ࡱ>  jbjbjVV p<<bsEEEEE$iiiP$ig#(#L5$5$5$m%:%% yf{f{f{f{f{f{fik^{f]E%i%i%%%{fEE5$5$4fG+G+G+%E5$E5$yfG+%yfG+G+Vm[5$0MF~i'6X*eff0gXl(lTm[m[\lE[ %%G+%%%%%{f{f*%%%g%%%%l%%%%%%%%% : Fidaxomicin (Dificid"!) National Drug Monograph February 2011 VA Pharmacy Benefits Management Services, Medical Advisory Panel, and VISN Pharmacist Executives The purpose of VA PBM Services drug monographs is to provide a comprehensive drug review for making formulary decisions. These documents will be updated when new clinical data warrant additional formulary discussion. Documents will be placed in the Archive section when the information is deemed to be no longer current. Executive Summary: 1-5 Fidaxomicin is a poorly absorbed, macrocyclic antibiotic with activity against Gram-Positive aerobes and anaerobes, including Clostridium difficile. It recently received FDA-approval for the treatment of C. difficile-associated diarrhea (CDAD) in adults. In two pivotal, phase III studies, adult patients with a diagnosis of CDAD and history of <1 recurrence were randomized to treatment with oral vancomycin or fidaxomicin. Patients with severe, complicated CDAD were excluded from the clinical trials. Fidaxomicin was found to be non-inferior to vancomycin in the primary efficacy endpoint, clinical cure. The majority of patients enrolled in the clinical trials were inpatients and the BI/NAP1/027 strain comprised approximately 40% of all isolates. In both phase III studies, the sustained clinical responses 25 days after the end of treatment were superior in patients treated with fidaxomicin. In a subgroup analysis, recurrence rates were significantly lower in fidaxomicin-treated patients who were >65 years old, had no prior episodes of CDAD, were not receiving concomitant antibiotics, and had a non-BI/NAP1/027 strain. The most commonly observed adverse events in clinical trials were gastrointestinal effects, including nausea, vomiting, and abdominal pain. Fidaxomicin is not metabolized via the cytochrome P450 pathway and minimal drug interactions were observed in pharmacokinetic studies. The SHEA/IDSA Guidelines for treatment of CDAD published in 2010 (prior to fidoxamicins FDA approval for CDAD) recommend oral metronidazole for mild/moderate episodes and oral vancomycin for severe episodes. For first recurrence, SHEA/IDSA guidelines recommend the same agent utilized for the initial episode (assuming appropriate based upon severity of infection) while the guidelines recommend vancomycin in a tapered and/or pulsed regimen for second recurrence with a lower level of evidence. Introduction The purposes of this monograph are to (1) evaluate the available evidence of safety, tolerability, efficacy, cost, and other pharmaceutical issues that would be relevant to evaluating fidaxomicin for possible addition to the VA National Formulary; (2) define its role in therapy; and (3) identify parameters for its rational use in the VA. Pharmacology/Pharmacokinetics1,6 Fidaxomicin is an unsaturated, 18-membered, macrocyclic antibiotic produced by the Actinomycete Dactylosporangium aurantiacum. Fidaxomicin exerts its antimicrobial effect via protein inhibition by inhibition of the RNA polymerase enzyme. Following an oral dose of fidaxomicin, high concentrations, ranging from 600-2000 mcg/mL, are achieved in the colon. Plasma levels of fidaxomicin in healthy volunteers as well as in patients with CDAD are in the ng/mL range due to poor absorption. Serum concentrations of fidaxomicin and its active metabolite, OP-1118, were increased 2-4 fold in patients over 65 years of age, but plasma levels remained in the ng/mL range. Metabolism of fidaxomicin occurs through hydrolysis at the isobutyryl ester to form the major, active metabolite, OP-1118. There appears to be no contribution of the CYP enzyme system in metabolism of fidaxomicin. Table 1: Fidaxomicin Pharmacokinetics ParameterFidaxomicinOP-1118Cmax (ng/mL)5.2 + 2.8112 + 6.06Tmax (hours)2 (1-5)1.02 (1-5)AUC0-t (ng*h/mL)48.3 + 18.4103 + 39.4AUC0-infinity (ng*hr/mL)62.9 + 19.5118 + 43.3Elimination half life (hours)11.7 + 4.811.2 + 3.01All data presented as mean + SD or range Table 2: Pharmacokinetic Comparison of Oral C.difficle Agents ParameterFidaxomicinMetronidazoleVancomycinMetabolismHydrolysisOxidation, glucuronidationNAEliminationFecal60-80% renal40-100% renalHalf-life11 hours6-14 hours4-6 hoursProtein Binding31%<20%30-55%BioavailabilityNegligible100%NegligibleMicrobiology1-2,7-11 In vitro activity Fidaxomicin is bacteriocidal against Gram-Positive anaerobes and aerobes, but lacks in vitro activity against Gram-Negative organisms. Fidaxomicin displays in vitro activity against Clostridia species, including Clostridium difficile. The MIC50 and MIC90 of fidaxomicin against C. difficile isolates obtained from 791 patients enrolled in the two, phase III clinical trials were 0.125 mcg/mL and 0.25 mcg/mL, respectively. No differences in MIC90 were noted in isolates obtained from patients who achieved a cure or failure with fidaxomicin or from patients who did or did not have disease recurrence. One patient treated with fidaxomicin in the clinical trials developed a recurrence and the fidaxomicin MIC was elevated at 16 mcg/mL. In vitro susceptibility criteria have not been established. Since the early 2000s, outbreaks of C.difficile caused by a unique strain were being increasingly reported in the United States and Canada. The strain is referred to as BI/NAP/027 and is named based on its restriction endonuclease pattern, pulsed-field gel electrophoresis pattern, and PCR ribotype designation. BI/NAP/027 is sometimes referred to as the hypervirulent strain because it produces both toxin A and B in addition to a binary toxin. BI/NAP/027 has been associated with higher mortality than non-BI/NAP/027 strains and has been shown to have higher metronidazole MICs. There are few epidemiologic studies available currently, but the BI/NAP/027 appears to account for 30-50% of all C.difficile strains isolated in United States hospitals. Outcomes in patients with the BI/NAP1/027 strain treated with fidaxomicin will be discussed in the efficacy section. Impact of gastrointestinal flora Disruption of normal gastrointestinal flora may contribute to disease severity in CDAD and likelihood of cure. Bacteroides species have been utilized as a marker for overall biota status, as they encompass almost 8% of total fecal biomass. Fidaxomicin has been evaluated in microbiologic studies to determine its impact on usual gut flora. Enterobacteriaceae overgrowth was used as a marker of suppression of normal gut flora. Fecal samples from 23 patients with mild-to-moderate CDAD who received fidaxomicin in doses ranging from 50-200 mg twice daily were compared with those from patients who received vancomycin 125 mg by mouth four times daily. Between day 0 and 10, the amount of Enterobacteriaceae species (represented as a percentage of total fecal microbiota) increased from 4.06% + 1.37 to 6.4% + 2.36 (p>0.05) in patients receiving fidaxomicin. In comparison, Enterobacteriacea colony percentage increased from 6.04% + 2.66 to 27.27% + 4.53 (p<0.05) in patients treated with vancomycin. Of note, patients in this study were not receiving concomitant antibiotics. An additional study focused on the effect of fidaxomicin specifically on Bacteroides group bacteria. In this study, 30 patients produced specimens for evaluation, and doses of fidaxomicin up to 200 mg twice daily for 10 days did not significantly suppress Bacteroides. Mean colony counts (expressed in log10 colony forming units + SD) were 7.0 + 2.9 on day 0 compared with 7.3 + 3.1 on day 10 (p=0.56). Bacteroides bacterial load was significantly reduced following 10 days of vancomycin 125 mg every 6 hours (7.4 + 2.7 vs. 3.6 + 1.9, p=0.03). FDA Approved Indication(s)1 Fidaxomicin is FDA-approved for treatment of CDAD in adults. Potential Off-label Uses According to clinicaltrials.gov, there are no on-going clinical trials evaluating fidaxomicin for other indications. Current VA National Formulary Alternatives1-2,5 Metronidazole (off-label for CDAD) and oral vancomycin (FDA-approved for CDAD) are available on the VA National Formulary. The Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA) Clinical Practice Guidelines for C.difficile Infection in Adults were updated in 2010 (prior to fidoxamicins FDA approval for CDAD). Disease severity classifications and treatment recommendations are provided below in Table 3. Table 3: SHEA/IDSA Guidelines: Disease Severity Classifications and Treatments SeverityClinical PresentationRecommended TreatmentInitial EpisodeMild or moderateWhite blood cell count <15 cells/mL, serum creatinine <1.5x pre-morbid level Oral metronidazole 500 mg three times daily for 10-14 daysSevereWhite blood cell count >15 cells/mL, serum creatinine >1.5x pre-morbid level Oral vancomycin 125 mg four times daily for 10-14 daysSevere, complicatedHypotension, shock, ileus, or megacolonOral vancomycin 500 mg four times daily for 10-14 days + IV metronidazole 500 mg every 8 hours + vancomycin retention enemaRecurrent EpisodesFirst recurrenceSame as for initial episode (if appropriate based upon severity of infection)Second recurrenceVancomycin in a tapered and/or pulsed regimen Dosage and Administration1 The recommended dose for fidaxomicin is 200 mg by mouth twice daily for 10 days. It can be administered with or without food. Data on the stability of crushing fidaxomicin tablets are unavailable at this time. Efficacy1-5,12 The efficacy of fidaxomicin 200 mg twice daily for the treatment of CDAD was studied in two, prospective, phase III, non-inferiority studies. The results of one of these studies were published in the New England Journal of Medicine in early 2011 while the other was presented in poster format at the 20th European Conference of Clinical Microbiology and Infectious Disease (ECCMID) in 2010. In both trials, the primary efficacy measure was clinical cure, defined as resolution of diarrhea (<3 unformed stools for two consecutive days) with maintenance of resolution throughout the treatment duration and no further requirement for CDAD treatment during four week follow-up. This was measured in both a modified intent-to-treat population (mITT) and a per protocol (PP) population. Patients in the mITT population had to receive at least one dose of study drug. The PP population included patients who received at least 3 days of treatment (if considered a failure) or 8 days of treatment (if considered clinically cured), adhered to the protocol, and were available for evaluation at end of therapy. Outcomes were also assessed based on strain of C.difficile isolated (BI/NAP1/027 vs. non-BI/NAP1/027 strain). Secondary outcomes were clinical recurrence and global cure; of note the FDA analysis indicated that recurrence rate calculations were not protected by subject randomization Recurrence was defined as reappearance of >3 diarrheal stools per day, presence of C.difficile toxin A or B, and need for retreatment within the first four weeks of completing initial therapy. Global cure was defined as the resolution of diarrhea without recurrence at any time up to the post-study visit. In addition, the package insert refers to sustained clinical response rather than global cure as this outcome was evaluated 25 days after the completion of therapy (Table 4) Table 4: Sustained Clinical Response Rates Reported in Prescribing Information FidaxomicinVancomycinDifference (95% CI)Study 00370%57%12.7 (4.4, 20.9)Study 00472%57%14.6 (5.8, 23.3) Summary of efficacy findings In the two non-inferiority studies of treatment for CDAD, oral fidaxomicin 200 mg twice daily was found to be non-inferior to oral vancomycin with regard to the primary efficacy endpoint in both the mITT and PP populations. In both phase III trials, recurrence rates were significantly lower in patients treated with fidaxomicin when compared to vancomycin. Global cure rates (or sustained clinical response rates) were significantly higher in patients treated with fidaxomicin than vancomycin. A pooled, retrospective analysis of the two pivotal trials was conducted to evaluate outcomes in patients receiving concomitant antibiotics for concurrent infections. The same efficacy measures were utilized. Concomitant antibiotics was defined as >1 oral or intravenous antibiotic during treatment or follow-up. Table 5: Outcomes in Patients on Any Concomitant Antibiotics OutcomeFidaxomicin (n=481)Vancomycin (n=518)p valueClinical cure (%)No concomitant antibiotics9079.40.04Any concomitant antibiotics92.392.80.80Recurrence at anytime (%)No concomitant antibiotics11.923.1<0.001Any concomitant antibiotics16.929.20.048Global cure (%)No concomitant antibiotics80.869.1<0.001Any concomitant antibiotic72.759.40.02 Outcomes were further assessed in patients receiving concomitant antibiotics that were considered high-risk based on expert opinion. High-risk antibiotics included fluroquinolones, second and third generation cephalosporins, and clindamycin. The difference in clinical cure was not significant when fidaxomicin was compared to vancomycin for patients with CDAD receiving high-risk concomitant antibiotics (88.6% vs. 75.4%, p=0.09). For further details on the efficacy results of the clinical trials, refer to  REF _Ref80503441 \h  \* MERGEFORMAT Appendix: Randomized Controlled Clinical Trials (page 7). Adverse Events (Safety Data)1-2 The most common adverse events reported in the clinical trials of fidaxomicin are listed below in Table 8. Table 6: Events Occuring in >2% of Patients in Clinical TrialsAdverse event [n(%)]Fidaxomicin (n=564)Vancomycin (n=583)Anemia14 (2)12 (2)Neutropenia14 (2)6 (1)Nausea62 (11)66 (11)Vomiting41 (7)37 (6)Abdominal pain33 (6)23 (4)Gastrointestinal hemorrhage20 (4)12 (2)Deaths and Other Serious Adverse Events Rates of death in the phase III trials were similar between fidaxomicin and vancomycin (6.4% and 6.5%, respectively). A total of 74 deaths occurred in these trials, with one additional death reported in a phase II trial. The most common causes of death were respiratory failure, pneumonia, sepsis and multi-organ failure. All of the deaths were deemed unrelated or unlikely to be related to the study drug by the investigator. A safety analysis by the FDA concluded that four deaths in the vancomycin group and five in the fidaxomicin group may have been due to lack of efficacy. Contraindications No contraindications are currently listed by the manufacturer. Warnings and Precautions Fidaxomicin is minimally absorbed and should not be used for treatment of systemic infections. Use of fidaxomicin in the absence of C.difficile infection is not expected to benefit patients and may promote development of drug resistant bacteria. Pregnancy and Lactation Pregnancy: Category B Nursing: Limited data are available regarding distribution of fidaxomicin into breast milk. Caution should be used if fidaxomicin is administered to a lactating female. Sentinel Events No data. Look-alike / Sound-alike (LA / SA) Error Risk Potential As part of a JCAHO standard, LASA names are assessed during the formulary selection of drugs. Based on clinical judgment and an evaluation of LASA information from four data sources (Lexi-Comp, USP Online LASA Finder, First Databank, and ISMP Confused Drug Name List), the following drug names may cause LASA confusion: LA/SA for generic name : fexofenadine LA/SA for trade name : Diflucan, Disalcid Drug Interactions1-2 Fidaxomicin does not undergo significant hepatic metabolism via the CYP enzyme or hepatic microenzyme systems. Pharmacokinetic analyses showed no significant impact on the kinetics of digoxin, midazolam, warfarin, or omeprazole with coadministration of fidaxomicin. These medications are substrates of P-glycoprotein (P-gp), CYP 3A4, CYP 2C9, and CYP 2C19, respectively. Therefore, no dosage adjustments are recommended. Fidaxomicin is a substrate of the P-glycoprotein (P-gp) efflux system. A pharmacokinetic study with co-administration of fidaxomicin and a potent P-gp inhibitor, cyclosporine, was conducted. Fidaxomicin plasma levels were increased, but not clinically significant. According to prescribing information, dose reductions are not recommended when fidaxomicin is administered with cyclosporine or other P-gp inhibitors. Acquisition Costs Listed below are the Federal Supply Schedule costs per day and per 10 day treatment of CDAD treatment options. Table 7: Cost Comparison DrugDoseCost/Day/patient ($)Cost/10 day treatment/patient ($)Metronidazole (oral)500 mg every 8 hours0.151.50Vancomycin (oral)125 mg every 6 hours36.05360.48250 mg every 6 hours66.86668.56Fidaxomicin (oral)200 mg every 12 hours209.602096.00Prices obtained in October 2011 Pharmacoeconomic Analysis There have been no pharmacoeconomic analyses of fidaxomicin published to date. Conclusions Fidaxomicin is a poorly absorbed, macrocyclic antibiotic that is FDA-approved for the treatment of CDAD in adults. In two pivotal, phase III studies, adult patients with a diagnosis of CDAD and history of <1 recurrence were randomized to treatment with oral vancomycin or fidaxomicin. Patients with severe, complicated CDAD were excluded from the clinical trials. Fidaxomicin was found to be non-inferior to vancomycin in the primary efficacy endpoint, clinical cure. The majority of patients enrolled in the clinical trials were inpatients and the BI/NAP1/027 strain comprised approximately 40% of all isolates. Recurrence rates in both phase III studies were significantly lower in patients treated with fidaxomicin. In a subgroup analysis, recurrence rates were significantly lower in fidaxomicin-treated patients who were >65 years old, had no prior episodes of CDAD, were not receiving concomitant antibiotics, and had a non-BI/NAP1/027 strain. Nausea, vomiting, and gastrointestinal upset were the most commonly observed adverse effects in clinical trials. The SHEA/IDSA Guidelines for treatment of CDAD published in 2010 (prior to fidoxamicin s FDA approval for CDAD) recommend oral metronidazole for mild/moderate episodes and oral vancomycin for severe episodes. References: Dificid"! package insert. Optimer Pharmaceuticals, Inc. San Diego CA 2011. Iarikov D. FDA Medical Review. NDA 201699, Dificid (fidaxomicin). April 2011. Louie TJ et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med 2011; 364: 422-31. Crook D et al. Randomized clinical trial (RCT) in Clostridium difficile infection (CDI) confirms equivalent cure rate and lower recurrence rate of fidaxomicin (FDX) versus vancomycin (VCN). Poster presented at the 20th European Conference of Clinical Microbiology and Infectious Disease (ECCMID) 2010. Cohen SH, Gerding DN, Johnson S et al. Clinical Practice Guidelines for Clostridium difficile Infection in Adults: 2010 Update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infection Control and Hospital Epidemiology 2010; 31(5): 431-55. Micromedex Healthcare Series. n.d. Thomson Reuters (Healthcare) Inc., Greenwood Village, CO. 24 Jan. 2006  HYPERLINK "http://www.thomsonhc.com" http://www.thomsonhc.com. Accessed Oct 2011. Goldstein EJC et al. Comparative susceptibilities to fidaxomicin (OPT-80) of isolates collected at baseline, recurrence, and failure from patients in two phase III trials of fidaxomicin against Clostridium difficile infection. Antimicrob Agents Chemother 2011; 55 (11): 5194-9. Freeland J et al. The changing epidemiology of Clostridium difficile infections. Clin Microbiol Rev 2010; 23: 529-549. Sullivan KM, Spooner LM. Fidaxomicin: a macrocyclic antibiotic for the management of Clostridium difficile infection. Ann Pharmacother 2010; 44: 352-9. Tannock GW et al. A new macrocyclic antibiotic, fidaxomicin (OPT-80), causes less alteration to the bowel microbiota of Clostridium difficile-infected patients than does vancomycin. Microbiology 2010; 156: 3354-9. Louie TJ et al. OPT-80 eliminates Clostridium difficile and is sparing of Bacteroides species during treatment of C.difficile infection. Antimicrob Agents Chemother 2009; 53 (1): 261-3. Mullane KM et al. Efficacy of fidaxomicin versus vancomycin as therapy for Clostridium difficile infection in individuals taking concomitant antibiotics for other concurrent infections. Clin Infec Dis 2011; 53: 440-9. Prepared 10/2011 by Elizabeth Oates, PharmD Contact person: Melinda Neuhauser, PharmD, MPH Appendix: Randomized Controlled Clinical Trials CitationLouie TJ, Miller MA, Mullane KM, et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med 2011;364:422-31. OPT-80-003 Study Group Iarikov D. FDA Medical Review. NDA 201699, Dificid (fidaxomicin). April 2011.Study GoalsTo determine if fidaxomicin was non-inferior to vancomycin in treatment of C.difficile infectionInterventionFidaxomicin (FDX) 200 mg twice daily or oral vancomycin (VCN) 125 mg four times daily for 10 daysMethodsStudy Design Prospective, multicenter, randomized, double-blind, non-inferiority trial 67 sites in the United States and Canada Stratification based on prior or no prior episode of CDAD in last 3 months Predefined subgroup analysis of outcomes based on age, inpatient status, prior episode of treatment of CDAD, disease severity, and strain type (BI/NAP1/027 vs. non-BI/NAP1/027) Baseline disease severity based on European Society of Clinical Microbiology and Infectious Disease (ESCMID) criteria to define baseline disease severity: Mild: 4 to 5 unformed bowel movements (UMBs) per day or WBC d"12,000/mm3 Moderate: 6 to 9 UBMs per day or WBC 12,001  15,000/mm3 Severe CDI: e"10 UBMs per day or WBC e"15,001/mm3 Efficacy Endpoints Primary endpoint: Clinical cure in mITT and PP populations Secondary endpoints: Recurrence and global cure Data Analysis Primary outcome utilized a one-sided lower 97.5% confidence interval (CI) with non-inferiority margin of -10% Secondary outcomes utilized a two-sided test of population proportions, p-value <0.05 considered significantCriteriaInclusion criteria Age >16 years Diagnosis of CDAD (presence of diarrhea in last 24 hours, presence of toxin A and/or B in stool specimen within 48 hours prior to randomization) Exclusion criteria Receipt of >4 doses of oral vancomycin or metronidazole in 24 hours before randomization Patients could be included if they had failed a 3-day course of metronidazole and continued to have diarrheal stools and a positive C.difficile toxin Use of other potentially effective treatments Presence of life-threatening or fulminant C.difficile infection or toxic megacolon Prior exposure to fidaxomicin History of ulcerative colitis or Crohns disease >1 recurrence of CDAD within prior 3 monthsResults Results (cont.) Baseline Demographics mITT PP FDX (n=287) VCN (n=309) FDX (n=265) VCN (n=283) Age (mean + SD) 60.3 + 16.9 62.9 + 16.9 59.9+17.1 62.7+17 Female (%) 57.1 54.7 57.4 54.8 UBM*/day (mean + SD) 8.1+4.2 8.3+5.4 8.2+4.3 8.4+5.5 Inpatient (%) 58.2 60.5 55.1 57.2 CDAD indication- diarrhea alone (%) 17.1 22 -- -- CDAD indication- diarrhea + other symptoms (%) 82.9 78 -- -- Metronidazole failure (%) 4.5 5.5 4.9 5.7 Treatment in last 24 hrs (%) 38.3 39.8 37.4 38.5 Any previous CDAD episode (%) 16.7 17.5 16.2 17 BI/NAP1/027 strain (%) 37.5 38.6 35.3 36.4 Baseline disease severity (%) Mild 22.3 25.9 -- -- Moderate 38.7 34.3 -- -- Severe 39 39.8 -- -- *UBM=unformed bowel movements Overall Results FDX VCN p value Clinical Cure (%) mITT 253/287 (88.2) 265/309 (85.8) NS PP (244/265) (92.1) 254/283 (89.8) NS Recurrence (%) mITT 39/253 (15.4) 67/265 (25.3) 0.005 PP 28/211 (13.3) 53/221 (24) 0.004 Global Cure (%) mITT 214/287 (74.6) 198/309 (64.1) 0.006 PP 206/265 (77.7) 190/283 (67.1) 0.006 Clinical Cure Rates- Subgroup Analysis (mITT)* Subgroup [n(%)] FDX VCN Age <65 150/165 (90.9) 134/157 (85.4) Age>65 103/122 (84.4) 131/152 (86.2) No prior episode 211/239 (88.3) 217/255 (85.1) Single prior episode 42/48 (87.5) 48/54 (88.9) Concomitant antibiotics 67/83 (80.7) 72/94 (76.6) No concomitant antibiotics 186/204 (91.2) 193/215 (89.8) Mild disease 59/64 (92.2) 68/80 (85) Moderate disease 102/111 (82.1) 109/123 (88.6) Severe disease 92/112 (82.1) 109/123 (88.6) BI/NAP/027 strain 59/75 (78.7) 67/83 (80.7) Non-BI/NAP1/027 117/125 (87.6) 250/292 (85.6) No response to metronidazole before study 13/13 (100) 15/17 (88.2) Response to metronidazole before study 240/274 (87.6) 250/292 (85.6) Inpatient 136/167 (81.4) 146/187 (78.1) Outpatient 117/120 (97.5) 119/122 (97.5) *No significant differences between any group; p values not reported Recurrence Rates- Subgroup Analysis (mITT) Subgroup [n(%)] FDX VCN p value Age <65 19/150 (12.7) 27/134 (20.1) 0.09 Age>65 20/103 (19.4) 40/131 (30.5) 0.05 No prior episode 30/211 (14.2) 52/217 (24) 0.01 Single prior episode 9/42 (21.4) 15/48 (31.2) 0.30 Concomitant antibiotics 14/81(17.3) 25/90 (27.8) 0.10 No concomitant antibiotics 25/172 (14.5) 42/175 (24) 0.03 Mild disease 7/59 (11.9) 20/68 (29.4) 0.02 Moderate disease 20/102 (19.6) 18/88 (20.5) 0.89 Severe disease 12/92 (13) 29/109 (26.6) 0.02 BI/NAP1/027 strain 16/59 (27.1) 14/67 (20.9) 0.42 Non-BI/NAP1/027 strain 12/117 (10.3) 34/121 (28.1) <0.001 Inpatient 24/136 (17.6) 40/146 (27.4) 0.05 Outpatient 15/117 (12.8) 27/119 (22.7) 0.05 Global Cure Rates - Subgroup Analysis (mITT) Subgroup [n(%)] FDX VCN Difference (95% CI) Age <65 132/166 (80) 106/156 (68) 11.6 (1.9, 20.9) Age>65 83/123 (67) 91/151 (60) 7.2 (-4.2, 18.3) No prior episode 182/241 (76) 164/253 (65) 10.7 (2.6, 18.6) Single prior episode 33/48 (69) 33/54 (61) 7.6 (-10.7, 25.3) Concomitant antibiotics 67/101 (66) 65/113 (58) 8.8 (-4.2, 21.4) No concomitant antibiotics 148/188 (79) 132/194 (68) 10.7 (1.8, 19.3) Non-severe disease 170/215 (79) 152/226 (67) 11.8 (3.5, 19.8) Severe disease 45/74 (61) 45/81 (56) 5.3 (-10.1, 20.3) Inpatient 112/168 (67) 106/186 (57) 9.7 (-0.4, 19.6) Outpatient 103/121 (85) 91/121 (75) 9.9 (-0.2, 19.7) ConclusionsFidaxomicin is non-inferior to vancomycin with respect to clinical cure in the treatment of CDAD. Recurrence rates are significantly lower with fidaxomicin while global cure rates are significantly higher with fidaxomicin. CitationCrook D et al. Randomized clinical trial (RCT) in Clostridium difficile infection (CDI) confirms equivalent cure rate and lower recurrence rate of fidaxomicin (FDX) versus vancomycin (VCN). Poster presented at the 20th European Conference of Clinical Microbiology and Infectious Disease (ECCMID) 2010. OPT-80-004 Study Group Iarikov D. FDA Medical Review. NDA 201699, Dificid (fidaxomicin). April 2011.Study GoalsTo determine if fidaxomicin was non-inferior to vancomycin in treatment of C.diffcile infectionInterventionFidaxomicin (FDX) 200 mg twice daily or oral vancomycin (VCN) 125 mg four times daily for 10 daysMethodsStudy Design Same study design as above Study conducted in sites throughout North America and EuropeCriteriaInclusion and exclusion criteria Same criteria as aboveResults  Baseline Demographics- mITT population FDX (n=252) VCN (n=257) Age (mean + SD) 64.3 + 17.9 62.5 + 18.4 Age >65 (%) 56.3 51 Female (%) 58.7 63 White (%) 92.1 92.6 Inpatient (%) 69 67.3 No previous episode (%) 84.1 86 UBM*/day (mean + SD) 7.5 + 4.4 7.4 + 4.4 CDAD indication- diarrhea alone (%) 74.6 74.7 CDAD indication- diarrhea + other symptoms (%) 25.4 25.3 CDAD antibiotic use within 24 hours (%) 89.3 85.6 Metronidazole failure (%) 4.8 3.1 BI/NAP1/027 strain (%) 52 47.9 *UBM=unformed bowel movements Results FDX VCN Difference (95% CI) Clinical Cure (%) mITT 221/252 (87.7) 223/257 (87) 0.9 (-4.8, 6.8) PP 198/216 (91.7) 213/235 (90.6) 1 (-4.3, 6.7) Recurrence (%) mITT 28/221 (12.7) 60/223 (26.9) -14.2 (-21.4, -6.8); p<0.001 PP 23/180 (12.8) 46/182 (25.3) -12.5(-20.3, -4.4); p=0.002 Global Cure (%) mITT 193/252 (76.6) 163/257 (63.4) 13.2 (5.2, 20.9); p=0.001 PP 172/216 (79.6) 154/235 (65.5) 14.1 (5.9, 22.1); p<0.001 Global Cure Rates- Subgroup Analysis (mITT) Subgroup [n(%)] FDX VCN Difference (95% CI) Age <65 89/111 (80) 84/125 (67) 13.0 (1.7, 23.7) Age>65 105/142 (74) 78/131 (60) 14.4 (3.2, 25.2) No prior episode 164/213 (77) 141/220 (64) 12.9 (4.3, 21.2) Single prior episode 30/40 (75) 21/36 (58) 16.7 (-4.4, 36.2) Concomitant antibiotics 71/101 (70) 61/100 (61) 9.3 (-3.8, 22.0) No concomitant antibiotics 123/152 (81) 101/156 (65) 16.2 (6.3, 25.7) Non-severe disease 150/190 (79) 133/195 (68) 10.7 (1.9, 19.3) Severe disease 44/63 (70) 29/61 (48) 22.3 (5.1, 38.2) Inpatient 132/175 (75) 106/172 (62) 13.8 (4.0, 23.3) Outpatient 62/78 (79) 56/84 (67) 12.8 (-0.9, 25.8) 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$IfK$L$Tl\ %^ 99 t044 laytMTI}J}Y}d}o}}ZL>>> $$Ifa$gdMK$ $$Ifa$gdMK$kd$IfK$L$Tl\ %^ 99 t044 laytMT}}}}}}ZL>>> $$Ifa$gdMK$ $$Ifa$gdMK$kd$IfK$L$Tl\ %^ 99 t044 laytMT}}}}}}ZL>>> $$Ifa$gdMK$ $$Ifa$gdMK$kdы$IfK$L$Tl\ %^ 99 t044 laytMT}}}MhZQD & F $Ifgdz $Ifgd;kd$IfK$L$Tl\ %^ 99 t044 laytMTData for clinical cure and recurrence rates between subgroups not available.ConclusionsClinical cure rates achieved with fidaxomicin are non-inferior to vancomycin in patients with CDAD. Recurrence rates are significantly lower with fidaxomicin while global cure rates are significantly higher with fidaxomicin.     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