Augmentin ES

for acute otitis media

Mamodikoe Makhene, M.D.

Prepared for Anti-infectives Advisory Committee meeting

January 30, 2001

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Overview

• Formulations and Indications

• Pivotal Studies – Bacteriologic/clinical study

• Safety

• Summary of issues from review

• Questions for the Committee

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Augmentin Approved formulations

• Augmentin (4:1)

40/10 mg/kg/day q8 hours

250mg Amox/62.5 mg Clav/5mL;

• Augmentin (7:1)

45/6.4mg/kg/day q12 hours

400mg Amox/57 mg Clav/5mL

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Augmentin Approved Indications

“For the treatment of acute otitis media caused by beta-lactamase-producing strains of Haemophilus influenzae and Moraxella (Branhamella) catarrhalis”

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Augmentin New Formulation

Augmentin ES

• 600mg Amox/42.9mg Clav/5mL 90/6.4mg/kg/day (14:1 ratio)

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Augmentin ES Proposed Labeling

Proposed Indication (by the sponsor)

• “Acute Otitis media--caused by -lactamase-producing strains of H. influenzae or M. catarrhalis, and S. pneumoniae (including penicillin-resistant strains, MIC value for penicillin 2 µg/mL) when suspected.”

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Augmentin ES Proposed Labeling

Proposed Dosage and Administration

Pediatric patients aged 12 weeks (3 months) and older

• “The recommended dose of Augmentin ES is 90 mg/kg/day divided q12h, based on the amoxicillin component.”

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Products currently approved for PRSP

• No anti-infective agent approved to treat AOM due to penicillin resistant S. pneumoniae

• Levofloxacin– Community-acquired pneumonia:

Streptococcus pneumoniae (including penicillin resistant strains with penicillin MIC 2 g/mL)

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Augmentin ES Studies

• Pivotal studies submitted – Bacteriologic study of Augmentin 14:1– clinical study of Augmentin 14:1 vs.

Augmentin 7:1– PK information

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Clinical study

• Augmentin 14:1 vs. Augmentin 7:1 for 10 days

• 11 December 1996-27 February 1997• 3 months to 12 years; n=453 • “All comers” trial not enriched for patients with

penicillin resistant S. pneumoniae• No tympanocenteses performed

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Clinical study

Study Visits

• Baseline

• On-therapy telephone contact days 3-5

• End of Therapy (EOT) days 12-14

• Test of Cure (TOC) days 22-28

• Interim visit (condition worsened/ not improved)

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Clinical Study

Primary Efficacy Endpoint

SB: clinical response at EOT days 12-14

FDA: clinical response at TOC days 22-28

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Clinical Study Demographics

14:1n (%)

7:1n (%)

Gender:

Male 98 (48.5) 92 (44)

Race: White 158 (78.2) 168 (80.4)

Black 18 (8.9) 22 (10.5)

Other 26 (12.9) 19 (9.1)

Age (years): Mean (SD) 3.14 (2.63) 3.18 (2.47)

< 2years 88 (43.6) 87 (41.6)

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Clinical Study Clinical response at TOC

FDA PP population Clinicalresponse

Augmentin 14:1 Augmentin 7:1

Success 96/116 (82.8) 94/120 (78.3)

[-6.5%,15.4%]

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Bacteriologic study

• Open label, non-comparative, multi-center study

• 24 February-5 November, 1999

• Augmentin 14:1 q12 hours for 10 days

• 3 to 48 months of age; n=521

• Tympanocentesis (baseline and on therapy or at time of failure)

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Bacteriologic Study

Population

• Strategies for enrichment for penicillin resistant S. pneumoniae (PRSP)– young age– failure of previous therapy for AOM– prophylaxis for recurrent OM– day care attendees

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Bacteriologic studyStudy Visits

Visit 1 Visit 2 Visit 3 Visit 4

Prelim On End of Test of

therapy therapy cure

(d1) (d4-6) (d12-15) (d25-28)

Interim (optional)

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Bacteriologic Study Procedures

• Tympanocentesis at baseline

• Repeat tympanocentesis:– patients with S. pneumoniae at baseline

retapped at on-therapy visit (d4-6) – all remaining patients retapped at on-

therapy visit (d4-6), or at the time declared clinical failure

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Bacteriologic study

Primary Efficacy Endpoint

SB: Bacteriologic response in patients with S. pneumoniae with penicillin MICs >2g/mL at on therapy visit (day 4-6 )

FDA: Bacteriologic response presumed from clinical response at TOC (d25-28)

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Bacteriologic Study

Secondary endpoints

• Clinical response at the EOT and TOC visits

• Bacteriologic response of other pathogens (on therapy and at EOT)

• Adverse experiences (AEs), especially diarrhea

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Bacteriologic Study

Assessment of Primary Clinical Outcome

SB: end of therapy visit (d12-15)

FDA: test of cure visit (d 25-28)

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Bacteriologic Study

Patient Enrollment and Disposition

• 521 patients received 1 dose of study therapy

• 359 had baseline pathogen (ITT) – 157 with S. pneumoniae– 41 with penicillin resistant strains of S.

pneumoniae (PRSP ITT)

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Bacteriologic Study Demographics

N=521

GenderMale 312 (59.9)

RaceWhite 311 (59.7)Black 90 (17.3)Other 120 (22.9)

Age (mos)Mean (SD) 18.6 (12)Median 14.4

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Bacteriologic Study Demographics

Overall ITT(%) PRSP ITT(%)

<18 months of age 35.4 78.0

Male 59.3 56.1

Day care 40.4 46.2

Prior antibiotics inpast 3 months

53.0 80.8

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Bacteriologic Study Baseline Presentation

Overall ITT PRSP ITT

Abnormal mobility 98 94.9

Abnormal opacity 98.3 94.9

Abnormal position 94.3 92.3

Otalgia 84.8 80.5

Purulence 7.2 12.2

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Bacteriologic Study

FDA Assessment 4 additional clinical failures in the FDA

analysis were considered successes in the sponsor’s analysis clinical presentation consistent with

AOM at either on therapy visit (n=2) or at TOC visit (n=2)

no additional anti-infective agents given

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Bacteriologic StudyOverall Clinical Response at

TOC-PRSP

n/N (%) 95% CI of thepoint estimate

PP

ITT*

14/34 41.2

15/41 36.6

(24.6-59.3)

(22.1-53.1)

*In the ITT analysis, patients with missing data werecounted as failures

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Bacteriologic StudyOverall Clinical Response at

TOC-PRSP (SB results)

n/N (%) 95% CI of thepoint estimate

PP

ITT

18/34 52.9

19/41 46.3

(35.1-70.2)

(30.7-62.6)

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Bacteriologic Study Clinical Response at TOC, by

MIC-PRSPPen MIC=2g/mLn/N (%)

Pen MIC=4g/mLn/N (%)

PP 9/20 (45.0) 5/14 (35.7)

ITT 9/23 (39.1) 6/18 (33.3)

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Bacteriologic StudyClinical responses in PRSP ITT population, by risk subgroup

Prior AOM/<18 months

MIC1 MIC2

No/No 24/31 (77.4) 3/5 (60)

No/Yes 32/41 (78) 7/15 (46.7)

Yes/No 9/13 (69.2) 3/4 (75)

Yes/Yes 15/24 (62.5) 2/17 (11.8)

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Bacteriologic StudyBacteriologic Response-PRSP

On TherapyS. pneumoniaePen MIC

ITTN/N (%)

PPn/N (%)

>2g/mL 38/41 (92.7) 31/33 (93.9)

2g/mL 22/23 (95.7) 19/19 (100)

4g/mL 16/18 (88.9) 12/14 (85.7)

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Bacteriologic Study Bacteriologic Eradication-TOC

• Bacteriologic response presumed from clinical response at TOC (d25-28)

• Some patients had taps at the time of failure – 2 patients with H. influenzae and PRSP

(pen MIC=2g/mL) at baseline

• no growth of PRSP, H. influenzae persisted

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Bacteriologic Study Presumed PRSP Response-

TOCS. pneumoniae ITT PPPen MIC n/N (%) n/N (%)

>2g/mL 19/41 (46.3) 18/34 (52.9)

2g/mL 13/23 (56.5) 13/20 (65.0)

4g/mL 6/18 (33.3) 5/14 (35.7)

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Bacteriologic Study Summary of Response Rates-

PRSP • Clinical response in PRSP at TOC :

41.2% (95% CI: 25- 59)

• Bacteriologic response for PRSP at on-therapy visit: 93.9%

• Presumed bacteriologic response at TOC: 52.9%

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Bacteriologic study Summary of Response Rates-

PRSP

Clinical response rates, by MIC:

• Pen MIC=4g/mL: 35.7%

• Pen MIC =2g/mL: 45.0%

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Bacteriologic StudySafety

Deaths and Serious Adverse Events

• no deaths (n=521)

• >1 SAE (n=7)– Diarrhea in 2/521 (0.04%) – Other SAEs: vomiting, asthma, pneumonia,

dehydration, overdose, injury

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Bacteriologic Study Safety

AEs leading to withdrawal N=521n (%)

AE leading to withdrawal 24 (4.6)

Diarrhea 15 (2.9)

Vomiting 7 (1.3)

Other AEs: abdominal pain, melena, rash,urticaria, contact dermatitis, infection, fever,dehydration

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Bacteriologic StudySafety

Protocol-Defined Diarrhea (PDD)*

N=521PDD n (%)Yes 70 (13.4)No 451 (86.6)

*Protocol Definition: 3 or more watery stools in a day, 2watery stools on 2 consecutive days or reported anadverse event of ‘diarrhea’.

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Bacteriologic study Summary of Safety

• No deaths

• Few patients with SAEs

• Diarrhea most common reason for withdrawal

• PDD in 13.4%

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Issues from review

a) Inconsistency between on-therapy bacteriologic responses and clinical outcomes at TOC

b) Clinical response results at TOC are difficult to interpret without:– natural history of AOM due to PRSP– approved comparator

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Other Issues from review

c) The proposed empiric treatment when AOM due to PRSP is suspected

d) Augmentin 7:1 adequately treats AOM due to H. influenzae and M. catarrhalis

e) Selection of timing of assessment of bacteriologic and clinical outcomes