Prescription Drug Information: Azithromycin

AZITHROMYCIN — azithromycin powder, for suspension
Dispensing Solutions, Inc.

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 and azithromycin for oral suspension 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-Lribo -hexopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-Dxylo -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 749.0. Azithromycin has the following structural formula:

Chemical Structure
(click image for full-size original)

Azithromycin, as the dihydrate, is a white crystalline powder with a molecular formula of C38 H72 N2 O12 •2H2 O and a molecular weight of 785.0.

Azithromycin tablets contain azithromycin dihydrate equivalent to 600 mg azithromycin. The tablets are supplied as white, modified oval-shaped, film-coated tablets. They also contain the following inactive ingredients: dibasic calcium phosphate anhydrous, pregelatinized starch, sodium croscarmellose, magnesium stearate, sodium lauryl sulfate and an aqueous film coat consisting of hypromellose, titanium dioxide, lactose and triacetin.

Azithromycin for oral suspension is supplied in a single dose packet containing azithromycin dihydrate equivalent to 1 g azithromycin. It also contains the following inactive ingredients: colloidal silicon dioxide, sodium phosphate tribasic, anhydrous; spray dried artificial banana flavor, spray dried artificial cherry flavor, and sucrose.

CLINICAL PHARMACOLOGY

Pharmacokinetics

Following oral administration, azithromycin is rapidly absorbed and widely distributed throughout the body. Rapid distribution of azithromycin into tissues and high concentration within cells result in significantly higher azithromycin concentrations in tissues than in plasma or serum. The 1 g single dose packet is bioequivalent to four 250 mg azithromycin capsules.

The pharmacokinetic parameters of azithromycin in plasma after dosing as per labeled recommendations in healthy young adults and asymptomatic HIV-seropositive adults (age 18–40 years old) are portrayed in the following chart:

MEAN (CV%) PK PARAMETER
DOSE/DOSAGE FORM(serum, except as indicated) Subjects Day No. Cmax (µg/mL) Tmax (hr) C24 (µg/mL) AUC (µg∙hr/mL) T½ (hr) UrinaryExcretion (% of dose)
*
AUC0–24;
0–last.
500 mg/250 mg capsule 12 Day 1 0.41 2.5 0.05 2.6* 4.5
and 250 mg on Days 2–5 12 Day 5 0.24 3.2 0.05 2.1* 6.5
1200 mg/600 mg tablets 12 Day 1 0.66 2.5 0.074 6.8 40
%CV (62%) (79%) (49%) (64%) (33%)
600 mg tablet/day 7 1 0.33 2.0 0.039 2.4*
%CV 25% (50%) (36%) (19%)
7 22 0.55 2.1 0.14 5.8* 84.5
%CV (18%) (52%) (26%) (25%)
600 mg tablet/day (leukocytes) 7 22 252 10.9 146 4763* 82.8
%CV (49%) (28%) (33%) (42%)

In these studies (500 mg Day 1, 250 mg Days 2–5), there was no significant difference in the disposition of azithromycin between male and female subjects. Plasma concentrations of azithromycin following single 500 mg oral and I.V. doses declined in a polyphasic pattern resulting in an average terminal half-life of 68 hours. With a regimen of 500 mg on Day 1 and 250 mg/day on Days 2–5, Cmin and Cmax remained essentially unchanged from Day 2 through Day 5 of therapy. However, without a loading dose, azithromycin Cmin levels required 5 to 7 days to reach steady-state.

In asymptomatic HIV-seropositive adult subjects receiving 600-mg azithromycin tablets once daily for 22 days, steady state azithromycin serum levels were achieved by Day 15 of dosing.

When azithromycin capsules were administered with food, the rate of absorption (Cmax ) of azithromycin was reduced by 52% and the extent of absorption (AUC) by 43%.

When the oral suspension of azithromycin was administered with food, the Cmax increased by 46% and the AUC by 14%.

The absolute bioavailability of two 600 mg tablets was 34% (CV=56%). Administration of two 600 mg tablets with food increased Cmax by 31% (CV=43%) while the extent of absorption (AUC) was unchanged (mean ratio of AUCs=1.00; CV=55%).

The AUC of azithromycin in 250 mg capsules was unaffected by coadministration of an antacid containing aluminum and magnesium hydroxide with azithromycin; however, the Cmax was reduced by 24%. Administration of cimetidine (800 mg) two hours prior to azithromycin had no effect on azithromycin absorption.

When studied in healthy elderly subjects from age 65 to 85 years, the pharmacokinetic parameters of azithromycin (500 mg Day 1, 250 mg Days 2–5) 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.

The high values in adults for apparent steady-state volume of distribution (31.1 L/kg) and plasma clearance (630 mL/min) suggest that the prolonged half-life is due to extensive uptake and subsequent release of drug from tissues. Selected tissue (or fluid) concentration and tissue (or fluid) to plasma/serum concentration ratios are shown in the following table:

AZITHROMYCIN CONCENTRATIONS FOLLOWING TWO 250 mg (500 mg) CAPSULES IN ADULTS
TISSUE ORFLUID TIME AFTER DOSE (h) TISSUE OR FLUIDCONCENTRATION(µg/g or µg/mL)* CORRESPONDINGPLASMA OR SERUMLEVEL (µg/mL) TISSUE (FLUID)PLASMA (SERUM)RATIO *
*
High tissue concentrations should not be interpreted to be quantitatively related to clinical efficacy. The antimicrobial activity of azithromycin is pH related. Azithromycin is concentrated in cell lysosomes which have a low intraorganelle pH, at which the drug’s activity is reduced. However, the extensive distribution of drug to tissues may be relevant to clinical activity.
Sample was obtained 2–4 hours after the first dose
Sample was obtained 10–12 hours after the first dose.
§
Dosing regimen of 2 doses of 250 mg each, separated by 12 hours.
Sample was obtained 19 hours after a single 500 mg dose.
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 significance 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 µg/mL) in the presence of non-inflamed meninges.

Following oral administration of a single 1200 mg dose (two 600 mg tablets), the mean maximum concentration in peripheral leukocytes was 140 µg/mL. Concentrations remained above 32 µg/mL for approximately 60 hr. The mean half-lives for 6 males and 6 females were 34 hr and 57 hr, respectively. Leukocyte to plasma Cmax ratios for males and females were 258 (±77%) and 175 (±60%), respectively, and the AUC ratios were 804 (±31%) and 541 (±28%), respectively. The clinical relevance of these findings is unknown.

Following oral administration of multiple daily doses of 600 mg (1 tablet/day) to asymptomatic HIV-seropositive adults, mean maximum concentration in peripheral leukocytes was 252 µg/mL (±49%). Trough concentrations in peripheral leukocytes at steady-state averaged 146 µg/mL (±33%). The mean leukocyte to serum Cmax ratio was 456 (±38%) and the mean leukocyte to serum AUC ratio was 816 (±31%). The clinical relevance of these findings is unknown.

The serum protein binding of azithromycin is variable in the concentration range approximating human exposure, decreasing from 51% at 0.02 µg/mL to 7% at 2 µg/mL. 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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