WARNINGS
Both animal and human data suggest that
AZACTAM (aztreonam for injection, USP) is rarely cross-reactive with other
beta-lactam antibiotics and weakly immunogenic. Treatment with aztreonam can
result in hypersensitivity reactions in patients with or without prior exposure.
(See
CONTRAINDICATIONS.)
Careful
inquiry should be made to determine whether the patient has any history of
hypersensitivity reactions to any allergens.
While
cross-reactivity of aztreonam with other beta-lactam antibiotics is rare,
this drug should be administered with caution to any patient with a history
of hypersensitivity to beta-lactams (eg, penicillins, cephalosporins, and/or
carbapenems). Treatment with aztreonam can result in hypersensitivity reactions
in patients with or without prior exposure to aztreonam. If an allergic reaction
to aztreonam occurs, discontinue the drug and institute supportive treatment
as appropriate (eg, maintenance of ventilation, pressor amines, antihistamines,
corticosteroids). Serious hypersensitivity reactions may require epinephrine
and other emergency measures. (See
ADVERSE REACTIONS.)
Clostridium
difficile–associated diarrhea (CDAD) has been reported with use of
nearly all antibacterial agents, including AZACTAM, and may range in severity
from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters
the normal flora of the colon leading to overgrowth of C. difficile.
C.
difficile produces toxins A and B which contribute to the development
of CDAD. Hypertoxin-producing strains of C. difficile cause
increased morbidity and mortality, as these infections can be refractory to
antimicrobial therapy and may require colectomy. CDAD must be considered in
all patients who present with diarrhea following antibiotic use. Careful medical
history is necessary since CDAD has been reported to occur over 2 months
after the administration of antibacterial agents.
If
CDAD is suspected or confirmed, ongoing antibiotic use not directed against C.
difficile may need to be discontinued. Appropriate fluid and electrolyte
management, protein supplementation, antibiotic treatment of C. difficile,
and surgical evaluation should be instituted as clinically indicated.
Rare
cases of toxic epidermal necrolysis have been reported in association with
aztreonam in patients undergoing bone marrow transplant with multiple risk
factors including sepsis, radiation therapy, and other concomitantly administered
drugs associated with toxic epidermal necrolysis.
PRECAUTIONS
General
Prescribing
AZACTAM in the absence of a proven or strongly suspected bacterial infection
or a prophylactic indication is unlikely to provide benefit to the patient
and increases the risk of the development of drug-resistant bacteria.
In
patients with impaired hepatic or renal function, appropriate monitoring is
recommended during therapy.
If an aminoglycoside is
used concurrently with aztreonam, especially if high dosages of the former
are used or if therapy is prolonged, renal function should be monitored because
of the potential nephrotoxicity and ototoxicity of aminoglycoside antibiotics.
The
use of antibiotics may promote the overgrowth of nonsusceptible organisms,
including Gram-positive organisms (Staphylococcus aureus and Streptococcus
faecalis) and fungi. Should superinfection occur during therapy,
appropriate measures should be taken.
Information for Patients
Patients
should be counseled that antibacterial drugs including AZACTAM should only
be used to treat bacterial infections. They do not treat viral infections
(eg, the common cold). When AZACTAM is prescribed to treat a bacterial infection,
patients should be told that although it is common to feel better early in
the course of therapy, the medication should be taken exactly as directed.
Skipping doses or not completing the full course of therapy may (1) decrease
the effectiveness of the immediate treatment and (2) increase the likelihood
that bacteria will develop resistance and will not be treatable by AZACTAM
or other antibacterial drugs in the future.
Diarrhea
is a common problem caused by antibiotics which usually ends when the antibiotic
is discontinued. Sometimes after starting treatment with antibiotics, patients
can develop watery and bloody stools (with or without stomach cramps and fever)
even as late as 2 or more months after having taken the last dose of the antibiotic.
If this occurs, patients should contact their physician as soon as possible.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies with aztreonam have not been conducted using an intravenous route of administration. A 104-week rat inhalation toxicology study to assess the carcinogenic potential of aztreonam demonstrated no drug-related increase in the incidence of tumors. Rats were exposed to aerosolized aztreonam for up to 4 hours per day. Peak plasma levels of aztreonam averaging approximately 6.8 mcg/mL were measured in rats at the highest dose level.
Genetic toxicology studies performed with aztreonam in vitro (Ames test, mouse lymphoma forward mutation assay, gene conversion assay, chromosome aberration assay in human lymphocytes) and in vivo (mouse bone marrow cytogenetic assay) did not reveal evidence of mutagenic or clastogenic potential.
A two-generation reproduction study in rats at daily doses of 150, 600, or 2400 mg/kg given prior to and during gestation and lactation, revealed no evidence of impaired fertility. Based on body surface area, the high dose is 2.9-fold greater than the maximum recommended human dose (MRHD) for adults of 8 g per day. There was a slightly reduced survival rate during the lactation period in the offspring of rats that received the highest dose, but not in offspring of rats that received lower doses of aztreonam.
Pregnancy
Pregnancy Category B
In pregnant women, aztreonam crosses the placenta and enters the fetal circulation.
Developmental toxicity studies in pregnant rats and rabbits with daily doses of aztreonam up to 1800 and 1200 mg/kg, respectively, revealed no evidence of embryotoxicity or fetotoxicity or teratogenicity. These doses, based on body surface area, are 2.2- and 2.9-fold greater than the MRHD for adults of 8 g per day. A peri/postnatal study in rats revealed no drug-induced changes in any maternal, fetal, or neonatal parameters. The highest dose used in this study, 1800 mg/kg/day, is 2.2 times the MRHD based on body surface area.
There are no adequate and well-controlled studies of aztreonam on human pregnancy outcomes. Because animal reproduction studies are not always predictive of human response, aztreonam should be used during pregnancy only if clearly needed.
Nursing Mothers
Aztreonam is excreted in human milk
in concentrations that are less than 1% of concentrations determined in simultaneously
obtained maternal serum; consideration should be given to temporary discontinuation
of nursing and use of formula feedings.
Pediatric Use
The safety and effectiveness of intravenous
AZACTAM have been established in the age groups 9 months to 16 years. Use
of AZACTAM in these age groups is supported by evidence from adequate and
well-controlled studies of AZACTAM in adults with additional efficacy, safety,
and pharmacokinetic data from noncomparative clinical studies in pediatric
patients. Sufficient data are not available for pediatric patients under 9
months of age or for the following treatment indications/pathogens: septicemia
and skin and skin-structure infections (where the skin infection is believed
or known to be due to H. influenzae type b). In pediatric
patients with cystic fibrosis, higher doses of AZACTAM may be warranted. (See
CLINICAL PHARMACOLOGY,
DOSAGE
AND ADMINISTRATION, and
CLINICAL
STUDIES.)
Geriatric Use
Clinical studies of AZACTAM did not
include sufficient numbers of subjects aged 65 years and over to determine
whether they respond differently from younger subjects. Other reported clinical
experience has not identified differences in responses between the elderly
and younger patients.9-12 In general, dose selection
for an elderly patient should be cautious, reflecting the greater frequency
of decreased hepatic, renal, or cardiac function, and of concomitant disease
or other drug therapy.
In elderly patients, the mean
serum half-life of aztreonam increased and the renal clearance decreased,
consistent with the age-related decrease in creatinine clearance.1-4 Since
aztreonam is known to be substantially excreted by the kidney, the risk of
toxic reactions to this drug may be greater in patients with impaired renal
function. Because elderly patients are more likely to have decreased renal
function, renal function should be monitored and dosage adjustments made accordingly
(see
DOSAGE AND ADMINISTRATION: Renal Impairment
in Adult Patients
and
Dosage
in the Elderly).
AZACTAM contains no
sodium.
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