Azithromycin

AZITHROMYCIN- azithromycin monohydrate powder, for suspension
Eon Labs, Inc.

Rx only

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 for Oral Suspension, USP contains the active ingredient azithromycin monohydrate, 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 monohydrate. 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 •H2 O, and its molecular weight is 767.00.

Azithromycin monohydrate has the following structural formula:

Chemical Structure
(click image for full-size original)

Azithromycin, as the monohydrate, is a white crystalline powder.

Azithromycin for Oral Suspension USP, off-white to light pink dry powder, is supplied in bottles containing azithromycin monohydrate powder equivalent to 300 mg, 600 mg, 900 mg, or 1200 mg azithromycin per bottle and the following inactive ingredients: xanthan gum; spray dried artificial cherry flavors; sodium carbonate monohydrate; FD&C Red No. 40; Dehydrated Alcohol; sucrose and compressible sugar. After constitution, each 5 mL of suspension contains 100 mg or 200 mg of azithromycin.

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*) 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

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

*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-∞ 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-∞ (mcg.hr/mL) 17.4 (6.2)* 14.9 (3.1)*
Serum T½ 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 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 mcg/mL to 7% at 2 mcg/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 Adults *
*
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.
Tissue or Fluid

Time After Dose (h)

Tissue or Fluid

Concentration

Corresponding Plasma or Serum Level (mcg/mL)

Tissue (Fluid) Plasma (Serum) Ratio

Skin 72-96 0.4 0.012 35
Lung 72-96 4.0 0.012 >100
Sputum 2-4 1.0 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

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 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.

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.

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