Azithromycin 500 mg · Dry-powder injectables

Azithromycin is a macrolide antibacterial drug [see Microbiology (12.4)] — Based on animal models of infection, the antibacterial activity of azithromycin appears to correlate with the ratio of area under the concentration-time curve to minimum inhibitory concentration (AUC/MIC) for certain pathogens (S. pneumoniae and S. aureus). The principal pharmacokinetic/pharmacodynamic parameter best associated with clinical and microbiological cure has not been elucidated in clinical trials with azithromycin.

Cardiac Electrophysiology — QTc interval prolongation was studied in a randomized, placebo-controlled parallel trial in 116 healthy subjects who received either chloroquine (1,000 mg) alone or in combination with oral azithromycin (500 mg, 1,000 mg, and 1,500 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, 1,000 mg and 1,500 mg azithromycin, respectively.

Since the mean Cmax of azithromycin following a 500 mg IV dose given over 1 hr is higher than the mean Cmax of azithromycin following the administration of a 1,500 mg oral dose, it is possible that QTc may be prolonged to a greater extent with IV azithromycin at close proximity to a one hour infusion of 500 mg.

In patients hospitalized with community-acquired pneumonia receiving single daily one-hour intravenous infusions for 2 to 5 days of 500 mg azithromycin at a concentration of 2 mg/mL, the mean Cmax ± S.D. achieved was 3.63 ± 1.60 mcg/mL, while the 24-hour trough level was 0.20 ± 0.15 mcg/mL, and the AUC24 was 9.60 ± 4.80 mcg·hr/mL.

The mean Cmax, 24-hour trough and AUC24 values were 1.14 ± 0.14 mcg/mL, 0.18 ± 0.02 mcg/mL, and 8.03 ± 0.86 mcg· hr/mL, respectively, in normal volunteers receiving a 3-hour intravenous infusion of 500 mg azithromycin at a concentration of 1 mg/mL. Similar pharmacokinetic values were obtained in patients hospitalized with community-acquired pneumonia who received the same 3-hour dosage regimen for 2 to 5 days.

a500 mg (2 mg/mL) for 2 to 5 days in community-acquired pneumonia patients.

Comparison of the plasma pharmacokinetic parameters following the 1st and 5th daily doses of 500 mg intravenous azithromycin showed only an 8% increase in Cmax but a 61% increase in AUC24 reflecting a threefold rise in C24 trough levels.

Following single-oral doses of 500 mg azithromycin (two 250 mg capsules) to 12 healthy volunteers, Cmax , trough level, and AUC24 were reported to be 0.41 mcg/mL, 0.05 mcg/mL, and 2.6 mcg·hr/mL, respectively. These oral values are approximately 38%, 83%, and 52% of the values observed following a single 500-mg I.V. 3-hour infusion (Cmax : 1.08 mcg/mL, trough: 0.06 mcg/mL, and AUC24: 5 mcg·hr/mL). Thus, plasma concentrations are higher following the intravenous regimen throughout the 24-hour interval.

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.

Tissue concentrations have not been obtained following intravenous infusions of azithromycin, but following oral administration in humans azithromycin has been shown to penetrate into tissues, including skin, lung, tonsil, and cervix.

Tissue levels were determined following a single oral dose of 500 mg azithromycin in 7 gynecological patients. Approximately 17 hr after dosing, azithromycin concentrations were 2.7 mcg/g in ovarian tissue, 3.5 mcg/g in uterine tissue, and 3.3 mcg/g in salpinx. Following a regimen of 500 mg on the first day followed by 250 mg daily for 4 days, concentrations in the cerebrospinal fluid were 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.

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

In a multiple-dose study in 12 normal volunteers utilizing a 500 mg (1 mg/mL) one-hour intravenous-dosage regimen for five days, the amount of administered azithromycin dose excreted in urine in 24 hr was about 11% after the 1st dose and 14% after the 5th dose. These values are greater than the reported 6% excreted unchanged in urine after oral administration of azithromycin. Biliary excretion is a major route of elimination for unchanged drug, following oral administration.

Patients with Renal Impairment — 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 GFR 10 to 80 mL/min compared to subjects with GFR >80 mL/min. The mean Cmax and AUC0-120 increased 61% and 35%, respectively in subjects with GFR <10 mL/min compared to subjects with GFR >80 mL/min.

Patients with Hepatic Impairment — The pharmacokinetics of azithromycin in subjects with hepatic impairment has not been established.

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