To reduce the development of drug-resistant bacteria and maintainthe effectiveness of AZACTAM® and other antibacterialdrugs, AZACTAM should be used only to treat or prevent infections that areproven or strongly suspected to be caused by bacteria.

DESCRIPTION

AZACTAM® (aztreonam injection)contains the active ingredient aztreonam, a monobactam. It was originallyisolated from Chromobacterium violaceum. It is a syntheticbactericidal antibiotic.

The monobactams, having a unique monocyclic beta-lactam nucleus,are structurally different from other beta-lactam antibiotics (eg, penicillins,cephalosporins, cephamycins). The sulfonic acid substituent in the 1-positionof the ring activates the beta-lactam moiety; an aminothiazolyl oxime sidechain in the 3-position and a methyl group in the 4-position confer the specificantibacterial spectrum and beta-lactamase stability.

Aztreonam is designated chemically as (Z)-2-[[[(2-amino-4-thiazolyl)[[(2S,3S)-2-methyl-4-oxo-1-sulfo-3-azetidinyl]carbamoyl]methylene]amino]oxy]-2-methylpropionicacid. Structural formula:

C13H17N5O8S2 MW 435.44

AZACTAM (aztreonam injection) in the GALAXY plastic container (PL2040) is a frozen, iso-osmotic, sterile, sodium-free, nonpyrogenic intravenoussolution. Each 50 mL of solution contains 1 g, or 2 g aztreonam with approximately1.7 g, or 700 mg dextrose hydrous, USP added to adjust osmolality, and approximately780 mg, or 1.6 g of arginine added for pH adjustment, respectively. Thawedsolutions have a pH in the range of 4.5 to 7.5. The solution is for intravenousadministration following thawing at room temperature or under refrigeration.

This GALAXY container is fabricated from a specially designed multilayerplastic (PL 2040). Solutions are in contact with the polyethylene layer ofthis container and can leach out certain chemical components of the plasticin very small amounts within the expiration period. The suitability of theplastic has been confirmed in tests in animals according to the USP biologicaltests for plastic containers as well as by tissue culture toxicity studies.

CLINICAL PHARMACOLOGY

Single 30-minute intravenous infusions of 500 mg, 1 g and 2 g dosesof AZACTAM in healthy subjects produced aztreonam peak serum levels of 54µg/mL, 90 µg/mL and 204 µg/mL, respectively, immediately afteradministration; at 8 hours, serum levels were 1 µg/mL, 3 µg/mL and6 µg/mL, respectively (Figure 1). Single 3-minute intravenous injectionsof the same doses resulted in serum levels of 58 µg/mL, 125 µg/mLand 242 µg/mL at 5 minutes following completion of injection.

Serum concentrations of aztreonam following completion of singleintravenous infusions of 500 mg, 1 g, and 2 g doses are depicted in Figure1.

The serum levels of aztreonam following single 500 mg, 1 g or 2g intravenous doses of AZACTAM (aztreonam injection) exceed the MIC90 for Neisseria sp., Haemophilusinfluenzae and most genera of the Enterobacteriaceae for8 hours (forEnterobacter sp., the 8-hour serum levels exceedthe MIC for 80% of strains). For Pseudomonas aeruginosa,a single 2 g intravenous dose produces serum levels that exceed the MIC90 forapproximately 4 to 6 hours. All of the above doses of AZACTAM result in averageurine levels of aztreonam that exceed the MIC90 forthe same pathogens for up to 12 hours.

When aztreonam pharmacokinetics were assessed for adult and pediatricpatients, they were found to be comparable (down to 9 months old). The serumhalf-life of aztreonam averaged 1.7 hours (1.5 to 2.0) in subjects with normalrenal function, independent of the dose. In healthy subjects, based on a 70kg person, the serum clearance was 91 mL/min and renal clearance was 56 mL/min;the apparent mean volume of distribution at steady-state averaged 12.6 liters,approximately equivalent to extracellular fluid volume.

In elderly patients, the mean serum half-life of aztreonam increasedand the renal clearance decreased, consistent with the age-related decreasein creatinine clearance.1-4 The dosage of AZACTAMshould be adjusted accordingly (see DOSAGEAND ADMINISTRATION: Renal Impairment in Adult Patients).

In patients with impaired renal function, the serum half-life ofaztreonam is prolonged. (See DOSAGE AND ADMINISTRATION:Renal Impairment in Adult Patients.) The serum half-life ofaztreonam is only slightly prolonged in patients with hepatic impairment sincethe liver is a minor pathway of excretion.

Average urine concentrations of aztreonam were approximately 1100µg/mL, 3500 µg/mL and 6600 µg/mL within the first 2 hours followingsingle 500 mg, 1 g and 2 g intravenous doses of AZACTAM (30-minute infusions),respectively. The range of average concentrations for aztreonam in the 8-to 12-hour urine specimens in these studies was 25 µg/mL to 120 µg/mL.In healthy subjects, aztreonam is excreted in the urine about equally by activetubular secretion and glomerular filtration. Approximately 60% to 70% of anintravenous dose was recovered in the urine by 8 hours. Urinary excretionof a single intravenous dose was essentially complete by 12 hours after injection.About 12% of a single intravenous radiolabeled dose was recovered in the feces.Unchanged aztreonam and the inactive beta-lactam ring hydrolysis product ofaztreonam were present in feces and urine.

Intravenous administration of a single 500 mg or 1 g dose of AZACTAMevery 8 hours for 7 days to healthy subjects produced no apparent accumulationof aztreonam or modification of its disposition characteristics; serum proteinbinding averaged 56% and was independent of dose.

Renal function was monitored in healthy subjects given aztreonam;standard tests (serum creatinine, creatinine clearance, BUN, urinalysis andtotal urinary protein excretion) as well as special tests (excretion of N-acetyl-β-glucosaminidase,alanine aminopeptidase and β2-microglobulin)were used. No abnormal results were obtained.

Aztreonam achieves measurable concentrations in the following bodyfluids and tissues: