(azithromycin tablets and azithromycin for oral suspension) contain the active ingredient azithromycin, an azalide, a subclass of macrolide antibiotics, for oral administration.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of ZITHROMAX® (azithromycin) and other bacterial drugs, ZITHROMAX (azithromycin) should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

                        

                           Distribution

The serum protein binding of azithromycin is variable in the concentration range approximating human exposure, decreasing from 51% at 0.02 ?g/mL to 7% at 2 ?g/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.
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.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 ?g/mL) in the presence of
non-inflamed meninges.

Special Populations

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).
The pharmacokinetics of azithromycin in subjects with hepatic impairment have not been
established.
There are no significant differences in the disposition of azithromycin between male and female
subjects. No dosage adjustment is recommended based on gender.
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.
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.
The similarity of the overall exposure 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.

Drug-Drug Interactions

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