Pharmacokinetics

Following oral administration of a single 500 mg dose (two 250 mg tablets) to 36 fasted healthy male volunteers, the mean (SD) pharmacokinetic parameters were AUC0-72 = 4.3 (1.2) mcg·h/mL; Cmax = 0.5 (0.2) mcg /mL; Tmax = 2.2 (0.9) hours.

With a regimen of 500 mg (two 250 mg capsules*) on day 1, followed by 250 mg daily (one 250 mg capsule) on days 2 through 5, the pharmacokinetic parameters of azithromycin in plasma in healthy young adults (18-40 years of age) are portrayed in the chart below. Cmin and Cmax remained essentially unchanged from day 2 through day 5 of therapy.

Pharmacokinetic Parameters (Mean)	Total n=12
	Day 1	Day 5
Cmax (mcg/mL)	0.41	0.24
Tmax (h)	2.5	3.2
AUC0-24 (mcg·h/mL)	2.6	2.1
Cmin (mcg/mL)	0.05	0.05
Urinary Excret. (% dose)	4.5	6.5

*Azithromycin 250 mg tablets are bioequivalent to 250 mg capsules in the fasted state.

Azithromycin 250 mg capsules are no longer commercially available.

In a two-way crossover study, 12 adult healthy volunteers (6 males, 6 females) received 1,500 mg of azithromycin administered in single daily doses over either 5 days (two 250 mg tablets on day 1, followed by one 250 mg tablet on days 2-5) or 3 days (500 mg per

day for days 1-3). Due to limited serum samples on day 2 (3-day regimen) and days 2-4 (5-day regimen), the serum concentration-time profile of each subject was fit to a 3-compartment model and the AUC0∞ for the fitted concentration profile was comparable between the 5-day and 3-day regimens.

* Total AUC for the entire 3-day and 5-day regimens
	3-Day Regimen		5-Day Regimen
Pharmacokinetic Parameter [mean (SD)]	Day 1	Day 3	Day 1	Day 5
Cmax (serum, mcg/mL)	0.44 (0.22)	0.54 (0.25)	0.43 (0.20)	0.24 (0.06)
Serum AUC0-∞ (mcg.hr/mL)	17.4 (6.2)*		14.9 (3.1)*
Serum T½	71.8 hr		68.9 hr

Median azithromycin exposure (AUC0-288) in mononuclear (MN) and polymorphonuclear (PMN) leukocytes following either the 5-day or 3-day regimen was more than a 1000-fold and 800-fold greater than in serum, respectively. Administration of the same total dose with either the 5-day or 3-day regimen may be expected to provide comparable concentrations of azithromycin within MN and PMN leukocytes.

Two azithromycin 250 mg tablets are bioequivalent to a single 500 mg tablet.

Absorption:  The absolute bioavailability of azithromycin 250 mg capsules is 38%.

In a two-way crossover study in which 12 healthy subjects received a single 500 mg dose of azithromycin (two 250 mg tablets) with or without a high fat meal, food was shown to increase Cmax by 23% but had no effect on AUC.

When azithromycin suspension was administered with food to 28 adult healthy male subjects, Cmax increased by 56% and AUC was unchanged.

The AUC of azithromycin was unaffected by co-administration of an antacid containing

aluminum and magnesium hydroxide with azithromycin capsules; however, the Cmax was reduced by 24%. Administration of cimetidine (800 mg) two hours prior to azithromycin had no effect on azithromycin absorption.

Distribution:  The serum protein binding of azithromycin is variable in the concentration range approximating human exposure, decreasing from 51% at 0.02 mcg/mL to 7% at 2 mcg/mL.

Following oral administration, azithromycin is widely distributed throughout the body with an apparent steady-state volume of distribution of 31.1 L/kg. Greater azithromycin concentrations in tissues than in plasma or serum were observed. High tissue concentrations should not be interpreted to be quantitatively related to clinical efficacy.

The antimicrobial activity of azithromycin is pH related and appears to be reduced with decreasing pH. However, the extensive distribution of drug to tissues may be relevant to clinical activity.

Selected tissue (or fluid) concentration and tissue (or fluid) to plasma/serum concentration ratios are shown in the following table:

AZITHROMYCIN CONCENTRATIONS FOLLOWING A 500 mg DOSE (TWO 250 mg CAPSULES) IN ADULTS*

* Azithromycin tissue concentrations were originally determined using 250 mg capsules. † Sample was obtained 2-4 hours after the first dose. ‡ Sample was obtained 10-12 hours after the first dose. § Dosing regimen of two doses of 250 mg each, separated by 12 hours. ¶ Sample was obtained 19 hours after a single 500 mg dose.
TISSUE OR FLUID	TIME AFTER DOSE (h)	TISSUE OR FLUID CONCENTRATION (mcg/g or mcg/mL)	CORRESPONDING PLASMA OR SERUM LEVEL (mcg/mL)	TISSUE (FLUID) PLASMA (SERUM) RATIO
SKIN	72-96	0.4	0.012	35
LUNG	72-96	4	0.012	>100
SPUTUM†	2-4	1	0.64	2
SPUTUM‡	10-12	2.9	0.1	30
TONSIL§	9-18	4.5	0.03	>100
TONSIL§	180	0.9	0.006	>100
CERVIX¶	19	2.8	0.04	70

The extensive tissue distribution was confirmed by examination of additional tissues and fluids (bone, ejaculum, prostate, ovary, uterus, salpinx, stomach, liver, and gallbladder). As there are no data from adequate and well-controlled studies of azithromycin treatment of infections in these additional body sites, the clinical importance of these tissue concentration data is unknown.

Following a regimen of 500 mg on the first day and 250 mg daily for 4 days, only very low concentrations were noted in cerebrospinal fluid (less than 0.01 mcg/mL) in the presence of non-inflamed meninges.

Metabolism: In vitro and in vivo studies to assess the metabolism of azithromycin have not been performed.

Elimination:  Plasma concentrations of azithromycin following single 500 mg oral and i.v. doses declined in a polyphasic pattern with a mean apparent plasma clearance of 630 mL/min and terminal elimination half-life of 68 hours. The prolonged terminal half-life is thought to be due to extensive uptake and subsequent release of drug from tissues.

Biliary excretion of azithromycin, predominantly as unchanged drug, is a major route of elimination. Over the course of a week, approximately 6% of the administered dose appears as unchanged drug in urine.

Special Populations

Drug-Drug Interactions

Drug interaction studies were performed with azithromycin and other drugs likely to be co-administered. The effects of co-administration of azithromycin on the pharmacokinetics of other drugs are shown in Table 1 and the effect of other drugs on the pharmacokinetics of azithromycin are shown in Table 2.

Co-administration of azithromycin at therapeutic doses had a modest effect on the pharmacokinetics of the drugs listed in Table 1. No dosage adjustment of drugs listed in Table 1 is recommended when co-administered with azithromycin.

Co-administration of azithromycin with efavirenz or fluconazole had a modest effect on the pharmacokinetics of azithromycin. Nelfinavir significantly increased the Cmax and AUC of azithromycin. No dosage adjustment of azithromycin is recommended when administered with drugs listed in Table 2. (See PRECAUTIONS - Drug Interactions.)

Table 1. Drug Interactions: Pharmacokinetic Parameters for Co-administered Drugs in the Presence of Azithromycin

* -90% Confidence interval not reported † NA - Not Available
Co-administered Drug	Dose of Co-administered Drug	Dose of Azithromycin	n	Ratio (with/without azithromycin) of Co-administered Drug Pharmacokinetic Parameters (90% CI); No Effect=1
				Mean Cmax	Mean AUC
Atorvastatin	10 mg/day×8 days	500 mg/day PO on days 6-8	12	0.83 (0.63 to 1.08)	1.01 (0.81 to 1.25)
Carbamazepine	200 mg/day×2 days, then 200 mg BID×8 days	500 mg/day PO for days 16-18	7	0.97 (0.88 to 1.06)	0.96 (0.88 to 1.06)
Cetirizine	20 mg/day×11 days	500 mg PO on day 7, then 250 mg/day on days 8-11	14	1.03 (0.93 to 1.14)	1.02 (0.92 to 1.13)
Didanosine	200 mg PO BID×21 days	1,200 mg/day PO on days 8-21	6	1.44 (0.85 to 2.43)	1.14 (0.83 to 1.57)
Efavirenz	400 mg/day×7 days	600 mg PO on day 7	14	1.04*	0.95*
Fluconazole	200 mg PO single dose	1,200 mg PO single dose	18	1.04 (0.98 to 1.11)	1.01 (0.97 to 1.05)
Indinavir	800 mg TID×5 days	1,200 mg PO on day 5	18	0.96 (0.86 to 1.08)	0.90 (0.81 to 1.00)
Midazolam	15 mg PO on day 3	500 mg/day PO×3 days	12	1.27 (0.89 to 1.81)	1.26 (1.01 to 1.56)
Nelfinavir	750 mg TID×11 days	1,200 mg PO on day 9	14	0.90 (0.81 to 1.01)	0.85 (0.78 to 0.93)
Rifabutin	300 mg/day×10 days	500 mg PO on day 1, then 250 mg/day on days 2-10	6	See footnote below	NA†
Sildenafil	100 mg on days 1 and 4	500 mg/day PO×3 days	12	1.16 (0.86 to 1.57)	0.92 (0.75 to 1.12)
Theophylline	4 mg/kg IV on days 1, 11, 25	500 mg PO on day 7, 250 mg/day on days 8-11	10	1.19 (1.02 to 1.40)	1.02 (0.86 to 1.22)
Theophylline	300 mg PO BID×15 days	500 mg PO on day 6, then 250 mg/day on days 7-10	8	1.09 (0.92 to 1.29)	1.08 (0.89 to 1.31)
Triazolam	0.125 mg on day 2	500 mg PO on day 1, then 250 mg/day on day 2	12	1.06*	1.02*
Trimethoprim/ Sulfamethoxazol	160 mg/800 mg/day PO×7 days	1,200 mg PO on day 7	12	0.85 (0.75 to 0.97)/ 0.90 (0.78 to 1.03)	0.87 (0.80 to 0.95/ 0.96 (0.88 to 1.03)
Zidovudine	500 mg/day PO×21 days	600 mg/day PO×14 days	5	1.12 (0.42 to 3.02)	0.94 (0.52 to 1.70)
Zidovudine	500 mg/day PO×21 days	1,200 mg/day PO×14 days	4	1.31 (0.43 to 3.97)	1.30 (0.69 to 2.43)

Mean rifabutin concentrations one-half day after the last dose of rifabutin were 60 ng/mL when co-administered with azithromycin and 71 ng/mL when co-administered with placebo.

Table 2. Drug Interactions: Pharmacokinetic Parameters for Azithromycin in the Presence of Co-administered Drugs (See PRECAUTIONS - Drug Interactions.)

* -90% Confidence interval not reported † NA - Not available
Co- administered Drug	Dose of Co- administered Drug	Dose of Azithromycin	n	Ratio (with/without co-administered drug) of Azithromycin Pharmacokinetic Parameters (90% CI); No Effect = 1
				Mean Cmax	Mean AUC
Efavirenz	400 mg/day ×7 days	600 mg PO on day 7	14	1.22 (1.04 to 1.42)	0.92*
Fluconazole	200 mg PO single dose	1,200 mg PO single dose	18	0.82 (0.66 to 1.02)	1.07 (0.94 to 1.22)
Nelfinavir	750 mg TID ×1 days	1,200 mg PO on day 9	14	2.36 (1.77 to 3.15)	2.12 (1.80 to 2.50)
Rifabutin	300 mg/day ×10 days	500 mg PO on day 1, then 250 mg/day on days 2 -10	6	See footnote below	NA†

Mean azithromycin concentrations one day after the last dose were 53 ng/mL when co-administered with 300 mg daily rifabutin and 49 ng/mL when co-administered with placebo.

Microbiology:Azithromycin acts by binding to the 50S ribosomal subunit of susceptible microorganisms and, thus, interfering with microbial protein synthesis. Nucleic acid synthesis is not affected.

Azithromycin concentrates in phagocytes and fibroblasts as demonstrated by in vitro incubation techniques. Using such methodology, the ratio of intracellular to extracellular concentration was >30 after one hour incubation. In vivo studies suggest that concentration in phagocytes may contribute to drug distribution to inflamed tissues.

Azithromycin has been shown to be active against most isolates of the following

microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGEsection.

Aerobic and facultative gram-positive microorganisms

 

Staphylococcus aureus

 

Streptococcus agalactiae

 

Streptococcus pneumoniae

 

Streptococcus pyogenes

NOTE: Azithromycin demonstrates cross-resistance with erythromycin-resistant gram-positive strains. Most strains of Enterococcus faecalis and methicillin-resistant staphylococci are resistant to azithromycin.

Aerobic and facultative gram-negative microorganisms

Haemophilus ducreyi

Haemophilus influenzae

Moraxella catarrhalis

Neisseria gonorrhoeae

“Other” microorganisms

Chlamydia pneumoniae

Chlamydia trachomatis

Mycoplasma pneumoniae

Beta-lactamase production should have no effect on azithromycin activity.

The following in vitro data are available, but their clinical significance is unknown.

At least 90% of the following microorganisms exhibit an in vitro minimum inhibitory

concentration (MIC) less than or equal to the susceptible breakpoints for azithromycin. However, the safety and effectiveness of azithromycin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled trials.

Aerobic and facultative gram-positive microorganisms

Streptococci (Groups C, F, G)

Viridans group streptococci

Aerobic and facultative gram-negative microorganisms

Bordetella pertussis

Legionella pneumophila

Anaerobic microorganisms

Peptostreptococcus species

Prevotella bivia

“Other” microorganisms

Ureaplasma urealyticum

Susceptibility Testing Methods: When available, the results of in vitro susceptibility test results for antimicrobial drugs used in resident hospitals should be provided to the physician as periodic reports which describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports may differ from susceptibility data obtained from outpatient use, but could aid the physician in selecting the most effective antimicrobial.

Dilution techniques: Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method1,3 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of azithromycin powder. The MIC values should be interpreted according to criteria provided in Table 1.

Diffusion techniques: Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure2,3 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 15-mcg azithromycin to test the susceptibility of microorganisms to azithromycin. The disk diffusion interpretive criteria are provided in Table 1.

Table 1. Susceptibility Interpretive Criteria for Azithromycin Susceptibility Test Result Interpretive Criteria

* The current absence of data on resistant strains precludes defining any category other than "susceptible." If strains yield MIC results other than susceptible, they should be submitted to a reference laboratory for further testing. † Susceptibility of streptococci including S. pneumoniae to azithromycin and other macrolides can be predicted by testing erythromycin.
	Minimum Inhibitory Concentrations (mcg/mL)			Disk Diffusion (zone diameters in mm)
Pathogen
	S	I	R*	S	I	R*
Haemophilus spp.	≤4	--	--	≥12	--	--
Staphylococcus aureus	≤2	4	≥8	≥18	14-17	≤13
Streptococci including S. pneumoniae†	≤0.5	1	≥2	≥18	14-17	≤13

No interpretive criteria have been established for testing Neisseria gonorrhoeae. This species is not usually tested.

A report of “susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound reaches the concentrations usually achievable. A report of “intermediate” indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test

should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone, which prevents small-uncontrolled technical factors from causing major discrepancies in interpretation. A report of “resistant” indicates that the pathogen is not likely to be inhibited if the antimicrobial compound reaches the concentrations usually achievable; other therapy should be selected.

QUALITY CONTROL

Standardized susceptibility test procedures require the use of quality control microorganisms to control the technical aspects of the test procedures. Standard azithromycin powder should provide the following range of values noted in Table 2. Quality control microorganisms are specific strains of organisms with intrinsic biological properties. QC strains are very stable strains, which will give a standard and repeatable susceptibility pattern. The specific strains used for microbiological quality control are not clinically significant.

Table 2. Acceptable Quality Control Ranges for Azithromycin

QC Strain	Minimum Inhibitory Concentrations (mcg/mL)	Disk Diffusion (zone diameters in mm)
Haemophilus influenzae ATCC 49247	1-4	13-21
Staphylococcus aureus ATCC 29213	0.5-2
Staphylococcus aureus  ATCC 25923		21-26
Streptococcus pneumoniae  ATCC 49619	0.06-0.25	19-25

 

Adults

 Acute bacterial exacerbations of chronic obstructive pulmonary disease due to Haemophilus influenzae, Moraxella catarrhalis or Streptococcus pneumoniae.

Acute bacterial sinusitis due to Haemophilus influenzae, Moraxella catarrhalis or Streptococcus pneumoniae.

Community-acquired pneumonia due to Chlamydia pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae or Streptococcus pneumoniae in patients appropriate for oral therapy.

NOTE: Azithromycin should not be used in patients with pneumonia who are judged to be inappropriate for oral therapy because of moderate to severe illness or risk factors such as any of the following:

patients with cystic fibrosis,

patients with nosocomially acquired infections,

patients with known or suspected bacteremia,

patients requiring hospitalization,

elderly or debilitated patients, or

patients with significant underlying health problems that may compromise their

ability to respond to their illness (including immunodeficiency or functional

asplenia).

Pharyngitis/tonsillitis caused by Streptococcus pyogenes as an alternative to first-line therapy in individuals who cannot use first-line therapy.

NOTE: Penicillin by the intramuscular route is the usual drug of choice in the

treatment of Streptococcus pyogenes infection and the prophylaxis of rheumatic fever.

Azithromycin is often effective in the eradication of susceptible strains of

Streptococcus pyogenes from the nasopharynx. Because some strains are resistant

to azithromycin, susceptibility tests should be performed when patients are treated

with azithromycin. Data establishing efficacy of azithromycin in subsequent

prevention of rheumatic fever are not available.

Uncomplicated skin and skin structure infections due to Staphylococcus aureus, Streptococcus pyogenes, or Streptococcus agalactiae. Abscesses usually require surgical drainage.

Urethritis and cervicitis due to Chlamydia trachomatis or Neisseria gonorrhoeae.

Genital ulcer disease in men due to Haemophilus ducreyi (chancroid). Due to the small number of women included in clinical trials, the efficacy of azithromycin in the treatment of chancroid in women has not been established.

Azithromycin, at the recommended dose, should not be relied upon to treat syphilis. Antimicrobial agents used in high doses for short periods of time to treat non-gonococcal urethritis may mask or delay the symptoms of incubating syphilis. All patients with sexually-transmitted urethritis or cervicitis should have a serologic test for syphilis and appropriate cultures for gonorrhea performed at the time of diagnosis.

Appropriate antimicrobial therapy and follow-up tests for these diseases should be initiated if infection is confirmed.

Appropriate culture and susceptibility tests should be performed before treatment to determine the causative organism and its susceptibility to azithromycin. Therapy with azithromycin may be initiated before results of these tests are known; once the results become available, antimicrobial therapy should be adjusted accordingly.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of azithromycin and other antibacterial drugs, azithromycin should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

Pediatric Patients

 (See PRECAUTIONS—Pediatric Useand CLINICAL STUDIES, Pediatric Patients.)

Acute otitis media caused by Haemophilus influenzae, Moraxella catarrhalis or Streptococcus pneumoniae. (For specific dosage recommendation, see DOSAGE AND ADMINISTRATION.)

Community-acquired pneumonia due to Chlamydia pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae or Streptococcus pneumoniae in patients appropriate for oral therapy. (For specific dosage recommendation, see DOSAGE AND ADMINISTRATION.)

NOTE: Azithromycin should not be used in pediatric patients with pneumonia who are judged to be inappropriate for oral therapy because of moderate to severe illness or risk factors such as any of the following:

patients with cystic fibrosis,

patients with nosocomially acquired infections,

patients with known or suspected bacteremia,

patients requiring hospitalization, or

patients with significant underlying health problems that may compromise their

ability to respond to their illness (including immunodeficiency or functional

asplenia).

Pharyngitis/tonsillitis caused by Streptococcus pyogenes as an alternative to first-line therapy in individuals who cannot use first-line therapy. (For specific dosage recommendation, see DOSAGE AND ADMINISTRATION.)

NOTE: Penicillin by the intramuscular route is the usual drug of choice in the treatment of Streptococcus pyogenes infection and the prophylaxis of rheumatic fever. Azithromycin is often effective in the eradication of susceptible strains of Streptococcus pyogenes from the nasopharynx. Because some strains are resistant to azithromycin, susceptibility tests should be performed when patients are treated with azithromycin. Data establishing efficacy of azithromycin in subsequent prevention of rheumatic fever are not available.

Appropriate culture and susceptibility tests should be performed before treatment to determine the causative organism and its susceptibility to azithromycin. Therapy with azithromycin may be initiated before results of these tests are known; once the results become available, antimicrobial therapy should be adjusted accordingly.

General

Because azithromycin is principally eliminated via the liver, caution should be exercised when azithromycin is administered to patients with impaired hepatic function. Due to the limited data in subjects with GFR <10 mL/min, caution should be exercised when prescribing azithromycin in these patients. (See CLINICAL PHARMACOLOGY - Special Populations - Renal Insufficiency.)

Prolonged cardiac repolarization and QT interval, imparting a risk of developing cardiac arrhythmia and torsades de pointes, have been seen in treatment with other macrolides. A similar effect with azithromycin cannot be completely ruled out in patients at increased risk for prolonged cardiac repolarization.

Prescribing azithromycin in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Information for Patients

Azithromycin oral suspension can be taken with or without food.

Patients should also be cautioned not to take aluminum- and magnesium-containing antacids and azithromycin simultaneously.

The patient should be directed to discontinue azithromycin immediately and contact a physician if any signs of an allergic reaction occur.

Patients should be counseled that antibacterial drugs including azithromycin should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When azithromycin is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of the therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by azithromycin or other antibacterial drugs in the future.

Drug I nteractions

Co-administration of nelfinavir at steady state with a single oral dose of azithromycin resulted in increased azithromycin serum concentrations. Although a dose adjustment of azithromycin is not recommended when administered in combination with nelfinavir, close monitoring for known side effects of azithromycin, such as liver enzyme abnormalities and hearing impairment, is warranted. (See ADVERSE REACTIONS.)

Azithromycin did not affect the prothrombin time response to a single dose of warfarin. However, prudent medical practice dictates careful monitoring of prothrombin time in all patients treated with azithromycin and warfarin concomitantly. Concurrent use of macrolides and warfarin in clinical practice has been associated with increased anticoagulant effects.

Drug interaction studies were performed with azithromycin and other drugs likely to be co-administered. (See CLINICAL PHARMACOLOGY-Drug-Drug Interactions.) When used in therapeutic doses, azithromycin had a modest effect on the pharmacokinetics of atorvastatin, carbamazepine, cetirizine, didanosine, efavirenz, fluconazole, indinavir, midazolam, rifabutin, sildenafil, theophylline (intravenous and oral), triazolam, trimethoprim/sulfamethoxazole or zidovudine. Co-administration with efavirenz, or fluconazole had a modest effect on the pharmacokinetics of azithromycin. No dosage adjustment of either drug is recommended when azithromycin is co-administered with any of the above agents.

Interactions with the drugs listed below have not been reported in clinical trials with azithromycin; however, no specific drug interaction studies have been performed to evaluate potential drug-drug interaction. Nonetheless, they have been observed with macrolide products. Until further data are developed regarding drug interactions when

azithromycin and these drugs are used concomitantly; careful monitoring of patients is advised:

Digoxin–elevated digoxin concentrations.

Ergotamine or dihydroergotamine–acute ergot toxicity characterized by severe

peripheral vasospasm and dysesthesia.

Terfenadine, cyclosporine, hexobarbital and phenytoin concentrations.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have not been performed to evaluate carcinogenic potential. Azithromycin has shown no mutagenic potential in standard laboratory tests: mouse lymphoma assay, human

lymphocyte clastogenic assay, and mouse bone marrow clastogenic assay. No evidence of impaired fertility due to azithromycin was found.

Pregnancy

Nursing Mothers

It is not known whether azithromycin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when azithromycin is administered to a nursing woman.

Pediatric Use

(See CLINICAL PHARMACOLOGY, INDICATIONS AND USAGE, and DOSAGE AND ADMINISTRATION.)

Acute Otitis Media (total dosage regimen: 30 mg/kg, see DOSAGE AND ADMINISTRATION): Safety and effectiveness in the treatment of pediatric patients with otitis media under 6 months of age have not been established.

Acute Bacterial Sinusitis (dosage regimen: 10 mg/kg on Days 1-3): Safety and effectiveness in the treatment of pediatric patients with acute bacterial sinusitis under 6 months of age have not been established. Use of azithromycin for the treatment of acute bacterial sinusitis in pediatric patients (6 months of age or greater) is supported by adequate and well-controlled studies in adults, similar pathophysiology of acute sinusitis in adults and pediatric patients, and studies of acute otitis media in pediatric patients.

Community-Acquired Pneumonia (dosage regimen: 10 mg/kg on Day 1 followed by

5 mg/kg on Days 2-5): Safety and effectiveness in the treatment of pediatric patients with community-acquired pneumonia under 6 months of age has not been established.

Safety and effectiveness for pneumonia due to Chlamydia pneumoniae and Mycoplasma pneumoniae were documented in pediatric clinical trials. Safety and effectiveness for pneumonia due to Haemophilus influenzae and Streptococcus pneumoniae were not documented bacteriologically in the pediatric clinical trial due to difficulty in obtaining specimens. Use of azithromycin for these two microorganisms is supported, however, by evidence from adequate and well-controlled studies in adults.

Pharyngitis/Tonsillitis (dosage regimen: 12 mg/kg on Days 1-5): Safety and effectiveness in the treatment of pediatric patients with pharyngitis/tonsillitis under 2 years of age have not been established.

Studies evaluating the use of repeated courses of therapy have not been conducted. (See CLINICAL PHARMACOLOGYandANIMAL TOXICOLOGY.)

Geriatric Use

Pharmacokinetic parameters in older volunteers (65-85 years old) were similar to those in younger volunteers (18-40 years old) for the 5-day therapeutic regimen. Dosage adjustment does not appear to be necessary for older patients with normal renal and hepatic function receiving treatment with this dosage regimen. (See CLINICAL PHARMACOLOGY.)

In multiple-dose clinical trials of oral azithromycin, 9% of patients were at least 65 years of age (458/4949) and 3% of patients (144/4949) were at least 75 years of age. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

5 mL of constituted solution of Azithromycin for Oral Suspension, 100 mg/5 mL and 200 mg/5 mL contain 11.2 mg and 1.4 mEq of sodium (Na+).

Clinical

Postmarketing Experience

Adverse events reported with azithromycin during the post-marketing period in adult and/or pediatric patients for which a causal relationship may not be established include:

Allergic:Arthralgia, edema, urticaria and angioedema.

Cardiovascular:Arrhythmias including ventricular tachycardia and hypotension. There have been rare reports of QT prolongation and torsades de pointes.

Gastrointestinal:Anorexia, constipation, dyspepsia, flatulence, vomiting/diarrhea rarely resulting in dehydration, pseudomembranous colitis, pancreatitis, oral candidiasis and rare reports of tongue discoloration.

General:Asthenia, paresthesia, fatigue, malaise and anaphylaxis (rarely fatal).

Genitourinary:Interstitial nephritis and acute renal failure and vaginitis.

Hematopoietic:Thrombocytopenia.

Liver/Biliary:Abnormal liver function including hepatitis and cholestatic jaundice, as well as rare cases of hepatic necrosis and hepatic failure, some of which have resulted in death.

Nervous System:Convulsions, dizziness/vertigo, headache, somnolence, hyperactivity, nervousness, agitation and syncope.

Psychiatric:Aggressive reaction and anxiety.

Skin/Appendages:Pruritus, rarely serious skin reactions including erythema multiforme, Stevens Johnson Syndrome and toxic epidermal necrolysis.

Special Senses:Hearing disturbances including hearing loss, deafness and/or tinnitus and rare reports of taste perversion.

Laboratory Abnormalities

Adults

* DUE TO THE INDICATED ORGANISMS (See INDICATIONS AND USAGE.)
Infection*	Recommended Dose/Duration of Therapy
Community-acquired pneumonia (mild severity) Pharyngitis/tonsillitis (second line therapy) Skin/skin structure (uncomplicated)	500 mg as a single dose on Day 1, followed by 250 mg once daily on Days 2 through 5.
Acute bacterial exacerbations of chronic obstructive pulmonary disease (mild to moderate)	500 mg QD x 3 days OR 500 mg as a single dose on Day 1, followed by 250 mg once daily on Days 2 through 5.
Acute bacterial sinusitis	500 mg QD x 3 days
Genital ulcer disease (chancroid)	One single 1 gram dose
Non-gonoccocal urethritis and cervicitis	One single 1 gram dose
Gonococcal urethritis and cervicitis	One single 2 gram dose

Azithromycin tablets can be taken with or without food.

Renal Insufficiency: No dosage adjustment is recommended for subjects with renal impairment (GFR ≤80 mL/min). The mean AUC0-120 was similar in subjects with GFR 10-80 mL/min compared to subjects with normal renal function, whereas it increased 35% in subjects with GFR <10 mL/min compared to subjects with normal renal function. Caution should be exercised when azithromycin is administered to subjects with severe renal impairment. (See CLINICAL PHARMACOLOGY, Special Populations, Renal Insufficiency.)

Hepatic Insufficiency: The pharmacokinetics of azithromycin in subjects with hepatic impairment has not been established. No dose adjustment recommendations can be made in patients with impaired hepatic function (See CLINICAL PHARMACOLOGY, Special Populations, Hepatic Insufficiency.)

No dosage adjustment is recommended based on age or gender. (See CLINICAL

PHARMACOLOGY, Special Populations.)

Pediatric Patients

Azithromycin for oral suspension can be taken with or without food.

Acute Otitis Media: The recommended dose of azithromycin for oral suspension for the treatment of pediatric patients with acute otitis media is 30 mg/kg given as a single dose or 10 mg/kg once daily for 3 days or 10 mg/kg as a single dose on the first day followed by 5 mg/kg/day on Days 2 through 5. (See chart below.)

Acute Bacterial Sinusitis:The recommended dose of azithromycin for oral suspension for the treatment of pediatric patients with acute bacterial sinusitis is 10 mg/kg once daily for 3 days. (See chart below.)

Community-Acquired Pneumonia:The recommended dose of Azithromycin for oral suspension for the treatment of pediatric patients with community-acquired pneumonia is 10 mg/kg as a single dose on the first day followed by 5 mg/kg on Days 2 through 5. (See chart below.)

PEDIATRIC DOSAGE GUIDELINES FOR OTITIS MEDIA, ACUTE BACTERIAL SINUSITIS AND COMMUNITY - ACQUIRED PNEUMONIA (Age 6 months and above, see PRECAUTIONS - Pediatric Use.) Based on Body Weight

* Effectiveness of the 3-day or 1-day regimen in pediatric patients with community-acquired pneumonia has not been established.
OTITIS MEDIA AND COMMUNITY-ACQUIRED PNEUMONIA: (5-Day Regimen)*
Dosing Calculated on 10 mg/kg/day Day 1 and 5 mg/kg/day Days 2 to 5.
Weight		100 mg/5 mL		200 mg/5 mL		Total mL per Treatment Course	Total mg per Treatment Course
Kg	Lbs.	Day 1	Days 2-5	Day 1	Days 2-5
5	11	2.5 mL (½ tsp)	1.25 mL (¼ tsp)			7.5 mL	150 mg
10	22	5 mL (1 tsp)	2.5 mL (½ tsp)			15 mL	300 mg
20	44			5 mL (1 tsp)	2.5 mL (½ tsp)	15 mL	600 mg
30	66			7.5 mL (1½ tsp)	3.75 mL (¾ tsp)	22.5 mL	900 mg
40	88			10 mL (2 tsp)	5 mL (1 tsp)	30 mL	1200 mg
50 and above	110 and above			12.5 mL (2½ tsp)	6.25 mL (1¼ tsp)	37.5 mL	1500 mg

* Effectiveness of the 5-day or 1-day regimen in pediatric patients with acute bacterial sinusitis has not been established.
OTITIS MEDIA AND ACUTE BACTERIAL SINUSITIS: (3-Day Regimen)*
Dosing Calculated on 10 mg/kg/day
Weight		100 mg/5 mL	200 mg/5 mL	Total mL per Treatment Course	Total mg per Treatment Course
Kg	Lbs.	Day 1-3	Day 1-3
5	11	2.5 mL (½ tsp)		7.5 mL	150 mg
10	22	5 mL (1 tsp)		15 mL	300 mg
20	44		5 mL (1 tsp)	15 mL	600 mg
30	66		7.5 mL (1½ tsp)	22.5 mL	900 mg
40	88		10 mL (2 tsp)	30 mL	1200 mg
50 and above	110 and above		12.5 mL (2½ tsp)	37.5 mL	1500 mg

OTITIS MEDIA: (1-Day Regimen)
Dosing Calculated on 30 mg/kg as a single dose
Weight		200 mg/5 mL	Total mL per Treatment Course	Total mg per Treatment Course
Kg	Lbs.	Day 1
5	11	3.75 mL (¾ tsp)	3.75 mL	150 mg
10	22	7.5 mL (1½ tsp)	7.5 mL	300 mg
20	44	15 mL (3 tsp)	15 mL	600 mg
30	66	22.5 mL (4½ tsp)	22.5 mL	900 mg
40	88	30 mL (6 tsp)	30 mL	1200 mg
50 and above	110 and above	37.5 mL (7½ tsp)	37.5 mL	1500 mg

The safety of re-dosing azithromycin in pediatric patients who vomit after receiving 30 mg/kg as a single dose has not been established. In clinical studies involving 487 patients with acute otitis media given a single 30 mg/kg dose of azithromycin, eight patients who vomited within 30 minutes of dosing were re-dosed at the same total dose.

Pharyngitis/Tonsillitis: The recommended dose of azithromycin for children with pharyngitis/tonsillitis is 12 mg/kg once daily for 5 days. (See chart below.)

PEDIATRIC DOSAGE GUIDELINES FOR PHARYNGITIS/TONSILLITIS (Age 2 years and above, see PRECAUTIONS - Pediatric Use.) Based on Body Weight

PHARYNGITIS/TONSILLITIS: (5-Day Regimen)
Dosing Calculated on 12 mg/kg/day for 5 days.
Weight		200 mg/5 mL	Total mL per Treatment Course	Total mg per Treatment Course
Kg	Lbs.	Day 1-5
8	18	2.5 mL (½ tsp)	12.5 mL	500 mg
17	37	5 mL (1 tsp)	25 mL	1000 mg
25	55	7.5 mL (1½ tsp)	37.5 mL	1500 mg
33	73	10 mL (2 tsp)	50 mL	2000 mg
40	88	12.5 mL (2½ tsp)	62.5 mL	2500 mg

Constituting instructions for Azithromycin Oral Suspension, 300, 600, 900, 1200 mg bottles. The table below indicates the volume of water to be used for constitution:

Amount of water to be added	Total volume after constitution (azithromycin content)	Azithromycin concentration after constitution
9 mL (300 mg) 9 mL (600 mg) 12 mL (900 mg) 15 mL (1200 mg)	15 mL (300 mg) 15 mL (600 mg) 22.5 mL (900 mg) 30 mL (1200 mg)	100 mg/5 mL 200 mg/5 mL 200 mg/5 mL 200 mg/5 mL

 Shake well before each use. Oversized bottle provides shake space. Keep tightly closed.

After mixing, store suspension at 5°to 30°C (41°to 86°F) and use within 10 days. Discard after full dosing is completed.

CLINICAL STUDIES

(SeeINDICATIONS AND USAGEandPediatric Patients.)

Pediatric Patients

From the perspective of evaluating pediatric clinical trials, Days 11-14 were considered

on-therapy evaluations because of the extended half-life of azithromycin. Day 11-14 data are provided for clinical guidance. Day 24-32 evaluations were considered the primary test of cure endpoint.

Acute Otitis Media

Safety and efficacy using azithromycin 30 mg/kg given over 5 days

Protocol 1

In a double-blind, controlled clinical study of acute otitis media performed in the United States, azithromycin (10 mg/kg on Day 1 followed by 5 mg/kg on Days 2-5) was compared to amoxicillin/clavulanate potassium (4:1). For the 553 patients who were evaluated for clinical efficacy, the clinical success rate (i.e., cure plus improvement) at the Day 11 visit was 88% for azithromycin and 88% for the control agent. For the 521 patients who were evaluated at the Day 30 visit, the clinical success rate was 73% for azithromycin and 71% for the control agent.

In the safety analysis of the above study, the incidence of treatment-related adverse events, primarily gastrointestinal, in all patients treated was 9% with azithromycin and 31% with the control agent. The most common side effects were diarrhea/loose stools (4% azithromycin vs. 20% control), vomiting (2% azithromycin vs. 7% control), and abdominal pain (2% azithromycin vs. 5% control).

Protocol 2

In a non-comparative clinical and microbiologic trial performed in the United States, where significant rates of beta-lactamase producing organisms (35%) were found, 131 patients were evaluable for clinical efficacy. The combined clinical success rate (i.e., cure and improvement) at the Day 11 visit was 84% for azithromycin. For the 122 patients who were evaluated at the Day 30 visit, the clinical success rate was 70% for azithromycin.

Microbiologic determinations were made at the pre-treatment visit. Microbiology was not reassessed at later visits. The following presumptive bacterial/clinical cure outcomes (i.e., clinical success) were obtained from the evaluable group:

Presumed Bacteriologic Eradication

	Day 11	Day 30
	Azithromycin	Azithromycin
S. pneumoniae	61/74 (82%)	40/56 (71%)
H. influenzae	43/54 (80%)	30/47 (64%)
M. catarrhalis	28/35 (80%)	19/26 (73%)
S. pyogenes	11/11 (100%)	7/7
Overall	177/217 (82%)	97/137 (73%)

In the safety analysis of this study, the incidence of treatment-related adverse events, primarily gastrointestinal, in all patients treated was 9%. The most common side effect was diarrhea (4%).

Protocol 3

In another controlled comparative clinical and microbiologic study of otitis media performed in the United States, azithromycin was compared to amoxicillin/clavulanate potassium (4:1). This study utilized two of the same investigators as Protocol 2 (above), and these two investigators enrolled 90% of the patients in Protocol 3. For this reason,

Protocol 3 was not considered to be an independent study. Significant rates of beta-lactamase producing organisms (20%) were found. Ninety-two (92) patients were evaluable for clinical and microbiologic efficacy. The combined clinical success rate (i.e., cure and improvement) of those patients with a baseline pathogen at the Day 11 visit was 88% for azithromycin vs. 100% for control; at the Day 30 visit, the clinical success rate was 82% for azithromycin vs. 80% for control.

Microbiologic determinations were made at the pre-treatment visit. Microbiology was not reassessed at later visits. At the Day 11 and Day 30 visits, the following presumptive bacterial/clinical cure outcomes (i.e., clinical success) were obtained from the evaluable group:

Presumed Bacteriologic Eradication

	Day 11		Day 30
	Azithromycin	Control	Azithromycin	Control
S. pneumoniae	25/29 (86%)	26/26 (100%)	22/28 (79%)	18/22 (82%)
H. influenzae	9/11 (82%)	9/9	8/10 (80%)	6/8
M. catarrhalis	7/7	5/5	5/5	2/3
S. pyogenes	2/2	5/5	2/2	4/4
Overall	43/49 (88%)	45/45 (100%)	37/45 (82%)	30/37 (81%)

In the safety analysis of the above study, the incidence of treatment-related adverse events, primarily gastrointestinal, in all patients treated was 4% with azithromycin and 31% with the control agent. The most common side effect was diarrhea/loose stools (2% azithromycin vs. 29% control).

Safety and efficacy using azithromycin 30 mg/kg given over 3 days

Protocol 4

In a double-blind, controlled, randomized clinical study of acute otitis media in pediatric patients from 6 months to 12 years of age, azithromycin (10 mg/kg per day for 3 days) was compared to amoxicillin/clavulanate potassium (7:1) in divided doses q12h for 10 days. Each patient received active drug and placebo matched for the comparator.

For the 366 patients who were evaluated for clinical efficacy at the Day 12 visit, the clinical success rate (i.e., cure plus improvement) was 83% for azithromycin and 88% for the control agent. For the 362 patients who were evaluated at the Day 24-28 visit, the clinical success rate was 74% for azithromycin and 69% for the control agent.

In the safety analysis of the above study, the incidence of treatment-related adverse events, primarily gastrointestinal, in all patients treated was 10.6% with azithromycin and 20.0% with the control agent. The most common side effects were diarrhea/loose stools (5.9% azithromycin vs. 14.6% control), vomiting (2.1% azithromycin vs. 1.1% control), and rash (0.0% azithromycin vs. 4.3% control).

Safety and efficacy using azithromycin 30 mg/kg given as a single dose

Protocol 5

A double blind, controlled, randomized trial was performed at nine clinical centers. Pediatric patients from 6 months to 12 years of age were randomized 1:1 to treatment with either azithromycin (given at 30 mg/kg as a single dose on Day 1) or amoxicillin/clavulanate potassium (7:1), divided q12h for 10 days. Each child received active drug, and placebo matched for the comparator.

Clinical response (Cure, Improvement, Failure) was evaluated at End of Therapy (Day 12-16) and Test of Cure (Day 28-32). Safety was evaluated throughout the trial for all treated subjects. For the 321 subjects who were evaluated at End of Treatment, the clinical success rate (cure plus improvement) was 87% for azithromycin, and 88% for the comparator. For the 305 subjects who were evaluated at Test of Cure, the clinical success rate was 75% for both azithromycin and the comparator.

In the safety analysis, the incidence of treatment-related adverse events, primarily gastrointestinal, was 16.8% with azithromycin, and 22.5% with the comparator. The most common side effects were diarrhea (6.4% with azithromycin vs. 12.7% with the comparator), vomiting (4% with each agent), rash (1.7% with azithromycin vs. 5.2% with the comparator) and nausea (1.7% with azithromycin vs. 1.2% with the comparator).

Protocol 6

In a non-comparative clinical and microbiological trial, 248 patients from 6 months to 12 years of age with documented acute otitis media were dosed with a single oral dose of azithromycin (30 mg/kg on Day 1).

For the 240 patients who were evaluable for clinical modified Intent-to-Treat (MITT) analysis, the clinical success rate (i.e., cure plus improvement) at Day 10 was 89% and for the 242 patients evaluable at Day 24-28, the clinical success rate (cure) was 85%.

Presumed Bacteriologic Eradication

	Day 10	Day 24-28
S. pneumoniae	70/76 (92%)	67/76 (88%)
H. influenzae	30/42 (71%)	28/44 (64%)
M. catarrhalis	10/10 (100%)	10/10 (100%)
Overall	110/128 (86%)	105/130 (81%)

In the safety analysis of this study, the incidence of treatment-related adverse events, primarily gastrointestinal, in all the subjects treated was 12.1%. The most common side effects were vomiting (5.6%), diarrhea (3.2%), and abdominal pain (1.6%).

Pharyngitis/Tonsillitis

In three double-blind controlled studies, conducted in the United States, azithromycin (12 mg/kg once a day for 5 days) was compared to penicillin V (250 mg three times a day for 10 days) in the treatment of pharyngitis due to documented Group A β-hemolytic streptococci (GABHS or S. pyogenes). Azithromycin was clinically and microbiologically statistically superior to penicillin at Day 14 and Day 30 with the following clinical success (i.e., cure and improvement) and bacteriologic efficacy rates (for the combined evaluable patient with documented GABHS):

Three U.S. Streptococcal Pharyngitis Studies, Azithromycin vs. Penicillin V, EFFICACY RESULTS

	Day 14	Day 30
Bacteriologic Eradication:
Azithromycin	323/340 (95%)	255/330 (77%)
Penicillin V	242/332 (73%)	206/325 (63%)
Clinical Success (Cure plus improvement):
Azithromycin	336/343 (98%)	310/330 (94%)
Penicillin V	284/338 (84%)	241/325 (74%)

Approximately 1% of azithromycin-susceptible S. pyogenes isolates were resistant to

azithromycin following therapy.

The incidence of treatment-related adverse events, primarily gastrointestinal, in all patients treated was 18% on azithromycin and 13% on penicillin. The most common side effects were diarrhea/loose stools (6% azithromycin vs. 2% penicillin), vomiting (6% azithromycin vs. 4% penicillin), and abdominal pain (3% azithromycin vs. 1% penicillin).

Adult Patients

In a randomized, double-blind controlled clinical trial of acute exacerbation of chronic bronchitis (AECB), azithromycin (500 mg once daily for 3 days) was compared with clarithromycin (500 mg twice daily for 10 days). The primary endpoint of this trial was the clinical cure rate at Day 21- 24. For the 304 patients analyzed in the modified intent to treat analysis at the Day 21-24 visit, the clinical cure rate for 3 days of azithromycin was 85% (125/147) compared to 82% (129/157) for 10 days of clarithromycin.

The following outcomes were the clinical cure rates at the Day 21-24 visit for the

bacteriologically evaluable patients by pathogen:

Pathogen	Azithromycin	Clarithromycin
	(3 Days)	(10 Days)
S. pneumoniae	29/32 (91%)	21/27 (78%)
H. influenzae	12/14 (86%)	14/16 (88%)
M. catarrhalis	11/12 (92%)	12/15 (80%)

In the safety analysis of this study, the incidence of treatment-related adverse events, primarily gastrointestinal, were comparable between treatment arms (25% with azithromycin and 29% with clarithromycin). The most common side effects were diarrhea, nausea and abdominal pain with comparable incidence rates for each symptom of 5-9% between the two treatment arms. (See ADVERSE REACTIONS.)

Acute Bacterial Sinusitis

In a randomized, double blind, double dummy controlled clinical trial of acute bacterial sinusitis; azithromycin (500 mg once daily for 3 days) was compared with amoxicillin/clavulanate (500/125 mg tid for 10 days). Clinical response assessments were made at Day 10 and Day 28. The primary endpoint of this trial was prospectively defined as the clinical cure rate at Day 28. For the 594 patients analyzed in the modified intent to treat analysis at the Day 10 visit, the clinical cure rate for 3 days of azithromycin was 88% (268/303) compared to 85% (248/291) for 10 days of amoxicillin/clavulanate. For the 586 patients analyzed in the modified intent to treat analysis at the Day 28 visit, the clinical cure rate for 3 days of azithromycin was 71.5% (213/298) compared to 71.5% (206/288), with a 97.5% confidence interval of –8.4 to 8.3, for 10 days of amoxicillin/clavulanate.

In the safety analysis of this study, the overall incidence of treatment-related adverse events, primarily gastrointestinal, was lower in the azithromycin treatment arm (31%) than in the amoxicillin/clavulanate arm (51%). The most common side effects were diarrhea

(17% in the azithromycin arm vs. 32% in the amoxicillin/clavulanate arm), and nausea (7% in the azithromycin arm vs. 12% in the amoxicillin/clavulanate arm). (See ADVERSE REACTIONS).

In an open label, noncomparative study requiring baseline transantral sinus punctures the following outcomes were the clinical success rates at the Day 7 and Day 28 visits for the modified intent to treat patients administered 500 mg of azithromycin once daily for 3 days with the following pathogens:

Pathogen	Azithromycin (500 mg per day for 3 Days)
	Day 7	Day 28
S. pneumoniae	23/26 (88%)	21/25 (84%)
H. influenzae	28/32 (87%)	24/32 (75%)
M. catarrhalis	14/15 (93%)	13/15 (87%)

The overall incidence of treatment-related adverse events in the noncomparative study was 21% in modified intent to treat patients treated with azithromycin at 500 mg once daily for 3 days with the most common side effects being diarrhea (9%), abdominal pain (4%) and nausea (3%). (See ADVERSE REACTIONS).