AZITHROMYCIN

AZITHROMYCIN- azithromycin anhydrous tablet, film coated
RxChange Co.

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

Azithromycin tablets 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)-ß-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 C38H72N2O12 , and its molecular weight is 749. Azithromycin has the following structural formula:

structure label
(click image for full-size original)

Anhydrous azithromycin is a white amorphous powder with a molecular formula of C38 H72 N2 O12 and a molecular weight of 749.Azithromycin tablet is supplied for oral administration as white, film-coated, oval shaped biconvex tablets containing anhydrous azithromycin 250 mg or 500 mg and the following inactive ingredients: microcrystalline cellulose, corn starch, croscarmellose sodium, magnesium trisilicate, magnesium stearate, colloidal silicon dioxide, hydroxypropyl cellulose, sodium lauryl sulfate, hypromellose, titanium dioxide and polyethylene glycol.

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 (18-40 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 1Day 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 2-5) or 3 days (500 mg per day for days 1-3). Due to limited serum samples on day 2 (3-day regimen) and days 2-4 (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.

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)
SerumAUC0–∞ (mcg•hr/mL) 17.4 (6.2)* 14.9 (3.1)*
Serum T1/2 71.8 hr 68.9 hr

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

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 ADULTS1
TISSUE OR FLUID TIME AFTER
DOSE (h) TISSUE OR FLUID
CONCENTRATION
(mcg/g or mcg/mL) CORRESPONDING
PLASMA OR SERUM LEVEL (mcg/mL) TISSUE (FLUID)
PLASMA (SERUM) RATIO
SKIN 72-96 0.4 0.012 35
LUNG 72-96 4 0.012 >100
SPUTUM* 2-4 1 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
1 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 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.

Special Populations
Renal Insufficiency
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). (See DOSAGE AND ADMINISTRATION.)

Hepatic Insufficiency
The pharmacokinetics of azithromycin in subjects with hepatic impairment have not been established.

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

Geriatric Patients
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.

Pediatric Patients
In two clinical studies, azithromycin for oral suspension was dosed at 10 mg/kg on day 1, followed by 5 mg/kg on days 2 through 5 to two groups of pediatric patients (aged 1-5 years and 5-15 years, respectively). The mean pharmacokinetic parameters on day 5 were Cmax=0.216 mcg/mL, Tmax=1.9 hours, and AUC0-24=1.822 mcg•hr/mL for the 1- to 5-year-old group and were Cmax=0.383 mcg/mL, Tmax=2.4 hours, and AUC0-24=3.109 mcg•hr/mL for the 5- to 15-year-old group.

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 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.
Pharmacokinetic Parameter
[mean (SD)] 3-Day Regimen
(20 mg/kg x 3 days) 5-Day Regimen
(12 mg/kg x 5 days)
n 11 17
Cmax (mcg/mL) 1.1 (0.4) 0.5 (0.4)
Tmax (hr) 2.7 (1.9) 2.2 (0.8)
Auc0-24 mcg•hr/mL 7.9 (2.9) 3.9 (1.9)
The similarity of the overall exposure (AUC0–∞) 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. (See DOSAGE AND ADMINISTRATION.)

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