Fidaxomicin Monograph - Veterans Affairs



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 Documents will be placed in the Archive section when the information is deemed to be no longer current.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 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 fidoxamicin’s 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

|Parameter |Fidaxomicin |OP-1118 |

|Cmax (ng/mL) |5.2 + 2.81 |12 + 6.06 |

|Tmax (hours) |2 (1-5) |1.02 (1-5) |

|AUC0-t (ng*h/mL) |48.3 + 18.4 |103 + 39.4 |

|AUC0-infinity (ng*hr/mL) |62.9 + 19.5 |118 + 43.3 |

|Elimination half life (hours) |11.7 + 4.8 |11.2 + 3.01 |

All data presented as mean + SD or range

Table 2: Pharmacokinetic Comparison of Oral C.difficle Agents

|Parameter |Fidaxomicin |Metronidazole |Vancomycin |

|Metabolism |Hydrolysis |Oxidation, glucuronidation |NA |

|Elimination |Fecal |60-80% renal |40-100% renal |

|Half-life |11 hours |6-14 hours |4-6 hours |

|Protein Binding |31% |0.05) in patients receiving fidaxomicin.  In comparison, Enterobacteriacea colony percentage increased from 6.04% + 2.66 to 27.27% + 4.53  (p1 oral or intravenous antibiotic during treatment or follow-up.

Table 5: Outcomes in Patients on Any Concomitant Antibiotics

|Outcome |Fidaxomicin (n=481) |Vancomycin (n=518) |p value |

|Clinical cure (%) | | | |

|No concomitant antibiotics |90 |79.4 |0.04 |

|Any concomitant antibiotics |92.3 |92.8 |0.80 |

|Recurrence at anytime (%) | | | |

|No concomitant antibiotics |11.9 |23.1 |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 Crohn’s disease |

| |>1 recurrence of CDAD within prior 3 months |

|Results | |

| |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 |

|Results (cont.) | |

| |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 |

| |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 |

| |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) |

| |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 ................
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