1. 1 Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development

2. 2 Azithromycin for Acute Otitis Media Rationale Bactericidal against the pathogens responsible for AOM

3. 3 Azithromycin for Acute Otitis Media Rationale 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

4. 4 Azithromycin for Acute Otitis Media Rationale 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

5. 5 Azithromycin for Acute Otitis Media Rationale 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

6. 6 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 uptake 1  Maximizes rate of compliance  Minimizes burden on caregiver 1 Fietta, et al., J. Chemotherapy 1997

7. 7 Azithromycin for Acute Otitis Media  Chemistry/Pharmacokinetics  Microbiology  Clinical Data  Conclusion

8. 8 Azithromycin: The First Azalide Antibiotic H3CH3C H3CH3C H 3 C H3CH3C H3CH3C N HO O O O O O O N O CH 3 OH Azithromycin

9. 9 Azithromycin Uptake by White Blood Cells Acid Vesicle pH 5.0 A AH+ A A Cytoplasm pH 7.2 Extracellular Blood, pH 7.4

10. 10 Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997

11. 11 Azithromycin Serum and Middle Ear Fluid Levels in Children Investigators Azithromycin Dose Assessment Time after Last Dose Serum mg/L MEF mg/L Scaglione, 199910 mg/kg24 hours*1.05/0.23 Dagan, 200010 mg/kg x 3d24-48 hours0.073.5 Pukander, 199610 mg/kg24 hours0.0438.6 10, 5 mg/kg24 hours0.0269.4 *Cells / middle ear fluid

12. 12 Azithromycin for Acute Otitis Media  Chemistry/Pharmacokinetics  Microbiology  Clinical Data  Conclusion

13. 13 Azithromycin: In Vitro Activity Hoban. CID 2001 OrganismNMIC 50 MIC 90 µg/ml Streptococcus pneumoniae4193  0.12 2 Haemophilus influenzae3116 12 Moraxella catarrhalis1411  0.12

14. 14 Azithromycin: In Vitro Activity a Hoban, CID 2001; b Shortridge, CID 1999; c Montanari, J Clin Microbiol 2001; d Jones, Diagn Microbiol Infec Dis 2000 OrganismMIC 50 MIC 90 µg/ml S. pneumoniae a N=4193  0.12 2 mef(A) b N=70 48 erm(B) c N=65>128 S. pneumoniae d N=1665 pen S1212 (73%)  0.12  0.25 pen I250 (15%)  0.25 16 pen R203 (12%)1>32

15. 15 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Agent MIC CutoffResistance to Penicillin (%) SusceptibleResistant IntermediateHigh Cefuroxime>2>20.135100 Erythromycin>1>13.23561 Trim-sulfa>4, >766.65192 Tetracycline>8>811926

16. 16 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 Antimicrobial Agent < 2 yr (N=284) 3-12 yr (N=134) > 13 yr (N=813) Penicillin496170 Amoxicillin687485 Ceftriaxone677786 Erythromycin637580 Clindamycin879596 % Susceptible

17. 17 Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant

18. 18 Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log 10 CFU/ml *MIC =0.06  g/ml

19. 19 Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log 10 CFU/ml *MIC =0.78  g/ml

20. 20 Azithromycin Chinchilla 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

21. 21 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (  g/ml) Day

22. 22 Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFUAzithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day

23. 23 Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive

24. 24 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

25. 25 Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%)36/45 (80%)Cure --75/122 (61%)Cure 168/257 (65%)181/264 (69%)Cure Amox/ClavAzithromycinOutcome Per Protocol *Medical officers assessment; no ITT analysis done

26. 26 Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Study 176Azithromycin n/N (%) S. pneumoniae40/56 (71) H. influenzae30/47 (64) M. catarrhalis19/26 (73) Study 128Azithromycin n/N (%) Amox/Clav n/N (%) S. pneumoniae22/28 (79)18/22 (82) H. influenzae8/10 (80)6/8 M. catarrhalis5/52/3

27. 27 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/ClavAzithromycin (2.3)19(1.4)14Abdominal Pain (4.1)34(1.7)17Vomiting (12.6)104(1.7)17Diarrhea No. with Common Adverse Events (23.0)190(7.2)70 No. Patients with Treatment-Related AEs 827975No. Patients (%)N N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies

28. 28 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

29. 29 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

30. 30 1998 FDA Guidance Acute 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

31. 31 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, m icrobiology 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

32. 32 Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015

33. 33 Single Dose Program Inclusion 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) 1998 FDA Guidance1015R-058195-001 Age: >6 monthsX 6 months to 12 years0.5-12 yrs 6 months to 5 years0.3-6.5 yrs Symptoms which help confirm the diagnosis of AOM Ear pain (tugging or rubbing)X93 1 77 1 96 1 Ear fullnessX79 1 Either Ear pain or fullness98 Discharge from external canalX20 1 Decreased hearingX46 1 Symptoms consistent with AOM (but nonspecific) 2 FeverX49 1 59 1 (sign) 1 IrritabilityX89 1 Lethargy68 1

34. 34 Single Dose Program Inclusion 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 Findings most consistent with AOM:FDA1015R-058195-001 Decreased/absent TM mobilityX2X2 92 1 97 2 100 Full/bulging TMX85 1 90 1 100 1 Marked TM rednessX91 1 82 1 99 1 Loss of landmarksX94100 1 Loss of light reflex-91 1 Abnormal tympanometryX100 Electroacoustic ReflectometryXXX Acoustic gradient angle < 708799-

35. 35 Single Dose Program Key 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 FDA1015R-058195-001 Recent antibiotic useXXXX Tympanostomy tubes presentXX(0%) Otitis externaX(0%) Chronic OMXXX Perforated eardrum (chronic)X Perforated eardrum (acute)(20%)X HypersensitivityXXX Significant Medical ConditionsXXX

36. 36 Single Dose Program Statistical Methods  Primary Endpoint: Clinical Cure  Primary Timepoint (Test of Cure): Day 28  Cure  Failure  Improvement (R-0581 and 95-001)

37. 37 Single Dose Program 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  Bacteriological Efficacy Population  Positive baseline culture for at least one relevant pathogen

38. 38 Single Dose Program Definition of Cure StudyDefinition of Cure 1015Complete resolution of the specific signs/symptoms. Persistence of middle ear effusion was not a factor. R-0581Complete resolution of all signs/symptoms. Middle ear effusion may or may not be present. 95-001Complete disappearance of all pre- treatment signs/symptoms. May include effusion.

39. 39 Study 95-001

40. 40 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

41. 41 Study 95-001 Experimental Design *Baseline tympanocentesis

42. 42 Study 95-001 Patient Disposition AzithromycinCeftriaxone Evaluation Groups1 Day3 Day Randomized66 Safety66 Efficacy Clinical at Day 28656664 Bacteriologic303533

43. 43 Study 95-001 Demographics 0%2% Black 98%97% White Race: 48%56% Male 2.3 (+ 1.4)2.5 (+ 1.3)Mean Age (Yrs, ±SD) 31 (47%)40 (61%) 2 Yrs - 12 Yrs 35 (53%)26 (39%)< 2 Yrs Age: N = 66 Single Dose N = 66 Azithromycin 2% 95% 55% 2.7 (+ 1.5) 40 (61%) 26 (39%) Three Day N = 66 Ceftriaxone 2% Hispanic 3%

44. 44 Study 95-001 Results AzithromycinCeftriaxone 1 Day N=66 3 Day N=66 Demographics Duration Since First Symptoms1.5 days 2.4 days1.7 days Range1-6 days 1-24 days1-9 days Concomitant Drug Use During Study Analgesic Use 21 (32%)28 (42%)29 (44%) Symptomatic Drugs for RTI03 (5%)2 (3%)

45. 45 Study 95-001 Clinical Efficacy Population 4 (6)Failure 5Improvement [- 5, 25]56 (86)Cure [-12,6]61 (94)Success 65Day 28 2 (3)Failure 36Improvement 26 Cure [-8,5]62 (97) Success 64 Day 14 66Randomized Patients 95% CI 1 [%]1 Day (%) 1 95% CI for (single dose azithromycin – comparator) 5 (8) 10 51 (77) 61 (92) 66 3 (5) 42 18 60 (95) 63 66 3 Day (%) 2 (3) 13 49 (77) 62 (97) 64 1 (2) 40 21 61 (98) 62 66 Ceftriaxone (%) Azithromycin

46. 46 Study 95-001 Clinical Outcome at Day 28 by Age 5 (16)6 (15)3 (8)Failure 26 (84)33 (85)37 (93)Cure 313940> 2 years of age 10 (30)9 (33)6 (24)Failure 23 (70)18 (67)19 (76)Cure 332725< 2 years of age Ceftriaxone (%)3 Day (%)1 Day (%) Azithromycin

47. 47 Study 95-001 Susceptibility  S. pneumoniae susceptibility (N=57)  Azithromycin  46 susceptible  11 resistant (MIC > 0.5  g/ml)  Ceftriaxone  All isolates were susceptible to ceftriaxone  All H. influenzae and M. catarrhalis were susceptible to azithromycin and ceftriaxone

48. 48 Study 95-001 Clinical Cure Per Baseline Pathogen at Day 28 AzithromycinCeftriaxone 1-DayN3-DayNN Overall86%2884%3284%32 S. pneumoniae85%2094%1783%23 H. influenzae88%869%1389%9 M. catarrhalis00100%200

49. 49 Study 95-001 Treatment Related Adverse Events* 0 (0) 3 (5) Vomiting 4 (6)0 (0)1 (2) Rash 4 (6)3 (5)2 (3) Diarrhea 6 (9) 7 (11)Patients w/ AE 66 Patients Treated Ceftriaxone3 Day1 Day 0 (0) Discontinued *2 or more events on any treatment regimen Azithromycin

50. 50 Study R-0581 Single Dose Therapy

51. 51 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

52. 52 Study R-0581 Visits and Assessments TimingData Day 1BaselineHistory 1, Physical, and 1 st Dose* Day 3-5TelephoneAEs, Compliance, Symptoms 1 Day 12-16End of TherapyAEs, Clinical Response 1 Day 28-32Test of CureAEs, Clinical Response 1 *Patients who vomited within 30 minutes were redosed 1 Including parental questionnaire

53. 53 Study R-0581 Patient Disposition AzithromycinAmoxicillin/Clavulanate Evaluation Groups Randomized175 Safety173 Efficacy at Day 28 Clinical151154

54. 54 Study R-0581 Demographics Azithromycin N = 173 Amoxicillin/Clavulanate N = 173 Age: < 2 Yrs75 (43%)63 (36%) 2 Yrs - 12 Yrs 98 (57%)110 (64%) Mean Age (Yrs, ±SD)2.7 (±2.3)3.4 (±2.8) % Male53% Race: White 50%52% Black 31%35% Hispanic 16%13%

55. 55 Study R-0581 Results Azithromycin N=173 Amox/Clav N=173 Demographics Duration Since First Symptoms3.4 days3.9 days Range1 - 18 days1 - 17 days History of AOM140 (81%)143 (83%) Number of Episodes of AOM in Last Year1.51.4 Concomitant Drug Use During Study Analgesic Use83 (48%) 78 (45%) Symptomatic Drugs for RTI 48 (28%)59 (34%)

56. 56 Study R-0581 Clinical Outcome 38 (25)37 (25)Failure 82Improvement [-7, 15]108 (70)112 (74)Cure [-10, 11]116 (75)114 (75)Success 154151Day 28 19 (12)21 (13)Failure 2134Improvement 121105 Cure [-9, 7]142 (88)139 (87) Success 161160 Day 14 173 Number of Patients 95% CI 1 [%] Amox/Clav (%) Azithromycin (%) 1 95% CI for (azithromycin – comparator)

57. 57 Study R-0581 Clinical Outcome at Day 28 by Age Cure 26 (49)24 (38) Failure [-8, 31] 95% CI 1 [%] Failure < 2 years of age 27 (51)40 (63) Cure 5364 > 2 years of age Amox/ClavAzithromycin 1 95% CI for (azithromycin – comparator) N (%) 72 (83) 15 (17) 87 81 (80) 20 (20) 101 [-10, 15]

58. 58 Study R-0581 Compliance Based on patients randomized to their study drug regimen Azithromycin Amoxicillin/ ClavulanateP - value 99%83%<0.001

59. 59 Study R-0581 Treatment Related Adverse Events* 7 (4%) Vomiting 9 (5%)3 (2%) 22 (13%) 11 (6%) Diarrhea 39 (23%) 29 (17%)Patients w/ AEs Rash Azithromycin N = 173 Amox/Clav N = 173 7(4%)4 (2%) Discontinued due to AE * Adverse Events greater than 2 percent in either regimen

60. 60 Study 1015 Single Dose Therapy

61. 61 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

62. 62 Study 1015 Visits and Assessments TimingData Day 1Baseline History, Physical, Tympanocentesis, and 1 st Dose* Day 5TelephoneAEs Day 10End of TherapyAEs, Clinical Response Day 24-28Test of CureAEs, Clinical Response *Patients who vomited within 30 minutes were redosed

63. 63 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

64. 64 Study 1015 Patient Disposition 242 Clinical at Day 28 127 Bacteriologic Efficacy Azithromycin 248Safety 248Enrolled Evaluation Groups

65. 65 Study 1015 Demographics Age: < 2 Yrs86 (35%) 2 Yrs - 12 Yrs162 (65%) Mean Age (Yrs, ±SD)3.4 (±3.0) % Male52% Race: White 46% Hispanic 44%

66. 66 Study 1015 Results DemographicsAzithromycin N=248 Duration Since First Symptoms2.5 days Range1 - 8 days History of AOM178 (72%) Number of Episodes of AOM in Last Year1.1 Concomitant Drug Use During Study Analgesic Use156 (63%) Symptomatic Drugs for RTI 46 (19%)

67. 67 Study 1015 Clinical Outcome 36 (15%)Failure [80,90]206 (85%)Cure 242Day 28 27 (11%)Failure 74Improvement 139 Cure [85,93]213 (89%) Success 240 Day 10 247Number of Patients 95% CI 1 [%] Azithromycin (%) 1 95% CI for azithromycin

68. 68 Study 1015 Clinical Outcome at Day 28 by Age 1117Failure [84, 94]89142Cure 159> 2 years of age 2319Failure [67, 87]7764Cure 83< 2 years of age 95% CI [%](%)N Azithromycin

69. 69 Study 1015 Clinical Outcome - Per Baseline Pathogen Day 10 Cure + ImprovementN Day 28 CureN Overall86%12281%124 S. pneumoniae92%7688%76 H. influenzae71%4264%44 M. catarrhalis100%10100%10

70. 70 Study 1015 MIC Distribution for S. pneumoniae (N=67) Percent of Patients Azithromycin MIC (  g/ml)

71. 71 Study 1015 Resistant 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

72. 72 Study 1015 Day 28 Outcome and MIC Distribution for S. pneumoniae (N=66) # of Patients Azithromycin MIC (  g/ml)

73. 73 Study 1015 Patient 0067 Failed Therapy 1 Susceptible to clindamycin; mef A gene identified 2 Resistant to clindamycin; erm B gene identified Left EarRight Ear ReflectometryCultureReflectometryCulture Baseline4H. influenzae, S. pneumoniae 1 MIC = 8  g/ml 2No Tap Day 43No Tap3S. pneumoniae 2 MIC > 256  g/ml Day 1034 Day 1931

74. 74 Study 1015 Strains From Patient 0067 Are Clonally Distinct 1 2 3 4 LaneSample 1,4MW markers 20067 (left ear) 30067 (right ear) MIC = 8MIC >256

75. 75 Study 1015 Outcome of S. pneumoniae AOM by Penicillin Susceptibility Penicillin Susceptibility *Penicillin MIC > 2  g/ml **Penicillin MIC > 0.125 - < 2  g/ml Intermediate** Resistant*Susceptible Cure12 (75%)6 (67%)38 (95%) Failure432

76. 76 Study 1015 Outcome of S. pneumoniae AOM by Penicillin Susceptibility Penicillin Susceptibility *Penicillin MIC > 2  g/ml **Penicillin MIC > 0.125 - < 2  g/ml Penicillin Resistant Isolates by Macrolide Susceptibility Resistant Susceptible 8  g/ml> 256  g/ml Cure31 2 Failure00 3 Intermediate** Resistant*Susceptible Cure12 (75%)6 (67%)38 (95%) Failure432

77. 77 Study 1015 Treatment Related Adverse Events* (2)4 Abdominal Pain (6)14 Vomiting (3)8 Diarrhea (12)30Patients w/ AEs (0)1Discontinued due to AEs 248Patients Treated (%)N * Adverse Events greater than 1%

78. 78 Study 1014 Three Day Dosing

79. 79 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

80. 80 Study 1014 Inclusion Criteria: Symptoms Symptoms consistent with AOM (but nonspecific) 2 Symptoms which help confirm the diagnosis of AOM (%) Age 26 1 XFever 1 Children had one or more of these signs and symptoms 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) XIrritability 25 1 XDecreased hearing 60 1 X Ear fullness 92 1 X Ear pain (tugging or rubbing) 0.5-11yrs X>6 months 1014 1998 FDA Guidance Either Ear pain or fullness 97

81. 81 Study 1014 Inclusion Criteria: Signs of Tympanic Membrane Involvement FDA1014 Findings most consistent with AOM Decreased/Absent TM MobilityX2X2 86 1,2 Full/Bulging TMX91 1 Marked TM RednessX96 1 Loss of landmarksX95 1 Loss of light reflex- 91 1 Abnormal tympanometryXX Electroacoustic ReflectometryXX Acoustic Gradient Angle < 7098 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level

82. 82 Study 1014 Key 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 FDA1014 Recent antibiotic useXX Tympanostomy tubes presentXX Otitis externaX(0%) Chronic OMX Perforated eardrum (chronic)X HypersensitivityX Significant medical conditionsX

83. 83 Study 1014 Visits and Assessments TimingData Day 1BaselineHistory, Physical, and 1 st Dose* Day 3-5 TelephoneAEs, Compliance Day 10 End of TherapyAEs, Clinical Response Day 24-28Test of CureAEs, Clinical Response *Patients who vomited within 30 minutes were redosed

84. 84 Study 1014 Statistical Methods  Primary Endpoint: Clinical Cure  Primary Timepoint: Day 28  Cure  Failure

85. 85 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

86. 86 Study 1014 Definition of Cure StudyDefinition of Cure 1014Complete resolution of specific signs/symptoms of acute otitis media. Persistence of middle ear effusion was not a factor.

87. 87 Study 1014 Patient Disposition AzithromycinAmoxicillin/Clavulanate Evaluation Groups Randomized188185 Safety188185 Efficacy at Day 28 Clinical182180

88. 88 Study 1014 Demographics Azithromycin N = 188 Amoxicillin/Clavulanate N = 185 Age: < 2 Yrs61 (32%)53 (29%) 2 Yrs - 12 Yrs 127 (68%)132 (71%) Mean Age (Yrs, ±SD)3.5 (+ 2.6)3.4 (+ 2.4) % Male51%49% Race: White 83%80% Black 6%5% Hispanic 8%9%

89. 89 Study 1014 Results Demographics Azithromycin N=188 Amox/Clav N=185 Duration Since First Symptoms1.2 days Range0 - 9 days0 - 8 days History of AOM153 (82%)158 (85%) Number of Episodes of AOM in Last Year1.21.4 Concomitant Drug Use During Study Analgesic Use94 (50%) 96 (52%) Symptomatic Drugs for RTI 77 (41%)70 (38%)

90. 90 Study 1014 Clinical Outcome 56 (31)48 (26)Failure [-5, 15]124 (69)134 (74)Cure 180182Day 28 22 (12)32 (17)Failure 4553Improvement 114100 Cure [-13,3]159 (88)153 (83) Success 181185 Day 10 185188Number of Patients 95% CI 1 [%] Amox/Clav (%) Azithromycin (%) 1 95% CI for (azithromycin – comparator)

91. 91 Study 1014 Clinical Outcome at Day 28 by Age [-5, 18](73)94(80)99Cure 128124> 2 years of age [-18, 23](58)30(60)35Cure 5258< 2 years of age (%)N N Amox/ClavAzithromycin 1 95% CI for (azithromycin – comparator) Failure (27)34(20)25 (42)22(40)23 95% CI 1 [%]

92. 92 Study 1014 Compliance Based on patients randomized to their study drug regimen AzithromycinAmoxicillin/ Clavulanate P- value 99%89%<0.001

93. 93 Study 1014 Treatment Related Adverse Events* (15) (20) AzithromycinAmox/Clav Patients Treated Discontinued due to AE Patients with AE Diarrhea Vomiting Rash 1 20 11 4 0 2 37 27 2 8 NN (1) (11) (6) (2) (0) (4) (1) % 188185 * Adverse events greater than 2% in either treatment regimen

94. 94 Summary of Clinical Data

95. 95 Acute Otitis Media Summary Clinical Cure at Day 28 [-5, 25] [-15, 17] 49/64 (77%)56/65 (86%)51/66 (77%) 95-001 AzSD-CTX Az3D-CTX [-5, 15] 124/180 (69%)134/182 (74%) 1014 Az-Amox/Clav 206/242 (85%) 1015 [-7, 15] 108/154 (70%)112/151 (74%) R-0581 Az-Amox/Clav 95% CIComparator Azithromycin Single Dose Azithromycin 3 DayStudy

96. 96 Effect of Age on Clinical Outcome < 2 years of age StudyDay 14*Day 28** AzithromycinComparatorAzithromycinComparator 101445/60 (75%)44/52 (85%)35/58 (60%)30/52 (58%) R058153/68 (78%)45/56 (80%)40/64 (63%)27/53 (51%) 95-00123/25 (92%) 1 30/31 (97%)19/25 (76%) 1 23/33 (70%) 101569/82 (84%)64/83 (77%) *Clinical success; **Clinical cure; 1 Single dose regimen

97. 97 Summary of Clinical Trials Clinical Cure by Baseline Pathogen at Day 28 Azithromycin Three Day Azithromycin Single DoseComparator Study 1015 S. pneumoniae67/76 (88%)N/A H. influenzae28/44 (64%) M. catarrhalis10/10 (100%) Study 95-001 S. pneumoniae16/17 (94%)17/20 (85%)19/23 (83%) H. influenzae9/13 (69%)7/88/9 M. catarrhalis2/20/0

98. 98 Treatment Related Adverse Events Azithromycin Regimens for AOM Vs. Comparator* 13 (1%) 1 (<1%)7 (1%)Abdominal pain 11 (1%)4 (2%)24 (5%)Vomiting 31 (3%)14 (6%)21 (4%)Diarrhea Patients with common AE’s: 69 (8%)26 (10%) 66 (14%) Patients with Related Adverse Events 888254487Number of Patients 531 Azithromycin Duration (Days) Comparator 23 (2%) 41 (4%) 171 (16%) 254 (23%) 1105 *Pivotal studies from 1, 3 and 5 day programs; All AE’s > 2 % 5 (1%) 0 (0%) 6 (1%)Nausea 18 (2%) 6 (1%) 0 (0%) 4 (1%)Rash 27 (2%)

99. 99 254 (23%) Treatment Related Adverse Events Azithromycin Regimens for AOM Vs. Comparator* 69 (8%)26 (10%) 66 (14%) Patients with Related Adverse Events 888254487Number of Patients 531 Azithromycin Duration (Days) Comparator 1105 *Pivotal studies from 1, 3 and 5 day programs 6.77.49.822.7 Related Adverse Events/Patient Year

100. 100 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

101. 101 Focus on Selected Topics  Vomiting of the single dose therapy  Historical comparison of cure rates at day 28  Timing of the clinical assessment

102. 102 The Influence of Vomiting on Outcome of Single Dose Therapy

103. 103 Patients Who Vomited Single Dose Therapy Clinical Outcome for Children Who Vomited on Day 1 22Missing 79 (19%)5 (15%)3 (9%)Fail 345 (81%)29 (85%)31 (91%)Cure/Improved No Vomiting Day 28Day 14 36/487 (7.4%)On the first day 52/487 (10.7%)Total Vomited No Vomiting 47 (11%) 383 (89%)

104. 104 Azithromycin AUC Values Following 2g and 3g Single Doses * AUC(0-24); ** AUC(0-infinity); ***AUC(0-288) AUC (  g·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) Individual values for subjects who vomited >2 hours post-dose

105. 105 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

106. 106 Azithromycin Vs Beta-lactams Comparative Trials for AOM: Clinical Cure at Day 28 Favors ComparatorFavors Azithromycin % Difference (95% CI) Azithromycin vs Amox/Clav (N=1864) Rodriquez, 1996 (Cefaclor) Pestalozza, 1992 (Amox/Clav) Pfizer, 134 (Amox/Clav) Pfizer, 128 (Amox/Clav) Dagan, 2000 (Amox/Clav) Pfizer, 178 (Amox/Clav) All Studies ( N=2127) Pfizer, 1014 (Amox/Clav) Pfizer, R-0581 (Amox/Clav) Azithromycin 5 Day Azithromycin 3 Day Azithromycin 1 Day Overall Pfizer, 95-001 (Ceftriaxone)

107. 107 S. pneumoniae Clinical Outcome Test of Cure Visit (Day 17-35)* % Successful Clinical Outcome, (95% CI) Cefdinir 5 Day Amox/Clav (Augmentin ES) Azithromycin – 5 Day Azithromycin – 1 Day* Azithromycin – 3 Day* Ceftriaxone Cefpodoxime proxetil Cefprozil Clinical Cure Clinical Success Cefdinir 10 Day *Product labels (PDR, 2001); Summary basis of approval; Sponsor study report

108. 108 H. influenzae Clinical Outcome Test of Cure Visit (Day 17-35)* % Successful Clinical Outcome (95% CI) Cefixime Amox/Clav (Augmentin ES) Ceftriaxone Cefpodoxime proxetil Azithromycin 3 Day Azithromycin 5 Day Azithromycin Single Dose Cefprozil Cefdinir 5 Day Clinical Success Clinical Cure *Product labels (PDR, 2001); Summary basis of approval; Sponsor study report Cefdinir 10 Day

109. 109 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

110. 110 Time to Additional 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 Proportion without Additional Antibiotic Day of First Antibiotic Use

111. 111 Percent Patients on Analgesics/Antipyretics By Study Day – R-0581 Days Percentage

112. 112 Percent Patients on Analgesics/Antipyretics By Study Day – 1014 Percentage Days

113. 113 Study R-0581 Parental Questionnaire How Sick Overall Has Child Been? Extremely Not at all Moderately

114. 114 Timing of Clinical Assessment Early time points Day 10-14 Overall clinical response vs beta-lactams Clinical outcome with H. influenzae at baseline

115. 115 Azithromycin Vs Beta-lactams Comparative Trials for AOM: Clinical Success at Day 14 Favors ComparatorFavors Azithromycin % Difference (95% CI) Azithromycin 5 Day Azithromycin vs Amox/Clav (N=3271) All Studies (N=3956) Rodriguez, 1996 (Cefaclor) Dagan, 2000 (Cefaclor) Mohs, 1993 (Amoxicillin) Arguedas, 1996 (Amox/Clav) Pfizer, 178 (Amox/Clav) Pfizer, 134 (Amox/Clav) Daniel, 1993 (Amox/Clav) Principi, 1995 (Amox/Clav) Schaad 1993 (Amox/Clav) Pfizer, 128 (Amox/Clav) Dagan, 2000 (Amox/Clav) Pestalozza, 1992 (Amox/Clav) Pfizer, 1014 (Amox/Clav) Pfizer, R-0581 (Amox/Clav) Azithromycin 3 Day Azithromycin 1 Day Overall Pfizer, 95-001 (Ceftriaxone)

116. 116 Timing of Clinical Assessment Early time points Day 10-14 Overall clinical response vs beta-lactams Clinical outcome with H. influenzae at baseline

117. 117 H. influenzae Clinical Outcome End of Therapy (Day 7-15)* % Clinical Success (95% CI) Azithromycin 1 Day Overall Erythromycin + sulfa Cefaclor Ceftibuten Clarithromycin Erythromycin Cefuroxime axetil Azithromycin 3 Day Clinical Success Cefpodoxime proxetil Ceftriaxone (Per Protocol) Amox/Clav (Per Protocol) Cefixime Amox/Clav (ITT) Azithromycin 5 Day Loracarbef Clinical Cure *Product labels (PDR, 2001); Summary basis of approval; Sponsor study report

118. 118 Azithromycin for Acute Otitis Media  Chemistry/Pharmacokinetics  Microbiology  Clinical Data  Conclusion

119. 119 Conclusions Azithromycin 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