To reduce the development of drug-resistant bacteria and maintain the effectiveness of AZACTAM^® (aztreonam for injection, USP) and other anti-bacterial drugs, AZACTAM should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

AZACTAM (aztreonam for injection, USP) is indicated for the treatment of the following infections caused by susceptible gram-negative microorganisms:

Urinary Tract Infections (complicated and uncomplicated), including pyelonephritis and cystitis (initial and recurrent) caused by Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Enterobacter cloacae, Klebsiella oxytoca*, Citrobacter species* and Serratia marcescens*.

Lower Respiratory Tract Infections, including pneumonia and bronchitis caused by Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Haemophilus influenzae, Proteus mirabilis, Enterobacter species and Serratia marcescens*.

Septicemia caused by Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Proteus mirabilis*, Serratia marcescens* and Enterobacter species.

Skin and Skin-Structure Infections, including those associated with postoperative wounds, ulcers and burns caused by Escherichia coli, Proteus mirabilis, Serratia marcescens, Enterobacter species, Pseudomonas aeruginosa, Klebsiella pneumoniae and Citrobacter species*.

Intra-abdominal Infections, including peritonitis caused by Escherichia coli, Klebsiella species including K. pneumoniae, Enterobacter species including E. cloacae*, Pseudomonas aeruginosa, Citrobacter species* including C. freundii* and Serratia species* including S. marcescens*.

Gynecologic Infections, including endometritis and pelvic cellulitis caused by Escherichia coli, Klebsiella pneumoniae*, Enterobacter species* including E. cloacae* and Proteus mirabilis*. AZACTAM is indicated for adjunctive therapy to surgery in the management of infections caused by susceptible organisms, including abscesses, infections complicating hollow viscus perforations, cutaneous infections and infections of serous surfaces. AZACTAM is effective against most of the commonly encountered gram-negative aerobic pathogens seen in general surgery.

Concurrent Therapy

Concurrent initial therapy with other antimicrobial agents and AZACTAM^® (aztreonam for injection, USP) is recommended before the causative organism(s) is known in seriously ill patients who are also at risk of having an infection due to gram-positive aerobic pathogens. If anaerobic organisms are also suspected as etiologic agents, therapy should be initiated using an anti-anaerobic agent concurrently with AZACTAM (see DOSAGE AND ADMINISTRATION). Certain antibiotics (e.g., cefoxitin, imipenem) may induce high levels of beta-lactamase in vitro in some gram-negative aerobes such as Enterobacter and Pseudomonas species, resulting in antagonism to many beta-lactam antibiotics including aztreonam. These in vitro findings suggest that such beta-lactamase inducing antibiotics not be used concurrently with aztreonam. Following identification and susceptibility testing of the causative organism(s), appropriate antibiotic therapy should be continued.

CONTRAINDICATIONS

This preparation is contraindicated in patients with known hypersensitivity to aztreonam or any other component in the formulation.

Dosage in Adult Patients

AZACTAM may be administered intravenously or by intramuscular injection. Dosage and route of administration should be determined by susceptibility of the causative organisms, severity and site of infection, and the condition of the patient.

The intravenous route is recommended for patients requiring single doses greater than 1 g or those with bacterial septicemia, localized parenchymal abscess (e.g., intra-abdominal abscess), peritonitis or other severe systemic or life-threatening infections.

The duration of therapy depends on the severity of infection. Generally, AZACTAM should be continued for at least 48 hours after the patient becomes asymptomatic or evidence of bacterial eradication has been obtained. Persistent infections may require treatment for several weeks. Doses smaller than those indicated should not be used.

Renal Impairment in Adult Patients

Prolonged serum levels of aztreonam may occur in patients with transient or persistent renal insufficiency. Therefore, the dosage of AZACTAM should be halved in patients with estimated creatinine clearances between 10 and 30 mL/min/1.73 m2 after an initial loading dose of 1g or 2g.

When only the serum creatinine concentration is available, the following formula (based on sex, weight, and age of the patient) may be used to approximate the creatinine clearance (Clcr). The serum creatinine should represent a steady state of renal function.

In patients with severe renal failure (creatinine clearance less than 10 mL/min/1.73 m2), such as those supported by hemodialysis, the usual dose of 500 mg, 1 g or 2 g should be given initially. The maintenance dose should be one-fourth of the usual initial dose given at the usual fixed interval of 6, 8 or 12 hours. For serious or life-threatening infections, in addition to the maintenance doses, one-eighth of the initial dose should be given after each hemodialysis session.

Dosage in The Elderly

Renal status is a major determinant of dosage in the elderly; these patients in particular may have diminished renal function. Serum creatinine may not be an accurate determinant of renal status. Therefore, as with all antibiotics eliminated by the kidneys, estimates of creatinine clearance should be obtained, and appropriate dosage modifications made if necessary.

AZACTAM (aztreonam for injection, USP) should be administered intravenously to pediatric patients with normal renal function. There are insufficient data regarding intramuscular administration to pediatric patients or dosing in pediatric patients with renal impairment. (See PRECAUTIONS: Pediatric Use.)

Because of the serious nature of infections due to Pseudomonas aeruginosa, dosage of 2 g every six or eight hours is recommended, at least upon initiation of therapy, in systemic infections caused by this organism in adults.

Preparation Of Parenteral Solutions

General

Upon the addition of the diluent to the container, contents should be shaken immediately and vigorously. Constituted solutions are not for multiple-dose use; should the entire volume in the container not be used for a single-dose, the unused solution must be discarded.

Depending upon the concentration of aztreonam and diluent used, constituted AZACTAM yields a colorless to light straw yellow solution which may develop a slight pink tint on standing (potency is not affected). Parenteral drug products should be inspected visually for particulate matter and discoloration whenever solution and container permit.

Admixtures With Other Antibiotics

Intravenous infusion solutions of AZACTAM not exceeding 2% w/v prepared with Sodium Chloride Injection USP 0.9% or Dextrose Injection USP 5%, to which clindamycin phosphate, gentamicin sulfate, tobramycin sulfate, or cefazolin sodium have been added at concentrations usually used clinically, are stable for up to 48 hours at room temperature or seven days under refrigeration. Ampicillin sodium admixtures with aztreonam in Sodium Chloride Injection USP 0.9% are stable for 24 hours at room temperature and 48 hours under refrigeration; stability in Dextrose Injection USP 5% is two hours at room temperature and eight hours under refrigeration.

Aztreonam-cloxacillin sodium and aztreonam-vancomycin hydrochloride admixtures are stable in Dianeal^® 137 (Peritoneal Dialysis Solution) with 4.25% Dextrose for up to 24 hours at room temperature.

Aztreonam is incompatible with nafcillin sodium, cephradine, and metronidazole. Other admixtures are not recommended since compatibility data are not available.

Intravenous (IV) Solutions

For Bolus Injection: The contents of an AZACTAM (aztreonam for injection, USP) 15 mL capacity vial should be constituted with 6 to 10 mL Sterile Water for Injection USP. For Infusion: Contents of the 100 mL capacity bottle should be constituted to a final concentration not exceeding 2% w/v (at least 50 mL of any appropriate infusion solution listed below per gram aztreonam). These solutions may be frozen immediately after constitution in the original container. (See Stability below.)

If the contents of a 15 mL capacity vial are to be transferred to an appropriate infusion solution, each gram of aztreonam should be initially constituted with at least 3 mL Sterile Water for Injection USP.

Sodium Chloride Injection USP, 0.9%
Ringer's Injection USP
Lactated Ringer's Injection USP
Dextrose Injection USP, 5% or 10%
Dextrose and Sodium Chloride Injection USP, 5%:0.9%,
5%:0.45% or 5%:0.2% Sodium Lactate Injection USP (M/6 Sodium Lactate)
Ionosol^® B and 5% Dextrose
Isolyte^® E
Isolyte^® E with 5% Dextrose
Isolyte^® M with 5% Dextrose
Normosol^® -R
Normosol^® -R and 5% Dextrose
Normosol^® -M and 5% Dextrose
Mannitol Injection USP, 5% or 10%
Lactated Ringer's and 5% Dextrose Injection
Plasma-Lyte^® M and 5% Dextrose
10% Travert^® Injection
10% Travert^® and Electrolyte No. 1 Injection
10% Travert^® and Electrolyte No. 2 Injection
10% Travert^® and Electrolyte No. 3 Injection

Intramuscular (IM) Solutions

The contents of an AZACTAM 15 mL capacity vial should be constituted with at least 3 mL of an appropriate diluent per gram aztreonam. The following diluents may be used:

Sterile Water for Injection USP
Sterile Bacteriostatic Water for Injection, USP (with benzyl alcohol or with methyl- and propylparabens)
Sodium Chloride Injection USP, 0.9%
Bacteriostatic Sodium Chloride Injection USP (with benzyl alcohol)

Stability Of IV And IM Solutions

AZACTAM solutions for IV infusion at concentrations not exceeding 2% w/v must be used within 48 hours following constitution if kept at controlled room temperature (59^°-86^° F/15^°-30^° C) or within seven days if refrigerated (36^°-46^° F/2^°-8^° C).

Frozen aztreonam infusion solutions may be stored for up to three months at -4^° F/-20^° C; frozen solutions may be thawed at controlled room temperature or by overnight refrigeration. Solutions that have been thawed and maintained at controlled room temperature or under refrigeration should be used within 24 or 72 hours after removal from the freezer, respectively. Solutions should not be refrozen.

AZACTAM solutions at concentrations exceeding 2% w/v, except those prepared with Sterile Water for Injection USP or Sodium Chloride Injection USP, should be used promptly after preparation; the two excepted solutions must be used within 48 hours if stored at controlled room temperature or within seven days if refrigerated.

Intravenous Administration

Bolus Injection: A bolus injection may be used to initiate therapy. The dose should be slowly injected directly into a vein, or the tubing of a suitable administration set, over a period of three to five minutes (see next paragraph regarding flushing of tubing).

Infusion: With any intermittent infusion of aztreonam and another drug with which it is not pharmaceutically compatible, the common delivery tube should be flushed before and after delivery of aztreonam with any appropriate infusion solution compatible with both drug solutions; the drugs should not be delivered simultaneously. Any AZACTAM (aztreonam for injection, USP) infusion should be completed within a 20 to 60 minute period. With use of a Y-type administration set, careful attention should be given to the calculated volume of aztreonam solution required so that the entire dose will be infused. A volume control administration set may be used to deliver an initial dilution of AZACTAM (see Preparation Of Parenteral Solutions, For Infusion) into a compatible infusion solution during administration; in this case, the final dilution of aztreonam should provide a concentration not exceeding 2% w/v.

Intramuscular Administration

The dose should be given by deep injection into a large muscle mass (such as the upper outer quadrant of the gluteus maximus or lateral part of the thigh). Aztreonam is well tolerated and should not be admixed with any local anesthetic agent.

AZACTAM^® (aztreonam for injection, USP)—Lyophilized
Single-dose 15 mL capacity vials:
500 mg/vial: Packages of 10 NDC 51479-040-05
1 g/vial: Packages of 10 NDC 51479-041-15
2 g/vial: Packages of 10 NDC 51479-042-15

Single-dose 100 mL capacity intravenous infusion bottles with bail bands:
1 g/bottle: Packages of 10 NDC 51479-041-10
2 g/bottle: Packages of 10 NDC 51479-042-10

Storage

Store original packages at room temperature; avoid excessive heat.

ALSO SUPPLIED AS:

AZACTAM^® (aztreonam injection) in Galaxy^® plastic container (PL 2040) as a frozen, 50 mL single-dose intravenous solution as follows:
1 g aztreonam/50 mL container: Packages of 24 NDC 51479-048-01
2 g aztreonam/50 mL container: Packages of 24 NDC 51479-049-01

REFERENCES

1. Naber KG, Dette GA, Kees F, Knothe H, Grobecker H. Pharmacokinetics, in vitro activity, therapeutic efficacy, and clinical safety of aztreonam vs. cefotaxime in the treatment of complicated urinary tract infections. J Antimicrob Chemother 1986; 17:517-527.
2. Creasey WA, Platt TB, Frantz M, Sugerman AA. Pharmacokinetics of aztreonam in elderly male volunteers. Br J Clin Pharmacol 1985; 19:233-237.
3. Meyers BR, Wilkinson P, Mendelson MH, et al. Pharmacokinetics of aztreonam in healthy elderly and young adult volunteers. J Clin Pharmacol 1993; 33:470-474.
4. Sattler FR, Schramm M, Swabb EA. Safety of aztreonam and SQ 26,992 in elderly patients with renal insufficiency. Rev Infect Dis 1985; 7 (suppl 4):S622-S627.
5. National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically— Fifth Edition. Approved Standard NCCLS Document M7-A5, Vol. 20, No. 2, NCCLS, Wayne PA, January 2000.
6. National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Disk Susceptibility Tests—Seventh Edition. Approved Standard NCCLS Document M2-A7, Vol. 20, No. 1, NCCLS, Wayne, PA, January 2000.
7. Deger F, Douchamps J, Freschi E, et al. Aztreonam in the treatment of serious gram-negative infections in the elderly. Int J Clin Pharmacol Ther and Toxicol 1988; 26:22-26.
8. Knockaert DC, Dejaeger E, Nestor L, et al. Aztreonam-flucloxacilin double beta-lactam treatment as empirical therapy of serious infections in very elderly patients. Age and Aging 1981; 20:135- 139.
9. Roelandts F. Clinical use of aztreonam in a psychogeriatric population. Acta Clin Belg 1992; 47:251-255.
10. Andrews R, Fasoli R, Scoggins WG, et al. Combined aztreonam and gentamicin therapy for pseudomonal lower respiratory tract infections. Clin Therap 1994; 16:236-252.
11. National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Susceptibility Testing—Eleventh Informational Supplement, NCCLS Document M100-S11, Vol. 21, No. 1, NCCLS, Wayne, PA, January 2001.

AZACTAM^® (aztreonam for injection, USP) is a registered trademark of Bristol-Myers Squibb Company licensed exclusively in the US to EPI. Galaxy^® , Dianeal^® , Plasma-Lyte^® , and Travert^® are registered trademarks of Baxter International, Inc. Ionosol^® and Normosol^® are registered trademarks of Abbott Laboratories Corporation. Isolyte^® is a registered trademark of McGraw Inc.

Manufactured by
Bristol-Myers Squibb Company
Princeton, NJ 08543 U.S.A.

Distributed by
Elan Biopharmaceuticals, a business unit of Elan Pharmaceuticals, Inc. (EPI),
a member of the Elan Group,
San Diego, CA 92121 USA
Made in Italy

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