Prescription Drug Guide

Azithromycin

Pharmacokinetics

In this study (TABLE 1), there was no significant difference in the disposition of azithromycin between male and female subjects. Plasma concentrations of azithromycin following single 500 mg oral and i.v. doses declined in a polyphasic pattern resulting in an average terminal half-life of 68 hours. With a regimen of 500 mg on day 1 and 250 mg/day on days 2-5, C_min and C_max remained essentially unchanged from day 2 through day 5 of therapy. However, without a loading dose, azithromycin C_min levels required 5 to 7 days to reach steady-state.

In an open, randomized, two-way crossover study, pharmacokinetic parameters (AUC_0-72, C_max, T_max) determined from 36 fasted healthy male volunteers who received two 250 mg commercial capsules and two 250 mg tablets. (See TABLE 2.)

When azithromycin capsules were administered with food to 11 adult healthy male subjects, the rate of absorption (C_max) of azithromycin from the capsule formulation was reduced by 52% and the extent of absorption (AUC) by 43%.

In an open label, randomized, two-way crossover study in 12 healthy subjects to assess the effect of a high fat standard meal on the serum concentrations of azithromycin resulting from the oral administration of two 250 mg film-coated tablets, it was shown that food increased C_max by 23% while there was no change in AUC.

When azithromycin suspension was administered with food to 28 adult healthy male subjects, the rate of absorption (C_max) was increased by 56% while the extent of absorption (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 C_max was reduced by 24%. Administration of cimetidine (800 mg) two hours prior to azithromycin had no effect on azithromycin absorption.

When studied in healthy elderly subjects from age 65 to 85 years, the pharmacokinetic parameters of azithromycin in elderly men were similar to those in young adults; however, in elderly women, although higher peak concentrations (increased by 30 to 50%) were observed, no significant accumulation occurred.

The high values in adults for apparent steady-state volume of distribution (31.1 L/kg) and plasma clearance (630 ml/min) suggest that the prolonged half-life is due to extensive uptake and subsequent release of drug from tissues.

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.

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.

There are no pharmacokinetic data available from studies in hepatically¾ or renally¾impaired individuals.

The effect of azithromycin on the plasma levels or pharmacokinetics of theophylline administered in multiple doses adequate to reach therapeutic steady-state plasma levels is not known. (See PRECAUTIONS.)

Selected tissue (or fluid) concentration and tissue (or fluid) to plasma/serum concentration ratios are shown in TABLE 3.

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 significance 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.

Pediatric

In two clinical studies, azithromycin for oral suspension was dosed at 10 mg/kg on day 1, followed by 5 mg/kg on days 2 through 5 to two groups of children (aged 1-5 years and 5-15 years, respectively). The mean pharmacokinetic parameters at day 5 were C_max=0.216 mcg/ml, T_max=1.9 hours, and AUC_0-24=1.822 mcg´hr/ml for the 1- to 5-year-old group and were C_max=0.383 mcg/ml, T_max=2.4 hours, and AUC_0-24=3.109 mcg´hr/ml for the 5- to 15- year-old group.

There are no pharmacokinetic data on azithromycin suspension when administered at a dose of 12 mg/kg/day in the presence or absence of food. (For the pediatric pharyngitis/tonsillitis dose, see DOSAGE AND ADMINISTRATION.)

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 strains of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE.

Gram-Positive Aerobes

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.

Gram-Negative Aerobes

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.

Azithromycin exhibits in vitro minimum inhibitory concentrations (MIC's) of 0.5 mg/ml or less against most (³90%) strains of streptococci and MIC's of 2.0 mcg/ml or less against most (³90%) strains of other listed microorganisms. 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.

Gram-Positive Aerobes

Streptococci (Groups C,F,G).
Viridans group streptococci.

Gram-Negative Aerobes

Bordetella pertussis.
Legionella pneumophila.

Anaerobic Microorganisms

Peptostreptococcus species.
Prevotella bivia.

“Other” Microorganisms

Ureaplasma urealyticum.

Susceptibility Testing

Azithromycin can be solubilized for in vitro susceptibility testing using dilution techniques by dissolving in a minimum amount of 95% ethanol and diluting to the working stock concentration with broth. Further dilutions may be made in water.

Dilution Techniques

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

For testing aerobic microorganisms other than Haemophilus species, Neisseria gonorrhoeae, and streptococci, see TABLE 4.

For testing Haemophilus species,^a see TABLE 5.

_aThese interpretive standards are applicable only to broth microdilution susceptibility testing with Haemophilus species using Haemophilus Test Medium.¹

The current absence of data on resistant strains precludes defining any categories other than “Susceptible.” Strains yielding MIC results suggestive of a “nonsusceptible” category should be submitted to a reference laboratory for further testing.

For testing Streptococci including S. pneumoniae,^b see TABLE 6.

^bThese interpretive standards are applicable only to broth microdilution susceptibility tests using cation-adjusted Mueller-Hinton broth with 2-5% lysed horse blood.

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 respond to monotherapy with azithromycin. 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 achievable drug concentrations are unlikely to be inhibitory; other therapy should be selected.

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard azithromycin powder should provide the MIC values found inTABLE 7.

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

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 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 15 mg azithromycin to test the susceptibility of microorganisms to azithromycin.

Reports from the laboratory providing results of the standard single-disk susceptibility test with a 15 mg azithromycin disk should be interpreted according to the criteria in TABLE 8.

For testing aerobic microorganisms (including streptococci)^c except Haemophilus species and Neisseria gonorrhoeae, see TABLE 8.

^c These zone diameter standards for streptococci apply only to tests performed using Mueller-Hinton agar supplemented with 5% sheep blood and incubated in 5% CO₂.

For testing Haemophilus species.^d, see TABLE 9.

^d These zone diameter standards apply only to tests with Haemophilus species using Haemophilus Test Medium (HTM).²

The current absence of data on resistant strains precludes defining any categories other than “Susceptible.” Strains yielding zone diameter results suggestive of a “nonsusceptible” category should be submitted to a reference laboratory for further testing.

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

Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for azithromycin.

As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 15 mg azithromycin disk should provide the zone diameters, listed in TABLE 10, in these laboratory test quality control strains.

CLINICAL STUDIES

Pediatric

(See INDICATIONS AND USAGE, Pediatric Use.)

From the perspective of evaluating pediatric clinical trials, days 11-14 (6-9 days after completion of the five-day regimen) were considered on-therapy evaluations because of the extended half-life of azithromycin. Day 11-14 data are provided for clinical guidance. Day 30 evaluations were considered the primary test of cure endpoint.

Acute Otitis Media

Efficacy 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 an antimicrobial/beta-lactamase inhibitor. In this study, very strict evaluability criteria were used to determine clinical response and safety results were obtained. 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 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).

Efficacy Protocol 2: In a noncomparative 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 in TABLE 11.

In the safety analysis of the study in TABLE 11, the incidence of adverse events, primarily gastrointestinal, in all patients treated was 9%. The most common side effect was diarrhea (4%).

Efficacy Protocol 3: In another controlled comparative clinical and microbiologic study of otitis media performed in the United States, azithromycin was compared to an antimicrobial/beta-lactamase inhibitor. This study utilized two of the same investigators as Efficacy Protocol 2 (above), and these two investigators enrolled 90% of the patients in Efficacy Protocol 3. For this reason, Efficacy 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 presumptive bacterial/clinical cure outcomes (i.e., clinical success) were obtained from the evaluable group shown in TABLE 12.

In the safety analysis of the study in TABLE 12, the incidence of 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).

Pharyngitis/Tonsillitis

In 3 double¾blind 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 b-hemolytic streptococci (GABHS or S. pyogenes). Azithromycin was clinically and microbiologically statistically superior to penicillin at day 14 and day 30 with clinical success (i.e., cure and improvement) and bacteriologic efficacy rates (for the combined evaluable patient with documented GABHS) as shown in TABLE 13.

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

The incidence of 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).

ANIMAL PHARMACOLOGY

Phospholipidosis (intracellular phospholipid accumulation) has been observed in some tissues of mice, rats, and dogs given multiple doses of azithromycin. It has been demonstrated in numerous organ systems (e.g., eye, dorsal root ganglia, liver, gallbladder, kidney, spleen, and pancreas) in dogs treated with azithromycin at doses which, expressed on a mg/kg basis, are only 2 times greater than the recommended adult human dose and in rats at doses comparable to the recommended adult human dose. This effect has been reversible after cessation of azithromycin treatment. Phospholipidosis has been observed to a similar extent in the tissues of neonatal rats and dogs given daily doses of azithromycin ranging from 10 days to 30 days. Based on the pharmacokinetic data, phospholipidosis has been seen in the rat (30 mg/kg dose) at observed C_max value of 1.3 mg/ml (6 times greater than the observed C_max of 0.216 mg/ml at the pediatric dose of 10 mg/kg). Similarly, it has been shown in the dog (10 mg/kg dose) at observed C_max value of 1.5 mg/ml (7 times greater than the observed same C_max and drug dose in the studied pediatric population). On mg/m² basis, 30 mg/kg dose in the rat (135 mg/m²) and 10 mg/kg dose in the dog (79 mg/m²) are approximately 0.4 and 0.6 times, respectively, the recommended dose in the pediatric patients with an average body weight of 25 kg. This effect, similar to that seen in the adult animals, is reversible after cessation of azithromycin treatment. The significance of these findings for animals and for humans is unknown