Fidaxomicin - id3461.securedata.netid3461.securedata.net/occpweb/Spring 2012/Fidaxomicin.pdfPrevious C. difficile Episode Recurrence 0% 5% 10% 15% 20% 25% 30% 35% MITT PP Fidaxomicin

1

Fidaxomicin

Nina Naeger Murphy, Pharm.D., BCPS Clinical Pharmacy Specialist – Infectious Diseases

MetroHealth Medical Center

Disclosure

! I have no conflicts of interest related to this presentation

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

Fidaxomicin

! Macrolide antibacterial

! FDA approved for treatment of Clostridium difficile-Associated Diarrhea

! Bactericidal against C. difficile in vitro, inhibiting RNA synthesis by RNA polymerases

Fidaxomicin (Dificid®) package labeling. Optimer Pharmaceuticals, Inc. May 2011.

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 Fidaxomicin (Dificid®) package labeling. Optimer Pharmaceuticals, Inc. May 2011.

Spectrum of Activity

! Predominantly active against species of clostridia, including C. difficile

! More active in vitro (8x) than vancomycin1

! Changes in bacteroides group counts, reflecting changes in GI flora, where not observed with fidaxomicin, while reductions were seen with vancomycin2

1Louie TJ, et al. N Eng J Med 2011;364:422-31. 2Louie TJ, et al. Antimicrob Agents Chemother 2009;53:261-3.

2

Clinical Efficacy

! Pivotal trials –  Louie TJ, et al. N Eng J Med 2011;364:422-31. – Cornely OA, et al. Lancet Infect Dis 2012;12:281-9.

! Pooled data – Mullane KM, et al. Clin Infect Dis 2011;53:440-7.

! 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.

Louie TJ, et al. N Engl J Med 2011;364:422-31.

! Treatment –  Fidaxomicin 200 mg PO Q 12 hours –  Vancomycin 125 mg PO Q 6 hours –  10 day course; 28 day follow-up

! Outcomes –  Primary: rate of clinical cure (non-inferiority margin -10%) –  Secondary: recurrence of CDI during the 4 week period

after the end of the course of therapy and global cure. ! Recurrence

–  Reappearance of >3 diarrheal stools per 24 hour period within 4 weeks after cessation of therapy

Methods


Results


629 patients enrolled and randomized

MITT Vancomycin

(n=309)

MITT Fidaxomicin

(n=287)

PP Vancomycin

(n=283)

PP Fidaxomicin

(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

Louie TJ, et al. N Engl J Med 2011;364:422-31. Louie TJ, et al. N Engl J Med 2011;364:422-31.

3

NAP1/BI/027 strain

7.8

24.4 25.523.6

0%

5%

10%

15%

20%

25%

30%

NAP1 Non-NAP1

Fidaxomicin

Vancomycin

Rec

urre

nce

p=0.93 p<0.001


Recurrence Rate Previous C. difficile Episode

Rec

urre

nce

0%

5%

10%

15%

20%

25%

30%

35%

MITT PP

FidaxomicinVancomycin


21.4

31.2

16.7

31.6 p=0.30

p=0.14

Conclusions ! Rates of clinical cure with fidaxomicin were

noninferior to vancomycin ! Fidaxomicin 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.

Cornely OA, et al. Lancet Infect Dis 2012;12:281-9.

Methods ! Treatment

–  Fidaxomicin 200 mg PO Q 12 hours –  Vancomycin 125 mg PO Q 6 hours –  10 day course; 28 day follow-up

! Outcomes –  Primary: rate of clinical cure (non-inferiority margin -10%) –  Secondary: recurrence of CDI during the 4 week period

after the end of the course of therapy and global cure. ! Recurrence

–  Reappearance of >3 diarrheal stools per 24 hour period within 4 weeks after cessation of therapy


Methods 535 patients enrolled and randomized

MITT Vancomycin

(n=252)

MITT Fidaxomicin

(n=257)

PP Vancomycin

(n=216)

PP Fidaxomicin

(n=235)


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


0%10%20%30%40%50%60%70%80%90%100%

MITT PP

MITT PP

MITT PP



Clinical cure Recurrence Sustained

Patie

nts

Results

87.8

87

91.7

90

.6

12.7

26.9

12

.8 25

.3

76.6

63

.4 79

.6

65.5

*

* *

*

*=p<0.05

9.2

22.2

27.4

38

0%

5%

10%

15%

20%

25%

30%

35%

40%

NAP1 Non-NAP1

Fidaxomicin

Vancomycin

NAP1/BI/027 strain


Rec

urre

nce

p=0.079

p=0.0003

Recurrence Rates Previous C. difficile Episode

Rec

urre

nce

0%

5%

10%

15%

20%

25%

30%

35%

40%

MITT


18.9

34.4 p=0.145


Clinical Cure Concomitant Antibiotics


0%10%20%30%40%50%60%70%80%90%100%

MITT

FidaxomicinVancomycinPa

tient

s

90.2

73.3

p=0.031

Concomitant antibiotics received during treatment and/or follow up period, days 1-40

Conclusions ! Rates of clinical cure with fidaxomicin were

noninferior to vancomycin

! Fidaxomicin 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


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! 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

Mullane KM, et al. Clin Infect Dis 2011;53:440-7.

Patients (n=999)

! Concomitant, non CDI, antibiotics were prescribed for 27.5% 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

! 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)


Effect of CA on CDI Treatment

70%

75%

80%

85%

90%

95%

CA No CA


Clin

ical

Cur

e

CA = concomitant, non CDI, antibiotics at any time

90

79.4

92.3 92.8 p=0.04

p=0.80


Effect of CA on Recurrence

0%

5%

10%

15%

20%

25%

30%

35%

CA No CA


Rec

urre

nce

CA = concomitant, non CDI, antibiotics at any time


16.9

29.7

11.9

23.1

p=0.048

P<0.001

Conclusions

! Treatment with CAs compromised initial response to CDI therapy and durability of response.

! Fidaxomicin was significantly more effective than vancomycin in achieving clinical cure in presence of CA and in preventing recurrence regardless of CA use.


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Warnings & Precautions

! Minimal systemic absorption

! Pregnancy category B

! Unknown if excreted in human milk

! Nausea (11%), vomiting (7%) and abdominal pain (6%) most common adverse effects


Drug-Drug Interactions

! Substrate of P-glycoprotein, but no clinically significant drug-drug interactions


Dosage & Storage

! Fidaxomicin 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


Cost Comparison Drug Dose AWP

LOT=10 days Fidaxomicin 200 mg PO BID $3360

Metronidazole 500 mg PO TID $21.45

Vancomycin PO 125-250 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

Cohen SH, et al. Infect Control Hosp Epidemiol 2010:31:431-55.

Type Data Treatment Initial episode, mild or moderate

WBC ≤15 SCr <1.5x pml

Metronidazole 500 mg PO TID x 10-14 days

A-I

Initial episode, severe

WBC ≥15 SCr ≥1.5x pml

Vancomycin 125 mg PO QID x 10-14 days

B-I

Initial episode, severe, complicated

Hypotension or shock, ileus, megacolon

Vancomycin 500 mg PO/NG QID + Metronidazole 500 mg IV Q 8h +/- Rectal vancomycin

C-III

1st Recurrence Same as initial episode A-II

2nd Recurrence Vancomycin in a tapered and/or pulsed regimen

B-III

SHEA=Society for Healthcare Epidemiology of America, IDSA = Infectious Diseases Society of America, pml = premorbid level

Conclusions

! 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

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Place In Therapy ! Not for routine use

! Possible considerations: – Patients with allergies or intolerances to 1st 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 years2, DM1, hypoalbuminemia2, PPIs2,3, CAs4

– Utility in patients with multiple CDI recurrences – Use in severe disease – Cost effectiveness

! 2010 SHEA/IDSA CDI guideline update in progress

1Shakov R, et al. Am J Infect Control 2011;39:194-8., 2Kim JW, et al. World J Gastroenterol 2010;16:357-7., 3Linsky A, et al. Arch Intern Med 2010;170:772-8., 4Garey KW, et al. J Hosp Infect 2008;70:298-304.

Thank you for your time and attention

Question 1

! Fidaxomicin is bactericidal against C. difficile and has over 90% 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

Documents

Fidaxomicin - id3461.securedata.netid3461.securedata.net/occpweb/Spring 2012/Fidaxomicin.pdfPrevious C. difficile Episode Recurrence 0% 5% 10% 15% 20% 25% 30% 35% MITT PP Fidaxomicin