group. Tle 4. Clinicl Response in Study 1 (ITT popultion) Medin TLUS (hours) Clinicl cure, (n=125) (n=129) 32.5 58.6 99 (79) 78 (60) Hzrd Rtio (p-vlue <0.001) in rtes (p-vlue <0.01) Estimte (97.5% CI) 2 (1.26, 2.50) 19 (5.3, 32.1) Microiologicl erdiction (defined s the sence of seline pthogen in culture of stool fter 72 hours of therpy) rtes for Study 1 re presented in Tle 5 for ptients with ny pthogen t seline nd for the suset of ptients with Escherichi coli t seline. Escherichi coli ws the only pthogen with sufficient numers to llow comprisons etween tretment groups. Even though hd microiologic ctivity similr to plceo, it demonstrted cliniclly significnt reduction in durtion of dirrhe nd higher clinicl cure rte thn plceo. Therefore, ptients should e mnged sed on clinicl response to therpy rther thn microiologic response. Tle 5. Microiologic Erdiction Rtes in Study 1 Sujects with Bseline Pthogen verll 48/70 (69) 41/61 (67) E. coli 38/53 (72) 40/54 (74) The results of Study 2 supported the results presented for Study 1. In ddition, this study provided evidence tht sujects treted with with fever nd/or lood in the stool t seline hd prolonged TLUS. These sujects hd lower clinicl cure rtes thn those without fever or lood in the stool t seline. Mny of the ptients with fever nd/or lood in the stool (dysentery-like dirrhel syndromes) hd invsive pthogens, primrily Cmpylocter jejuni, isolted in the seline stool. Also in this study, the mjority of the sujects treted with who hd Cmpylocter jejuni isolted s sole pthogen t seline filed tretment nd the resulting clinicl cure rte for these ptients ws 23.5% (4/17). In ddition to not eing different from plceo, the microiologic erdiction rtes for sujects with Cmpylocter jejuni isolted t seline were much lower thn the erdiction rtes seen for Escherichi coli. In n unrelted open-lel, phrmcokinetic study of orl 200 mg tken every 8 hours for 3 dys, 15 dult sujects were chllenged with Shigell flexneri 2, of whom 13 developed dirrhe or dysentery nd were treted with. Although this open-lel chllenge tril ws not dequte to ssess the effectiveness of in the tretment of shigellosis, the following oservtions were noted: eight sujects received rescue tretment with ciprofloxcin either ecuse of lck of response to tretment within 24 hours (2), or ecuse they developed severe dysentery (5), or ecuse of recurrence of Shigell flexneri in the stool (1); five of the 13 sujects received ciprofloxcin lthough they did not hve evidence of severe disese or relpse. 14.2 Heptic Encephlopthy The efficcy of 550 mg tken orlly two times dy ws evluted in rndomized, plceo-controlled, doule-lind, multi-center 6-month tril of dult sujects from the U.S., Cnd nd Russi who were defined s eing in remission (Conn score of 0 or 1) from heptic encephlopthy (HE). Eligile sujects hd 2 episodes of HE ssocited with chronic liver disese in the previous 6 months. A totl of 299 sujects were rndomized to receive either (n=140) or plceo (n=159) in this study. Ptients hd men ge of 56 yers (rnge, 21-82 yers), 81% <65 yers of ge, 61% were mle nd 86% White. At seline, 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 seline. No ptients were enrolled with MELD score of >25. Nine percent of the ptients were Child-Pugh Clss C. Lctulose ws concomitntly used y 91% of the ptients in ech tretment rm of the study. Per the study protocol, ptients were withdrwn from the study fter experiencing rekthrough HE episode. ther resons for erly study discontinution included: dverse rections ( 6%; plceo 4%), ptient request to withdrw ( 4%; plceo 6%) nd other ( 7%; plceo 5%). The primry endpoint ws the time to first rekthrough overt HE episode. A rekthrough overt HE episode ws defined s mrked deteriortion in neurologicl function nd n increse of Conn score to Grde 2. In ptients with seline Conn score of 0, rekthrough overt HE episode ws defined s n increse in Conn score of 1 nd sterixis grde of 1. Brekthrough overt HE episodes were experienced y 31 of 140 sujects (22%) in the group nd y 73 of 159 sujects (46%) in the plceo group during the 6-month tretment period. Comprison of Kpln-Meier estimtes of event-free curves showed significntly reduced the risk of HE rekthrough y 58% during the 6-month tretment period. Presented elow in Figure 1 is the Kpln-Meier eventfree curve for ll sujects (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 Tretment, Dy 170) (ITT Popultion) Note: pen dimonds nd open tringles represent censored sujects. 1 Event-free refers to non-occurrence of rekthrough HE. When the results were evluted y the following demogrphic nd seline chrcteristics, the tretment effect of 550 mg in reducing the risk of rekthrough overt HE recurrence ws consistent for: sex, seline Conn score, durtion of current remission nd dietes. The differences in tretment effect could not e ssessed in the following supopultions due to smll smple size: non-white (n=42), seline 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 y HE) were reported for 19 of 140 sujects (14%) nd 36 of 159 sujects (23%) in the nd plceo groups respectively. Comprison of Kpln-Meier estimtes of event-free curves showed significntly reduced the risk of HE-relted hospitliztions y 50% during the 6-month tretment period. Comprison of Kpln-Meier estimtes of event-free curves is shown in Figure 2. 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 Tretment, Dy 170) (ITT Popultion) Note: pen dimonds nd open tringles represent censored sujects. 1 Event-free refers to non-occurrence of HE-relted hospitliztion. 14.3 Irritle Bowel Syndrome with Dirrhe The efficcy of for the tretment of IBS-D ws estlished in 3 rndomized, multi-center, doule-lind, plceo-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 plceo (n=634) for 14 dys nd then followed for 10-week tretment-free period. The Rome II criteri further ctegorizes IBS ptients into 3 sutypes: dirrhe-predominnt IBS (IBS-D), constiption-predominnt IBS (IBS-C), or lternting IBS (owel hits lternting etween dirrhe nd constiption). Ptients with oth 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 e consecutive, in the preceding 12 months of dominl discomfort or pin tht hs two out of three fetures: 1. Relieved with defection; nd/or 2. nset ssocited with chnge in frequency of stool; nd/or 3. nset ssocited with chnge in form (ppernce) of stool. Symptoms tht Cumultively Support the Dignosis of Irritle Bowel Syndrome: Anorml stool frequency (for reserch purposes norml my e defined s greter thn 3 owel movements per dy nd less thn 3 owel movements per week); Anorml stool form (lumpy/hrd or loose/wtery stool); Anorml stool pssge (strining, urgency, or feeling of incomplete evcution); Pssge of mucus; Bloting or feeling of dominl 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-lel for 14 dys. f 2438 evlule 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 doulelind phse of the study. These ptients were scheduled to receive 550 mg three times dy (n=328) or plceo (n=308) for two dditionl 14-dy repet tretment courses seprted y 10 weeks. See Figure 3. Figure 3: Tril 3 Study Design 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 dominl pin or discomfort (uncomfortle senstion not descried s pin) t lest 3 dys/month in lst 3 months ssocited with two or more of the following: 1. Improvement with defection; 2. nset ssocited with chnge in frequency of stool; 3. nset ssocited with chnge in form (ppernce) of stool. Trils 1 nd 2 - Results Trils 1 nd 2 included 1258 IBS-D ptients (309, 314 plceo); (315, 320 plceo). The primry endpoint for oth 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 Suject Glol Assessment (SGA) question: In regrds to your IBS symptoms, compred to the wy you felt efore 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 y more ptients receiving thn those receiving plceo during the month following 2 weeks of tretment (SGA-IBS Weekly Results: 41% vs. 31%, p=0.0125; 41% vs. 32%, p=0.0263 (See Tle 6). Tle 6. Adequte Relief of IBS Symptoms During the Month Following Two Weeks of Tretment n=309 Tril 1 n=314 Adequte Relief of IBS 126 (41) 98 (31) Symptoms Tretment (95% CI ) 10% (2.1%, 17.1%) n=315 Tril 2 n=320 Adequte Relief of IBS 128 (41) 103 (32) Symptoms Tretment (95% CI ) 8% (1.0%, 15.9%) Confidence Intervl The p-vlue for the primry endpoint for Tril 1 nd for Tril 2 ws <0.05. The trils exmined composite endpoint which defined responders y IBS-relted dominl pin nd stool consistency mesures. Ptients were monthly responders if they met oth of the following criteri: experienced 30% decrese from seline in dominl 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 dominl pin nd stool consistency in Trils 1 nd 2 (see Tle 7). Tle 7. Efficcy Responder Rtes in Tril 1 nd 2 During the Month Following Two Weeks of Tretment n=309 Tril 1 n=314 Pin nd 144 (47) 121 (39) Pin 159 (51) 132 (42) 244 (79) 212 (68) n=315 Tril 2 n=320 Pin nd 147 (47) 116 (36) Pin 165 (52) 138 (43) 233 (74) 206 (64) Tretment (95% CI ) 8% (0.3%, 15.9%) 9% (1.8%, 17.5%) 11% (4.4%, 18.2%) Tretment (95% CI ) 11% (2.7%, 18.0%) 9% (1.5%, 17.0%) 10% (2.3%, 16.7%) Confidence Intervl The p-vlue for the composite endpoint for Tril 1 nd 2 ws <0.05 nd <0.01, respectively. Tril 3 - Results In TARGET 3, 2579 ptients were scheduled to receive n initil 14-dy course of open-lel followed y 4 weeks of tretment-free follow-up. At the end of the followup period, ptients were ssessed for response to tretment. Ptients were considered responder if they chieved oth of the following: 30% improvement from seline in the weekly verge dominl pin score sed on the dily question: In regrds to your specific IBS symptoms of dominl pin, on scle of 0-10, wht ws your worst IBS-relted dominl pin over the lst 24 hours? Zero mens you hve no pin t ll; Ten mens the worst possile pin you cn imgine. t lest 50% reduction in the numer of dys in week with dily stool consistency of Bristol Scle type 6 or 7 compred with seline where 6=fluffy pieces with rgged edges, mushy stool; 7=wtery stool, no solid pieces; entirely liquid. were then followed for recurrence of their IBS-relted symptoms of dominl pin or mushy/wtery stool consistency for up to 20 tretment-free weeks. When ptients experienced recurrence of their symptoms of dominl pin or mushy/wtery stool consistency for 3 weeks of rolling 4-week period, they were rndomized into the doule-lind, plceo-controlled repet tretment phse. f 1074 ptients who responded to open-lel, 382 experienced period of symptom inctivity or decrese tht did not require repet tretment y the time they discontinued, including ptients who completed the 22 weeks fter initil tretment with. See Figure 3. verll, 1257 of 2579 ptients (49%) were nonresponders in the open-lel phse nd per the study protocol were withdrwn from the study. ther resons for discontinution include: ptient request (5%), ptient lost to follow-up (4%), dverse rection (3%), nd other (0.8%). There were 1074 (44%) of 2438 evlule ptients who responded to initil tretment with improvement in dominl pin nd stool consistency. The response rte for ech IBS symptom during the open-lel phse of Tril 3 is similr to the rtes seen in Trils 1 nd 2 (see Tle 7). A totl of 636 ptients susequently hd sign nd symptom recurrence nd were rndomized to the repet tretment phse. The medin time to recurrence for ptients who experienced initil response during the open-lel phse with ws 10 weeks (rnge 6 to 24 weeks). The nd plceo tretment groups hd similr seline IBS symptom scores t the time of recurrence nd rndomiztion to the doule-lind phse, ut symptom scores were less severe thn t study entry into the open-lel phse. Ptients were deemed to hve recurrent signs nd symptoms y the following criteri: return of dominl pin or lck of stool consistency for t lest 3 weeks during 4-week follow-up period. The primry endpoint in the doulelind, plceo-controlled portion of the tril ws the proportion of ptients who were responders to repet tretment in oth IBS-relted dominl pin nd stool consistency s defined ove during the 4 weeks following the first repet tretment with. The primry nlysis ws performed using the worst cse nlysis method where ptients with <4 dys of diry entries in given week re considered s non-responders for tht week. More ptients receiving were monthly responders for dominl pin nd stool consistency in the primry nlysis in Tril 3 (see Tle 8). Tle 8. Efficcy Responder Rtes in Tril 3 in Given Week for t Lest 2 Weeks During Weeks 3 to 6 of the Doule- Blind, First Repet Tretment Phse Comined Responder : Pin nd c Pin ( 30% reduction in dominl pin) ( 50% reduction from seline in dys/week with loose or wtery stools) (n=308) (n=328) 97 (31) 125 (38) 130 (42) 166 (51) 154 (50) 170 (52) Tretment (95% CI ) 7% (0.9%, 16.9%) 9% (1.6%, 17.0%) 2% (-4.7%, 11.0%) Confidence Intervls were derived sed on CMH test djusting for center nd ptients time to recurrence during mintennce phse. Primry endpoint c Sujects were IBS-relted dominl pin nd stool consistency responders if they were oth weekly IBS-relted dominl pin responders nd weekly stool consistency responders in given week for t lest 2 weeks during Weeks 3 to 6 in the doule-lind first repet tretment phse. Weekly responder in IBS-relted dominl pin ws defined s 30% or greter improvement from seline in the weekly verge dominl pin score. Weekly responder in stool consistency ws defined s 50% or greter reduction in the numer of dys in week with stool consistency of type 6 or 7 compred with seline. The p-vlue for this composite endpoint ws <0.05. Thirty six of 308 (11.7%) of plceo ptients nd 56 of 328 (17.1%) of -treted ptients responded to the first repet tretment nd did not hve recurrence of signs nd symptoms through the tretment-free follow-up period (10 weeks fter first repet tretment). The response rte difference ws 5.4% with 95% confidence intervl (1.2% to 11.6%).
15 REFERENCES 1. Methods for Dilution Antimicroil Susceptiility Tests for Bcteri tht Grow Aeroiclly; Approved Stndrd Ninth Edition. CLSI document M07-A9. Wyne, PA: Clinicl nd Lortory Stndrds Institute, 2012. 2. Methods for Antimicroil Susceptiility Testing of Aneroic Bcteri; Approved Stndrd Eighth Edition. CLSI document M11-A8. Wyne, PA: Clinicl nd Lortory Stndrds Institute, 2012. 3. Performnce Stndrds for Antimicroil Susceptiility Testing; Twenty-Fourth Informtionl Supplement. CLSI document M100-S2. Wyne, PA: Clinicl nd Lortory Stndrds Institute, 2014. 16 HW SUPPLIED/STRAGE AND HANDLING The 200 mg tlet is pink-colored, round, iconvex tlet with Sx deossed on one side. It is ville in the following presenttion: NDC 65649-301-03, ottles of 30 tlets The 550 mg tlet is pink-colored, ovl, iconvex tlet with rfx deossed on one side. It is ville in the following presenttions: NDC 65649-303-02, ottles of 60 tlets NDC 65649-303-03, crton of 60 tlets, Unit NDC 65649-303-04, crton of 42 tlets, Unit 9494600 (insert) 9494700 (outsert) Rev. 11/2015 Storge Store Tlets t 20 to 25 C (68 to 77 F); excursions permitted to 15 to 30 C (59 to 86 F) [See USP Controlled Room Temperture]. 17 PATIENT CUNSELING INFRMATIN Persistent Dirrhe For those ptients eing treted for trvelers dirrhe, discontinue if dirrhe persists more thn 24-48 hours or worsens. Advise the ptient to seek medicl cre for fever nd/or lood in the stool [see Wrnings nd Precutions (5.1)]. Clostridium difficile-associted Dirrhe Clostridium difficile-ssocited dirrhe (CDAD) hs een reported with use of nerly ll nticteril gents, including, nd my rnge in severity from mild dirrhe to ftl colitis. Tretment with ntiiotics lters the norml flor of the colon which my led to C. difficile. Ptients cn develop wtery nd loody stools (with or without stomch crmps nd fever) even s lte s two or more months fter hving tken the lst dose of the ntiiotic. If dirrhe occurs fter therpy or does not improve or worsens during therpy, dvise ptients to contct physicin s soon s possile [see Wrnings nd Precutions (5.4)]. Administrtion with Food Inform ptients tht my e tken with or without food. Anticteril Resistnce Counsel ptients tht nticteril drugs including should only e used to tret cteril infections. They do not tret virl infections (e.g., the common cold). When is prescried to tret cteril infection, ptients should e told tht lthough it is common to feel etter erly in the course of therpy, the mediction should e tken exctly s directed. Skipping doses or not completing the full course of therpy my (1) decrese the effectiveness of the immedite tretment nd (2) increse the likelihood tht cteri will develop resistnce nd will not e tretle y or other nticteril drugs in the future. Severe Heptic Impirment Inform ptients with severe heptic impirment (Child- Pugh Clss C) tht there is n increse in systemic exposure to [see Wrnings nd Precutions (5.4)]. Distriuted y: Slix Phrmceuticls Bridgewter, NJ 08807 USA The Xifxn 200 mg nd 550 mg products nd the Xifxn trdemrk re licensed y Alf Wssermnn S.p.A. to Slix Phrmceuticls or its ffilites. Rifximin for Trvelers Dirrhe, Heptic encephlopthy nd IBS re protected y US Ptent Nos. 7,045,620; 7,612,199; 7,902,206; 7,906,542; 8,158,781; 8,158,644; 8,193,196; 8,518,949; 8,741,904; 8,835,452; nd 8,853,231. Rifximin for Trvelers Dirrhe is lso protected y US Ptent No. 7,928,115. Rifximin for Heptic encephlopthy is lso protected y US Ptent No. 8,642,573; 8,829,017; 8,946,252; nd 8,969,398. Rifximin for IBS is lso protected y US Ptent Nos. 6,861,053; 7,452,857; 7,718,608; nd 8,309,569. We site: www.slix.com