Azithromycin

AZITHROMYCIN- azithromycin monohydrate powder, for suspension
MedVantx, Inc.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of azithromycin for oral suspension and other antibacterial drugs, azithromycin for oral suspension should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

DESCRIPTION

Azithromycin for Oral Suspension USP contains the active ingredient azithromycin, USP, an azalide, a subclass of macrolide antibiotics, for oral administration. Azithromycin, USP 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, USP is derived from erythromycin; however, it differs chemically from erythromycin in that a methyl-substituted nitrogen atom is incorporated into the lactone ring. Azithromycin, USP has the following structural formula:

structural formula
(click image for full-size original)

C38 H72 N2 O12 M.W. 748.98

Azithromycin, USP, as the monohydrate, is a white to off-white crystalline powder with a molecular formula of C38 H72 N2 O12 •H2 O and a molecular weight of 767. 5 mL of constituted suspension of Azithromycin for Oral Suspension USP, 100 mg/5 mL and 200 mg/5 mL, contains 6 mg of sodium.

Azithromycin for Oral Suspension USP is supplied in bottles containing azithromycin monohydrate powder equivalent to 300 mg, 600 mg, 900 mg, or 1200 mg azithromycin, USP per bottle and the following inactive ingredients: arabic gum, artificial aromatic substances, ethyl vanillin, FD&C Red #40, hydroxypropyl cellulose, maltodextrin, nature aromatic substances, nature identical aromatic substances, sucrose, tribasic sodium phosphate dodecahydrate, vanillin, and xanthan gum. After constitution, each 5 mL of suspension contains 100 mg or 200 mg of azithromycin, USP. The dry powder before constitution is off-white to pinkish in color. The suspension after constitution is pink to red in color.

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 to 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*) 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 to 24 (mcg•h/mL)

2.6

2.1

Cmin (mcg/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 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 to ∞ for the fitted concentration profile was comparable between the 5 day and 3 day regimens.

*
Total AUC for the entire 3 day and 5 day regimens

3 Day Regimen

5 Day Regimen

Pharmacokinetic Parameter [mean (SD)]

Day 1

Day 3

Day 1

Day 5

Cmax (serum, mcg/mL)

0.44 (0.22)

0.54 (0.25)

0.43 (0.20)

0.24 (0.06)

Serum AUC0 to ∞ (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.

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 coadministration 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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