Azithromycin

AZITHROMYCIN- azithromycin monohydrate tablet, film coated
McKesson Packaging Services a Business Unit of McKesson Corporation

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 bacteria.

DESCRIPTION

Azithromycin tablets, USP contain the active ingredient azithromycin, an azalide, a subclass of macrolide antibiotics, for oral administration. Azithromycin has the chemical name (2R,3S,4R,5R,8R,10R, 11R,12S,13S,14R) -13-[(2,6-dideoxy-3-C -methyl-3-O -methyl-α-L-ribo -hexopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo -hexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one. Azithromycin is derived from erythromycin; however, it differs chemically from erythromycin in that a methyl-substituted nitrogen atom is incorporated into the lactone ring. Its molecular formula is C38 H72 N2 O12 , and its molecular weight is 749. Azithromycin has the following structural formula:

structure
(click image for full-size original)

Azithromycin, as the monohydrate, is a white crystalline powder with a molecular formula of C38 H72 N2 O12 •H2 O and a molecular weight of 767.

Each azithromycin tablet, intended for oral administration, contains azithromycin monohydrate equivalent to either 250 mg or 500 mg of azithromycin. In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, lecithin, magnesium stearate, microcrystalline cellulose, polyvinyl alcohol, pregelatinized starch, sodium lauryl sulfate, sodium starch glycolate, talc, titanium dioxide and xanthan gum.

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) 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 1) 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 to 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

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 to 5) or 3 days (500 mg per day for days 1 to 3). Due to limited serum samples on day 2 (3-day regimen) and days 2 to 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
*
Total AUC for the entire 3-day and 5-day regimens

Cmax (serum,

mcg/mL)

0.44 (0.22)

0.54 (0.25)

0.43 (0.2)

0.24 (0.06)

Serum AUC0-∞

(mcg•hr/mL)

17.4 (6.2)*

14.9 (3.1)*

Serum T1/2

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.


1

Azithromycin 250 mg tablets are bioequivalent to 250 mg capsules in the fasted state. Azithromycin 250 mg capsules are no longer commercially available.

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.

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