zinacef
Generic Name: (
cefuroxime)
Dosage Type: injection, solution zinacef
Generic Name: (
cefuroxime)
Dosage Type: injection, powder, lyophilized, for solution Organization: GlaxoSmithKline
To reduce the development of drug-resistant bacteria
and maintain the effectiveness of ZINACEF and other antibacterial
drugs, ZINACEF should be used only to treat or prevent infections
that are proven or strongly suspected to be caused by bacteria.
DESCRIPTION
Cefuroxime is a semisynthetic, broad-spectrum, cephalosporin
antibiotic for parenteral administration. It is the sodium salt of
(6R,7R)-3-carbamoyloxymethyl-7-[Z-2-methoxyimino-2-(fur-2-yl)acetamido]ceph-3-em-4-carboxylate,
and it has the following chemical structure:
The empirical formula is C16H15N4NaO8S, representing a molecular weight
of 446.4.
ZINACEF contains approximately 54.2 mg
(2.4 mEq) of sodium per gram of cefuroxime activity.
ZINACEF in sterile crystalline form is supplied in vials
equivalent to 750 mg, 1.5 g, or 7.5 g of cefuroxime
as cefuroxime sodium and in ADD-Vantage® vials equivalent
to 750 mg or 1.5 g of cefuroxime as cefuroxime sodium. Solutions
of ZINACEF range in color from light yellow to amber, depending on
the concentration and diluent used. The pH of freshly constituted
solutions usually ranges from 6 to 8.5.
ZINACEF
is available as a frozen, iso-osmotic, sterile, nonpyrogenic solution
with 750 mg or 1.5 g of cefuroxime as cefuroxime sodium.
Approximately 1.4 g of Dextrose Hydrous, USP has been added to
the 750-mg dose to adjust the osmolality. Sodium Citrate Hydrous,
USP has been added as a buffer (300 mg and 600 mg to the
750-mg and 1.5-g doses, respectively). ZINACEF contains approximately
111 mg (4.8 mEq) and 222 mg (9.7 mEq) of sodium
in the 750-mg and 1.5-g doses, respectively. The pH has been adjusted
with hydrochloric acid and may have been adjusted with sodium hydroxide.
Solutions of premixed ZINACEF range in color from light yellow to
amber. The solution is intended for intravenous (IV) use after thawing
to room temperature. The osmolality of the solution is approximately
300 mOsmol/kg, and the pH of thawed solutions ranges from 5 to
7.5.
The plastic container for the frozen solution
is fabricated from a specially designed multilayer plastic, PL 2040.
Solutions are in contact with the polyethylene layer of this container
and can leach out certain chemical components of the plastic in very
small amounts within the expiration period. The suitability of the
plastic has been confirmed in tests in animals according to USP biological
tests for plastic containers as well as by tissue culture toxicity
studies.
CLINICAL PHARMACOLOGY
After intramuscular (IM) injection of a 750-mg dose
of cefuroxime to normal volunteers, the mean peak serum concentration
was 27 mcg/mL. The peak occurred at approximately 45 minutes
(range, 15 to 60 minutes). Following IV doses of 750 mg
and 1.5 g, serum concentrations were approximately 50 and 100 mcg/mL,
respectively, at 15 minutes. Therapeutic serum concentrations
of approximately 2 mcg/mL or more were maintained for 5.3 hours
and 8 hours or more, respectively. There was no evidence of accumulation
of cefuroxime in the serum following IV administration of 1.5-g doses
every 8 hours to normal volunteers. The serum half-life after
either IM or IV injections is approximately 80 minutes.
Approximately 89% of a dose of cefuroxime is excreted
by the kidneys over an 8-hour period, resulting in high urinary concentrations.
Following the IM administration of a 750-mg single dose,
urinary concentrations averaged 1,300 mcg/mL during the first
8 hours. Intravenous doses of 750 mg and 1.5 g produced
urinary levels averaging 1,150 and 2,500 mcg/mL, respectively,
during the first 8-hour period.
The concomitant
oral administration of probenecid with cefuroxime slows tubular secretion,
decreases renal clearance by approximately 40%, increases the peak
serum level by approximately 30%, and increases the serum half-life
by approximately 30%. Cefuroxime is detectable in therapeutic concentrations
in pleural fluid, joint fluid, bile, sputum, bone, and aqueous humor.
Cefuroxime is detectable in therapeutic concentrations
in cerebrospinal fluid (CSF) of adults and pediatric patients with
meningitis. The following table shows the concentrations of cefuroxime
achieved in cerebrospinal fluid during multiple dosing of patients
with meningitis.
Table 1.
Concentrations of Cefuroxime Achieved in Cerebrospinal Fluid During
Multiple Dosing of Patients with Meningitis
|
Patients
|
Dose
|
Number of Patients
|
Mean (Range) CSF Cefuroxime Concentrations (mcg/mL) Achieved Within
8 Hours Post Dose
|
|
Pediatric
patients
(4 weeks to 6.5 years)
|
200 mg/kg/day,
divided q 6 hours
|
5
|
6.6
(0.9-17.3)
|
|
Pediatric
patients
(7 months to 9 years)
|
200 to 230 mg/kg/day, divided q 8 hours
|
6
|
8.3
(<2-22.5)
|
|
Adults
|
1.5 grams q 8 hours
|
2
|
5.2
(2.7-8.9)
|
|
Adults
|
1.5 grams q 6 hours
|
10
|
6.0
(1.5-13.5)
|
Cefuroxime is approximately 50% bound to serum
protein.
Microbiology
Cefuroxime has
in vitro activity against a wide range of gram-positive and gram-negative
organisms, and it is highly stable in the presence of beta-lactamases
of certain gram-negative bacteria. The bactericidal action of cefuroxime
results from inhibition of cell-wall synthesis.
Cefuroxime is usually active against the following organisms in
vitro.
Aerobes, Gram-positive
Staphylococcus aureus,
Staphylococcus epidermidis, Streptococcus pneumoniae, and Streptococcus pyogenes (and other streptococci).
NOTE: Most strains of enterococci, e.g., Enterococcusfaecalis (formerly Streptococcus
faecalis), are resistant to cefuroxime. Methicillin-resistant
staphylococci and Listeriamonocytogenes are resistant to cefuroxime.
Aerobes, Gram-negative
Citrobacter spp., Enterobacter spp., Escherichia coli, Haemophilus influenzae (including ampicillin-resistant
strains), Haemophilus parainfluenzae,
Klebsiella spp. (including Klebsiella pneumoniae), Moraxella (Branhamella) catarrhalis (including ampicillin- and
cephalothin-resistant strains), Morganella
morganii (formerly Proteus
morganii), Neisseria gonorrhoeae (including penicillinase- and non–penicillinase-producing
strains), Neisseria meningitidis, Proteus
mirabilis, Providencia rettgeri (formerly Proteus rettgeri), Salmonella spp., and Shigella spp.
NOTE: Some strains of Morganella morganii,
Enterobacter cloacae, and Citrobacter spp. have been shown by in vitro tests to be resistant to cefuroxime
and other cephalosporins. Pseudomonas and Campylobacter spp., Legionella spp., Acinetobacter calcoaceticus, and most
strains of Serratia spp. and Proteus vulgaris are resistant to most
first- and second-generation cephalosporins.
Anaerobes
Gram-positive and gram-negative cocci (including Peptococcus and Peptostreptococcus spp.), gram-positive
bacilli (including Clostridium spp.), and gram-negative bacilli (including Bacteroides and Fusobacterium spp.).
NOTE: Clostridium difficile and most strains of Bacteroides fragilis are resistant to cefuroxime.
Susceptibility Tests
Diffusion Techniques
Quantitative methods that require measurement of
zone diameters give an estimate of antibiotic susceptibility. One
such standard procedure1 that has been recommended for
use with disks to test susceptibility of organisms to cefuroxime uses
the 30-mcg cefuroxime disk. Interpretation involves the correlation
of the diameters obtained in the disk test with the minimum inhibitory
concentration (MIC) for cefuroxime.
A report
of “Susceptible” indicates that the pathogen is likely
to be inhibited by generally achievable blood levels. A report of“Moderately Susceptible” suggests that the organism
would be susceptible if high dosage is used or if the infection is
confined to tissues and fluids in which high antibiotic levels are
attained. A report of “Intermediate” suggests an equivocable
or indeterminate result. A report of “Resistant” indicates
that achievable concentrations of the antibiotic are unlikely to be
inhibitory and other therapy should be selected.
Reports from the laboratory giving results of the standard single-disk
susceptibility test for organisms other than Haemophilus spp. and Neisseriagonorrhoeae with a 30-mcg
cefuroxime disk should be interpreted according to the following criteria:
|
Zone Diameter (mm)
|
Interpretation
|
|
=18
|
(S) Susceptible
|
|
15-17
|
(MS) Moderately Susceptible
|
|
=14
|
(R) Resistant
|
Results for Haemophilus spp. should be interpreted according to the following criteria:
|
Zone Diameter (mm)
|
Interpretation
|
|
=24
|
(S) Susceptible
|
|
21-23
|
(I) Intermediate
|
|
=20
|
(R) Resistant
|
Results for Neisseriagonorrhoeae should be interpreted
according to the following criteria:
|
Zone Diameter (mm)
|
Interpretation
|
|
=31
|
(S) Susceptible
|
|
26-30
|
(MS) Moderately Susceptible
|
|
=25
|
(R) Resistant
|
Organisms should be tested with the cefuroxime
disk since cefuroxime has been shown by in vitro tests to be active
against certain strains found resistant when other beta-lactam disks
are used. The cefuroxime disk should not be used for testing susceptibility
to other cephalosporins.
Standardized procedures
require the use of laboratory control organisms. The 30-mcg cefuroxime
disk should give the following zone diameters.
1. Testing for organisms other than Haemophilus spp. and Neisseria
gonorrhoeae:
|
Organism
|
Zone Diameter (mm)
|
|
Staphylococcusaureus ATCC 25923
|
27-35
|
|
Escherichia coli ATCC 25922
|
20-26
|
2. Testing for Haemophilus spp.:
|
Organism
|
Zone Diameter (mm)
|
|
Haemophilus influenzae ATCC
49766
|
28-36
|
3. Testing for Neisseria
gonorrhoeae:
|
Organism
|
Zone Diameter (mm)
|
|
Neisseriagonorrhoeae ATCC 49226
|
33-41
|
|
Staphylococcusaureus ATCC 25923
|
29-33
|
Dilution Techniques
Use a standardized dilution method1 (broth,
agar, microdilution) or equivalent with cefuroxime powder. The MIC
values obtained for bacterial isolates other than Haemophilus spp. and Neisseriagonorrhoeae should be interpreted according to the following
criteria:
|
MIC (mcg/mL)
|
Interpretation
|
|
=8
|
(S) Susceptible
|
|
16
|
(MS) Moderately Susceptible
|
|
=32
|
(R) Resistant
|
MIC values obtained for Haemophilus spp. should be interpreted according to the
following criteria:
|
MIC (mcg/mL)
|
Interpretation
|
|
=4
|
(S) Susceptible
|
|
8
|
(I) Intermediate
|
|
=16
|
(R) Resistant
|
MIC values obtained for Neisseria gonorrhoeae should be interpreted according to
the following criteria:
|
MIC (mcg/mL)
|
Interpretation
|
|
=1
|
(S) Susceptible
|
|
2
|
(MS) Moderately Susceptible
|
|
=4
|
(R) Resistant
|
As with standard diffusion techniques, dilution
methods require the use of laboratory control organisms. Standard
cefuroxime powder should provide the following MIC values.
1. For organisms other than Haemophilus spp. and Neisseria
gonorrhoeae:
|
Organism
|
MIC (mcg/mL)
|
|
Staphylococcusaureus ATCC 29213
|
0.5-2.0
|
|
Escherichiacoli ATCC 25922
|
2.0-8.0
|
2. For Haemophilus spp.:
|
Organism
|
MIC (mcg/mL)
|
|
Haemophilusinfluenzae ATCC 49766
|
0.25-1.0
|
3. For Neisseria gonorrhoeae:
|
Organism
|
MIC (mcg/mL)
|
|
Neisseriagonorrhoeae ATCC 49226
|
0.25-1.0
|
|
Staphylococcusaureus ATCC 29213
|
0.25-1.0
|
INDICATIONS AND USAGE
ZINACEF is indicated for the treatment of patients
with infections caused by susceptible strains of the designated organisms
in the following diseases:
-
Lower Respiratory Tract Infections, including
pneumonia, caused by Streptococcus
pneumoniae, Haemophilus influenzae (including ampicillin-resistant
strains), Klebsiella spp., Staphylococcusaureus (penicillinase-
and non–penicillinase-producing strains), Streptococcus pyogenes, and Escherichia coli.
-
Urinary Tract Infections caused by Escherichia coli and Klebsiella spp.
-
Skin and SkinStructure Infections caused
by Staphylococcus aureus (penicillinase- and non–penicillinase-producing
strains), Streptococcuspyogenes, Escherichia coli, Klebsiella spp.,
and Enterobacter spp.
-
Septicemia caused by Staphylococcus aureus (penicillinase-
and non–penicillinase-producing strains), Streptococcus pneumoniae, Escherichia coli, Haemophilusinfluenzae (including ampicillin-resistant
strains), and Klebsiella spp.
-
Meningitis caused by Streptococcus pneumoniae, Haemophilus influenzae (including ampicillin-resistant strains),Neisseria meningitidis, and Staphylococcusaureus (penicillinase- and
non–penicillinase-producing strains).
-
Gonorrhea: Uncomplicated and disseminated
gonococcal infections due to Neisseria gonorrhoeae (penicillinase- and non–penicillinase-producing
strains) in both males and females.
-
Bone and Joint Infections caused by Staphylococcusaureus (penicillinase- and
non–penicillinase-producing strains).
Clinical microbiological studies in skin and skinstructure
infections frequently reveal the growth of susceptible strains of
both aerobic and anaerobic organisms. ZINACEF has been used successfully
in these mixed infections in which several organisms have been isolated.
In certain cases of confirmed or suspected gram-positive
or gram-negative sepsis or in patients with other serious infections
in which the causative organism has not been identified, ZINACEF may
be used concomitantly with an aminoglycoside (see PRECAUTIONS). The
recommended doses of both antibiotics may be given depending on the
severity of the infection and the patient's condition.
To reduce the development of drug-resistant bacteria
and maintain the effectiveness of ZINACEF and other antibacterial
drugs, ZINACEF 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.
Prevention
The preoperative
prophylactic administration of ZINACEF may prevent the growth of susceptible
disease-causing bacteria and thereby may reduce the incidence of certain
postoperative infections in patients undergoing surgical procedures
(e.g., vaginal hysterectomy) that are classified as clean-contaminated
or potentially contaminated procedures. Effective prophylactic use
of antibiotics in surgery depends on the time of administration. ZINACEF
should usually be given one-half to 1 hour before the operation
to allow sufficient time to achieve effective antibiotic concentrations
in the wound tissues during the procedure. The dose should be repeated
intraoperatively if the surgical procedure is lengthy.
Prophylactic administration is usually not required after
the surgical procedure ends and should be stopped within 24 hours.
In the majority of surgical procedures, continuing prophylactic administration
of any antibiotic does not reduce the incidence of subsequent infections
but will increase the possibility of adverse reactions and the development
of bacterial resistance.
The perioperative
use of ZINACEF has also been effective during open heart surgery for
surgical patients in whom infections at the operative site would present
a serious risk. For these patients it is recommended that therapy
with ZINACEF be continued for at least 48 hours after the surgical
procedure ends. If an infection is present, specimens for culture
should be obtained for the identification of the causative organism,
and appropriate antimicrobial therapy should be instituted.
CONTRAINDICATIONS
ZINACEF is contraindicated in patients with known
allergy to the cephalosporin group of antibiotics.
WARNINGS
BEFORE THERAPY WITH ZINACEF IS INSTITUTED, CAREFUL
INQUIRY SHOULD BE MADE TO DETERMINE WHETHER THE PATIENT HAS HAD PREVIOUS
HYPERSENSITIVITY REACTIONS TO CEPHALOSPORINS, PENICILLINS, OR OTHER
DRUGS. THIS PRODUCT SHOULD BE GIVEN CAUTIOUSLY TO PENICILLIN-SENSITIVE
PATIENTS. ANTIBIOTICS SHOULD BE ADMINISTERED WITH CAUTION TO ANY PATIENT
WHO HAS DEMONSTRATED SOME FORM OF ALLERGY, PARTICULARLY TO DRUGS.
IF AN ALLERGIC REACTION TO ZINACEF OCCURS, DISCONTINUE THE DRUG. SERIOUS
ACUTE HYPERSENSITIVITY REACTIONS MAY REQUIRE EPINEPHRINE AND OTHER
EMERGENCY MEASURES.
Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all
antibacterial agents, including ZINACEF, 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 two 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.
When the colitis is not relieved by drug
discontinuation or when it is severe, oral vancomycin is the treatment
of choice for antibiotic-associated pseudomembranous colitis produced
by Clostridium difficile. Other
causes of colitis should also be considered.
PRECAUTIONS
General
Although ZINACEF
rarely produces alterations in kidney function, evaluation of renal
status during therapy is recommended, especially in seriously ill
patients receiving the maximum doses. Cephalosporins should be given
with caution to patients receiving concurrent treatment with potent
diuretics as these regimens are suspected of adversely affecting renal
function.
The total daily dose of ZINACEF should
be reduced in patients with transient or persistent renal insufficiency
(see DOSAGE AND ADMINISTRATION), because high and prolonged serum
antibiotic concentrations can occur in such individuals from usual
doses.
As with other antibiotics, prolonged
use of ZINACEF may result in overgrowth of nonsusceptible organisms.
Careful observation of the patient is essential. If superinfection
occurs during therapy, appropriate measures should be taken.
Broad-spectrum antibiotics should be prescribed with
caution in individuals with a history of gastrointestinal disease,
particularly colitis.
Nephrotoxicity has been
reported following concomitant administration of aminoglycoside antibiotics
and cephalosporins.
As with other therapeutic
regimens used in the treatment of meningitis, mild-to-moderate hearing
loss has been reported in a few pediatric patients treated with cefuroxime.
Persistence of positive CSF (cerebrospinal fluid) cultures at 18 to
36 hours has also been noted with cefuroxime injection, as well
as with other antibiotic therapies; however, the clinical relevance
of this is unknown.
Cephalosporins may be associated
with a fall in prothrombin activity. Those at risk include patients
with renal or hepatic impairment, or poor nutritional state, as well
as patients receiving a protracted course of antimicrobial therapy,
and patients previously stabilized on anticoagulant therapy. Prothrombin
time should be monitored in patients at risk and exogenous Vitamin
K administered as indicated.
Prescribing ZINACEF
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.
Information for Patients
Patients should be counseled
that antibacterial drugs, including ZINACEF, should only be used to
treat bacterial infections. They do not treat viral infections (e.g.,
the common cold). When ZINACEF 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 ZINACEF 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.
Drug Interactions
In common with other antibiotics, cefuroxime may
affect the gut flora, leading to lower estrogen reabsorption and reduced
efficacy of combined estrogen/progesterone oral contraceptives.
Drug/Laboratory Test Interactions
A false-positive
reaction for glucose in the urine may occur with copper reduction
tests (Benedict's or Fehling's solution or with CLINITEST® tablets) but not with enzyme-based tests for glycosuria.
As a false-negative result may occur in the ferricyanide test, it
is recommended that either the glucose oxidase or hexokinase method
be used to determine blood plasma glucose levels in patients receiving
ZINACEF.
Cefuroxime does not interfere with
the assay of serum and urine creatinine by the alkaline picrate method.
Carcinogenesis, Mutagenesis, Impairment
of Fertility
Although lifetime
studies in animals have not been performed to evaluate carcinogenic
potential, no mutagenic activity was found for cefuroxime in the mouse
lymphoma assay and a battery of bacterial mutation tests. Positive
results were obtained in an in vitro chromosome aberration assay,
however, negative results were found in an in vivo micronucleus test
at doses up to 10 g/kg. Reproduction studies in mice at doses
up to 3,200 mg/kg/day (3.1 times the recommended maximum
human dose based on mg/m2) have revealed no impairment
of fertility.
Reproductive studies revealed
no impairment of fertility in animals.
Pregnancy
Teratogenic Effects
Pregnancy Category B. Reproduction studies have
been performed in mice at doses up to 6,400 mg/kg/day (6.3 times
the recommended maximum human dose based on mg/m2) and
rabbits at doses up to 400 mg/kg/day (2.1 times the recommended
maximum human dose based on mg/m2) and have revealed no
evidence of impaired fertility or harm to the fetus due to cefuroxime.
There are, however, no adequate and well-controlled studies in pregnant
women. Because animal reproduction studies are not always predictive
of human response, this drug should be used during pregnancy only
if clearly needed.
Nursing Mothers
Since cefuroxime
is excreted in human milk, caution should be exercised when ZINACEF
is administered to a nursing woman.
Pediatric Use
Safety and effectiveness
in pediatric patients below 3 months of age have not been established.
Accumulation of other members of the cephalosporin class in newborn
infants (with resulting prolongation of drug half-life) has been reported.
Geriatric Use
: Of the 1,914 subjects
who received cefuroxime in 24 clinical studies of ZINACEF, 901
(47%) were 65 and over while 421 (22%) were 75 and over. No overall
differences in safety or effectiveness were observed between these
subjects and younger subjects, and other reported clinical experience
has not identified differences in responses between the elderly and
younger patients, but greater susceptibility of some older individuals
to drug effects cannot be ruled out. This drug is known to be substantially
excreted by the kidney, and 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, care should
be taken in dose selection, and it may be useful to monitor renal
function (see DOSAGE AND ADMINISTRATION).
ADVERSE REACTIONS
ZINACEF is generally well tolerated. The most common
adverse effects have been local reactions following IV administration.
Other adverse reactions have been encountered only rarely.
Local Reactions
Thrombophlebitis
has occurred with IV administration in 1 in 60 patients.
Gastrointestinal
Gastrointestinal
symptoms occurred in 1 in 150 patients and included diarrhea
(1 in 220 patients) and nausea (1 in 440 patients). The
onset of pseudomembranous colitis may occur during or after antibacterial
treatment (see WARNINGS).
Hypersensitivity Reactions
Hypersensitivity
reactions have been reported in fewer than 1% of the patients treated
with ZINACEF and include rash (1 in 125). Pruritus, urticaria, and
positive Coombs' test each occurred in fewer than 1 in 250 patients,
and, as with other cephalosporins, rare cases of anaphylaxis, drug
fever, erythema multiforme, interstitial nephritis, toxic epidermal
necrolysis, and Stevens-Johnson syndrome have occurred.
Blood
A decrease in
hemoglobin and hematocrit has been observed in 1 in 10 patients
and transient eosinophilia in 1 in 14 patients. Less common reactions
seen were transient neutropenia (fewer than 1 in 100 patients)
and leukopenia (1 in 750 patients). A similar pattern and incidence
were seen with other cephalosporins used in controlled studies. As
with other cephalosporins, there have been rare reports of thrombocytopenia.
Hepatic
Transient rise
in SGOT and SGPT (1 in 25 patients), alkaline phosphatase (1
in 50 patients), LDH (1 in 75 patients), and bilirubin (1
in 500 patients) levels has been noted.
Kidney
Elevations in
serum creatinine and/or blood urea nitrogen and a decreased creatinine
clearance have been observed, but their relationship to cefuroxime
is unknown.
Postmarketing Experience with ZINACEF
Products
In addition
to the adverse events reported during clinical trials, the following
events have been observed during clinical practice in patients treated
with ZINACEF and were reported spontaneously. Data are generally insufficient
to allow an estimate of incidence or to establish causation.
Immune System Disorders
Cutaneous vasculitis.
Neurologic
Seizure.
Non-site specific
Angioedema.
Cephalosporin-class Adverse Reactions
In addition
to the adverse reactions listed above that have been observed in patients
treated with cefuroxime, the following adverse reactions and altered
laboratory tests have been reported for cephalosporin-class antibiotics:
Adverse Reactions
Vomiting, abdominal pain, colitis, vaginitis including
vaginal candidiasis, toxic nephropathy, hepatic dysfunction including
cholestasis, aplastic anemia, hemolytic anemia, hemorrhage.
Several cephalosporins, including ZINACEF, have been
implicated in triggering seizures, particularly in patients with renal
impairment when the dosage was not reduced (see DOSAGE AND ADMINISTRATION).
If seizures associated with drug therapy should occur, the drug should
be discontinued. Anticonvulsant therapy can be given if clinically
indicated.
Altered Laboratory Tests
Prolonged prothrombin time, pancytopenia, agranulocytosis.
OVERDOSAGE
Overdosage of cephalosporins can cause cerebral
irritation leading to convulsions. Serum levels of cefuroxime can
be reduced by hemodialysis and peritoneal dialysis.
DOSAGE AND ADMINISTRATION
Dosage
Adults
The usual adult dosage range for ZINACEF is 750 mg
to 1.5 grams every 8 hours, usually for 5 to 10 days.
In uncomplicated urinary tract infections, skin and skinstructure
infections, disseminated gonococcal infections, and uncomplicated
pneumonia, a 750-mg dose every 8 hours is recommended. In severe
or complicated infections, a 1.5-gram dose every 8 hours is recommended.
In bone and joint infections, a 1.5-gram dose every 8 hours
is recommended. In clinical trials, surgical intervention was performed
when indicated as an adjunct to therapy with ZINACEF. A course of
oral antibiotics was administered when appropriate following the completion
of parenteral administration of ZINACEF.
In
life-threatening infections or infections due to less susceptible
organisms, 1.5 grams every 6 hours may be required. In bacterial
meningitis, the dosage should not exceed 3 grams every 8 hours.
The recommended dosage for uncomplicated gonococcal infection is 1.5 grams
given intramuscularly as a single dose at 2 different sites together
with 1 gram of oral probenecid. For preventive use for clean-contaminated
or potentially contaminated surgical procedures, a 1.5-gram dose administered
intravenously just before surgery (approximately one-half to 1 hour
before the initial incision) is recommended. Thereafter, give 750 mg
intravenously or intramuscularly every 8 hours when the procedure
is prolonged.
For preventive use during open
heart surgery, a 1.5-gram dose administered intravenously at the induction
of anesthesia and every 12 hours thereafter for a total of 6 grams
is recommended.
Impaired Renal Function
A reduced dosage must be employed when renal functionis impaired. Dosage should be determined by the degree of renal impairment
and the susceptibility of the causative organism (see Table 2).
Table 2. Dosage of ZINACEF in Adults
With Reduced Renal Function
|
Creatinine Clearance mL/min)
|
Dose
|
Frequency
|
|
>20
|
750 mg-1.5 grams
|
q8h
|
|
10-20
|
750 mg
|
q12h
|
|
<10
|
750 mg
|
q24h*
|
When only serum creatinine is available, the following
formula2 (based on sex, weight, and age of the patient)
may be used to convert this value into creatinine clearance. The serum
creatinine should represent a steady state of renal function.
| Males: Creatinine clearance (mL/min) = |
Weight (kg) x (140 - age) |
|
|
72 x serum creatinine (mg/dL) |
Females: 0.85 x male value
Note: As with antibiotic therapy
in general, administration of ZINACEF should be continued for a minimum
of 48 to 72 hours after the patient becomes asymptomatic or after
evidence of bacterial eradication has been obtained; a minimum of
10 days of treatment is recommended in infections caused by Streptococcus pyogenes in order to guard
against the risk of rheumatic fever or glomerulonephritis; frequent
bacteriologic and clinical appraisal is necessary during therapy of
chronic urinary tract infection and may be required for several months
after therapy has been completed; persistent infections may require
treatment for several weeks; and doses smaller than those indicated
above should not be used. In staphylococcal and other infections involving
a collection of pus, surgical drainage should be carried out where
indicated.
Pediatric Patients Above
3 Months of Age
Administration of 50 to 100 mg/kg/day in equally
divided doses every 6 to 8 hours has been successful for most
infections susceptible to cefuroxime. The higher dosage of 100 mg/kg/day
(not to exceed the maximum adult dosage) should be used for the more
severe or serious infections.
In bone and joint
infections, 150 mg/kg/day (not to exceed the maximum adult dosage)
is recommended in equally divided doses every 8 hours. In clinical
trials, a course of oral antibiotics was administered to pediatric
patients following the completion of parenteral administration of
ZINACEF.
In cases of bacterial meningitis,
a larger dosage of ZINACEF is recommended, 200 to 240 mg/kg/day
intravenously in divided doses every 6 to 8 hours.
In pediatric patients with renal insufficiency, the frequency
of dosing should be modified consistent with the recommendations for
adults.
Preparation of Solution and Suspension
The directions
for preparing ZINACEF for both IV and IM use are summarized in Table
3.
For Intramuscular Use
Each 750-mg vial of ZINACEF should be constituted
with 3.0 mL of Sterile Water for Injection. Shake gently to disperse
and withdraw completely the resulting suspension for injection.
For Intravenous Use
Each 750-mg vial should be constituted with 8.3 mL
of Sterile Water for Injection. Withdraw completely the resulting
solution for injection.
Each 1.5-gram vial
should be constituted with 16.0 mL of Sterile Water for Injection,
and the solution should be completely withdrawn for injection.
The 7.5-gram pharmacy bulk vial should be constituted
with 77 mL of Sterile Water for Injection; each 8 mL of
the resulting solution contains 750 mg of cefuroxime.
Each 750-mg and 1.5-gram infusion pack should be constituted
with 100 mL of Sterile Water for Injection, 5% Dextrose Injection,
0.9% Sodium Chloride Injection, or any of the solutions listed under
the Intravenous portion of the COMPATIBILITY AND STABILITY section.
Table 3. Preparation of Solution and
Suspension
|
Strength
|
Amount of Diluent to Be Added
(mL)
|
Volume
to Be Withdrawn
|
Approximate Cefuroxime Concentration
(mg/mL)
|
|
|
750-mg
Vial
|
3.0 (IM)
|
Total*
|
225
|
|
|
750-mg
Vial
|
8.3 (IV)
|
Total
|
90
|
|
|
1.5-gram
Vial
|
16.0 (IV)
|
Total
|
90
|
|
|
750-mg
Infusion pack
|
100 (IV)
|
—
|
7.5
|
|
|
1.5-gram
Infusion pack
|
100 (IV)
|
—
|
15
|
|
|
7.5-gram
Pharmacy bulk package
|
77 (IV)
|
Amount Needed†
|
95
|
|
Administration
After constitution,
ZINACEF may be given intravenously or by deep IM injection into a
large muscle mass (such as the gluteus or lateral part of the thigh).
Before injecting intramuscularly, aspiration is necessary to avoid
inadvertent injection into a blood vessel.
Intravenous Administration
The IV route may be preferable for patients with
bacterial septicemia or other severe or life-threatening infections
or for patients who may be poor risks because of lowered resistance,
particularly if shock is present or impending.
For direct intermittent IV administration, slowly inject the solution into a vein over a period of 3 to 5 minutes
or give it through the tubing system by which the patient is also
receiving other IV solutions.
For intermittent IV infusion with a Y-type
administration set, dosing can be accomplished through the
tubing system by which the patient may be receiving other IV solutions.
However, during infusion of the solution containing ZINACEF, it is
advisable to temporarily discontinue administration of any other solutions
at the same site.
ADD-Vantage vials are to
be constituted only with 50 or 100 mL of 5% Dextrose Injection,
0.9% Sodium Chloride Injection, or 0.45% Sodium Chloride Injection
in Abbott ADD-Vantage flexible diluent containers (see Instructions
for Constitution). ADD-Vantage vials that have been joined to Abbott
ADD-Vantage diluent containers and activated to dissolve the drug
are stable for 24 hours at room temperature or for 7 days
under refrigeration. Joined vials that have not been activated may
be used within a 14-day period; this period corresponds to that for
use of Abbott ADD-Vantage containers following removal of the outer
packaging (overwrap).
Freezing solutions of
ZINACEF in the ADD-Vantage system is not recommended.
For continuous IV infusion, a solution of ZINACEF may be added to an IV infusion pack containing
one of the following fluids: 0.9% Sodium Chloride Injection; 5% Dextrose
Injection; 10% Dextrose Injection; 5% Dextrose and 0.9% Sodium Chloride
Injection; 5% Dextrose and 0.45% Sodium Chloride Injection; or 1/6 M
Sodium Lactate Injection.
Solutions of ZINACEF,
like those of most beta-lactam antibiotics, should not be added to
solutions of aminoglycoside antibiotics because of potential interaction.
However, if concurrent therapy with ZINACEF and an aminoglycoside
is indicated, each of these antibiotics can be administered separately
to the same patient.
Directions for Use of ZINACEF Frozen
in Galaxy® Plastic Containers
ZINACEF supplied
as a frozen, sterile, iso-osmotic, nonpyrogenic solution in plastic
containers is to be administered after thawing either as a continuous
or intermittent IV infusion. The thawed solution of the premixed product
is stable for 28 days if stored under refrigeration (5°C)
or for 24 hours if stored at room temperature (25°C). Do not refreeze.
Thaw container at room temperature (25°C) or under refrigeration
(5°C). Do not force thaw by immersion in water baths or by microwave
irradiation. Components of the solution may precipitate in the frozen
state and will dissolve upon reaching room temperature with little
or no agitation. Potency is not affected. Mix after solution has reached
room temperature. Check for minute leaks by squeezing bag firmly.
Discard bag if leaks are found as sterility may be impaired. Do not
add supplementary medication. Do not use unless solution is clear
and seal is intact.
Use sterile equipment.
Caution
Do not use plastic containers in series connections.
Such use could result in air embolism due to residual air being drawn
from the primary container before administration of the fluid from
the secondary container is complete.
Preparation for Administration
-
Suspend container from eyelet support.
-
Remove protector from outlet port at bottom of container.
-
Attach administration set. Refer to complete directions
accompanying set.
COMPATIBILITY AND STABILITY
Intramuscular
When constituted
as directed with Sterile Water for Injection, suspensions of ZINACEF
for IM injection maintain satisfactory potency for 24 hours at
room temperature and for 48 hours under refrigeration (5°C).
After the periods mentioned above any unused suspensions
should be discarded.
Intravenous
When the 750-mg,
1.5-g, and 7.5-g pharmacy bulk vials are constituted as directed with
Sterile Water for Injection, the solutions of ZINACEF for IV administration
maintain satisfactory potency for 24 hours at room temperature
and for 48 hours (750-mg and 1.5-g vials) or for 7 days
(7.5-g pharmacy bulk vial) under refrigeration (5°C). More dilute
solutions, such as 750 mg or 1.5 g plus 100 mL of Sterile
Water for Injection, 5% Dextrose Injection, or 0.9% Sodium Chloride
Injection, also maintain satisfactory potency for 24 hours at
room temperature and for 7 days under refrigeration.
These solutions may be further diluted to concentrations
of between 1 and 30 mg/mL in the following solutions and will
lose not more than 10% activity for 24 hours at room temperature
or for at least 7 days under refrigeration: 0.9% Sodium Chloride
Injection; 1/6 M Sodium Lactate Injection; Ringer's Injection,
USP; Lactated Ringer's Injection, USP; 5% Dextrose and 0.9% Sodium
Chloride Injection; 5% Dextrose Injection; 5% Dextrose and 0.45% Sodium
Chloride Injection; 5% Dextrose and 0.225% Sodium Chloride Injection;
10% Dextrose Injection; and 10% Invert Sugar in Water for Injection.
Unused solutions should be discarded after the time periods
mentioned above.
ZINACEF has also been found
compatible for 24 hours at room temperature when admixed in IV
infusion with heparin (10 and 50 U/mL) in 0.9% Sodium Chloride
Injection and Potassium Chloride (10 and 40 mEq/L) in 0.9% Sodium
Chloride Injection. Sodium Bicarbonate Injection, USP is not recommended
for the dilution of ZINACEF.
The 750-mg and
1.5-g ZINACEF ADD-Vantage vials, when diluted in 50 or 100 mL
of 5% Dextrose Injection, 0.9% Sodium Chloride Injection, or 0.45%
Sodium Chloride Injection, may be stored for up to 24 hours at
room temperature or for 7 days under refrigeration.
Frozen Stability
Constitute the
750-mg, 1.5-g, or 7.5-g vial as directed for IV administration in
Table 3. Immediately withdraw the total contents of the 750-mg
or 1.5-g vial or 8 or 16 mL from the 7.5-g bulk vial and add
to a Baxter VIAFLEX®MINI-BAG™ containing 50 or 100 mL of 0.9% Sodium Chloride
Injection or 5% Dextrose Injection and freeze. Frozen solutions are
stable for 6 months when stored at -20°C. Frozen solutions
should be thawed at room temperature and not refrozen. Do not force
thaw by immersion in water baths or by microwave irradiation. Thawed
solutions may be stored for up to 24 hours at room temperature
or for 7 days in a refrigerator.
Note: Parenteral drug products should be
inspected visually for particulate matter and discoloration before
administration whenever solution and container permit.
As with other cephalosporins, ZINACEF powder as well
as solutions and suspensions tend to darken, depending on storage
conditions, without adversely affecting product potency.
Directions for Dispensing
Pharmacy Bulk Package—Not
for Direct Infusion
The pharmacy bulk package is for use in a pharmacy
admixture service only under a laminar flow hood. Entry into the vial
must be made with a sterile transfer set or other sterile dispensing
device, and the contents dispensed in aliquots using aseptic technique.
The use of syringe and needle is not recommended as it may cause leakage
(see DOSAGE AND ADMINISTRATION). AFTER INITIAL WITHDRAWAL USE ENTIRE
CONTENTS OF VIAL PROMPTLY. ANY UNUSED PORTION MUST BE DISCARDED WITHIN
24 HOURS.
HOW SUPPLIED
ZINACEF in the dry state should be stored between
15° and 30°C (59° and 86°F) and protected from
light. ZINACEF is a dry, white to off-white powder supplied in vials
and infusion packs as follows:
NDC 0173-0352-10
750-mg* Vial (Tray of 10)
NDC 0173-0354-10
1.5-g* Vial (Tray of 10)
NDC 0173-0353-32
750-mg* Infusion Pack (Tray of 10)
NDC 0173-0356-32 1.5-g* Infusion Pack (Tray of 10)
NDC 0173-0400-00 7.5-g* Pharmacy Bulk Package
(Tray of 6)
NDC 0173-0436-00 750-mg ADD-Vantage
Vial (Tray of 25)
NDC 0173-0437-00 1.5-g ADD-Vantage
Vial (Tray of 10)
(The above ADD-Vantage vials
are to be used only with Abbott ADD-Vantage diluent containers.)
ZINACEF frozen as a premixed solution of cefuroxime injection
should not be stored above -20°C. ZINACEF is supplied frozen
in 50-mL, single-dose, plastic containers as follows:
NDC 0173-0424-00 750-mg* Plastic Container (Carton of
24)
NDC 0173-0425-00 1.5-g* Plastic
Container (Carton of 24)
*Equivalent
to cefuroxime.
REFERENCES
-
National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Susceptibility
Testing. Third Informational Supplement. NCCLS Document
M100-S3, Vol. 11, No. 17. Villanova, Pa: NCCLS; 1991.
-
Cockcroft DW, Gault MH. Prediction of creatinine
clearance from serum creatinine. Nephron. 1976;16:31-41.
GlaxoSmithKline
Research Triangle
Park, NC 27709
ZINACEF® (cefuroxime
for injection):
GlaxoSmithKline
Research Triangle Park, NC 27709
ZINACEF® (cefuroxime injection):
Manufactured
for GlaxoSmithKline
Research Triangle Park,
NC 27709
by Baxter Healthcare Corporation, Deerfield,
IL 60015
ZINACEF is a registered trademark of
GlaxoSmithKline.
ADD-Vantage is a registered
trademark of Abbott Laboratories.
CLINITEST is a registered trademark of Ames Division, Miles Laboratories,
Inc.
GALAXY and VIAFLEX are registered trademarks of Baxter International
Inc.
February 2007 RL-2355
-----------------------------------------------------------------------------------------------------------------
Tear Away
ZINACEF®
(cefuroxime for injection)
Instructions for Constitution of ADD-Vantage® Vials
To Open Diluent Container:
Peel the corner of the ADD-Vantage diluent
overwrap and remove flexible diluent container. Some opacity of the
plastic flexible container due to moisture absorption during the sterilization
process may be observed. This is normal and does not affect the solution
quality or safety. The opacity will diminish gradually.
To Assemble Vial and Flexible
Diluent Container(Use Aseptic
Technique):
1. Remove the protective
covers from the top of the vial and the vial port on the diluent container
as follows:
a. To remove the breakaway vial
cap, swing the pull ring over the top of the vial and pull down far
enough to start the opening (see Figure 1), then pull straight
up to remove the cap (see Figure 2). Note: Once the breakaway cap has been removed, do not access vial with
syringe.
b. To remove the vial port cover, grasp the tab
on the pull ring, pull up to break the 3 tie strings, then pull back
to remove the cover (see Figure 3).
2.
Screw the vial into the vial port until it will go no further. THE
VIAL MUST BE SCREWED IN TIGHTLY TO ASSURE A SEAL. This occurs approximately
one-half turn (180°) after the first audible click (see Figure 4).
The clicking sound does not assure a seal; the vial must be turned
as far as it will go. Note: Once
vial is seated, do not attempt to remove (see Figure 4).
3. Recheck the vial to assure that it is tight
by trying to turn it further in the direction of assembly.
4. Label appropriately.
To Prepare
Admixture:
1. Squeeze the bottom of the diluent
container gently to inflate the portion of the container surrounding
the end of the drug vial.
2. With the other
hand, push the drug vial down into the container, telescoping the
walls of the container. Grasp the inner cap of the vial through the
walls of the container (see Figure 5).
3. Pull the inner cap from the drug vial (see Figure 6). Verify
that the rubber stopper has been pulled out, allowing the drug and
diluent to mix.
4. Mix container contents thoroughly and use within
the specified time.
Preparation for Administration
(Use Aseptic Technique):
1. Confirm the activation
and admixture of vial contents.
2. Check for
leaks by squeezing container firmly. If leaks are found, discard unit
as sterility may be impaired.
3. Close flow
control clamp of administration set.
4. Remove
cover from outlet port at bottom of container.
5. Insert piercing pin of administration set into port with a twisting
motion until the pin is firmly seated. Note: See full directions on administration set carton.
6. Lift the free end of the hanger loop on the bottom of the vial,
breaking the 2 tie strings. Bend the loop outward to lock it in the
upright position, then suspend container from hanger.
7. Squeeze and release drip chamber to establish proper fluid level
in chamber.
8. Open flow control clamp and clear
air from set. Close clamp.
9. Attach set to
venipuncture device. If device is not indwelling, prime and make venipuncture.
10. Regulate rate of administration with flow control
clamp.
WARNING: Do
not use flexible container in series connections.
GlaxoSmithKline
Research Triangle
Park, NC 27709
February 2007 RL-2355
Revised: 02/2007GlaxoSmithKline