SUPPLEMENT ARTICLE Safety Analysis of Fidaxomicin in Comparison Clostridium difficile With Oral Vancomycin for Infections KarlWeiss,1RobinL.Allgren,2andSarahSellers3 1DepartmentofInfectiousDiseasesandMicrobiology,Maisonneuve-RosemontHospital,FacultyofMedicine,UniversityofMontreal,Quebec,Canada; 2BreakthroughBioDevelopment,LLC,SanDiego,California,and3q-Vigilance,LLC,Barrington,Illinois FidaxomicinisanovelmacrocyclicantibioticrecentlyapprovedbytheUSFoodandDrugAdministrationfor the treatment of Clostridium difficile–associated diarrhea in adults. We reviewed safety datafrom nonclinical studies and clinical trials (phases 1, 2A, and 3) with fidaxomicin. In nonclinical studies, fidaxomicin was administered orally at approximately 1g/kg/d to dogs for up to 3 months with no significant target-organ toxicities observed. A total of 728 adults have received oral fidaxomicin in clinical trialsto date: 116 healthy volunteers and 612 patients with C. difficile infection. In phase 3 clinical trials, fidaxomicin was well toler- ated, with a safety profile comparable with oral vancomycin. There were no differences in the incidence of death or serious adverse events between the 2 drugs. Fidaxomicin appears to be well tolerated. Continued monitoring of adverse events in the postmarketing setting will provide additional information about the full safetyprofileoffidaxomicin. Clostridium difficile was recognized as the causative 1995, the Centers for Disease Control and Prevention agent for antibiotic-associated colitis in 1978 [1], recommended that vancomycin not be used orally for first observed in conjunction with clindamycin treat- CDI in hospital settings as a strategy to prevent the ment [2]. Since then, C. difficile infection (CDI) has emergence of VRE and vancomycin intermediate Sta- become an increasingly challenging nosocomial infec- phylococcusaureus. tionwithseveremedicalconsequences[3–6]. Priortotheapprovaloffidaxomicin,oralvancomy- Hamster animal models showed some protective cin was the only agent approved by the US Food and and beneficial effect from oral vancomycin, which Drug Administration (FDA) for the treatment of anti- quickly became the treatment drug of choice [7, 8]. biotic-associated pseudomembranous colitis produced However, the use of all vancomycin formulations by C. difficile. Metronidazole was subsequently used (parvules and intravenous vancomycin used orally) off-label and, as a much less expensive alternative, hadtobelimitedeitherbecauseofitshighprice(par- became the de facto first-line treatment for mild to vules)ortocurtailthepotentialriskfortheemergence moderate cases of CDI [8,10].Other antibiotics have of vancomycin-resistant enterococci (VRE) [9]. In been tried in the past (fusidic acid, bacitracin, rifaxi- min, and nitazoxanide), but only limited clinical data are available for the treatment of CDI [11]. Thus, Correspondence: Karl Weiss, MD, FRCPC, Maisonneuve-Rosemont Hospital, there has been a need for new therapies to treat this 5415L’Assomption,Montreal,QC,CanadaH1T2M4([email protected]). challengingdisease. ClinicalInfectiousDiseases 2012;55(S2):S110–15 Ideally, drugs against C. difficile should be mini- ©TheAuthor2012.PublishedbyOxfordUniversityPressonbehalfoftheInfectious DiseasesSocietyofAmerica.Allrightsreserved.ForPermissions,pleaseemail: mally absorbed, remain in the intestinal lumen, and journals.permissions@oup.com.ThisisanOpenAccessarticledistributedunder have a narrow spectrum of activity, preserving the thetermsoftheCreativeCommonsAttributionNon-CommercialLicense(http:// creativecommons.org/licenses/by-nc/3.0), which permits unrestricted non- normalmicrobiotaofthegut. commercialuse,distribution,andreproductioninanymedium,providedtheoriginal Fidaxomicin has a narrow-spectrum antibacterial workisproperlycited. DOI:10.1093/cid/cis390 profile, with potent bactericidal activity specifically (cid:129) (cid:129) S110 CID 2012:55 (Suppl2) Weissetal againstC.difficile.Itdisplaysmoderateinvitroactivityagainst (half maximal inhibitory concentration greater than the someGram-positivebacteria(S.aureusandEnterococcusspp.) highestnominaldosetestedof10µg/mL). and is inactive against Gram-negative organisms and yeast. Thepotentialforreproductivetoxicitywasassessedinafer- Fidaxomicin is minimally absorbed from the gastrointestinal tilitystudyinratsandembryo-fetaldevelopmentstudiesinrats (GI) tract, with plasma concentrations in the nanogram-per- and rabbits. Fidaxomicin did not affect the fertility of male milliliterrangeafteroraldosing. and female ratsatintravenousdosesof6.3mg/kg,resultingin In2phase3trials,fidaxomicindemonstratednoninferiority systemic exposure approximately 100 times that in humans. to vancomycin for clinical response in the treatment of CDI Fidaxomicin at the highest dose tested in rats (15mg/kg/d) and superiority to vancomycin for sustained clinical response andrabbits(7.5mg/kg/d)exhibitednomaternal,reproductive, (curewithout recurrence during the30-dayfollow-up period). orembryo-fetaldevelopmentaltoxicity. The efficacy results are presented in detail elsewhere [12,13]. Thegenotoxicityoffidaxomicinwasassessedininvitro(bac- The safety results from nonclinical and clinical studies are terial reverse mutation and chromosomal aberration assays) summarizedinthefollowingsections. and in vivo (rat micronucleus assay) studies. Additionally, the mainactive metabolite OP-1118 was evaluated for genotoxicity in vitro (bacterial reverse mutation and chromosomal aberra- NONCLINICALSAFETYSTUDIES tionassays).Overall,resultsfromgenotoxicitytestsshowedthat fidaxomicin is not expected to be genotoxic in humans. Long- A standard battery of nonclinical studies was conducted to term carcinogenicitystudieshave notbeenconducted toevalu- assess the safety of fidaxomicin, including general toxicity atethecarcinogenicpotentialoffidaxomicin. (acute and repeated dose for up to 3 months), safety pharma- cology,reproductivetoxicity,andgenotoxicitystudies[13]. SAFETYPROFILEINCLINICALTRIALS For a single intravenous fidaxomicin dose in rats, the 50% lethaldosewasapproximately200mg/kgandthenoobserved During the clinical development of fidaxomicin, 728 subjects adverse effect level(NOAEL) was determinedto be62.5mg/kg; received fidaxomicin: 116 healthy adult volunteers in phase 1 at this NOAEL dose, the peak plasma level of fidaxomicin was studies and 612 adults with CDI in phase 2A and 3 studies. 3000–10200ng/mL, which is at least 300-fold higher than the In the phase 1 and 2A studies, subjects were exposed to doses maximum concentration observed in humans. The toxicity of of fidaxomicin ranging 100–450mg. No significant dose- fidaxomicin was also evaluated in a repeated-dose setting in relatedadverseevents(AEs)wereobserved[14,15]. rats and monkeys at oral doses up to 90mg/kg/d for 28 days; The safety and efficacy of fidaxomicin were compared with there were no drug-related deaths or effects on clinical oral vancomycin in 2 randomized, double-blinded pivotal observations. In a 3-month study in dogs, the NOAEL oral phase 3 studies. One was performed in North America [12], dose was the highest dose of 9.6g/d (equivalent to 94–1160 and the other was performed in both North America and mg/kg/d). Although some emesis and soft stools were observed Europe [13]. In both phase 3 studies, fidaxomicin was admin- at the highest doses in this study, these were attributed to the istered orally at 200mg every 12 hours for 10 days, and van- very large doses delivered (5%–7% of daily food intake). They comycin was administered orally at 125mg every 6 hours for were not exacerbated with continued dosing and were not 10 days (the currently recommended dose for nonfulminant associated with changes in food consumption or weight gain disease). In these studies, 564 subjects with CDI were treated betweengroups or with histological changes. Thisindicatesthat with fidaxomicin and 583 were treated with vancomycin, high fecal levels of fidaxomicin (up to milligram-per-gram respectively.Overall,86.7%ofsubjectscompletedafullcourse levels) are not associated with GI toxicity. None of these oftreatment. studies revealed evidence of toxicity to the bone marrow/ Ofthe1147subjectsevaluableforthepooledphase3safety hematopoietic system,liver,kidney, orother targetorgan. analysis, 567 (49.4%) were aged ≥65 years (272 treated with The hERG channel, a potassium ion channel, mediates the fidaxomicin and 295 treated with vancomycin), reflecting that repolarizing currentinthecardiacactionpotential.Whenthis the elderly are disproportionately affected by CDI. Subjects channel’s ability to conduct electrical current across the cell were mainly white (90%), female (58%), and in-patients membrane is inhibited or compromised, by either drugs or (64%). Many subjects enrolled in the phase 3 program were rare mutations in some families, it can result in a potentially acutely ill, with concomitant acute and chronic medical con- fatal disordercalled long-QT syndrome. An in vitro assay has ditionsinadditiontoCDI. beenestablishedtoscreendrugsforhERGinhibition. Intheseclinicalstudies,thesafetyprofileoffidaxomicinwas In vitro, neither fidaxomicin nor its main metabolite OP- comparable with that of the active comparator vancomycin. 1118 had an inhibitory effect on the hERG channel current For example, the total number of deaths in the phase 3 trials (cid:129) (cid:129) SafetyAnalysisofFidaxomicin CID 2012:55 (Suppl2) S111 wassimilarforfidaxomicin(36of564;6.4%)andvancomycin subjects had other risk factors for GI bleeding, such as recent (38of583;6.5%;P=notsignificant).Noneofthesedeathswas bowel surgery, coagulopathies, or concomitant medications believedtobeduetostudydrugtoxicity,buttheywereattribu- with anticoagulant properties. For fidaxomicin subjects, the tedtothesubject’s significantunderlying morbidities. Nine of early GI bleeding events tended to be mild self-limited events the deaths were deemed possibly related to progression of the (such as a single bloody bowel movement or intermittent underlying CDI: 5 for fidaxomicin and 4 for vancomycin bleeding from preexisting rectal hemorrhoids) not requiring (5 men, 4 women; mean days on therapy, 6.78). In terms of intervention. Fidaxomicin was not associated with an increase any serious AEs (SAEs) or general AEs, the overall rates also inbleedingeventsinother(non-GI)organsystems. were similar (Table 1). The vast majority of all events were Three patients in the fidaxomicin arm developed megaco- ratedasnotrelatedtostudydrugbytheinvestigators. lon,anunfortunatecomplicationofCDI.Onesubjectreceived Rates for discontinuation of dosing due to an AE were also only 2 doses before his condition worsened. For the 2 other comparableforbothdrugsinthephase3trials.Therewere33 subjects,megacolonwasdiagnosedwithatreatmentfailureon of564(5.9%)and40of583(6.9%)subjectsinthefidaxomicin days 3and 6oftherapy,respectively.Onevancomycinsubject and vancomycin arms, respectively, who stopped their treat- presentedwithalarge-intestineperforationonday31andwas ment due to an AE (P=.48). Vomitingwasthe most frequent foundtohavetoxicmegacolonduringcolectomy. AE leading to study drug discontinuation. This occurred for 0.5%ofsubjectsinbothtreatmentgroups[16]. HematologicSafety Anemia was reported in 2% of both fidaxomicin and vanco- GISafety mycin subjects. Leukopenia (eg, decreases in white blood cell Because the majority of fidaxomicin remains in the intestinal counts or neutrophils) were observed in 14 of 564 (2.5%) fi- lumen and exerts its activity there, GI AEs in the fidaxomicin daxomicin subjects and 6 of 583 (1.0%) vancomycin subjects phase 3 studies were evaluated closely. In the phase 3 studies, (P=.06). There was no apparent explanation for this finding thenumberofoverallGIAEsandSAEswassimilarbetweenthe except that more patients received antineoplastic or immuno- fidaxomicin and vancomycin groups. Slightly more GI AEs led modulating agents in the fidaxomicin group (11.9% vs 8.2%; todiscontinuationfromthestudyinthefidaxomicingroupthan P=.04) [13]. Nearly all these reported events of leukopenia inthevancomycingroup(2.3%vs1.4%;P=.24),butdeathsdue occurred in subjects with underlying hematologic malignan- to a GI AE tended to occur less frequently in the fidaxomicin cies,recentbonemarrowtransplant,and/orrecentchemother- groupthanthevancomycingroup(0.5%vs1.0%;P=.51). apy. No specific bone marrow toxicity was observed with Some form of GI bleeding occurred in 23 fidaxomicin- fidaxomicin in the nonclinical studies [13]. The main clinical treated patients (23 of 564; 4.1%) and 18 vancomycin-treated concern regarding leukopenia is that it could lead to an in- patients (18 of 583; 3.1%; P=.37). All GI bleeding events in creased incidence of serious infections. However, it should fidaxomicin subjects were deemed not related or unlikely also be noted that no overall increased incidence of infections related to the drug by the investigators. Also, many of these with fidaxomicin vs vancomycin was observed in the phase 3 studies (22.9% vs 20.8%, respectively). The incidence of infec- tionsresulting indeathwas2.0% forfidaxomicinsubjectsand Table1. AdverseEventsinPhase3Trials 1.9% for vancomycin subjects. No adverse effect on platelet countswasobservedinnonclinicalorclinicalstudies. Fidaxomicin, Vancomycin, 400mg(n= 500mg(n= SubjectsWith≥1AE 564),No.(%) 583),No.(%) CardiacSafety AnyAE 385(68.3) 382(65.5) Electrocardiograms(ECGs)wereobtainedbeforethefirstdose AEsbyseverity and at the end of therapy. No significant changes in ECGs Mild 160(28.4) 171(29.3) were observed during the study period. Therewere no signifi- Moderate 117(20.7) 113(19.4) cant corrected QT (QTc) interval modifications for either Severe 108(19.1) 98(16.8) group in the phase 3 studies (Table 2). There was no associ- AEsleadingtodiscontinuationof 33(5.9) 40(6.9) ation between QTc interval prolongation and increased fidax- studydrug AEsleadingtodosemodificationor 2(0.4) 8(1.4) omicin level. One patient receiving oral vancomycin in a useofconcomitantmedication phase 3 trial developed torsades de pointes. Deaths due to SeriousAEs 145(25.7) 135(23.2) cardiac events occurred in 0.4% of fidaxomicin subjects and AEsresultingindeath 36(6.4) 38(6.5) 1.2% of vancomycin subjects (P=.18). In a subgroup analysis Abbreviation:AE,adverseevent. with high plasma levels (fidaxomicin plus OP–1118 levels (cid:129) (cid:129) S112 CID 2012:55 (Suppl2) Weissetal Table 2. Summary of 12-Lead Electrocardiogram Corrected QT Table 3. Summary Statistics for Changes in Liver Function Pa- Interval Results (Bazett’s and Fridericia’s corrections): Phase 3 rametersBetweenBaselineandEndofTherapy:Phase3Studies Studies Fidaxomicin400 Vancomycin Bazett’s Fridericia’s Parameter mg(n=564) 500mg(n=583) ALT(U/L) Fidaxomicin Vancomycin Fidaxomicin Vancomycin QTc (n=501), (n=503), (n=501), (n=503), Patients,No. 482 478 intervals No(%) No.(%) No.(%) No.(%) Meanchange 6.1 −0.3 ChangesinQTcintervalfrombaseline(ms) SD 48.62 71.52 Medianchange 2 2 >30 42(8.7) 32(6.6) 37(7.7) 35(7.2) Alkalinephosphatase(U/L) >60 6(1.2) 6(1.2) 6(1.2) 5(1.0) QTcintervalatendofstudy(ms) Patients,No. 502 506 Meanchange 3 2.7 >450 96(19.2) 109(21.7) 43(8.6) 54(10.7) SD 59.07 47.19 >480 26(5.2) 34(6.8) 13(2.6) 16(3.2) >500 12(2.4) 14(2.8) 7(1.4) 11(2.2) Medianchange −1 1 AST(U/L) Onlysubjectswithbothbaselineandend-of-studyelectrocardiogramvalues Patients,No. 473 459 areincludedinthisevaluation. Meanchange 3 −4.5 Abbreviation:QTc,correctedQT. SD 24.26 136.48 Medianchange 2 2 Bilirubin(mmol/L) ≥150ng/mL), there was no association between QTc interval Patients,No. 485 481 Meanchange −0.65 −0.92 prolongationanddruglevels. SD 5.17 15.19 Medianchange 0 0 HepaticSafety Directbilirubin(mmol/L) In the phase 3 clinical studies, the incidence of AEs involving Patients,No. 443 433 abnormalliverfunctiontest (LFT)resultswassimilarbetween Meanchange −0.33 −0.47 fidaxomicin and vancomycin (3.2% vs 2.6%; P=.53). No sig- SD 2.88 7.51 nificant changes in mean LFT results were observed in either Medianchange 0 0 group (Table 3). The numbers of subjects with normal LFT Abbreviations:ALT,alanineaminotransferase;AST,aspartateaminotransferase; results at baseline but a later LFT result at least 3 times the SD,standarddeviation. upper limit of normal (ULN) were 6 for fidaxomicin and 5 for vancomycin. No subject in either group had an increase inaspartateoralanineaminotransferaselevelto>3timesULN UseinPregnancy with an increase in bilirubin level >2 times ULN. Adverse To date, there are no meaningful data available for fidaxomi- events were also examined for subjects with and without ab- cin use during pregnancy in humans. Onewoman with B-cell normal LFT results at baseline. The overall incidence of AEs was similar for fidaxomicin- and vancomycin-treated subjects lymphoma in a phase 3 study receiving fidaxomicin and also receiving numerous other agents (including methotrexate and withandwithouttheseabnormallaboratoryparameters. vincristine) had a multiple-birth pregnancy. Her pregnancy test was negative at enrollment and became positive on day UseinRenalImpairment 25. She delivered 3 live and 1 dead fetuses; 1 female fetus was No specific safety studies have been carried out to date with foundtohaveacleftpalate. fidaxomicin in subjects with renal or hepatic impairment. However, 48% of subjects in the phase 3 studies had renal insufficiency at baseline, and the safety of fidaxomicin was DISCUSSION examinedinsubgroupsofsubjectswhohadvaryingdegreesof renalinsufficiencybasedonestimatedcreatinineclearanceand In phase 3 trials, the overall safety profile of fidaxomicin was characterized as either mild (51–79mL/min), moderate (31– comparablewiththatoforalvancomycin.Therewasnodiffer- 50mL/min),orsevere(≤30mL/min).Noclinicallysignificant enceintheincidenceofdeathsorSAEsbetweenthefidaxomi- differences in the incidence of AEs between fidaxomicin and cin and vancomycin arms. There was a numerical imbalance vancomycin subjects were observed within subpopulations inAEsrelatedtoGIhemorrhage(4.1%vs3.1%)andleukope- withmild,moderate,orsevererenalinsufficiency. nia (4.1% vs 1.7%) between the fidaxomicin and vancomycin (cid:129) (cid:129) SafetyAnalysisofFidaxomicin CID 2012:55 (Suppl2) S113 groups, but no causal relationship between fidaxomicin and Bristol-Myers-Squibb, Genzyme Corp, GlaxoSmithKline, Optimer, theseeventscouldbeestablished. Pharma,Pfizer,Roche,andTheravance.R.L.A.andS.S.arepaidconsult- ants to Optimer Pharmaceuticals, Inc, regarding pharmacovigilance and The oral formulation of vancomycin has been on the pharmacoepidemiology,respectively. market for >2 decades. Vancomycin can be administered to AllauthorshavesubmittedtheICMJEFormforDisclosureofPotential children and pregnant women, and its long-term adminis- Conflicts of Interest. 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