**FDA Briefing Package:**

**Zithromax (Azithromycin) Oral Suspension**

**Single-Dose and Three-Day Treatment of Acute Otitis Media**

Anti-Infective Drugs Advisory Committee

November 7, 2001

**Table of Contents**

List of Abbreviations [3](#list-of-abbreviations)

Glossary of Terms [4](#glossary-of-terms)

Background [5](#background)

Microbiology [6](#microbiology)

Clinical Pharmacology and Biopharmaceutics
[8](#clinical-pharmacology-and-biopharmaceutics)

Study A0661014: Clinical-Only Study of Azi Three-Day Treatment
[10](#study-a0661014-clinical-only-study-of-azi-three-day-treatment)

Study R-0581: Clinical-Only Study of Azi One-Day Treatment
[12](#study-r-0581-clinical-only-study-of-azi-one-day-treatment)

Study A0661015: Single-Tap Study of Azi One-Day Treatment
[14](#study-a0661015-single-tap-study-of-azi-one-day-treatment)

Study AZM-NY-95-001: Supportive Single-Tap Study
[16](#study-azm-ny-95-001-supportive-single-tap-study)

Efficacy [17](#efficacy)

Safety [18](#safety)

Current AOM Guidance [20](#current-aom-guidance)

References [21](#references)

# List of Abbreviations

AE -- Adverse Event

Amox/Clav -- Amoxicillin and Clavulanic Acid

AOM -- Acute Otitis Media

AUC~0-~ -- Area under the Serum Concentration-Time Curve

AUC~0-24~ -- Area under the Serum Concentration-Time Curve for 24 Hours

Azi -- Azithromycin

CFTX -- Ceftriaxone

EOT -- End-of-Therapy Visit

IM -- Intramuscular

MIC -- Minimum Inhibitory Concentration

MITT -- Modified Intent-to-Treat Population

TM -- Tympanic Membrane

TOC -- Test-of-Cure Visit

# Glossary of Terms

The following definitions are provided as terms that identify consistent
features of particular study designs used in AOM trials. These terms
will be used in this briefing package and during the advisory committee
meeting for consistency and for ease of reference to particular designs.

[Clinical-Only Study]{.underline} -- A comparative study of antibiotics
for the treatment of AOM that does not include the use of
tympanocentesis. Subjects are enrolled in the study based on the
presence of clinical signs and symptoms of AOM. Outcome is based on
resolution or improvement of clinical signs and symptoms at time points
following completion of antimicrobial treatment. The objective of this
study is to demonstrate similar clinical outcomes for a test drug and
comparator at a defined time point.

Microbiologic studies include tympanocentesis for isolation of bacterial
pathogens from middle ear fluid. These studies fall into two categories:

[Single-Tap Study]{.underline} -- A study, often non-comparative, in
which tympanocentesis is performed at study entry. Subjects are enrolled
based on clinical signs and symptoms, and tympanocentesis is performed
to identify patients with bacterial pathogens. Outcome is based on
resolution or improvement of clinical signs and symptoms at time points
following completion of antibiotic treatment, similar to clinical only
studies. The objective of the study is to demonstrate favorable clinical
outcomes in subjects with pathogens identified by tympanocentesis at
study entry.

[Double-Tap Study]{.underline} -- A study in which tympanocentesis is
performed at study entry and during therapy. Subjects are enrolled based
on clinical signs and symptoms, and tympanocentesis is performed to
identify patients with bacterial pathogens. Outcome is based on
eradication of pathogens from a second tympanocentesis performed within
a few days (typically 3-6) after study entry. Clinical outcome at later
visits may also be assessed. The objective of the study is to
demonstrate favorable rates of bacterial eradication in subjects with
pathogens identified by tympanocentesis at study entry.

# Background

Zithromax (azithromycin) has been approved in the United States with a
5-day dosing regimen for the treatment of a number of infectious
diseases, including acute exacerbation of chronic bronchitis,
pharyngitis/tonsillitis, community-acquired pneumonia, and uncomplicated
skin and skin structure infections in adults, as well as acute otitis
media and pharyngitis/tonsillitis in children. In adults, the
recommended total dose of azithromycin administered over 5 days is 1,500
mg (500 mg on day 1 and 250 mg on days 2-5). In children, the
recommended total dose of azithromycin administered over the 5 days is
30 mg/kg (10mg/kg on day 1 and 5 mg/kg on days 2-5) to treat acute
otitis media. This will be referred to as the five-day regimen
throughout this document. These approvals were based on data
demonstrating the safety and effectiveness of azithromycin compared with
standard regimens approved for the treatment of these conditions. The
studies supporting use of this five-day regimen for treatment of AOM are
described in the clinical studies section of the label for Zithromax
oral suspension. Excerpted information from the label is provided as
Reference 1.

The application under review seeks to shorten the duration of treatment
for AOM. The same total dose of azithromycin (30 mg/kg) given in the
five-day regimen is proposed to be given in one or three days. In the
one-day treatment regimen, a single dose of 30 mg/kg of azithromycin is
given. The three-day treatment regimen gives 10 mg/kg of azithromycin
once daily for three days. Pfizer, Inc. has submitted the following
pivotal studies for approval of the one-day and three-day treatment
regimens.

**Pivotal Studies for this Application**

+--------------+------------+--------------+-------------+------------+
| **Otitis     | **Design** | **Azi Dose** | **Azi       | **Com      |
| Media        |            |              | Duration**  | parators** |
| Studies**    |            |              |             |            |
+--------------+------------+--------------+-------------+------------+
| A0661014     | Clin       | 10 mg/kg     | 3 days      | Amox/Clav  |
|              | ical-Only, |              |             |            |
|              |            |              |             | (A         |
|              | Do         |              |             | ugmentin®) |
|              | uble-Blind |              |             |            |
+--------------+------------+--------------+-------------+------------+
| R-0581       | Clin       | 30 mg/kg     | Single Dose | Amox/clav  |
|              | ical-Only, |              |             |            |
|              |            |              |             |            |
|              | Do         |              |             |            |
|              | uble-Blind |              |             |            |
+--------------+------------+--------------+-------------+------------+
| A0661015     | S          | 30 mg/kg     | Single Dose | None       |
|              | ingle-Tap, |              |             |            |
|              |            |              |             |            |
|              | Open-label |              |             |            |
+--------------+------------+--------------+-------------+------------+

Additional supportive evidence from a single-tap study (AZM-NY-95-001)
performed at a single center in Costa Rica was submitted. This study
compared the one-day and three-day regimens to ceftriaxone for treatment
of AOM.

# Microbiology

The class of antimicrobials known as the macrolides includes
azithromycin, erythromycin, clarithromycin, and dirithromycin.
Azithromycin is a member of the azalide subclass of macrolides and is
proposed for treatment of acute otitis media caused by *Streptococcus
pneumoniae, Moraxella catarrhalis,* and *Haemophilus influenzae*. The
microbiological information of interest is the spectrum of azithromycin
versus these potential pathogens, and the mechanisms of resistance
mediated by these pathogens that may affect efficacy.

### In vitro spectrum of activity

The table on the following page provides a brief summary representing
the in vitro susceptibility of *Streptococcus pneumoniae, Moraxella
catarrhalis,* and *Haemophilus influenzae* to azithromycin. The *S.
pneumoniae* susceptibility profile represents isolates from U. S.
medical centers from 1996-1997 and 1999-2000. These and other
surveillance studies suggest that susceptibility and resistance profiles
for these agents of the macrolide class are virtually identical to each
other and justify the use of erythromycin susceptibility testing for
other members of this class. These surveillance studies, performed at
sequential intervals of time, also show that macrolide, and thus
azithromycin resistance is increasing, especially in the penicillin
intermediate and resistant strains. Surveillance studies also
demonstrate that erythromycin resistant rates vary from 6.1% to 53.7% in
participating medical centers and that approximately 25% of the *S.
pneumoniae* are resistant to macrolides.^1^

At least 8 U. S. surveillance studies for *Haemophilus influenzae* and 4
for *Moraxella catarrhalis* have been performed in the last 15 years.
The results of current studies of community acquired respiratory tract
isolates^3^ and isolates from outpatient clinics^4^ are presented in
Table 1 and clearly show that greater than 90 percent of the isolates
examined remain susceptible to azithromycin at the current breakpoint.
Less than 0.3 percent of the *Haemophilus influenzae* isolates have been
shown to be resistant to azithromycin.

**Mechanisms of Action**

Azithromycin acts by binding reversibly to the 23S rRNA component of the
50S ribosomal subunit of susceptible microorganisms, thereby blocking
the translocation reaction of polypeptide chain elongation.

### Mechanisms of Resistance

Point mutation or modification (methylation) of the target site
resulting in reduced affinity of the drug to the target mediates
resistance to macrolides in clinical pathogens. Resistance is also
mediated by decreased permeability (efflux) resulting in decreased drug
concentration. Finally, it may be due to modification of the
antimicrobial (esterases, acetyltransferase, and phosphotransferase)
resulting in inactivation of the macrolide. Of these resistant
mechanisms, modification of the target site, 23S ribosomal RNA, by
methylation ([e]{.underline}rythromycin [r]{.underline}esistance
[m]{.underline}ethylase, *erm*) and efflux (*mef(A*[)]{.underline}) are
found in the pathogens of interest.

The two predominant macrolide resistance mechanisms in *S. pneumoniae*
are expression of the *mef(A)* and *erm*(B) genes. In the U.S. the
predominant resistant determinant appears to be *mef(A)*, accounting for
\~66.5% macrolide resistance. Generally, strains with *mef(A)* have
erythromycin (EM) MICs of 1-32 g/mL and clindamycin (CM) MICs 0.125
g/mL. Strains with *erm*(B) determinants usually have EM MICs 64 g/mL
and CM MICs 8.0 g/mL.

Some *Haemophilus influenzae* and other gram-negative species have
innate resistance to macrolides, thought to be mediated by the broad
specificity efflux pump AcrAB-TolC. As seen from Table 1, the
*Haemophilus influenzae* MIC~90~ is 2.0 g/mL and shows that a majority
of the strains are below the susceptible breakpoint of 4 g/mL.

Azithromycin in vitro spectrum of activity for select pathogens

+-------------------+---------+---------------+--------+--------+-----+
| Pathogen          | \#      | MIC range     | M      | M      | Ref |
|                   | strains |               | IC~50~ | IC~90~ |     |
+-------------------+---------+---------------+--------+--------+-----+
| *S. pneumoniae*   | 1531    | 0.03 - \>64   | 0.12   | 16.0   | [   |
|                   |         |               |        |        | ^1] |
| PEN ^S^           | 1008    | 0.03 - \>64   | 0.12   | 0.25   |     |
|                   |         |               |        |        |     |
| PEN ^I^           | 194     | 0.03 - \>64   | 0.25   | \>64   |     |
|                   |         |               |        |        |     |
| PEN ^R^           | 329     | 0.06 - \>64   | 8.0    | \>64   |     |
|                   |         |               |        |        |     |
| EM                | 1531    | 0.06 - \>64   | 0.06   | 8.0    |     |
+-------------------+---------+---------------+--------+--------+-----+
| *S. pneumoniae*   | \-\-\-- | \-\-\--       | \      | \      | [   |
|                   |         |               | -\-\-- | -\-\-- | ^2] |
| PEN ^S^           | 2849    | 0.125 - 64    |        |        |     |
|                   |         |               | 0.125  | 0.125  |     |
| PEN ^I^           | 1059    | 0.125 - 64    |        |        |     |
|                   |         |               | 0.125  | 4.0    |     |
| PEN ^R^           | 581     | 0.125 - 64    |        |        |     |
|                   |         |               | 1.0    | 64     |     |
+-------------------+---------+---------------+--------+--------+-----+
| *H. influenzae*   | 1077    | 0.125 - \>16  | 2.0    | 2.0    | [   |
|                   |         |               |        |        | ^3] |
|                   | 1032    | 0.03 - 16     | 1.0    | 2.0    |     |
|                   |         |               |        |        | [   |
|                   |         |               |        |        | ^4] |
+-------------------+---------+---------------+--------+--------+-----+
| *M. catarrhalis*  | 503     | 0.125 - 0.25  | 0.125  | 0.125  | 3   |
|                   |         |               |        |        |     |
|                   | 444     | 0.03 - \>64   | 0.06   | 0.12   | 4   |
+-------------------+---------+---------------+--------+--------+-----+

# Clinical Pharmacology and Biopharmaceutics 

The pharmacokinetic parameter that appears to be most predictive of
azithromycin efficacy is the ratio of the area under the serum
concentration-time curve (AUC~0-~) to the organism\'s minimal inhibitory
concentration (MIC), the AUC~0-~/MIC ratio. The concept of accelerated
dosing assumes that the pharmacokinetics of azithromycin are linear
across the proposed dosing range, resulting in a similar exposure
(AUC~0-~) and AUC~0-~/MIC by administering the same total dose.

**Pharmacokinetics in pediatric subjects:**

The pharmacokinetics of azithromycin following the administration of 20
mg/kg/day 3 days, 12 mg/kg/day 5 days, and 10 mg/kg/day 3 days were
evaluated in pediatric subjects with pharyngitis/tonsillitis or other
bacterial infections. The studies were non-comparative and the 1-day
regimen (30 mg/kg) was not evaluated. Blood samples were collected for
only 24 hours following the last dose. Thus, the area under the serum
concentration-time curve for 24 hrs (AUC~0-24~) following the last dose
is the only measure of exposure that can be assessed. The AUC ~0-24~
following the last dose were 3.93, 7.92, and 2.35 g\*hr/mL for 20
mg/kg/day, 12 mg/kg/day, and 10 mg/kg/day, respectively. Since the
half-life of azithromycin is approximately 68 hours, accumulation is
still occurring at day 3 and day 5. After correction for the
administered dose, the results demonstrate that the exposure from the
3-day regimen ranged from 28% less to 21% greater than the 5-day
regimen. Although the AUC~0-24~ is similar among the regimens, the
reviewer is unable to conclude that the overall exposure (AUC~0-~) from
3-day and 5-day regimens is similar since the studies were not designed
to provide this information.

**Pharmacokinetics in adult subjects (3-day vs. 5-day):**

The pharmacokinetics of azithromycin following the administration of 500
mg/day 3 days vs. 500 mg on day 1 followed by 250 mg 4 days were
evaluated in three comparative studies with healthy adult subjects
(066-087, AZM-NY-90-011, and AZM-F-93-004). The data from AZM-NY-90-011
were excluded from the analysis since the accuracy of the analytical
methods was outside of the 15% acceptable range. Limited blood samples
were obtained from study 066-087, excluding the first and last dosing
interval, and introduced uncertainty in the results from the
non-parametric analysis. Thus, the raw data from study 066-087 were fit
to a 3-compartment, oral absorption model using Win Nonlin (version
3.1). The AUC~0-~ from the 3-day regimen was compared to the 5-day
regimen of each study using a geometric mean ratio (GMR, 3-day/5-day)
and 90% confidence interval. The GMR (90% confidence interval) for study
AZM-F-93-004 was 0.933 (0.798 to 1.092). Thus, the AUC~0-~ from the
3-day and 5-day regimens was similar. The GMR for study 066-087 using
observed and simulated concentrations was 1.185 and 1.118, respectively.
The 90% confidence interval exceeded 1.25 in both instances. The two
studies support that the AUC~0-~ associated with a 3-day regimen is
similar to a 5-day regimen.

**Pharmacokinetics in adult subjects (1-day vs. 3-day):**

The pharmacokinetics of azithromycin following the administration of
1,500 mg as a single dose vs. 500 mg/day 3 days were evaluated in a
comparative study with healthy adult subjects (GA2000). The analytical
methods in this study had a lower limit of quantitation (LLOQ)
approximately 5-fold greater than previous studies, resulting in
azithromycin concentrations below the LLOQ within 48 hours in the
majority subjects following a single dose and by the end of each dosing
interval in most subjects for the 3-day regimen. Using the data
provided, the AUC~0-~ GMR (90% confidence interval) was 1.235 (0.935 to
1.632) and the sponsor concluded that the exposure from the two regimens
was similar. However, the sponsor used azithromycin concentrations below
the LLOQ to estimate the terminal elimination rate constant and AUC~0-~
in both regimens. The reviewer estimated the AUC~0-t~ using
concentrations above the LLOQ. The AUC~0-t~ GMR was 0.829 but included
data from only five subjects. Since the exposure from the 1-day regimen
may be less than the 3-day regimen, the reviewer is unable to state that
the overall exposure is similar between the two regimens.

**Pharmacokinetics in adult subjects (1-day vs. 5-day):**

The sponsor did not conduct a study comparing the AUC~0-~ resulting from
1,500 mg as a single dose vs. 500 mg on day 1 followed by 250 mg/day 4
days.

# Study A0661014: Clinical-Only Study of Azi Three-Day Treatment

**vs. Amox/Clav for AOM**

Study A0661014 was a double-blind, multicenter, randomized trial
comparing 10 mg/kg daily dose of azithromycin for 3 days with a ten-day
course of amox/clav (45 mg/kg/day given BID) in the treatment of AOM in
children ages 6 months to 12 years. This was a clinical-only study with
enrollment of 373 patients from 28 U. S. study sites.

The following table shows the clinical outcomes for the MITT and per
protocol populations as reported by the applicant. Outcomes are reported
for end of therapy (Study day 8 to 12) and test of cure (Study day 20 to
32) visits.

Study A0661014: Clinical Outcomes

+--------------------+---------------+---------------+---------------+
|                    | **A           | **Amox/Clav** | **95%         |
|                    | zithromycin** |               | Confidence    |
|                    |               | **N (%)**     | Interval of   |
|                    | **N (%)**     |               | Difference**  |
+--------------------+---------------+---------------+---------------+
| #                  |               |               |               |
| ## MITT Population |               |               |               |
+--------------------+---------------+---------------+---------------+
| Patients evaluable | 185 (100)     | 181 (100)     | -12.9, 2.7    |
| at EOT             |               |               |               |
|                    | 153 (83)      | 159 (88)      |               |
| Success (Cured or  |               |               |               |
| Improved)          | 32 (17)       | 22 (12)       |               |
|                    |               |               |               |
| Failure            |               |               |               |
+--------------------+---------------+---------------+---------------+
| Patients evaluable | 182 (100)     | 180 (100)     | \- 5.2, 14.6  |
| at TOC             |               |               |               |
|                    | 134 (74)      | 124 (69)      |               |
| Cure               |               |               |               |
|                    | 48 (26)       | 56 (31)       |               |
| Failure            |               |               |               |
+--------------------+---------------+---------------+---------------+
| ### Per P          |               |               |               |
| rotocol Population |               |               |               |
+--------------------+---------------+---------------+---------------+
| Patients evaluable | 166 (100)     | 151 (100)     | -13.6, 4.2    |
| at EOT             |               |               |               |
|                    | 134 (81)      | 129 (85)      |               |
| Success (Cured or  |               |               |               |
| Improved)          | 32 (19)       | 22 (15)       |               |
|                    |               |               |               |
| Failure            |               |               |               |
+--------------------+---------------+---------------+---------------+
| Patients evaluable | 179 (100)     | 175 (100)     | \- 5.4, 14.7  |
| at TOC             |               |               |               |
|                    | 131 (73)      | 120 (69)      |               |
| Cure               |               |               |               |
|                    | 48 (27)       | 55 (31)       |               |
| Failure            |               |               |               |
+--------------------+---------------+---------------+---------------+
| EOT = Day 8 -- 12; |               |               |               |
| TOC = Day 20 -- 32 |               |               |               |
+--------------------+---------------+---------------+---------------+

The results of this clinical study support the conclusion that 10
mg/kg/day for 3 days of azithromycin has similar effectiveness to a
ten-day course of amoxicillin/clavulanate in the treatment of AOM. The
end of therapy and test of cure analyses of the per protocol population
support those of the MITT population.

In this study, 114 (31%) of the treated patients were 1 month to 2 years
of age, and 259 (69%) were \>2 years of age. The following table shows
the clinical outcomes by age for the MITT population.

Study A0661014: Clinical Outcomes by Age (MITT Population)

+--------------------+---------------+---------------+---------------+
|                    | **A           | **Amox/Clav** | **95%         |
|                    | zithromycin** |               | Confidence    |
|                    |               | **N (%)**     | Interval of   |
|                    | **N (%)**     |               | Difference**  |
+--------------------+---------------+---------------+---------------+
| #### Age 2 years   |               |               |               |
+--------------------+---------------+---------------+---------------+
| Patients evaluable | 60 (100)      | 52 (100)      | -26.2, 7.0    |
| at EOT             |               |               |               |
|                    | 45 (75)       | 44 (85)       |               |
| Success (Cured or  |               |               |               |
| Improved)          | 15 (25)       | 8 (15)        |               |
|                    |               |               |               |
| Failure            |               |               |               |
+--------------------+---------------+---------------+---------------+
| Patients evaluable | 58 (100)      | 52 (100)      | -17.7, 23.1   |
| at TOC             |               |               |               |
|                    | 35 (60)       | 30 (58)       |               |
| Cure               |               |               |               |
|                    | 23 (40)       | 22 (42)       |               |
| Failure            |               |               |               |
+--------------------+---------------+---------------+---------------+
| #### Age \>2 years |               |               |               |
+--------------------+---------------+---------------+---------------+
| Patients evaluable | 127 (100)     | 129 (100)     | -13.1, 4.9    |
| at EOT             |               |               |               |
|                    | 108 (85)      | 115 (89)      |               |
| Success (Cured or  |               |               |               |
| Improved)          | 19 (15)       | 14 (11)       |               |
|                    |               |               |               |
| Failure            |               |               |               |
+--------------------+---------------+---------------+---------------+
| Patients evaluable | 124 (100)     | 128 (100)     | -4.8, 17.6    |
| at TOC             |               |               |               |
|                    | 99 (80)       | 94 (73)       |               |
| Cure               |               |               |               |
|                    | 25 (20)       | 34 (27)       |               |
| Failure            |               |               |               |
+--------------------+---------------+---------------+---------------+
| EOT = Day 8 -- 12; |               |               |               |
| TOC = Day 20 --32  |               |               |               |
+--------------------+---------------+---------------+---------------+

When outcomes were evaluated by patient age [\<]{.underline} 2 years or
\> 2 years, response rates between the treatment groups were similar.
For both drugs, children \> 2 years were more likely to have a
successful clinical response than were children [\<]{.underline} 2
years.

This clinical-only study of AOM includes an unknown proportion of
patients with sterile middle ear fluid. The results reported here must
be correlated with those from microbiologic studies using diagnostic
tympanocenteses.

AOM has a high spontaneous resolution rate, and the effect of
antimicrobial treatment is limited. Because there was no placebo group
in this study, the true effect of the study drugs is unknown.

# Study R-0581: Clinical-Only Study of Azi One-Day Treatment 

**vs. Amox/Clav for AOM**

Study R-0581 was a double-blind, double-dummy, multicenter, randomized
trial comparing a single 30 mg/kg dose of azithromycin with a ten day
course of amoxicillin/clavulanate (45 mg/kg/day given BID) in the
treatment of acute otitis media (AOM) in children 6 months to 12 years
of age. This was a clinical-only study with enrollment of 350 patients
(175 azithromycin, 175 amoxicillin/clavulanate) from nine U.S. study
sites.

The following table shows the clinical outcomes for the modified
intent-to-treat (MITT) and per protocol populations as reported by the
applicant. Outcomes are reported for end of therapy (Study day 12 to 16)
and test of cure (Study day 28 to 32) visits.

Study R-0581: Clinical Outcomes

+--------------------+---------------+---------------+--------------+---+
|                    | **A           | ###           | **95%        |   |
|                    | zithromycin** | ### Amox/Clav | Confidence   |   |
|                    |               |               | Interval of  |   |
|                    | **N (%)**     | **N (%)**     | Difference** |   |
+--------------------+---------------+---------------+--------------+---+
| ##                 |               |               |              |   |
| ## MITT Population |               |               |              |   |
+--------------------+---------------+---------------+--------------+---+
| Patients evaluable | 160 (100)     | 161 (100)     | -9.2, 6.5    |   |
| at EOT             |               |               |              |   |
|                    | 139 (87)      | 142 (88)      |              |   |
| Success (Cured or  |               |               |              |   |
| Improved)          | 21 (13)       | 19 (12)       |              |   |
|                    |               |               |              |   |
| Failure            |               |               |              |   |
+--------------------+---------------+---------------+--------------+---+
| Patients evaluable | 151 (100)     | 154 (100)     | -10.2, 10.5  |   |
| at TOC             |               |               |              |   |
|                    | 114 (75)      | 116 (75)      |              |   |
| Cure               |               |               |              |   |
|                    | 37 (25)       | 38 (25)       |              |   |
| Failure            |               |               |              |   |
+--------------------+---------------+---------------+--------------+---+
| #### Per P         |               |               |              |   |
| rotocol Population |               |               |              |   |
+--------------------+---------------+---------------+--------------+---+
| Patients evaluable | 147 (100)     | 148 (100)     | -9.2, 7.7    |   |
| at EOT             |               |               |              |   |
|                    | 127 (86)      | 129 (87)      |              |   |
| Success (Cured or  |               |               |              |   |
| Improved)          | 20 (14)       | 19 (13)       |              |   |
|                    |               |               |              |   |
| Failure            |               |               |              |   |
+--------------------+---------------+---------------+--------------+---+
| Patients evaluable | 144 (100)     | 142 (100)     | -11.8, 9.7   |   |
| at TOC             |               |               |              |   |
|                    | 107 (74)      | 107 (75)      |              |   |
| Cure               |               |               |              |   |
|                    | 37 (26)       | 35 (25)       |              |   |
| Failure            |               |               |              |   |
+--------------------+---------------+---------------+--------------+---+
| EOT = End of       |               |               |              |   |
| Therapy (Day 12 to |               |               |              |   |
| 16); TOC = Test of |               |               |              |   |
| Cure (Day 28 to    |               |               |              |   |
| 32)                |               |               |              |   |
+--------------------+---------------+---------------+--------------+---+

The results of this clinical study support the conclusion that a single
30 mg/kg dose of azithromycin has similar effectiveness to a ten day
course of amoxicillin/clavulanate in the treatment of AOM. The end of
therapy and test of cure analyses of the per protocol population support
those of the MITT population.

In this study, 138 (40%) of the treated patients were [\<]{.underline} 2
years of age, and 208 (60%) were \> 2 years of age. The following table
shows the clinical outcomes by age for the MITT population.

Study R-0581: Clinical Outcomes by Age (MITT Population)

+---------------------+---------------+---------------+---------------+
|                     | **A           | ###           | **95%         |
|                     | zithromycin** | ### Amox/Clav | Confidence    |
|                     |               |               | Interval of   |
|                     | **N (%)**     | **N (%)**     | Difference**  |
+---------------------+---------------+---------------+---------------+
| **Age               |               |               |               |
| [\<]{.underline} 2  |               |               |               |
| Years**             |               |               |               |
+---------------------+---------------+---------------+---------------+
| Patients evaluable  | 68 (100)      | 56 (100)      | -18, 13.7     |
| at EOT              |               |               |               |
|                     | 53 (78)       | 45 (80)       |               |
| Success (Cured or   |               |               |               |
| Improved)           | 15 (22)       | 11 (20)       |               |
|                     |               |               |               |
| Failure             |               |               |               |
+---------------------+---------------+---------------+---------------+
| Patients evaluable  | 64 (100)      | 53 (100)      | -12.2, 27.1   |
| at TOC              |               |               |               |
|                     | 41 (64)       | 30 (57)       |               |
| Cure                |               |               |               |
|                     | 23 (36)       | 23 (43)       |               |
| Failure             |               |               |               |
+---------------------+---------------+---------------+---------------+
| **Age \> 2 Years**  |               |               |               |
+---------------------+---------------+---------------+---------------+
| Patients evaluable  | 92 (100)      | 105 (100)     | -7.1, 9.3     |
| at EOT              |               |               |               |
|                     | 86 (93)       | 97 (92)       |               |
| Success (Cured or   |               |               |               |
| Improved)           | 6 (7)         | 8 (8)         |               |
|                     |               |               |               |
| Failure             |               |               |               |
+---------------------+---------------+---------------+---------------+
| Patients evaluable  | 87 (100)      | 101 (100)     | -12.7, 10.3   |
| at TOC              |               |               |               |
|                     | 73 (84)       | 86 (85)       |               |
| Cure                |               |               |               |
|                     | 14 (16)       | 15 (15)       |               |
| Failure             |               |               |               |
+---------------------+---------------+---------------+---------------+
| EOT=End of Therapy  |               |               |               |
| (Day 12 to 16);     |               |               |               |
| TOC=Test of Cure    |               |               |               |
| (Day 28 to 32)      |               |               |               |
+---------------------+---------------+---------------+---------------+

When outcomes were evaluated by patient age [\<]{.underline} 2 years or
\> 2 years, response rates between the treatment groups were similar.
For both drugs, children \> 2 years were more likely to have a
successful clinical response than were children [\<]{.underline} 2
years.

The same caveats noted with study A0661014 apply to this study. These
include the enrollment of patients with sterile middle ear fluid, the
need for correlation with microbiologic studies, the high spontaneous
resolution rate, and inability to compare outcomes directly to placebo
treatment.

# Study A0661015: Single-Tap Study of Azi One-Day Treatment 

**for AOM**

Study A0661015 was an open-label, non-comparative, multi-center trial of
AOM using a single 30 mg/kg dose of azithromycin in children 6 months to
12 years of age. The study design included tympanocentesis performed at
baseline to identify patients with bacterial AOM. Outcomes are based on
clinical assessments at specified time points. This study enrolled 248
patients from 22 U. S. and Latin American study sites.

The following table shows the clinical outcomes for the MITT and per
protocol populations as reported by the applicant. Outcomes are reported
for EOT (Study day 8 to 12) and TOC (Study day 20 to 32) visits.

Study A0661015: Clinical Outcomes

+-----------------------+-----------------------+-----------------------+
|                       | **Azithromycin**      | **95% Confidence      |
|                       |                       | Interval of Point     |
|                       | **N (%)**             | Estimate**            |
+-----------------------+-----------------------+-----------------------+
| #### MITT Population  |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Patients evaluable at | 240 (100)             | 84.5, 93.0            |
| EOT                   |                       |                       |
|                       | 213 (89)              |                       |
| > Success (Cured or   |                       |                       |
| > Improved)           | 27 (11)               |                       |
| >                     |                       |                       |
| > Failure             |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Patients evaluable at | 242 (100)             | 80.4, 89.8            |
| TOC                   |                       |                       |
|                       | 206 (85)              |                       |
| > Cure                |                       |                       |
| >                     | 39 (15)               |                       |
| > Failure             |                       |                       |
+-----------------------+-----------------------+-----------------------+
| #### Pe               |                       |                       |
| r Protocol Population |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Patients evaluable at | 215 (100)             | 83.9, 92.9            |
| EOT                   |                       |                       |
|                       | 190 (88)              |                       |
| > Success (Cured or   |                       |                       |
| > Improved)           | 25 (12)               |                       |
| >                     |                       |                       |
| > Failure             |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Patients evaluable at | 229 (100)             | 80.3, 90.0            |
| TOC                   |                       |                       |
|                       | 195 (85)              |                       |
| > Cure                |                       |                       |
| >                     | 34 (15)               |                       |
| > Failure             |                       |                       |
+-----------------------+-----------------------+-----------------------+
| EOT = Day 8 to 12;    |                       |                       |
| TOC = Day 20 to 32    |                       |                       |
+-----------------------+-----------------------+-----------------------+

Clinical outcomes in MITT patients with a pathogen identified at the
baseline visit are shown in the following table.

Study A0661015: Clinical Outcome by Baseline Pathogen (MITT Population)

+-------------+--------+--------+--------+--------+--------+--------+
| **EOT       | ***H.  |        | ***M.  |        | ***S.  |        |
| As          | influ  |        | catarr |        | pneum  |        |
| sessment:** | enzae* |        | halis* |        | oniae* |        |
|             | (N     |        | (N     |        | (N     |        |
|             | =42)** |        | =10)** |        | =76)** |        |
+-------------+--------+--------+--------+--------+--------+--------+
| Outcome     | N (%)  | 95% CI | N (%)  | 95% CI | N (%)  | 95% CI |
+-------------+--------+--------+--------+--------+--------+--------+
| Success     | 30 (   | 56.6,  | 10     | 95.0,  | 70     | 85.4,  |
|             | 71%)   | 86.3   | (100%) | 100    | (92%)  | 98.8   |
| Cure        |        |        |        |        |        |        |
|             | 18     |        | 5      |        | 49     |        |
| Improvement | (43%)  |        | (50%)  |        | (64%)  |        |
|             |        |        |        |        |        |        |
| Failure     | 12     |        | 5      |        | 21     |        |
|             | (29%)  |        | (50%)  |        | (28%)  |        |
|             |        |        |        |        |        |        |
|             | 12     |        | 0 (    |        | 6 (    |        |
|             | (29%)  |        | 0%)    |        | 8%)    |        |
+-------------+--------+--------+--------+--------+--------+--------+
| **TOC       | ***H.  |        | ***M.  |        | ***S.  |        |
| As          | influ  |        | catarr |        | pneum  |        |
| sessment:** | enzae* |        | halis* |        | oniae* |        |
|             | (N     |        | (N     |        | (N     |        |
|             | =44)** |        | =10)** |        | =76)** |        |
+-------------+--------+--------+--------+--------+--------+--------+
| Outcome     | N (%)  | 95% CI | N (%)  | 95% CI | N (%)  | 95% CI |
+-------------+--------+--------+--------+--------+--------+--------+
| #####  Cure | 28     | 48.3,  | 10     | 95.0,  | 67     | 80.2,  |
|             | (64%)  | 79.0   | (100%) | 100    | (88%)  | 96.1   |
| Failure     |        |        |        |        |        |        |
|             | 16     |        | 0 (    |        | 9      |        |
|             | (36%)  |        | 0%)    |        | (12%)  |        |
+-------------+--------+--------+--------+--------+--------+--------+

Of particular note, 12 of 76 (16%) *S. pneumoniae* isolates were
resistant to azithromycin. The clinical success rates at EOT and TOC
were 10/12 and 8/12, respectively.

This Single-Tap study demonstrates clinical cure rates at EOT roughly
similar to those for azithromycin-treated patients in the "Clinical
Only" studies. However, the success rates for patients with *H.
influenzae* identified by baseline tympanocentesis are lower than for
the overall population. These lower cure rates for patients with *H.
influenzae* at baseline are similar to cure rates for patients treated
with the approved regimen of azithromycin.

In this study, 86 (35%) of the treated patients were 2 years of age, and
162 (65%) were \>2 years of age. The following table shows clinical
outcomes by age for the MITT population.

Study A0661015: Clinical Outcomes by Age (MITT Population)

+-----------------------+-----------------------+-----------------------+
|                       | **Azithromycin**      | **95% Confidence      |
|                       |                       | Interval of Point     |
|                       | **N (%)**             | Estimate**            |
+-----------------------+-----------------------+-----------------------+
| #### Age 2 years      |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Patients evaluable at | 82 (100)              | 75.6, 92.7            |
| EOT                   |                       |                       |
|                       | 69 (84)               |                       |
| > Success (Cured or   |                       |                       |
| > Improved)           | 13 (16)               |                       |
| >                     |                       |                       |
| > Failure             |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Patients evaluable at | 83 (100)              | 67.5, 86.7            |
| TOC                   |                       |                       |
|                       | 64 (77)               |                       |
| > Cure                |                       |                       |
| >                     | 19 (23)               |                       |
| > Failure             |                       |                       |
+-----------------------+-----------------------+-----------------------+
| #### Age \>2 years    |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Patients evaluable at | 158 (100)             | 86.4, 95.9            |
| EOT                   |                       |                       |
|                       | 144 (91)              |                       |
| > Success (Cured or   |                       |                       |
| > Improved)           | 14 (9)                |                       |
| >                     |                       |                       |
| > Failure             |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Patients evaluable at | 159 (100)             | 84.2, 94.4            |
| TOC                   |                       |                       |
|                       | 142 (89)              |                       |
| > Cure                |                       |                       |
| >                     | 17 (11)               |                       |
| > Failure             |                       |                       |
+-----------------------+-----------------------+-----------------------+
| EOT = End of Therapy  |                       |                       |
| (Day 8 to 12); TOC =  |                       |                       |
| Test of Cure (Day 20  |                       |                       |
| to 32)                |                       |                       |
+-----------------------+-----------------------+-----------------------+

Children \> 2 years of age were more likely to have a successful
clinical response than were children 2 years. Similar results are seen
when patients with a baseline pathogen are grouped by age, as shown in
the following table.

Study A0661015: Clinical Outcome by Baseline Pathogen and Age (MITT
Population)

+------------------+------------+------------+------------+------------+
|                  | ***H.      |            | ***S.      |            |
|                  | inf        |            | pne        |            |
|                  | luenzae*** |            | umoniae*** |            |
+------------------+------------+------------+------------+------------+
| **EOT            | **2        | **\>2      | **2        | **\>2      |
| Assessment:**    | years**    | years**    | years**    | years**    |
+------------------+------------+------------+------------+------------+
| Outcome          | N (%)      | N (%)      | N (%)      | N (%)      |
+------------------+------------+------------+------------+------------+
| Success          | 11 (61%)   | 19 (79%)   | 23 (92%)   | 47 (92%)   |
|                  |            |            |            |            |
| Failure          | 7 (39%)    | 5 (21%)    | 2 ( 8%)    | 4 ( 8%)    |
+------------------+------------+------------+------------+------------+
| **TOC            |            |            |            |            |
| Assessment:**    |            |            |            |            |
+------------------+------------+------------+------------+------------+
| Outcome          | N (%)      | N (%)      | N (%)      | N (%)      |
+------------------+------------+------------+------------+------------+
| #####  Cure      | 10 (53%)   | 18 (72%)   | 20 (80%)   | 47 (92%)   |
|                  |            |            |            |            |
| Failure          | 9 (47%)    | 7 (28%)    | 5 (20%)    | 4 ( 8%)    |
+------------------+------------+------------+------------+------------+

# Study AZM-NY-95-001: Supportive Single-Tap Study 

**of One-Day Azi vs. Three-Day Azi vs. IM Ceftriaxone**

Study AZM-NY-95-001 was a single center (Costa Rica) trial of AOM
comparing a single 30 mg/kg dose of azithromycin, 10 mg/kg daily of
azithromycin for 3 days, and 50 mg/kg of IM CFTX. Initially, the study
used a double-dummy, double-blind design, but due to the color of
reconstituted CFTX the injection was unblinded. The investigator
remained blinded to the dose regimen of azithromycin. This was a
single-tap study with outcome assessments at EOT (days 9 to 19) and
follow-up (days 26 to 44). One hundred ninety-eight subjects (66 azi
single dose; 66 azi 3-day; 66 CFTX) were randomized to treatment.
Ninety-eight subjects (30 azi single dose; 35 azi 3-day; and 33 CFTX)
had an appropriate pathogen isolated at baseline, and were included in
the evaluation of clinical response by baseline pathogen.

Clinical success (cure or improvement) was reported for 93.8% of azi
single dose, 92.4% of azi 3-day, and 96.9% of CFTX patients at the
follow-up visit.

Clinical outcomes in MITT patients with *H. influenzae* or *S.
pneumoniae* at the baseline visit are shown in the following table.
There were only two patients with *M. catarrhalis* enrolled in the
study. Both patients were treated with the 3-day regimen of azithromycin
and both were clinical cures.

Study AZM-NY-95-001: Clinical Outcome by Baseline Pathogen (MITT
Population)

+-------------+--------+--------+--------+--------+--------+--------+
| **EOT       | ***H.  |        |        | ***S.  |        |        |
| As          | i      |        |        | p      |        |        |
| sessment:** | nfluen |        |        | neumon |        |        |
|             | zae*** |        |        | iae*** |        |        |
+-------------+--------+--------+--------+--------+--------+--------+
| Outcome     | 1-Day  | 3-Day  | CFTX   | 1-Day  | 3-Day  | CFTX   |
|             | Azi    | Azi    |        | Azi    | Azi    |        |
|             |        |        | N (%)  |        |        | N (%)  |
|             | N (%)  | N (%)  |        | N (%)  | N (%)  |        |
+-------------+--------+--------+--------+--------+--------+--------+
| Total       | 9      | 15     | 10     | 21     | 18     | 23     |
| Patients    | (100%) | (100%) | (100%) | (100%) | (100%) | (100%) |
|             |        |        |        |        |        |        |
| Success     | 8      | 14     | 10     | 20     | 15     | 23     |
|             | (89%)  | (93%)  | (100%) | (95%)  | (83%)  | (100%) |
| Failure     |        |        |        |        |        |        |
|             | 1      | 1 (7%) | 0      | 0      | 0      | 0      |
| Missing     | (11%)  |        |        |        |        |        |
|             |        | 0      | 0      | 1 (5%) | 3      | 0      |
|             | 0      |        |        |        | (17%)  |        |
+-------------+--------+--------+--------+--------+--------+--------+
| **TOC       | ***H.  |        |        | ***S.  |        |        |
| As          | i      |        |        | p      |        |        |
| sessment:** | nfluen |        |        | neumon |        |        |
|             | zae*** |        |        | iae*** |        |        |
+-------------+--------+--------+--------+--------+--------+--------+
| Outcome     | 1-Day  | 3-Day  | CFTX   | 1-Day  | 3-Day  | CFTX   |
|             | Azi    | Azi    |        | Azi    | Azi    |        |
|             |        |        | N (%)  |        |        | N (%)  |
|             | N (%)  | N (%)  |        | N (%)  | N (%)  |        |
+-------------+--------+--------+--------+--------+--------+--------+
| ##### Total | 9      | 15     | 10     | 21     | 18     | 23     |
|             | (100%) | (100%) | (100%) | (100%) | (100%) | (100%) |
| #####  Cure |        |        |        |        |        |        |
|             | 7      | 11     | 9      | 20     | 17     | 23     |
| Failure     | (78%)  | (74%)  | (90%)  | (95%)  | (94%)  | (100%) |
|             |        |        |        |        |        |        |
| Missing     | 1      | 2      | 0      | 0      | 0      | 0      |
|             | (11%)  | (13%)  |        |        |        |        |
|             |        |        | 1      | 1 (5%) | 1 (6%) | 0      |
|             | 1      | 2      | (10%)  |        |        |        |
|             | (11%)  | (13%)  |        |        |        |        |
+-------------+--------+--------+--------+--------+--------+--------+

# Efficacy

The descriptions of the individual clinical studies summarize the
outcome information supplied by the applicant in support of the one-day
and three-day dosage regimens for treatment of acute otitis media. The
clinical studies section of the label for the Zithromax oral suspension
(Ref. #1) summarizes the information provided in support of the five-day
regimen.

The clinical-only study of the five-day treatment regimen showed
clinical outcomes at EOT of 88% for azi and the control agent. Clinical
outcomes at TOC were 73% for azi and 71% for the comparator. The
clinical-only study for the three-day regimen (study A0661014) showed
MITT cure rates of 83% for azi and 88% for amox/clav at EOT. At TOC, the
cure rates were 74% for azi and 69% for amox/clav. The clinical-only
study for the one-day regimen (study R-0581) showed MITT cure rates of
87% for azi and 88% for amox/clav at EOT. At TOC, the cure rates were
75% in both treatment arms.

The clinical outcomes for patients with *S. pneumoniae* and *H.
influenzae* at EOT and TOC for the different treatment regimens are
summarized in the following table.

+-----------------+----------+----------+--------------+-------------+
| **Dose Groups** | **30     | **10     | **10 mg/kg   | **C         |
|                 | mg/kg -- | mg/kg x  | -- Day 1**   | omparator** |
|                 | SD**     | 3**      |              |             |
|                 |          |          | **5 mg/kg -- |             |
|                 | **(On    | **(Thre  | Days 2-5**   |             |
|                 | e-Day)** | e-Day)** |              |             |
|                 |          |          | **           |             |
|                 |          |          | (Five-Day)** |             |
+-----------------+----------+----------+--------------+-------------+
| ####            |          |          |              |             |
|  EOT Assessment |          |          |              |             |
+-----------------+----------+----------+--------------+-------------+
| *H. influenzae* | 38/51    | 14/15    | 52/65 (80%)  | 19/19       |
|                 | (74%)    | (93%)    |              | (100%)      |
+-----------------+----------+----------+--------------+-------------+
| *S. pneumoniae* | 90/97    | 15/18    | 86/103 (84%) | 39/39       |
|                 | (92%)    | (83%)    |              | (100%)      |
+-----------------+----------+----------+--------------+-------------+
| ####            |          |          |              |             |
|  TOC Assessment |          |          |              |             |
+-----------------+----------+----------+--------------+-------------+
| *H. influenzae* | 35/53    | 11/15    | 38/57 (67%)  | 15/18 (83%) |
|                 | (66%)    | (74%)    |              |             |
+-----------------+----------+----------+--------------+-------------+
| *S. pneumoniae* | 87/97    | 17/18    | 62/84 (74%)  | 41/45 (91%) |
|                 | (90%)    | (94%)    |              |             |
+-----------------+----------+----------+--------------+-------------+

In a review of the published literature, there was additional
information regarding clinical and microbiologic efficacy from two
comparative double-tap studies conducted by Dagan et al. Of particular
note are the relatively low bacterial eradication rates for patients
with *H. influenzae* treated with azithromycin in both of these studies.
The articles, References 2 and 3, are provided in this package for your
review.

# Safety

### Number of Subjects Treated

**Phase 2-4 Studies**

As of the June 30, 2000 cutoff date, 2590 subjects received azithromycin
in the Phase 2-4 pooled studies. A total of 1897 subjects received other
antibiotics in the comparative trials. The number of subjects receiving
azithromycin and the individual comparative agents in the U. S./Canada
and outside North America in the pooled Phase 2-4 studies is provided
below.

  ------------------------ ------------------- --------------------- -----------
                           **Number of                               
                           Subjects Treated**                        

  **Treatment**            **U.S./Canadian**   **Non-North           **Total**
                                               American**            

  Azithromycin             518                 2072                  2590

  Amox/Clav                358                 423                   781

  Penicillin V             0                   394                   394

  Cefaclor                 0                   315                   315

  Clarithromycin           0                   307                   307

  Erythromycin             0                   19                    19

  CFTX                     0                   66                    66

  Cefixime                 0                   15                    15

  TOTAL                    876                 3611                  4487
  ------------------------ ------------------- --------------------- -----------

**Adverse Events**

A summary of the most common treatment-related adverse events is
presented below for subjects who received azithromycin or a comparator
in Phase 2-4 studies. Information on the five-day dose regimen is from
the original NDA application. Caution should be taken in making
comparisons between the five-day regimen and the shorter duration
regimens. Caution should also be taken in making comparisons with all
comparator patients, since patients who participated in studies of
pharyngitis are included in this group. For instance, part of the reason
for a higher frequency of headache in the comparator is likely related
to the expected occurrence of that AE in pharyngitis patients.

Commonly Reported Treatment-Related Adverse Events (5 Subjects in Either
Azithromycin or Comparator Group)

+-----------------+----------+----------+--------------+-------------+
| **Dose Groups** | **30     | **10     | **10 mg/kg   | **C         |
|                 | mg/kg -- | mg/kg x  | -- Day 1**   | omparator** |
|                 | SD**     | 3**      |              |             |
|                 |          |          | **5 mg/kg -- |             |
|                 | **(On    | **(Thre  | Days 2-5**   |             |
|                 | e-Day)** | e-Day)** |              |             |
|                 |          |          | **           |             |
|                 |          |          | (Five-Day)** |             |
+-----------------+----------+----------+--------------+-------------+
| Subjects with   | 13.6     | 8.6      | 5.9          | 12.1        |
| AE              | (66/487) | (1       | (112/1888)   | (230/1897)  |
|                 |          | 48/1729) |              |             |
+-----------------+----------+----------+--------------+-------------+
| ########        |          |          |              |             |
|  Adverse Events |          |          |              |             |
+-----------------+----------+----------+--------------+-------------+
| Vomiting        | 4.9      | 2.3      | 1.1          | 2.4         |
|                 | (24/487) | (        | (21/1888)    | (92/1897)   |
|                 |          | 39/1729) |              |             |
+-----------------+----------+----------+--------------+-------------+
| Diarrhea        | 4.3      | 2.6      | 1.8          | 8.9         |
|                 | (21/487) | (        | (33/1888)    | (169/1897)  |
|                 |          | 45/1729) |              |             |
+-----------------+----------+----------+--------------+-------------+
| Abdominal pain  | 1.4      | 1.7      | 1.2          | 2.0         |
|                 | (7/487)  | (        | (22/1888)    | (37/1897)   |
|                 |          | 30/1729) |              |             |
+-----------------+----------+----------+--------------+-------------+
| Nausea          | 1.0      | 0.4      | 0.5 (9/1888) | 1.2         |
|                 | (5/487)  | (7/1729) |              | (22/1897)   |
+-----------------+----------+----------+--------------+-------------+
| Rash            | 1.0      | 0.6      | 0.4 (7/1888) | 3.0         |
|                 | (5/487)  | (        |              | (57/1897)   |
|                 |          | 10/1729) |              |             |
+-----------------+----------+----------+--------------+-------------+
| Headache        | 0.0      | 0.1      | 0.3 (5/1888) | 1.1         |
|                 | (0/487)  | (2/1729) |              | (21/1897)   |
+-----------------+----------+----------+--------------+-------------+

Of note in this table, vomiting was reported at a higher frequency in
subjects who received the one-day azithromycin regimen. Diarrhea and
nausea were also more frequent in this group, though even higher rates
were seen in the comparator group. Higher rates of rash and diarrhea
among patients in the comparator group are not surprising, since the
comparator agents include beta-lactams and Augmentin in particular.

The following table notes the incidence of vomiting and diarrhea by day
of onset and azi treatment group. Most of the vomiting noted with the
one-day regimen occurs during the first day of treatment.

Percent (n/N) of Subjects Reporting Treatment-Related Vomiting and
Diarrhea by Day and Treatment Group

+-------------------+---------------+--------------+-------------------+
| **Total Dose**    | **30 mg/kg**  |              |                   |
+-------------------+---------------+--------------+-------------------+
| **Dose Group**    | **30 mg/kg -- | **10 mg/kg x | **10 mg/kg -- Day |
|                   | SD**          | 3**          | 1**               |
|                   |               |              |                   |
|                   | **(One-Day)** | **(          | **5 mg/kg -- Days |
|                   |               | Three-Day)** | 2-5**             |
|                   |               |              |                   |
|                   |               |              | **(Five-Day)**    |
+-------------------+---------------+--------------+-------------------+
| *Vomiting*        |               |              |                   |
|                   |               |              |                   |
| Overall           |               |              |                   |
|                   |               |              |                   |
| Day 1             |               |              |                   |
|                   |               |              |                   |
| Day 2             |               |              |                   |
|                   |               |              |                   |
| Day 3             |               |              |                   |
|                   |               |              |                   |
| Day 4             |               |              |                   |
|                   |               |              |                   |
| Day 5             |               |              |                   |
+-------------------+---------------+--------------+-------------------+
|                   | 4.9 (24/487)  | 2.3          | 1.1 (21/1888)     |
|                   |               | (39/1729)    |                   |
+-------------------+---------------+--------------+-------------------+
|                   | 4.7 (23/487)  | 1.2          | 0.5 (9/1888)      |
|                   |               | (21/1729)    |                   |
+-------------------+---------------+--------------+-------------------+
|                   | 0.2 (1/487)   | 0.6          | 0.4 (7/1888)      |
|                   |               | (10/1729)    |                   |
+-------------------+---------------+--------------+-------------------+
|                   | 0.0 (0/487)   | 0.1 (2/1729) | 0.2 (3/1863)      |
+-------------------+---------------+--------------+-------------------+
|                   | 0.0 (0/487)   | 0.0 (0/1729) | 0.0 (0/1857)      |
+-------------------+---------------+--------------+-------------------+
|                   | 0.0 (0/487)   | 0.0 (0/1729) | 0.0 (0/1851)      |
+-------------------+---------------+--------------+-------------------+
| ######## Diarrhea |               |              |                   |
|                   |               |              |                   |
| Overall           |               |              |                   |
|                   |               |              |                   |
| Day 1             |               |              |                   |
|                   |               |              |                   |
| Day 2             |               |              |                   |
|                   |               |              |                   |
| Day 3             |               |              |                   |
|                   |               |              |                   |
| Day 4             |               |              |                   |
|                   |               |              |                   |
| Day 5             |               |              |                   |
+-------------------+---------------+--------------+-------------------+
|                   | 4.3 (21/487)  | 2.6          | 1.8 (33/1888)     |
|                   |               | (45/1729)    |                   |
+-------------------+---------------+--------------+-------------------+
|                   | 1.6 (8/487)   | 0.5 (9/1729) | 0.6 (11/1888)     |
+-------------------+---------------+--------------+-------------------+
|                   | 1.6 (8/487)   | 1.0          | 0.4 (8/1888)      |
|                   |               | (17/1729)    |                   |
+-------------------+---------------+--------------+-------------------+
|                   | 0.4 (2/487)   | 0.5 (8/1729) | 0.4 (7/1863)      |
+-------------------+---------------+--------------+-------------------+
|                   | 0.0 (0/487)   | 0.1 (1/1729) | 0.2 (3/1857)      |
+-------------------+---------------+--------------+-------------------+
|                   | 0.0 (0/487)   | 0.1 (2/1729) | 0.1 (2/1851)      |
+-------------------+---------------+--------------+-------------------+
| SD = Single Dose; |               |              |                   |
| x3 = 3 days, x5 = |               |              |                   |
| 5 days            |               |              |                   |
+-------------------+---------------+--------------+-------------------+

**Serious Adverse Events:**

Of the 2152 subjects in the studies relevant to the claims, 8 reported
serious adverse events. Five of the eight subjects received azithromycin
and 3 received a comparator. The events reported by the
azithromycin-treated subjects consisted of convulsions, diarrhea,
enterocolitis, gastroenteritis, vomiting, dehydration, abscess, pleural
effusion and pneumonia. Comparator-treated subjects reported fever,
febrile convulsions, abdominal pain, gastroenteritis, vomiting,
dehydration, otitis media, and upper respiratory tract infection. All
serious adverse events reported by subjects in the studies relevant to
the claims were considered unrelated to treatment by the investigator.

# Current AOM Guidance 

The following outlines the studies described in the current draft
Guidance for Industry on AOM trials. This information is provided to
outline the general recommendations made by the FDA to pharmaceutical
firms performing AOM studies, and also to generate some discussion about
these recommendations during the advisory committee meeting.

The draft Guidance recommends two trials, a clinical only study and a
microbiologic study.

**Clinical only study:**

-   Multicenter trial with rigid case definition

-   Typically in children 6 months of age

-   Baseline tympanocentesis not necessary; however, tympanocentesis of
    failures strongly encouraged

**Microbiologic study:**

-   At least 2 investigators in geographically diverse areas

-   Baseline tympanocentesis necessary for microbiologic etiology

-   Repeat tympanocentesis strongly encouraged in therapeutic failures

-   25 *S. pneumoniae* (for PRSP, discuss with Division*),* 25 *H.
    influenzae,*

15 *M. catarrhalis* from the microbiologic study

-   if clinical and microbiologic efficacy against three pathogens not
    adequate, restricted product to second line therapy

### Case Definition

Clinical diagnosis of AOM at entry based on:

1.  history and physical examination

2.  pneumatic otoscopy findings:

swollen bulging tympanic membrane (TM) which may be erythematous

loss of light reflex and TM landmarks, abnormal TM mobility

3.  tympanometry or acoustic reflectometry

Exclude patients with tympanostomy tubes, otitis externa but not those
with perforated TMs

### Primary efficacy endpoints 

-   Clinical and Microbiologic outcomes at test of cure visit (TOC) 2-4
    weeks after study entry

-   Microbiologic eradication presumed from the clinical response at TOC
    visit, for the majority of patients

-   Negative culture at the on therapy visit not evidence of documented
    eradication

A complete copy of the draft guidance on AOM is provided as Reference 4.

# References

1.  Excerpted Information from Zithromax Oral Suspension Label

2.  Dagan R et al., "Bacteriologic and Clinical Efficacy of
    Amoxicillin/Clavulanate vs. Azithromycin in Acute Otitis Media"
    *Pediatric Infectious Diseases Journal* 19(2):95-104, February 2000.

3.  Dagan R et al., "Bacteriologic Efficacies of Oral Azithromycin and
    Oral Cefaclor in Treatment of Acute Otitis Media in Infants and
    Young Children" Antimicrobial Agents and Chemotherapy 44(1):43-50,
    January 2000.

4.  FDA, Center for Drug Evaluation and Research, DRAFT Guidance for
    Industry "Acute Otitis Media -- Developing Antimicrobial Drugs for
    Treatment" July 1998.

5.  Marchant CD et al., " Measuring the Comparative Efficacy of
    Antibacterial Agents for Acute Otitis Media: The Pollyanna
    Phenomenon" *The Journal of Pediatrics* 120(1):72-77, January 1992.

6.  Klein JO et al., "Microbiologic Efficacy of Antibacterial Drugs for
    Acute Otitis Media" *Pediatric Infectious Diseases Journal*
    12(12):973-975, December 1993.

7.  Carlin SA et al., "Host Factors and Early Therapeutic Response in
    Acute Otitis Media" *The Journal of Pediatrics* 118(2):178-183,
    February 1991.

[^1]: Doren, G. V., K.P. Heilmann, H.K. Huynh, et.al. 2001.
    Antimicrobial Resistance among Clinical Isolates of *Streptococcus
    pneumoniae* in the United States during 1999-2000, Including a
    Comparison of Resistant Rates since 1994-1995. Antimicrob. Agents
    Chemother. 45:1721-1729.

[^2]: Mason, E.O. Jr., L.B. Lamberth, N.L. Kershaw, et.al. 2000.
    *Streptococcus pneumoniae* in the USA: In vitro susceptibility and
    pharmacodynamic analysis. J. Antimicrob. Chemother. 45:623-631.

[^3]: Doren, G.V., R.N. Jones, M. A. Pfaller, et.al. 1999. *Haemophilus
    influenzae* and *Moraxella catarrhalis* from patients with
    Community-Acquired Respiratory Tract Infections: Antimicrobial
    Susceptibility Patterns from the SENTRY Antimicrobial Surveillance
    Program (United States and Canada 1997). Antimicrob. Agents
    Chemother. 43:385-389.

[^4]: Thornsberry, C., P.T. Ogilvie, H. P. Holley, et. al. 1999. Survey
    of Susceptibility of *Streptococcus pneumoniae*, *Haemophilus
    influenzae,* and *Moraxella catarrhalis* Isolates to 26
    Antimicrobial Agents: A Prospective U.S. Study. Antimicrob. Agents
    Chemother. 43:2612-2623.