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AZACTAM 1g INJECTION

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

AZACTAM 1g INJECTION

COMPOSITION
Aztreonam is chemically designated as (Z)-2-[[[(2-amino-4-thiazolyl)-[[(2S,3S) -2-methyl-4-oxo-1-sulfo-3-azetidinyl] carbamoyl]methylene]-amino]oxy]-2-methylpropionic acid. AZACTAM is sodium free and contains approximately 780 mg 1-arginine per gram of aztreonam.

PHARMACOLOGICAL CLASSIFICATION
Category A20.1. Antibiotic and antibiotic combinations.

PHARMACOLOGICAL ACTION
Aztreonam is a synthetic monocyclic beta-lactam antibiotic (monobactam) with bactericidal activity against a wide spectrum of gram-negative aerobic pathogens. The monobactams, which were originally derived from a bacterium, Chromobacterium violaceum, have a novel single nuclear ring structure.
Pharmacokinetics in Adults: Single 30 minute intravenous infusions of 0,5, 1, and 2 gram doses AZACTAM in healthy volunteers produced serum levels of 54, 90 and 204 mcg/mL respectively, immediately after administration. Single 3 minute intravenous infusions of the same doses resulted in peak serum levels of 58, 125 and 242 mcg/mL at 5 minutes following completion of infusion of the drug. Serum levels of aztreonam 8 hours after start of 3 or 30 minute infusions were 1, 3 and 6 mcg/mL respectively.
After intramuscular administration, maximum serum aztreonam concentrations occur at about one hour. After identical single intravenous or intramuscular doses of AZACTAM, either 0,5 or 1 gram, the serum concentrations of aztreonam are comparable at 1 hour (1,5 hours from start of intravenous infusions) with similar slopes of serum concentrations thereafter.
After single 0,5, 1 and 2 gram intravenous doses of AZACTAM (30 minute infusion) average urine concentrations of aztreonam were approximately 1100, 3500 and 6600 mcg/mL respectively within the first two hours. After intramuscular injection of a single 0,5 or 1 gram dose of AZACTAM urinary levels were approximately 500 and 1200 mcg/mL respectively within the first two hours, declining to 180 and 470 mcg/mL in the 6 to 8 hour specimens. The range of average concentrations for aztreonam in the 8 to 12 hour urine specimens in the above studies was 25 to 120 mcg/mL.
The serum levels of aztreonam following single 0,5g or 1g (intramuscular or intravenous) or 2g (intravenous) doses of AZACTAM exceed the in vitro MIC₉₀ for Neisseria sp., H. influenzae and most genera of the Enterobacteriaceae for 8 hours (for Enterobacter sp. the 8 hour serum levels exceed the MIC for 80% of strains). For P. aeruginosa, a single 2g intravenous dose produces serum levels that exceed the MIC₉₀ for approximately 4-6 hours. All of the above doses of AZACTAM result in average urine levels of aztreonam which exceed the MIC₉₀ for the same pathogens for up to 12 hours.
The serum half-life of aztreonam averaged 1,7 hours (1,5 to 2,0) in subjects with normal renal function, independent of the dose and route of administration. In healthy subjects, based on a 70 kg 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 litres, approximately equivalent to extracellular fluid volume. Serum protein binding averaged 56%.
In healthy subjects aztreonam is excreted in the urine about equally by active tubular secretion and glomerular filtration. Approximately 60-70% of the intravenous or intramuscular dose administered was recovered in the urine by 8 hours. Urinary excretion of a single parenteral dose was essentially complete by 12 hours after injection. About 12% of a single intravenous radiolabelled dose was recovered in the faeces. Both unchanged aztreonam and the inactive beta-lactam ring hydrolysis product were present in the faeces and in urine.
In patients with impaired renal function the serum half-life of aztreonam is prolonged.
Since the liver is a minor pathway of excretion, the serum half-life of aztreonam is slightly prolonged in patients with hepatic impairment.
Pharmacokinetics in Paediatrics: The pharmacokinetics of AZACTAM in paediatric patients are dependent on age and body mass. Data obtained after single doses for various patient subgroups are listed in the following table.

Pharmacokinetic Parameters for Paediatric Patients

Age (Mass)	Intrav Dose (mg/kg)	Mean Serum Concentration (mcg/mL)		Mean Urine Concentration (mcg/mL)		Mean Serum Half-life (hours)	Serum Clearance (mL/min/kg)
		Timea		Timea
		Peak	Hours 6.00	Hours 0-3	Hours 6-12
1 week-2 years	50c	186	7,4	3675	196	1,2	2,51
2-12 years	30b	141	5,8	3727	506	1,7	2,50

a Peak concentrations were measured within 15 minutes after the end of the infusion; other times are relative to the end of the infusion
b 3-minute infusion
c 30 minute infusion

In paediatric patients, during the 24 hours following administration, approximately 75% of the administered dose AZACTAM is excreted unchanged in the urine about 1 to 4% is excreted as the open beta-lactam ring hydrolysis product of aztreonam.
Studies in vitro demonstrated that aztreonam, at concentration up to 660 mcg/mL, did not displace bilirubin from albumin, either in purified bilirubin-albumin solution or in hyperbilirubinemic neonatal serum.
Pharmacokinetics in the Elderly: In a study of healthy male subjects (65-75 years) the average elimination half-life of aztreonam (2,1 hr) was slightly longer than found in healthy males. This finding is consistent with normally diminished renal function in healthy elderly subjects.
Microbiology: Aztreonam exhibits specific activity in vitro against a wide spectrum of gram-negative aerobic pathogens. Aztreonam has no activity on gram-positive or anaerobic micro-organisms. The bactericidal action of aztreonam from the inhibition of bacterial cell wall synthesis due to a high affinity of the antibiotic for Penicillin Binding Protein 3 (PBP3). The molecular structure of aztreonam is highly resistant to hydrolysis by beta-lactamases. Aztreonam maintains its microbiologic activity over a broad pH range of 6-8, as well as in the presence of human serum and under aerobic conditions.
Aztreonam is not an inducer of beta-lactamase activity. Aztreonam is effective in vitro against many strains of the following susceptible organisms in clinical infections:
Escherichia coli
Enterobacter species
Klebsiella pneumoniae and K. oxytoca
Proteus mirabilis
Proteus morganni
Pseudomonas aeruginosa
Serratia marcescens
Neisseria gonorrhoea (including pencillinase-producing strains)
Haemophilus influenzae (including ampicillin-resistant and other penicillinase-producing strains.)
Citrobacter species
Aztreonam and aminoglycosides are synergistic in vitro for many strains of Enterobacteriaceae and most strains of P. aeruginosa.

INDICATIONS
AZACTAM is indicated for the treatment of :

1.	Pyelonephritis and cystitis, when caused by susceptible organisms.
2.	Gonorrhoea: Acute uncomplicated urogenital or anorectal infections due to beta-lactamase producing or non-producing strains of N. gonorrhoea.

Concurrent Therapy: AZACTAM may be used concurrently with other antibiotics. In seriously ill patients, additional antibiotic therapy should be initiated concurrently with AZACTAM to provide broad-spectrum coverage while awaiting results of organism identification and susceptibility testing. Based on the susceptibility testing results, the appropriate antibiotics should be continued.

CONTRA-INDICATIONS
In patients with known allergy to the medicine. Safety in pregnancy and lactating women has not been established. Dosage information is not available for new-borns less than one week old. Safety longer than 28 days has not been established.

WARNINGS
BEFORE AZACTAM THERAPY IS INSTITUTED, CAREFUL INQUIRY SHOULD BE MADE CONCERNING PREVIOUS HYPERSENSITIVITY REACTIONS TO CEPHALOSPORINS AND PENICILLIN. AZACTAM SHOULD BE ADMINISTERED WITH CAUTION TO PENICILLIN-SENSITIVE PATIENTS. THERE IS EVIDENCE OF PARTIAL CROSS-ALLERGINICITY BETWEEN THE PENICILLINS AND THE CEPHALOSPORINS. PATIENTS HAVE BEEN REPORTED TO HAVE HAD SEVERE REACTIONS, INCLUDING ANAPHYLAXIS, TO BOTH MEDICINES.
If such severe reactions should occur, Azactam should be discontinued and the patient treated with the appropriate agents, eg adrenaline, corticosteroids, aminophylline and antihistamines.
Pseudomembranous colitis has been reported with many broad-spectrum antibiotics, therefore it is important to consider its diagnosis in patients who develop diarrhoea in association with its use. Such colitis may be life-threatening and appropriate measures should be taken, including discontinuation of the antibiotic.
Efficacy of Azactam in the prophylaxis of rheumatic fever has not been established.

DOSAGE AND DIRECTIONS FOR USE
Before instituting treatment, appropriate specimens should be obtained for isolation of the causative organism(s), and for determination of susceptibility to aztreonam. Treatment with AZACTAM may be started empirically before results of the susceptibility testing are available.
Adults: AZACTAM may be administered intravenously or by intramuscular injection.
Dosage and route of administration should be determined by susceptibility of the causative organisms, severity of infection, and the condition of the patient.
A single dose of 1g AZACTAM administered intramuscularly is effective in the treatment of acute uncomplicated gonorrhoea and acute uncomplicated cystitis.
The intravenous route is recommended for patients requiring single doses greater than 1g. Because of the serious nature of infections due to Pseudomonas aeruginosa, dosage of 2g every 6 or 8 hours is recommended, at least for initial therapy in infections caused by this organism.
Renal Impairment: 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/1,73m² 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.

Males: Clcr        =

weight (kg) x (140 - age)         72 x serum creatinine (mg/dL)

Females:        0,85 x above value

This formulation gives an estimate of creatinine clearance and can be used for initial maintenance therapy, but is advisable to do a formal creatinine clearance in all patients with renal insufficiency.
In patients with severe renal failure (creatinine clearance less than 10 mL/min/1,73m²) such as those supported by hemodialysis, the usual initial dose of 500 mg, 1g or 2g should be given. 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.
Paediatrics: The usual dosage for patients older than 1 week is 30 mg/kg every 6 to 8 hours. For severe infections in patients two years of age or older, 50 mg/kg every 6 or 8 hours is recommended.
Constitution: Immediately after the addition of the diluent the contents should be shaken vigorously. Vials of constituted AZACTAM are not intended for multiple-dose use. Should the entire volume in the container not be used for a single does, the unused solution must be discarded.
Intramuscular Administration
AZACTAM should be constituted with at least 3 mL of diluent per gram of aztreonam. AZACTAM is 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). Since AZACTAM is well tolerated no local anaesthetic agent is required.
The following diluents may be used for constituting AZACTAM for intramuscular injection.:
Sodium Chloride Injection USP
Bacteriostatic Sodium Chloride Injection USP with Benzyl Alcohol or parabens
Water for Injection USP
Bacteriostatic Water for Injection USP with Benzyl Alcohol or parabens.
The recommended volumes of diluent for constitution are:

Single Dose Vial (g)	Volume of Diluent (mL)
1	3,0

Solutions prepared for intramuscular injection must be used within 24 hours if stored under controlled room temperature (15-30°C) or within 72 hours if refrigerated (2-8°C).
Intravenous Administration
For bolus injection: The selected dose should be constituted with 6 to 10 mL of Water for Injection USP, and the resulting solution slowly injected directly into the vein over a period of 3 to 5 minutes.
For infusion: Reconstitute the 1g vial with at least 3 mL of Water for Injection USP. The resulting initial solution should be diluted with an appropriate infusion solution to a final concentration not exceeding 2% m/v (at least 50 mL solution). The AZACTAM infusion should be administered over a 20 to 60 minute period.
With intermittent infusion of AZACTAM and another medicine via a common delivery tube, the tube should be flushed before and after delivery of AZACTAM with any appropriate infusion solution compatible with both drug solutions. The medicines should not be delivered simultaneously.
A volume control administration set may be used to deliver the initial solution of AZACTAM into a compatible infusion solution being administered. With use of Y-tube administration sets, careful attention should be given to the calculated volume of AZACTAM solution required so that the entire dose will be infused.
Intravenous infusion solutions of AZACTAM prepared with Sodium Chloride Injection USP 0,9% or Dextrose Injection USP 5%, to which clindamycin phosphate, gentamycin sulphate, tobramycin sulphate or cefazolin sodium have been added at concentrations usually used clinically, are stable for up to 24 hours at room temperature or 72 hours 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 is incompatible with nafcillin sodium, cephradine and metronidazole. When used together they should be given as separate injections.
The following intravenous solutions may be used as diluents for the administration of AZACTAM by intravenous infusion.
Sodium Chloride Injection USP
Ringer's Injection USP
Lactated Ringer's Injection USP
Dextrose Injection (5%) USP or (10%) USP
Dextrose (5%) with Sodium Chloride (0.9%) Injection USP
Dextrose (5%) with Sodium Chloride (0.45%) Injection USP
Dextrose (5%) with Sodium Chloride (0.2%) Injection USP
Sodium Lactate (M/6 Sodium Lactate)
Solutions prepared for intravenous infusion must be used within 24 hours following constitution if kept under controlled room temperature (15-30°C) or within 72 hours if refrigerated (2-8°C).
Solutions may be frozen immediately after constitution in the original container. Frozen 1% or 2% aztreonam infusion solutions may be thawed at controlled room temperature (15-30°C) or by overnight refrigeration (2-8°C). Solutions that have been thawed and maintained at controlled room temperature or thawed and maintained under refrigeration should be used within 24 or 72 hours respectively, after removal from the freezer. Solutions should not be re-frozen.
Solutions more concentrated than 2% m/v should be used promptly after constitution, except when the diluent is Water for Injection, USP or Sodium Chloride Injection, USP. These solutions must be used within 48 hours if stored at controlled room temperature (15-30°C) or within 7 days if refrigerated.

SIDE EFFECTS AND SPECIAL PRECAUTIONS
Dermatological: Rash, pruritus, purpura, erythema multiforme, petechiae, urticaria and exfoliative dermatitis.
Haematologic: Eosinophilia; increases in prothrombin and partial thromboplastin time; change in platelet count, neutropenia, anemia, bleeding and positive Coombs Test have occurred.
Hepato-biliary: Elevations of hepatic transamines and alkaline phosphatase levels, jaundice and hepatitis may occur. The abnormal liver function is usually reversible after discontinuation of Azactam.
Gastrointestinal: Diarrhoea, nausea and/or vomiting, abdominal cramps, mouth ulcer and altered taste. Pseudomembranous colitis has been reported.
Local Reactions: Discomfort at the IV or IM injection site, phlebitis/thrombophlebitis.
Miscellaneous: Instances of the following reactions have been reported. Vaginitis, candidiasis, hypotension, anaphylaxis, seizure, diplopia, weakness, paraesthesia, confusion, dizziness, vertigo, insomnia, ECG changes, tinnitus, diaphoresis, headache, breast tenderness, halitosis, muscle aches, fever, malaise, sneezing and nasal congestion. Increase in serum creatinine was uncommon. There have been reports of diarrhoea accompanied by Clostridium difficile, usually in association with the concurrent use of other antibiotics or cancer chemotherapeutic agents. Transient flushing, dyspnea and chest pain have been reported.
Aztreonam should be given with caution to any patient with a history of allergic reaction to structurally related compounds. If an allergic reaction occurs, AZACTAM should be discontinued and treatment initiated according to standard practices.
In patients with impaired hepatic function, appropriate monitoring of liver function is recommended during therapy.
Therapy with AZACTAM may result in overgrowth of nonsusceptible organisms which may require treatment.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
Treatment of overdose should be symptomatic and supportive.

IDENTIFICATION
AZACTAM is a white to off-white free flowing sterile non-pyrogenic powder blend of aztreonam and L-arginine which upon constitution is intended for intravenous or intramuscular administration. The pH of AZACTAM solution depending on the type and amount of diluent used, ranges between 4,5 and 7,5.

PRESENTATION
15 mL vial.

STORAGE INSTRUCTIONS
Store at room temperature not exceeding 25°C. Avoid excessive heat. See Dosage and Directions for Use for stability of prepared solutions.
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBERS
AZACTAM 1g:        U/20.1/151

NAME AND ADDRESS OF APPLICANT
Bristol-Myers Squibb (Pty) Ltd*
47 Van Buuren Road
BEDFORDVIEW
2008

DATE OF PUBLICATION
March 1998

Authorised user of the ^TM AZACTAM.

1998P03

Updated on this site: February 2001
Current: June 2005
Source: Pharmaceutical Industry
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