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Zithromax

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Zithromax

Zithromax

CLINICAL PHARMACOLOGY

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) μg·h/mL; Cmax = 0.5 (0.2) μg/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 (μg/mL) 0.41 0.24
Tmax (h) 2.5 3.2
AUC0-24 (μg•h/mL) 2.6 2.1
Cmin (μg/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.

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

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 μg/mL to 7% at 2 μg/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 ADULTS1

TISSUE OR FLUID TIME AFTER DOSE (h) TISSUE OR FLUID CONCENTRATION (μg/g or μg/mL) CORRESPONDING PLASMA OR SERUM LEVEL (μg/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
1Azithromycin 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.

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 μg/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

Renal Insufficiency

Azithromycin pharmacokinetics were investigated in 42 adults (21 to 85 years of age) with varying degrees of renal impairment. Following the oral administration of a single 1,000 mg dose of azithromycin, mean Cmax and AUC0-120 increased by 5.1% and 4.2%, respectively in subjects with mild to moderate renal impairment (GFR 10 to 80 mL/min) compared to subjects with normal renal function (GFR > 80 mL/min). The mean Cmax and AUC0-120 increased 61% and 35%, respectively in subjects with severe renal impairment (GFR < 10 mL/min) compared to subjects with normal renal function (GFR > 80 mL/min). (See DOSAGE AND ADMINISTRATION.)

Hepatic Insufficiency

The pharmacokinetics of azithromycin in subjects with hepatic impairment have not been established.

Gender

There are no significant differences in the disposition of azithromycin between male and female subjects. No dosage adjustment is recommended based on gender.

Geriatric Patients

When studied in healthy elderly subjects aged 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.

Pediatric Patients

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 pediatric patients (aged 1-5 years and 5-15 years, respectively). The mean pharmacokinetic parameters on day 5 were Cmax=0.216 μg/mL, Tmax=1.9 hours, and AUC0-24=1.822 μg·hr/mL for the 1-to 5-year-old group and were Cmax=0.383 μg/mL, Tmax=2.4 hours, and AUC0-24=3.109 μg·hr/mL for the 5-to 15-year-old group.

Two clinical studies were conducted in 68 pediatric patients aged 3-16 years to determine the pharmacokinetics and safety of azithromycin for oral suspension. Azithromycin was administered following a low-fat breakfast.

The first study consisted of 35 pediatric patients treated with 20 mg/kg/day (maximum daily dose 500 mg) for 3 days of whom 34 patients were evaluated for pharmacokinetics.

In the second study, 33 pediatric patients received doses of 12 mg/kg/day (maximum daily dose 500 mg) for 5 days of whom 31 patients were evaluated for pharmacokinetics.

In both studies, azithromycin concentrations were determined over a 24 hour period following the last daily dose. Patients weighing above 25.0 kg in the 3-day study or 41.7 kg in the 5-day study received the maximum adult daily dose of 500 mg. Eleven patients (weighing 25.0 kg or less) in the first study and 17 patients (weighing 41.7 kg or less) in the second study received a total dose of 60 mg/kg. The following table shows pharmacokinetic data in the subset of pediatric patients who received a total dose of 60 mg/kg.

Pharmacokinetic Parameter [mean (SD)] 3-Day Regimen (20 mg/kg x 3 days) 5-Day Regimen (12 mg/kg x 5 days)
n 11 17
Cmax (μg/mL) 1.1 (0.4) 0.5 (0.4)
Tmax (hr) 2.7 (1.9) 2.2 (0.8)
AUC0-24μg•hr/mL) 7.9 (2.9) 3.9 (1.9)

The similarity of the overall exposure (AUC0-∞) between the 3-day and 5-day regimens in pediatric patients is unknown.

Single dose pharmacokinetics in pediatric patients given doses of 30 mg/kg have not been studied. (See DOSAGE AND ADMINISTRATION.)

Drug-Drug Interactions

Drug interaction studies were performed with azithromycin and other drugs likely to be co­administered. 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

Co-administered Drug Dose of Co­administered Drug Dose of Azithromycin n Ratio (with/without azithromycin) of Co-administered Drug Pharmacokinetic Parameters (90% CI); No Effect = 1.00
Mean Cmax Mean AUC
Atorvastatin 10 mg/day x 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 x 2 days, then 200 mg BID x 18 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 x 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 x 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 x 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 x 3 days 12 1.27
(0.89 to 1.81)
1.26
(1.01 to 1.56)
Nelfinavir 750 mg TID x 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 x 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 x 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 x 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/ Sulfamethoxazole 160 mg/800 mg/day PO x 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 x 21 days 600 mg/day PO x 14 days 5 1.12
(0.42 to 3.02)
0.94
(0.52 to 1.70)
Zidovudine 500 mg/day PO x 21 days 1,200 mg/day PO x 14 days 4 1.31
(0.43 to 3.97)
1.30
(0.69 to 2.43)
NA -Not Available
* -90% Confidence interval not reported
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 Co­administered Drugs (See PRECAUTIONS: DRUG INTERACTIONS.)

Co-administered Drug Dose of Co­administered Drug Dose of Azithromycin n Ratio (with/without co-administered drug) of Azithromycin Pharmacokinetic Parameters (90% CI); No Effect = 1.00
Mean Cmax Mean AUC
Efavirenz 400 mg/day x 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 x 11 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 x 10 days 500 mg PO on day 1, then 250 mg/day on days 2­10 6 See footnote below NA
NA – Not available
* -90% Confidence interval not reported
Mean azithromycin concentrations one day after the last dose were 53 ng/mL when coadministered with 300 mg daily rifabutin and 49 ng/mL when coadministered with placebo.

Pharmacodynamics

Cardiac Electrophysiology

QTc interval prolongation was studied in a randomized, placebo-controlled parallel trial in 116 healthy subjects who received either chloroquine (1000 mg) alone or in combination with azithromycin (500 mg, 1000 mg, and 1500 mg once daily). Co-administration of azithromycin increased the QTc interval in a dose-and concentration-dependent manner. In comparison to chloroquine alone, the maximum mean (95% upper confidence bound) increases in QTcF were 5 (10) ms, 7 (12) ms and 9 (14) ms with the co-administration of 500 mg, 1000 mg and 1500 mg azithromycin, respectively.

Microbiology

Mechanism of Action

Azithromycin binds to the 23S rRNA of the bacterial 50S ribosomal subunit. It blocks protein synthesis by inhibiting the transpeptidation/translocation step of protein synthesis and by inhibiting the assembly of the 50S ribosomal subunit.

Azithromycin concentrates in phagocytes and fibroblasts as demonstrated by in vitro incubation techniques.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.

Mechanism of Resistance

The most frequently encountered mechanism of resistance to azithromycin is modification of the 23S rRNA at positions corresponding to A2058 and A2059 in the Escherichia coli numbering system. In addition to cross resistance with other macrolides (erythromycin and clarithromycin), ribosomal modification may determine resistance to other antibiotic classes (lincosamides and streptogramins B) that bind to overlapping ribosomal sites. Azithromycin has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections [see INDICATIONS AND USAGE].

Gram-positive bacteria

Staphylococcus aureus
Streptococcus agalactiae

Streptococcus pneumoniae

Streptococcus pyogenes

Gram-negative bacteria

Haemophilus ducreyi
Haemophilus influenzae

Moraxella catarrhalis

Neisseria gonorrhoeae

“Other” bacteria

Chlamydophila pneumoniae
Chlamydia trachomatis

Mycoplasma pneumoniae

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

At least 90% of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the azithromycin susceptible breakpoint of ≤ 4mcg/mL. However, safety and effectiveness of azithromycin in treating clinical infections due to these bacteria have not been established in adequate and well-controlled trials.

Gram-positive bacteria

Beta-hemolytic streptococci (Groups C, F, G)
Viridans group streptococci

Gram-negative bacteria

Bordetella pertussis

Anaerobic bacteria

Peptostreptococcus species
Prevotella bivia

“Other” bacteria

Ureaplasma urealyticum
Legionella pneumophila

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 method1,2 (broth or agar) or equivalent with standardized inoculum concentration and standardized concentration of azithromycin powder. The MIC values should be interpreted according to criteria provided in Table 3.

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 concentration. This procedure uses paper disks impregnated with 15-mcg azithromycin to test the susceptibility of bacteria to azithromycin. The disk diffusion interpretive criteria are provided in Table 3.

Table 3: Susceptibility Test Interpretive Criteria for Azithromycin Susceptibility Test Result Interpretive Criteria

  Minimum Inhibitory Concentrations (mcg/mL) Disk Diffusion (zone diameters in
mm)
S I R S I R
Haemophilus influenzaea ≤ 4 ≥ 12
Staphylococcus aureus ≤ 2 4 ≥ 8 ≥ 18 14-17 ≤ 13
Streptococci including S. pneumoniae ≤ 0.5 1 ≥ 2 ≥ 18 14-17 ≤ 13
Susceptibility to azithromycin must be tested in ambient air.
aInsufficient information is available to determine Intermediate or Resistant interpretive criteria The ability to correlate MIC values and plasma drug levels is difficult as azithromycin concentrates in macrophages and tissues [see CLINICAL PHARMACOLOGY].

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 laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individual performing the test. Standard azithromycin powder should provide the following range of MIC values noted in Table 4. For the diffusion technique using the azithromycin 15 mcg disk, the criteria in Table 4 should be achieved.

Table 4: Acceptable Quality Control Ranges for Azithromycin

QC Strain Minimum Inhibitory Concentrations (mcg/mL) Disk Diffusion (zone diameters in mm)
Haemophilus influenzae ATCC* 49247 1.0-4.0 13-21
Staphylococcus aureus ATCC 29213 0.5-2.0
Staphylococcus aureus ATCC 25923 21-26
Streptococcus pneumoniae ATCC 49619 0.06-0.25 19-25
Susceptibility to azithromycin must be tested in ambient air.
*ATCC = American Type Culture Collection

Clinical Studies

(See INDICATIONS AND USAGE and Pediatric Use.)

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 Azithromycin Day 30 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 0/76 (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

Acute Bacterial Exacerbations of Chronic Obstructive Pulmonary Disease

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 (3 Days) Clarithromycin(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 Day28
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).

Animal Toxicology

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 the basis of mg/m², are approximately equal to the recommended adult human dose, and in rats treated at doses approximately one-sixth of the recommended adult human dose. This effect has been shown to be 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 Cmax value of 1.3 μg/mL (six times greater than the observed Cmax of 0.216 μg/mL at the pediatric dose of 10 mg/kg). Similarly, it has been shown in the dog (10 mg/kg dose) at observed Cmax value of 1.5 μg/mL (seven times greater than the observed same Cmax and drug dose in the studied pediatric population). On a mg/m² basis, 30 mg/kg dose in the neonatal rat (135 mg/m²) and 10 mg/kg dose in the neonatal dog (79 mg/m²) are approximately 0.5 and 0.3 times, respectively, the recommended dose in the pediatric patients with an average body weight of 25 kg. Phospholipidosis, 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.

Distributed by: Pfizer Labs, Division of Pfizer Inc, NY, NY 10017. Revised January 2013

REFERENCES

1. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard -Ninth Edition. CLSI document M07-A9. CLSI 950 West Valley Rd, Suite 250, Wayne, PA 19087, 2012.

2. CLSI, Performance Standards for Antimicrobial Susceptibility Testing; Twenty-Second Informational Supplement. CLSI document M100-S22. CLSI, Wayne, PA 19087, 2012.

3. CLSI. Performance Standards for Antimicrobial Disk Susceptibility Tests; Approved Standard ­Eleventh Edition. CLSI document M02-A11. CLSI, Wayne, PA 19087, 2012.

Last reviewed on RxList: 3/12/2013
This monograph has been modified to include the generic and brand name in many instances.

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