! Macrolide antibacterial. Fidaxomicin (Dificid ) package labeling. Optimer Pharmaceuticals, Inc. May 2011.

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1 Disclosure! I have no conflicts of interest related to this presentation Nina Naeger Murphy, Pharm.D., BCPS Clinical Pharmacy Specialist Infectious Diseases MetroHealth Medical Center Learning Objectives! Describe mechanism of action, pharmacology and spectrum of activity of fidaxomicin! List pros and cons of fidaxomicin therapy based upon recent clinical trial data and cost! Macrolide antibacterial! FDA approved for treatment of Clostridium difficile-associated Diarrhea! Bactericidal against C. difficile in vitro, inhibiting RNA synthesis by RNA polymerases (Dificid ) package labeling. Optimer Pharmaceuticals, Inc. May Pharmacology! Minimal systemic absorption! Distribution confined to GI tract! Primarily transformed by hydrolysis at the isobutyryl ester to form the active metabolite, OP-1118! Half-life of 1-3 hours! Excreted mainly in feces (Dificid ) package labeling. Optimer Pharmaceuticals, Inc. May Spectrum of Activity! Predominantly active against species of clostridia, including C. difficile! More active in vitro (8x) than vancomycin 1! Changes in bacteroides group counts, reflecting changes in GI flora, where not observed with fidaxomicin, while reductions were seen with vancomycin 2 1 Louie TJ, et al. N Eng J Med 2011;364: Louie TJ, et al. Antimicrob Agents Chemother 2009;53:

2 Clinical Efficacy! Pivotal trials Louie TJ, et al. N Eng J Med 2011;364: ! Pooled data! Phase 3, prospective, multicenter, double-blind, randomized, parallel-group, non-inferiority trial! Site: United States and Canada! Patients 16 years of age and older with diagnosis of C. difficile infection (CDI)! Exclusions Life-threatening CDI, toxic megacolon, previous exposure to fidaxomicin, history of ulcerative colitis or Crohn s disease, or > 1 occurrence of CDI within 3 months before study.! Treatment 200 mg PO Q 12 hours 125 mg PO Q 6 hours 10 day course; 28 day follow-up! Outcomes Primary: rate of clinical cure (non-inferiority margin -) Secondary: recurrence of CDI during the 4 week period after the end of the course of therapy and global cure.! Reappearance of >3 diarrheal stools per 24 hour period within 4 weeks after cessation of therapy Methods Results 629 patients enrolled and randomized (n=309) (n=283) (n=287) (n=265) Patients (n=596)! Modified intent to treat population 59.4% inpatient 17.1% had previous episode of C. difficile infection 38.1% had NAP1/BI/027 strain 2

3 NAP1/BI/027 strain p=0.93 p< Rate Previous C. difficile Episode p= p= NAP1 Non-NAP1! Rates of clinical cure with fidaxomicin were noninferior to vancomycin! was associated with a significantly lower rate of recurrence of C. difficile infection associated with non-nap1/bi/027 strains! Phase 3, prospective, multicenter, double-blind, randomized, parallel-group, non-inferiority trial! Site: Europe, Canada, United States! Patients 16 years of age and older with diagnosis of C. difficile infection (CDI)! Exclusions Life-threatening CDI, toxic megacolon, previous exposure to fidaxomicin, history of ulcerative colitis or Crohn s disease, or > 1 occurrence of CDI within 3 months before study. Methods! Treatment 200 mg PO Q 12 hours 125 mg PO Q 6 hours 10 day course; 28 day follow-up! Outcomes Primary: rate of clinical cure (non-inferiority margin -) Secondary: recurrence of CDI during the 4 week period after the end of the course of therapy and global cure.! Reappearance of >3 diarrheal stools per 24 hour period within 4 weeks after cessation of therapy Methods 535 patients enrolled and randomized (n=252) (n=216) (n=257) (n=235) 3

4 Patients (n=509)! Modified intent to treat population 68.2% inpatient 14.9% had previous episode of C. difficile infection 33.2% had NAP1/BI/027 strain 24.4% had severe infection Patients Results Clinical cure Sustained =p<0.05 NAP1/BI/027 strain p=0.079 Rates Previous C. difficile Episode 4 38 p= p= NAP1 Non-NAP1 Clinical Cure Concomitant Antibiotics Patients p= ! Rates of clinical cure with fidaxomicin were noninferior to vancomycin! was associated with a significantly lower rate of recurrence of C. difficile infection associated with non-nap1/bi/027 strains! Exposure to concomitant antibiotics reduced clinical cure rate with vancomycin when compared to fidaxomicin Concomitant antibiotics received during treatment and/or follow up period, days

5 Patients (n=999)! Pooled data from Phase 3 Louie TJ, et al. and Cornely OA, et al. trials! Rates of cure, recurrence, and global cure were determined for subgroups of subjects defined by concomitant antibiotic (CA) use and treatment groups! Concomitant, non CDI, antibiotics were prescribed for 27. of subjects at some time during the study (days 1-40)! 36.7% of subjects received >1 class of CA! CA use was similar between fidaxomicin and vancomycin groups Effect of CA on Outcomes Effect of CA on CDI Treatment! CAs concurrent with CDI treatment was associated with: Lower cure rate (84.4% vs. 92.6%, p<0.001) Extended time to resolution of diarrhea (97 vs. 54 hours, p<0.001)! CA administration at any time was associated with a lower global cure rate (65.8% vs. 74.7%, p=0.005) Clinical Cure p= CA 79.4 p= No CA CA = concomitant, non CDI, antibiotics at any time Effect of CA on p= CA 29.7 P< No CA CA = concomitant, non CDI, antibiotics at any time! Treatment with CAs compromised initial response to CDI therapy and durability of response.! was significantly more effective than vancomycin in achieving clinical cure in presence of CA and in preventing recurrence regardless of CA use. 5

6 Warnings & Precautions! Minimal systemic absorption! Pregnancy category B Drug-Drug Interactions! Substrate of P-glycoprotein, but no clinically significant drug-drug interactions! Unknown if excreted in human milk! Nausea (11%), vomiting (7%) and abdominal pain (6%) most common adverse effects (Dificid ) package labeling. Optimer Pharmaceuticals, Inc. May (Dificid ) package labeling. Optimer Pharmaceuticals, Inc. May Dosage & Storage! 200 mg PO BID for 10 days! May be taken with or without food! No dosage adjustments for renal or hepatic dysfunction! Supplied as 200 mg film-coated tablet! Store at room temperature (Dificid ) package labeling. Optimer Pharmaceuticals, Inc. May Cost Comparison Drug Dose AWP LOT=10 days 200 mg PO BID $3360 Metronidazole 500 mg PO TID $21.45 PO mg PO QID $625 - $1155 $40 - $80 Capsules Compounded solution with AWP used for IV vancomycin AWP = Average wholesale price LOT = Length of therapy SHEA/IDSA Guidelines for CDI Type Data Treatment Initial episode, mild or moderate Initial episode, severe Initial episode, severe, complicated WBC 15 SCr <1.5x pml WBC 15 SCr 1.5x pml Hypotension or shock, ileus, megacolon Cohen SH, et al. Infect Control Hosp Epidemiol 2010:31: Metronidazole 500 mg PO TID x days 125 mg PO QID x days 500 mg PO/NG QID + Metronidazole 500 mg IV Q 8h +/- Rectal vancomycin A-I B-I C-III 1 st Same as initial episode A-II 2 nd in a tapered and/ or pulsed regimen SHEA=Society for Healthcare Epidemiology of America, IDSA = Infectious Diseases Society of America, pml = premorbid level B-III! Similar CDI cure rate compared to vancomycin! Lower recurrence rate in non-nap1 CDI compared to vancomycin! More effective than vancomycin in achieving CDI clinical cure and preventing recurrence in presence of concomitant antibiotics! Less deleterious effect on host GI flora 6

7 ! Not for routine use Place In Therapy! Possible considerations: Patients with allergies or intolerances to 1 st line agents Patients on concomitant, non CDI, antibiotics Guided therapy using C. difficile PCR to detect non-nap1 strains Place in Therapy! More data needed to determine: Who is at highest risk for recurrence! Age >65 years 2, DM 1, hypoalbuminemia 2, Is 2,3, CAs 4 Utility in patients with multiple CDI recurrences Use in severe disease Cost effectiveness! 2010 SHEA/IDSA CDI guideline update in progress 1 Shakov R, et al. Am J Infect Control 2011;39:194-8., 2 Kim JW, et al. World J Gastroenterol 2010;16:357-7., 3 Linsky A, et al. Arch Intern Med 2010;170:772-8., 4 Garey KW, et al. J Hosp Infect 2008;70: Question 1 Thank you for your time and attention! is bactericidal against C. difficile and has over 9 oral bioavailability A. True B. False! Answer: B Question 2! In clinical trials, rates of C. difficile recurrence were significantly higher in patients with the BI/NAP1/027 epidemic strain when treated with fidaxomicin versus treatment with vancomycin A. True B. False! Answer: B Question 3! Which statement(s) about fidaxomicin is/are true? A. Metabolized by cytochrome P450 enzymes B. A substrate of the efflux transporter, P-glycoprotein C. Systemic absorption D. Noninferior to vancomycin in the treatment of C. difficile infection E. A and B F. B and D G. None of the above! Answer: F 7