AZACTAM

AZACTAM ® (aztreonam for injection, USP) contains the active ingredient aztreonam, a monobactam. It was originally isolated from Chromobacterium violaceum . It is a synthetic bactericidal 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-position of the ring activates the beta-lactam moiety; an aminothiazolyl oxime side chain in the 3-position and a methyl group in the 4-position confer the specific antibacterial 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-methylpropionic acid. Structural formula: C 13 H 17 N 5 O 8 S 2 MW 435.44 AZACTAM is a sterile, nonpyrogenic, sodium-free, white powder containing 0.78 grams arginine per 1 gram of aztreonam and 1.54 grams arginine per 2 grams of aztreonam. Following constitution, the product is for intramuscular or intravenous use. Aqueous solutions of the product have a pH in the range of 4.5 to 7.5. aztreonam chemical structure

To reduce the development of drug-resistant bacteria and maintain the effectiveness of AZACTAM (aztreonam for injection, USP) and other antibacterial 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 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. ———————————— * Efficacy for this organism in this organ system was studied in fewer than 10 infections. Concurrent Therapy Concurrent initial therapy with other antimicrobial agents and AZACTAM 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 (eg, 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.

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. Table 2: Azactam Dosage Guidelines for Adults* Type of Infection Dose Frequency (hours) * Maximum recommended dose is 8 g per day. Urinary tract infections 500 mg or 1 g 8 or 12 Moderately severe systemic infections 1 g or 2 g 8 or 12 Severe systemic or life-threatening infections 2 g 6 or 8 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. The intravenous route is recommended for patients requiring single doses greater than 1 g or those with bacterial septicemia, localized parenchymal abscess (eg, 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 m 2 after an initial loading dose of 1g or 2 g. 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. weight (kg) × (140−age) Males: Clcr = ——————————————— 72 × serum creatinine (mg/dL) Females: 0.85 × above value In patients with severe renal failure (creatinine clearance less than 10 mL/min/1.73 m 2 ), 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. Dosage in Pediatric Patients AZACTAM 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 .) Table 3: Azactam Dosage Guidelines for Pediatric Patients* Type of Infection Dose Frequency (hours) * Maximum recommended dose is 120 mg/kg/day. Mild to moderate infections 30 mg/kg 8 Moderate to severe infections 30 mg/kg 6 or 8 CLINICAL STUDIES A total of 612 pediatric patients aged 1 month to 12 years were enrolled in uncontrolled clinical trials of aztreonam in the treatment of serious Gram-negative infections, including urinary tract, lower respiratory tract, skin and skin-structure, and intra-abdominal infections. Preparation of Parenteral Solutions General Upon the addition of the diluent to the container, contents should be shaken immediately and vigorously . Use constituted solution immediately. Discard any remaining unused constituted solution. 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 controlled room temperature 15°C to 30°C (59°F to 86°F) or 7 days under refrigeration 2°C to 8°C (36°F to 46°F). Ampicillin sodium admixtures with aztreonam in Sodium Chloride Injection, USP 0.9% are stable for 24 hours at controlled room temperature 15°C to 30°C (59°F to 86°F) and 48 hours under refrigeration 2°C to 8°C (36°F to 46°F); stability in Dextrose Injection, USP 5% is 2 hours at controlled room temperature 15°C to 30°C (59°F to 86°F) and 8 hours under refrigeration 2°C to 8°C (36°F to 46°F). 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 controlled room temperature 15°C to 30°C (59°F to 86°F). Aztreonam is incompatible with nafcillin sodium, cephradine, and metronidazole. Other admixtures are not recommended since compatibility data are not available. Intravenous Solutions For Bolus Injection: The vial contents should be constituted with 6 mL to 10 mL Sterile Water for Injection, USP. For Infusion: If the vial contents 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. Further dilution may be obtained with one of the following intravenous infusion solutions: 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 Intramuscular Solutions The vial contents 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 Intravenous and Intramuscular Solutions AZACTAM solutions for intravenous infusion at concentrations not exceeding 2% w/v must be used within 48 hours following constitution if kept at controlled room temperature 15°C to 30°C (59°F to 86°F) or within 7 days if refrigerated 2°C to 8°C (36°F to 46°F). 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 2 excepted solutions must be used within 48 hours if stored at controlled room temperature 15°C to 30°C (59°F to 86°F) or within 7 days if refrigerated 2°C to 8°C (36°F to 46°F). 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 3 to 5 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 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: Intravenous 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. 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. Table 2: Azactam Dosage Guidelines for Adults* Type of Infection Dose Frequency (hours) * Maximum recommended dose is 8 g per day. Urinary tract infections 500 mg or 1 g 8 or 12 Moderately severe systemic infections 1 g or 2 g 8 or 12 Severe systemic or life-threatening infections 2 g 6 or 8 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. The intravenous route is recommended for patients requiring single doses greater than 1 g or those with bacterial septicemia, localized parenchymal abscess (eg, 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 m 2 after an initial loading dose of 1g or 2 g. 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. weight (kg) × (140−age) Males: Clcr = ——————————————— 72 × serum creatinine (mg/dL) Females: 0.85 × above value In patients with severe renal failure (creatinine clearance less than 10 mL/min/1.73 m 2 ), 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. CLINICAL STUDIES A total of 612 pediatric patients aged 1 month to 12 years were enrolled in uncontrolled clinical trials of aztreonam in the treatment of serious Gram-negative infections, including urinary tract, lower respiratory tract, skin and skin-structure, and intra-abdominal infections. Preparation of Parenteral Solutions General Upon the addition of the diluent to the container, contents should be shaken immediately and vigorously . Use constituted solution immediately. Discard any remaining unused constituted solution. 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 controlled room temperature 15°C to 30°C (59°F to 86°F) or 7 days under refrigeration 2°C to 8°C (36°F to 46°F). Ampicillin sodium admixtures with aztreonam in Sodium Chloride Injection, USP 0.9% are stable for 24 hours at controlled room temperature 15°C to 30°C (59°F to 86°F) and 48 hours under refrigeration 2°C to 8°C (36°F to 46°F); stability in Dextrose Injection, USP 5% is 2 hours at controlled room temperature 15°C to 30°C (59°F to 86°F) and 8 hours under refrigeration 2°C to 8°C (36°F to 46°F). 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 controlled room temperature 15°C to 30°C (59°F to 86°F). Aztreonam is incompatible with nafcillin sodium, cephradine, and metronidazole. Other admixtures are not recommended since compatibility data are not available. Intravenous Solutions For Bolus Injection: The vial contents should be constituted with 6 mL to 10 mL Sterile Water for Injection, USP. For Infusion: If the vial contents 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. Further dilution may be obtained with one of the following intravenous infusion solutions: 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 Intramuscular Solutions The vial contents 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 Intravenous and Intramuscular Solutions AZACTAM solutions for intravenous infusion at concentrations not exceeding 2% w/v must be used within 48 hours following constitution if kept at controlled room temperature 15°C to 30°C (59°F to 86°F) or within 7 days if refrigerated 2°C to 8°C (36°F to 46°F). 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 2 excepted solutions must be used within 48 hours if stored at controlled room temperature 15°C to 30°C (59°F to 86°F) or within 7 days if refrigerated 2°C to 8°C (36°F to 46°F). 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 3 to 5 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 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: Intravenous 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. General Upon the addition of the diluent to the container, contents should be shaken immediately and vigorously . Use constituted solution immediately. Discard any remaining unused constituted solution. 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 controlled room temperature 15°C to 30°C (59°F to 86°F) or 7 days under refrigeration 2°C to 8°C (36°F to 46°F). Ampicillin sodium admixtures with aztreonam in Sodium Chloride Injection, USP 0.9% are stable for 24 hours at controlled room temperature 15°C to 30°C (59°F to 86°F) and 48 hours under refrigeration 2°C to 8°C (36°F to 46°F); stability in Dextrose Injection, USP 5% is 2 hours at controlled room temperature 15°C to 30°C (59°F to 86°F) and 8 hours under refrigeration 2°C to 8°C (36°F to 46°F). 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 controlled room temperature 15°C to 30°C (59°F to 86°F). Aztreonam is incompatible with nafcillin sodium, cephradine, and metronidazole. Other admixtures are not recommended since compatibility data are not available. Intravenous Solutions For Bolus Injection: The vial contents should be constituted with 6 mL to 10 mL Sterile Water for Injection, USP. For Infusion: If the vial contents 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. Further dilution may be obtained with one of the following intravenous infusion solutions: 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 For Bolus Injection: The vial contents should be constituted with 6 mL to 10 mL Sterile Water for Injection, USP. For Infusion: If the vial contents 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. Further dilution may be obtained with one of the following intravenous infusion solutions: 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 Intramuscular Solutions The vial contents 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 Intravenous and Intramuscular Solutions AZACTAM solutions for intravenous infusion at concentrations not exceeding 2% w/v must be used within 48 hours following constitution if kept at controlled room temperature 15°C to 30°C (59°F to 86°F) or within 7 days if refrigerated 2°C to 8°C (36°F to 46°F). 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 2 excepted solutions must be used within 48 hours if stored at controlled room temperature 15°C to 30°C (59°F to 86°F) or within 7 days if refrigerated 2°C to 8°C (36°F to 46°F). 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 3 to 5 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 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: Intravenous 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. 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 3 to 5 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 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: Intravenous 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.

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

Local reactions such as phlebitis/thrombophlebitis following intravenous administration, and discomfort/swelling at the injection site following intramuscular administration occurred at rates of approximately 1.9% and 2.4%, respectively. Systemic reactions (considered to be related to therapy or of uncertain etiology) occurring at an incidence of 1% to 1.3% include diarrhea, nausea and/or vomiting, and rash. Reactions occurring at an incidence of less than 1% are listed within each body system in order of decreasing severity: Hypersensitivity —anaphylaxis, angioedema, bronchospasm Hematologic —pancytopenia, neutropenia, thrombocytopenia, anemia, eosinophilia, leukocytosis, thrombocytosis Gastrointestinal —abdominal cramps; rare cases of C. difficile –associated diarrhea, including pseudomembranous colitis, or gastrointestinal bleeding have been reported. Onset of pseudomembranous colitis symptoms may occur during or after antibiotic treatment. (See WARNINGS .) Dermatologic —toxic epidermal necrolysis (see WARNINGS ), purpura, erythema multiforme, exfoliative dermatitis, urticaria, petechiae, pruritus, diaphoresis Cardiovascular —hypotension, transient ECG changes (ventricular bigeminy and PVC), flushing Respiratory —wheezing, dyspnea, chest pain Hepatobiliary —hepatitis, jaundice Nervous System —seizure, confusion, encephalopathy, vertigo, paresthesia, insomnia, dizziness Musculoskeletal —muscular aches Special Senses —tinnitus, diplopia, mouth ulcer, altered taste, numb tongue, sneezing, nasal congestion, halitosis Other —vaginal candidiasis, vaginitis, breast tenderness Body as a Whole —weakness, headache, fever, malaise Pediatric Adverse Reactions Of the 612 pediatric patients who were treated with AZACTAM in clinical trials, less than 1% required discontinuation of therapy due to adverse events. The following systemic adverse events, regardless of drug relationship, occurred in at least 1% of treated patients in domestic clinical trials: rash (4.3%), diarrhea (1.4%), and fever (1.0%). These adverse events were comparable to those observed in adult clinical trials. In 343 pediatric patients receiving intravenous therapy, the following local reactions were noted: pain (12%), erythema (2.9%), induration (0.9%), and phlebitis (2.1%). In the US patient population, pain occurred in 1.5% of patients, while each of the remaining 3 local reactions had an incidence of 0.5%. The following laboratory adverse events, regardless of drug relationship, occurred in at least 1% of treated patients: increased eosinophils (6.3%), increased platelets (3.6%), neutropenia (3.2%), increased AST (3.8%), increased ALT (6.5%), and increased serum creatinine (5.8%). In US pediatric clinical trials, neutropenia (absolute neutrophil count less than 1000/mm 3 ) occurred in 11.3% of patients (8/71) younger than 2 years receiving 30 mg/kg every 6 hours. AST and ALT elevations to greater than 3 times the upper limit of normal were noted in 15% to 20% of patients aged 2 years or above receiving 50 mg/kg every 6 hours. The increased frequency of these reported laboratory adverse events may be due to either increased severity of illness treated or higher doses of AZACTAM administered. Adverse Laboratory Changes Adverse laboratory changes without regard to drug relationship that were reported during clinical trials were: Hepatic —elevations of AST (SGOT), ALT (SGPT), and alkaline phosphatase; signs or symptoms of hepatobiliary dysfunction occurred in less than 1% of recipients (see above). Hematologic —increases in prothrombin and partial thromboplastin times, positive Coombs’ test. Renal —increases in serum creatinine.