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Treatment of Acute Otitis Media With Azithromycin. Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development. Azithromycin for Acute Otitis Media Rationale. Bactericidal against the pathogens responsible for AOM.

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treatment of acute otitis media with azithromycin

Treatment of Acute Otitis Media With Azithromycin

Michael Dunne, MD

Vice President

Clinical Development, Infectious Diseases

Pfizer Global Research and Development

azithromycin for acute otitis media rationale
Azithromycin for Acute Otitis MediaRationale
  • Bactericidal against the pathogens responsible for AOM
azithromycin for acute otitis media rationale3
Azithromycin for Acute Otitis MediaRationale
  • Bactericidal against the pathogens responsible for AOM
  • Pharmacokinetic profile suited for treatment of infection
    • Reaches effective concentrations in middle ear
    • Sustained concentrations in white blood cells
    • Complete course of therapy in single dose
    • Optimizes compliance
azithromycin for acute otitis media rationale4
Azithromycin for Acute Otitis MediaRationale
  • Bactericidal against the pathogens responsible for AOM
  • Pharmacokinetic profile suited for treatment of infection
    • Reaches effective concentrations in middle ear
    • Sustained concentrations in white blood cells
    • Complete course of therapy in single dose
    • Optimizes compliance
  • Well tolerated, safe antibiotic
    • Recommended in penicillin allergic patients
    • Over 40 million prescriptions for oral suspension
azithromycin for acute otitis media rationale5
Azithromycin for Acute Otitis MediaRationale
  • Bactericidal against the pathogens responsible for AOM
  • Pharmacokinetic profile suited for treatment of infection
    • Reaches effective concentrations in middle ear
    • Sustained concentrations in white blood cells
    • Complete course of therapy in single dose
    • Optimizes compliance
  • Well tolerated, safe antibiotic
    • Recommended in penicillin allergic patients
    • Over 40 million prescriptions for oral suspension
  • Clinical efficacy equivalent to approved therapies
    • Originally established in five day regimen
    • Extended to shorter regimens of three day and single dosing
advantages of single dose azithromycin
Advantages of Single Dose Azithromycin
  • Provides best drug levels early in course of infection
  • Takes advantage of important host defenses
    • Maximal neutrophil recruitment optimizes azithromycin delivery
    • Febrile response increases azithromycin uptake1
  • Maximizes rate of compliance
  • Minimizes burden on caregiver

1Fietta, et al., J.Chemotherapy 1997

azithromycin for acute otitis media
Azithromycin for Acute Otitis Media
  • Chemistry/Pharmacokinetics
  • Microbiology
  • Clinical Data
  • Conclusion
azithromycin the first azalide antibiotic

H3C

CH3

CH3

N

HO

H3C

N

OH

H3

C

CH3

HO

CH3

O

O

CH3

HO

O

H3

C

CH3

O

O

OH

CH3

CH3

O

CH3

H3

C

O

Azithromycin

Azithromycin: The First Azalide Antibiotic
azithromycin uptake by white blood cells

Acid Vesicle pH 5.0 A

A

A

AH+

AH+

AH+

Extracellular Blood, pH 7.4

Cytoplasm pH 7.2

AzithromycinUptake by White Blood Cells
acute otitis media histopathology
Acute Otitis MediaHistopathology

S. Giebink, M.D., FDA AC presentation, November 1997

azithromycin for acute otitis media12
Azithromycin for Acute Otitis Media
  • Chemistry/Pharmacokinetics
  • Microbiology
  • Clinical Data
  • Conclusion
azithromycin in vitro activity14
Azithromycin: In Vitro Activity

aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000

antimicrobial resistance to s pneumoniae according to penicillin susceptibility 1998
Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998

Whitney. NEJM 2000

susceptibility of s pneumoniae to macrolides and penicillin in the u s from surveillance studies
Susceptibility of S. pneumoniae to Macrolidesand Penicillin in the U.S. From Surveillance Studies

% Resistant

Year

azithromycin bactericidal activity against streptococcus pneumoniae
AzithromycinBactericidal Activity Against Streptococcus pneumoniae*

Log10 CFU/ml

Time (hours)

*MIC =0.06 g/ml

azithromycin bactericidal activity against haemophilus influenzae
AzithromycinBactericidal Activity Against Haemophilus influenzae*

Log10 CFU/ml

Time (hours)

*MIC =0.78 g/ml

azithromycin chinchilla model of aom due to h influenzae
AzithromycinChinchilla Model of AOM due to H. influenzae

Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS

Day 0: Otomicroscopic exam of TM and tympanometry

Culture middle ear fluid (MEF)

Initiate therapy via orogastric feeding tube

Day 3: Otomicroscopic exam and tympanometry

Culture and collect MEF and serum

Continue therapy

Day 5: Otomicroscopic exam and tympanometry

Culture and collect MEF

Complete therapy

Day 7-10: Repeat exams; Culture and collect MEF

Babl. 40th ICAAC 2000

azithromycin chinchilla middle ear fluid concentrations
AzithromycinChinchilla Middle Ear Fluid Concentrations

Azithromycin (mg/ml)

Azithromycin Therapy

Day

Total MEF = frozen/thawed middle ear fluid

Babl. 40th ICAAC 2000

azithromycin chinchilla model of aom due to h influenzae22
AzithromycinChinchilla Model of AOM due to H. influenzae

MEDIAN CFU FOR NTHI BY TREATMENT GROUP

Log scale CFU

Day

* Sterile ears with <10CFU

Azithromycin therapy

Babl. 40th ICAAC 2000

azithromycin chinchilla model of aom due to h influenzae23
AzithromycinChinchilla Model of AOM due to H. influenzae

Percent Culture Positive

Day

Babl. 40th ICAAC 2000

azithromycin for acute otitis media24
Azithromycin for Acute Otitis Media
  • Chemistry/Pharmacokinetics
  • Microbiology
  • Clinical Program
    • Overview of Five Day Program
    • Single Dose
    • Three Day Dosing
    • Focus on Selected Topics
  • Conclusion
azithromycin 5 day program clinical outcome at day 30
Azithromycin 5 Day ProgramClinical Outcome at Day 30*

Per Protocol

Study

Outcome

Azithromycin

Amox/Clav

Cure

181/264 (69%)

168/257 (65%)

134

176

Cure

75/122 (61%)

--

Cure

36/45 (80%)

27/35 (77%)

128

*Medical officers assessment; no ITT analysis done

azithromycin 5 day program treatment related adverse events
Azithromycin 5 Day Program Treatment Related Adverse Events*

Azithromycin

Amox/Clav

N

(%)

N

(%)

No. Patients

975

827

No. Patients with Treatment-Related AEs

70

(7.2)

190

(23.0)

No. with Common Adverse Events

Diarrhea

17

(1.7)

104

(12.6)

Vomiting

17

(1.7)

34

(4.1)

Abdominal Pain

14

(1.4)

19

(2.3)

*Protocols 128,134,178,322,334,337; Amox/Clav comparative studies

azithromycin for acute otitis media28
Azithromycin for Acute Otitis Media
  • Chemistry/Pharmacokinetics
  • Microbiology
  • Clinical Program
    • Overview of Five Day Program
    • Single Dose
    • Three Day Dosing
    • Focus on Selected Topics
  • Conclusion
regimens used in azithromycin clinical program for treatment of acute otitis media
Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media
  • Five Day Dosing
    • 30 mg/kg: 10 mg/kg then 5,5,5,5
    • Approved in United States in 1995
  • Three Day Dosing
    • 30 mg/kg: 10 mg/kg qd X 3
    • Approved in Europe in 1990
  • Single Dose Therapy
    • 30 mg/kg: given as single dose
1998 fda guidance acute otitis media
1998 FDA GuidanceAcute Otitis Media

“Clinical-only” Trial

  • One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized
    • Test-of-Cure visit (2 - 4 weeks from initiation of therapy)

Clinical/Microbiologic Trial

  • One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug
  • For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates
azithromycin overview of single dose and three day programs
Azithromycin Overview of Single Dose and Three Day Programs

Pivotal Studies

  • Single dose program

R-0581: double-blind, randomized, comparative clinical trial

1015: open, noncomparative, microbiology study

  • Three day dosing

1014: double-blind, randomized, comparative clinical trial

Supportive Study

95-001: randomized comparative single center study

        • Baseline tympanocentesis performed
        • Compares three day dosing with single dose therapy with ceftriaxone
single dose program

Single Dose Program

Phase 2 Study 95-001

Phase 3 Study R-0581 Study 1015

single dose program inclusion criteria symptoms
Single Dose ProgramInclusion Criteria: Symptoms

1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever

2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance)

single dose program inclusion criteria signs of tympanic membrane disease
Single Dose ProgramInclusion Criteria: Signs of Tympanic Membrane Disease

1 Any one of these findings

2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level

single dose program key exclusion criteria
Single Dose ProgramKey Exclusion Criteria

Other exclusions variably applied across studies include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, concurrent ergotamine or digitalis, weight > 40kg

single dose program statistical methods
Single Dose ProgramStatistical Methods
  • Primary Endpoint: Clinical Cure
  • Primary Timepoint (Test of Cure): Day 28
    • Cure
    • Failure
    • Improvement (R-0581 and 95-001)
single dose program statistical methods37
Single Dose ProgramStatistical Methods
  • Clinical Efficacy Population
    • At least one dose of study medication
    • Diagnosis of AOM at baseline
    • Analyzed at Day 28
      • Return for visit at Day 28
      • Concomitant antibiotic for failure counts as failure
  • Bacteriological Efficacy Population
    • Positive baseline culture for at least one relevant pathogen
study 95 001 methods
Study 95-001 Methods
  • Objectives
    • Pilot study to compare the safety and efficacy of single dose azithromycin, azithromycin dosing over 3 days and single dose ceftriaxone in children with acute otitis media
  • Design
    • Prospective
    • Single-center in Costa Rica
    • Performed in 1995-1997
study 95 001 experimental design
Study 95-001 Experimental Design

*Baseline tympanocentesis

study 95 001 demographics
Study 95-001Demographics

Azithromycin

Ceftriaxone

Single Dose

N = 66

Three Day

N = 66

N = 66

Age:

< 2 Yrs

26 (39%)

26 (39%)

35 (53%)

2 Yrs - 12 Yrs

40 (61%)

40 (61%)

31 (47%)

Mean Age (Yrs, ±SD)

2.5 (+ 1.3)

2.7 (+ 1.5)

2.3 (+ 1.4)

% Male

56%

55%

48%

Race:

White

97%

95%

98%

Black

2%

2%

0%

Hispanic

2%

3%

2%

study 95 001 clinical efficacy population
Study 95-001 Clinical Efficacy Population

1 Day (%)

Azithromycin

3 Day (%)

Ceftriaxone

(%)

95% CI1 [%]

Randomized Patients

66

66

66

Day 14

64

63

62

Success

62 (97)

60 (95)

61 (98)

[-8,5]

Cure

26

18

21

Improvement

36

42

40

Failure

2 (3)

3 (5)

1 (2)

Day 28

65

66

64

Success

61 (94)

61 (92)

62 (97)

[-12,6]

Cure

56 (86)

51 (77)

49 (77)

[- 5, 25]

Improvement

5

10

13

Failure

4 (6)

5 (8)

2 (3)

1 95% CI for (single dose azithromycin – comparator)

study 95 001 clinical outcome at day 28 by age
Study 95-001 Clinical Outcome at Day 28 by Age

1 Day (%)

3 Day (%)

Ceftriaxone (%)

Azithromycin

< 2 years of age

25

27

33

Cure

19 (76)

18 (67)

23 (70)

Failure

6 (24)

9 (33)

10 (30)

> 2 years of age

40

39

31

Cure

37 (93)

33 (85)

26 (84)

Failure

3 (8)

6 (15)

5 (16)

study 95 001 susceptibility
Study 95-001 Susceptibility
  • S. pneumoniae susceptibility (N=57)
    • Azithromycin
      • 46 susceptible
      • 11 resistant (MIC > 0.5 mg/ml)
    • Ceftriaxone
      • All isolates were susceptible to ceftriaxone
  • All H. influenzae and M. catarrhalis were susceptible to azithromycin and ceftriaxone
study 95 001 treatment related adverse events
Study 95-001 Treatment Related Adverse Events*

Azithromycin

1 Day

3 Day

Ceftriaxone

Patients Treated

66

66

66

Discontinued

0 (0)

0 (0)

0 (0)

Patients w/ AE

7 (11)

6 (9)

6 (9)

Diarrhea

2 (3)

3 (5)

4 (6)

Rash

1 (2)

0 (0)

4 (6)

0 (0)

Vomiting

3 (5)

0 (0)

*2 or more events on any treatment regimen

study r 0581

Study R-0581

Single Dose Therapy

study r 058151
Study R-0581
  • Objective
    • Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM
  • Design
    • Multicenter, randomized
      • All sites in the United States
    • Double blind, double dummy
      • Azithromycin: 30 mg/kg single oral dose
      • Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days
      • Matching placebo for each active study drug
study r 0581 visits and assessments
Study R-0581 Visits and Assessments

*Patients who vomited within 30 minutes were redosed

1 Including parental questionnaire

study r 0581 clinical outcome
Study R-0581 Clinical Outcome

Azithromycin (%)

Amox/Clav (%)

95% CI1[%]

Number of Patients

173

173

Day 14

160

161

Success

139 (87)

142 (88)

[-9, 7]

Cure

105

121

Improvement

34

21

Failure

21 (13)

19 (12)

Day 28

151

154

Success

114 (75)

116 (75)

[-10, 11]

Cure

112 (74)

108 (70)

[-7, 15]

Improvement

2

8

Failure

37 (25)

38 (25)

1 95% CI for (azithromycin – comparator)

study r 0581 clinical outcome at day 28 by age
Study R-0581 Clinical Outcome at Day 28 by Age

95% CI1[%]

Azithromycin

Amox/Clav

N (%)

N (%)

< 2 years of age

64

53

Cure

40 (63)

27 (51)

[-8, 31]

Failure

24 (38)

26 (49)

87

101

> 2 years of age

[-10, 15]

Cure

72 (83)

81 (80)

Failure

15 (17)

20 (20)

1 95% CI for (azithromycin – comparator)

study r 0581 compliance
Study R-0581Compliance

Based on patients randomized to their study drug regimen

study r 0581 treatment related adverse events

Amox/Clav N = 173

Azithromycin N = 173

Discontinued due to AE

4 (2%)

7(4%)

Patients w/ AEs

29 (17%)

39 (23%)

Diarrhea

11 (6%)

22 (13%)

Vomiting

7 (4%)

7 (4%)

3 (2%)

9 (5%)

Rash

Study R-0581 Treatment Related Adverse Events*

* Adverse Events greater than 2 percent in either regimen

study 1015

Study 1015

Single Dose Therapy

study 101561
Study 1015
  • Objectives
    • To assess per-pathogen clinical response rates
    • To provide additional data on the safety and toleration of the single dose regimen
  • Design
    • Prospective
    • Open-label
    • Non-comparative
    • Multi-center
study 1015 visits and assessments
Study 1015 Visits and Assessments

*Patients who vomited within 30 minutes were redosed

study 1015 endpoints
Study 1015 Endpoints

Primary Efficacy Endpoint

  • Clinical response by baseline pathogen at day 28
      • Initial local laboratory isolation of pathogen with confirmation by central laboratory

Secondary Efficacy Endpoints

  • Clinical response at day 28 (test of cure)
  • Clinical response at day 10

Safety Evaluation

study 1015 patient disposition

Azithromycin

Evaluation Groups

Enrolled

248

Safety

248

Efficacy

Clinical at Day 28

242

Bacteriologic

127

Study 1015Patient Disposition
study 1015 clinical outcome
Study 1015 Clinical Outcome

Azithromycin (%)

95% CI1 [%]

Number of Patients

247

Day 10

240

Success

213 (89%)

[85,93]

Cure

139

Improvement

74

Failure

27 (11%)

Day 28

242

Cure

206 (85%)

[80,90]

Failure

36 (15%)

1 95% CI for azithromycin

study 1015 clinical outcome at day 28 by age
Study 1015 Clinical Outcome at Day 28 by Age

Azithromycin

N

(%)

95% CI[%]

< 2 years of age

83

Cure

64

77

[67, 87]

Failure

19

23

> 2 years of age

159

Cure

142

89

[84, 94]

Failure

17

11

study 1015 mic distribution for s pneumoniae n 67
Study 1015MIC Distribution for S. pneumoniae (N=67)

Percent of Patients

Azithromycin MIC (mg/ml)

study 1015 resistant s pneumoniae
Study 1015Resistant S. Pneumoniae
  • S. pneumoniae MIC = 8 g/ml
    • 7 baseline isolates
    • All sensitive to clindamycin
    • All with mef A gene by PCR
  • S. pneumoniae MIC >256 g/ml
    • 5 baseline isolates
    • All resistant to clindamycin
    • All with erm B gene by PCR
study 1015 day 28 outcome and mic distribution for s pneumoniae n 66
Study 1015Day 28 Outcome and MIC Distribution for S. pneumoniae (N=66)

# of Patients

Azithromycin MIC (mg/ml)

study 1015 patient 0067 failed therapy
Study 1015 Patient 0067 Failed Therapy

1Susceptible to clindamycin; mef A gene identified

2Resistant to clindamycin; erm B gene identified

study 1015 outcome of s pneumoniae aom by penicillin susceptibility
Penicillin SusceptibilityStudy 1015Outcome of S. pneumoniae AOM by Penicillin Susceptibility

*Penicillin MIC > 2 mg/ml

**Penicillin MIC > 0.125 - < 2 mg/ml

study 1015 outcome of s pneumoniae aom by penicillin susceptibility76
Penicillin SusceptibilityStudy 1015Outcome of S. pneumoniae AOM by Penicillin Susceptibility

*Penicillin MIC > 2 mg/ml

**Penicillin MIC > 0.125 - < 2 mg/ml

study 1015 treatment related adverse events
Study 1015 Treatment Related Adverse Events*

N

(%)

Patients Treated

248

Discontinued due to AEs

1

(0)

Patients w/ AEs

30

(12)

Diarrhea

8

(3)

Vomiting

14

(6)

Abdominal Pain

4

(2)

* Adverse Events greater than 1%

study 1014

Study 1014

Three Day Dosing

study 101479
Study 1014
  • Objectives
    • Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM
  • Design
    • Multicenter, randomized
    • All sites in the United States
    • Double blind, double dummy
      • Azithromycin: 10 mg/kg/day for 3 days
      • Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days
      • Matching placebo for each active study drug
study 1014 inclusion criteria symptoms
Study 1014Inclusion Criteria: Symptoms

1998 FDA Guidance

1014

Age

>6 months

X

0.5-11yrs

Symptoms which help confirm the diagnosis of AOM (%)

Ear pain (tugging or rubbing)

X

921

Ear fullness

X

601

Either Ear pain or fullness

97

Decreased hearing

X

251

Symptoms consistent with AOM (but nonspecific) 2

Fever

X

261

Irritability

X

1 Children had one or more of these signs and symptoms

2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance)

study 1014 inclusion criteria signs of tympanic membrane involvement
Study 1014Inclusion Criteria: Signs of Tympanic Membrane Involvement

1 Any one of these findings

2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level

study 1014 key exclusion criteria
Study 1014Key Exclusion Criteria

Other exclusions include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, neutropenia, immunosuppressant therapy, cystic fibrosis, retraction pockets, cholesteatoma, phenylketonuria, anticipated use of probenecid or allopurinol

study 1014 visits and assessments
Study 1014 Visits and Assessments

*Patients who vomited within 30 minutes were redosed

study 1014 statistical methods
Study 1014Statistical Methods
  • Primary Endpoint: Clinical Cure
  • Primary Timepoint: Day 28
    • Cure
    • Failure
study 1014 statistical methods85
Study 1014 Statistical Methods
  • Clinical Efficacy Population
    • At least one dose of study medication
    • Diagnosis of AOM at baseline
    • Analyzed at Day 28
      • Return for visit at Day 28
      • Concomitant antibiotic for failure counts as failure
study 1014 clinical outcome
Study 1014Clinical Outcome

Azithromycin (%)

Amox/Clav (%)

95% CI1 [%]

Number of Patients

188

185

Day 10

185

181

Success

153 (83)

159 (88)

[-13,3]

Cure

100

114

Improvement

53

45

Failure

32 (17)

22 (12)

Day 28

182

180

Cure

134 (74)

124 (69)

[-5, 15]

Failure

48 (26)

56 (31)

1 95% CI for (azithromycin – comparator)

study 1014 clinical outcome at day 28 by age
Study 1014 Clinical Outcome at Day 28 by Age

Azithromycin

Amox/Clav

95% CI1 [%]

N

(%)

N

(%)

< 2 years of age

58

52

Cure

35

(60)

30

(58)

[-18, 23]

23

(40)

22

(42)

Failure

> 2 years of age

124

128

Cure

99

(80)

94

(73)

[-5, 18]

25

(20)

34

(27)

Failure

1 95% CI for (azithromycin – comparator)

study 1014 compliance
Study 1014Compliance

Based on patients randomized to their study drug regimen

study 1014 treatment related adverse events
Study 1014 Treatment Related Adverse Events*

Azithromycin

Amox/Clav

N

%

N

%

188

185

Patients Treated

1

(1)

2

(1)

Discontinued due to AE

20

(11)

37

(20)

Patients with AE

11

27

(6)

(15)

Diarrhea

(2)

4

2

(1)

Vomiting

0

(0)

(4)

8

Rash

* Adverse events greater than 2% in either treatment regimen

acute otitis media summary clinical cure at day 28
Acute Otitis MediaSummary Clinical Cure at Day 28

Study

Azithromycin 3 Day

Azithromycin Single Dose

Comparator

95% CI

[-7, 15]

R-0581Az-Amox/Clav

112/151 (74%)

108/154 (70%)

1015

206/242 (85%)

[-5, 15]

1014

Az-Amox/Clav

134/182 (74%)

124/180 (69%)

[-5, 25]

[-15, 17]

95-001AzSD-CTX Az3D-CTX

51/66 (77%)

56/65 (86%)

49/64 (77%)

effect of age on clinical outcome 2 years of age
Effect of Age on Clinical Outcome< 2 years of age

*Clinical success; **Clinical cure; 1Single dose regimen

treatment related adverse events azithromycin regimens for aom vs comparator
Treatment Related Adverse Events Azithromycin Regimens for AOM Vs. Comparator*

Azithromycin Duration (Days)

Comparator

1

3

5

Number of Patients

487

254

888

1105

Patients with Related Adverse Events

66 (14%)

26 (10%)

69 (8%)

254 (23%)

Patients with common AE’s:

Diarrhea

21 (4%)

14 (6%)

31 (3%)

171 (16%)

Vomiting

24 (5%)

4 (2%)

11 (1%)

41 (4%)

Abdominal pain

7 (1%)

1 (<1%)

13 (1%)

23 (2%)

Nausea

6 (1%)

0 (0%)

5 (1%)

18 (2%)

Rash

4 (1%)

0 (0%)

6 (1%)

27 (2%)

*Pivotal studies from 1, 3 and 5 day programs; All AE’s > 2 %

treatment related adverse events azithromycin regimens for aom vs comparator99
Treatment Related Adverse EventsAzithromycin Regimens for AOM Vs. Comparator*

Azithromycin Duration (Days)

Comparator

1

3

5

Number of Patients

487

254

888

1105

Patients with Related Adverse Events

66 (14%)

26 (10%)

69 (8%)

254 (23%)

Related Adverse Events/Patient Year

6.7

7.4

9.8

22.7

*Pivotal studies from 1, 3 and 5 day programs

azithromycin for acute otitis media100
Azithromycin for Acute Otitis Media
  • Chemistry/Pharmacokinetics
  • Microbiology
  • Clinical Program
    • Overview of Five Day Program
    • Single Dose
    • Three Day Dosing
    • Focus on Selected Topics
  • Conclusion
focus on selected topics
Focus on Selected Topics
  • Vomiting of the single dose therapy
  • Historical comparison of cure rates at day 28
  • Timing of the clinical assessment
patients who vomited single dose therapy

Total

52/487 (10.7%)

On the first day

36/487 (7.4%)

Patients Who Vomited Single Dose Therapy

Clinical Outcome for Children Who Vomited on Day 1

Day 14

Day 28

Vomited

No Vomiting

Vomited

No Vomiting

Cure/Improved

31 (91%)

383 (89%)

29 (85%)

345 (81%)

Fail

3 (9%)

47 (11%)

5 (15%)

79 (19%)

Missing

2

2

azithromycin auc values following 2g and 3g single doses

Individual values for subjects who vomited >2 hours post-dose

AUC (mg·hr/ml)

2 g

(n=36)

2 g

(n=36)

2 g

(n=35)

2 g

(n=35)

3 g

(n=8)

3 g

(n=8)

3 g

(n=27)

3 g

(n=27)

* AUC(0-24); ** AUC(0-infinity); ***AUC(0-288)

AzithromycinAUC Values Following 2g and 3g Single Doses
historical comparison of cure rates at test of cure visit day 28

Historical Comparison of Cure Rates at Test of Cure Visit (Day 28)

Clinical response vs beta-lactams

  • Empiric treatment
  • S. pneumoniae at baseline
  • H. influenzae at baseline
azithromycin vs beta lactams comparative trials for aom clinical cure at day 28

Azithromycin 5 Day

Pfizer, 178 (Amox/Clav)

Pfizer, 134 (Amox/Clav)

Pfizer, 128 (Amox/Clav)

Dagan, 2000 (Amox/Clav)

Azithromycin 3 Day

Rodriquez, 1996 (Cefaclor)

Pestalozza, 1992 (Amox/Clav)

Pfizer, 1014 (Amox/Clav)

Pfizer, 95-001 (Ceftriaxone)

Azithromycin 1 Day

Pfizer, R-0581 (Amox/Clav)

Pfizer, 95-001 (Ceftriaxone)

Overall

Azithromycin vs Amox/Clav (N=1864)

All Studies ( N=2127)

Azithromycin Vs Beta-lactamsComparative Trials for AOM: Clinical Cure at Day 28

% Difference (95% CI)

Favors Comparator

Favors Azithromycin

s pneumoniae clinical outcome test of cure visit day 17 35

Clinical Success

Azithromycin – 5 Day

Cefpodoxime proxetil

Amox/Clav (Augmentin ES)

Clinical Cure

Cefprozil

Cefdinir 5 Day

Cefdinir 10 Day

Azithromycin – 1 Day*

Ceftriaxone

Azithromycin – 3 Day*

S. pneumoniae Clinical Outcome Test of Cure Visit (Day 17-35)*

*Product labels (PDR, 2001);

Summary basis of approval;

Sponsor study report

% Successful Clinical Outcome, (95% CI)

h influenzae clinical outcome test of cure visit day 17 35

Clinical Success

Azithromycin 5 Day

Cefpodoxime proxetil

Amox/Clav (Augmentin ES)

Cefixime

Clinical Cure

Cefprozil

Cefdinir 5 Day

Azithromycin Single Dose

Ceftriaxone

Azithromycin 3 Day

*Product labels (PDR, 2001);

Summary basis of approval;

Sponsor study report

% Successful Clinical Outcome (95% CI)

H. influenzae Clinical OutcomeTest of Cure Visit (Day 17-35)*

Cefdinir 10 Day

timing of clinical assessment

Timing of Clinical Assessment

Early (on therapy) time points

Additional antibiotic

Analgesics use

Parental questionnaire

Day 10-14

Overall clinical response vs beta-lactams

Clinical outcome with H. influenzae at baseline

time to additional antibiotic use
Time to Additional Antibiotic Use

Proportion without

Additional Antibiotic

Day of First Antibiotic Use

  • Azithromycin studies R-0581, 95-001, 1014
  • Comparators combine amoxicillin/clavulanate and ceftriaxone
  • Time to failure = time to concomitant antibiotic use for failure
study r 0581 parental questionnaire
Study R-0581Parental Questionnaire

How Sick Overall Has Child Been?

Not at all

Moderately

Extremely

timing of clinical assessment114

Timing of Clinical Assessment

Early time points

Day 10-14

Overall clinical response vs beta-lactams

Clinical outcome with H. influenzae at baseline

azithromycin vs beta lactams comparative trials for aom clinical success at day 14

Azithromycin 5 Day

Pfizer, 178 (Amox/Clav)

Pfizer, 134 (Amox/Clav)

Pfizer, 128 (Amox/Clav)

Dagan, 2000 (Amox/Clav)

Azithromycin 3 Day

Rodriguez, 1996 (Cefaclor)

Dagan, 2000 (Cefaclor)

Mohs, 1993 (Amoxicillin)

Arguedas, 1996 (Amox/Clav)

Pestalozza, 1992 (Amox/Clav)

Daniel, 1993 (Amox/Clav)

Principi, 1995 (Amox/Clav)

Schaad 1993 (Amox/Clav)

Pfizer, 1014 (Amox/Clav)

Pfizer, 95-001 (Ceftriaxone)

Azithromycin 1 Day

Pfizer, R-0581 (Amox/Clav)

Pfizer, 95-001 (Ceftriaxone)

Overall

Azithromycin vs Amox/Clav (N=3271)

All Studies (N=3956)

Azithromycin Vs Beta-lactamsComparative Trials for AOM: Clinical Success at Day 14

% Difference (95% CI)

Favors Comparator

Favors Azithromycin

timing of clinical assessment116

Timing of Clinical Assessment

Early time points

Day 10-14

Overall clinical response vs beta-lactams

Clinical outcome with H. influenzae at baseline

h influenzae clinical outcome end of therapy day 7 15

Clinical Success

Azithromycin 1 Day Overall

Azithromycin 3 Day

Azithromycin 5 Day

Cefpodoxime proxetil

Amox/Clav (Per Protocol)

Amox/Clav (ITT)

Cefixime

Cefaclor

Ceftibuten

Cefuroxime axetil

Clarithromycin

Erythromycin

Erythromycin + sulfa

Clinical Cure

Ceftriaxone (Per Protocol)

Loracarbef

% Clinical Success (95% CI)

H. influenzae Clinical OutcomeEnd of Therapy (Day 7-15)*

*Product labels (PDR, 2001);

Summary basis of approval;

Sponsor study report

azithromycin for acute otitis media118
Azithromycin for Acute Otitis Media
  • Chemistry/Pharmacokinetics
  • Microbiology
  • Clinical Data
  • Conclusion
conclusions azithromycin for acute otitis media
ConclusionsAzithromycin for Acute Otitis Media
  • Effective, empiric treatment of acute otitis media
    • As a single dose or over three days
  • Well tolerated, safe antibiotic
  • Optimizes compliance
    • Complete course of therapy in single dose
    • Eases burden on the caregiver
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