AZITHROMYCIN
AZITHROMYCIN — azithromycin anhydrous tablet, film coated
WOCKHARDT LIMITED
DESCRIPTION
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)-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:
38 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 600 mg. In addition, each tablet contains the following inactive ingredients: microcrystalline cellulose, corn starch, croscarmellose sodium, magnesium trisilicate, magnesium stearate, colloidal silicon dioxide, hydroxypropyl cellulose, sodium lauryl sulfate, and an aqueous film coat consisting of hypromellose, titanium dioxide and polyethylene glycol.Structure
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:
| DOSE/DOSAGE FORM (serum, except as indicated) | Subjects | Day No. | Cmax (mcg/mL) | Tmax (hr) | C24 (mcg/mL) | AUC (mcg•hr/mL) | T½ (hr) | Urinary Excretion (% of dose) |
| 500 mg/250 mg capsule | 12 | Day 1 | 0.41 | 2.5 | 0.05 | 2.6a | — | 4.5 |
| and 250 mg on Days 2-5 | 12 | Day 5 | 0.24 | 3.2 | 0.05 | 2.1a | — | 6.5 |
| 1200 mg/600 mg tablets | 12 | Day 1 | 0.66 | 2.5 | 0.074 | 6.8b | 40 | — |
| %CV | (62%) | (79%) | (49%) | (64%) | (33%) | |||
| 600 mg tablet/day | 7 | 1 | 0.33 | 2 | 0.039 | 2.4a | ||
| %CV | (25%) | (50%) | (36%) | (19%) | ||||
| 7 | 22 | 0.55 | 2.1 | 0.14 | 5.8a | 84.5 | — | |
| %CV | (18%) | (52%) | (26%) | (25%) | — | |||
| 600 mg tablet/day (leukocytes) | 7 | 22 | 252 | 10.9 | 146 | 4763a | 82.8 | — |
| %CV | (49%) | (28%) | (33%) | (42%) | — | — |
b 0-last
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; CV=55%).
The AUC of azithromycin in 250 mg capsules was unaffected by co-administration of an antacid containing aluminum and magnesium hydroxide with azithromycin tablets; 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:
| TISSUE OR FLUID | TIME AFTER DOSE (h) | TISSUE OR FLUID CONCENTRATION (mcg/g or mcg/mL)1 | 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 |
* 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.
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 mcg/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 mcg/mL. Concentrations remained above 32 mcg/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 mcg/mL (±49%). Trough concentrations in peripheral leukocytes at steady-state averaged 146 mcg/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.
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