tazicef
Generic Name: (
ceftazidime)
Dosage Type: injection, powder, for solution Organization: Hospira Worldwide, Inc.
for intravenous
or intramuscular
use
PRESCRIBING
INFORMATION
Rx only
To reduce the development of drug-resistant bacteria and maintain
the effectiveness of Tazicef (ceftazidime) and other antibacterial
drugs, Tazicef (ceftazidime) should be used only to treat or prevent
infections that are proven or strongly suspected to be caused by bacteria.
DESCRIPTION
Ceftazidime is a semisynthetic, broad-spectrum, beta-lactam
antibiotic for parenteral administration. It is the pentahydrate of
pyridinium, 1-[[7-[[(2-amino-4-thiazolyl)[(1-carboxy-1-methylethoxy)
imino] ace-tyl]amino]-2-carboxy-8-oxo-5-thia-1-azabicyclo(4.2.0.)oct-2-en-3-yl]
methyl]-, hydroxide, inner salt, [6R-[6a,7ß(Z)]]. It has
the following structure:
The molecular formula is C22H32N6012S2, representing a molecular weight of 636.6.
Tazicef (ceftazidime for injection, USP) is a sterile,
dry, powdered mixture of ceftazidime pentahydrate and sodium carbonate.
The sodium carbonate at a concentration of 118 mg/gram of ceftazidime
activity has been admixed to facilitate dissolution. The total sodium
content of the mixture is approximately 54 mg (2.3 mEq)/gram of ceftazidime
activity.
Tazicef in sterile crystalline form is supplied in vials equivalent to 1
gram or 2 grams of anhydrous ceftazidime, in piggyback vials equivalent
to 1 gram or 2 grams of anhydrous ceftazidime and in ADD-Vantage® vials equivalent to 1 gram or 2 grams of anhydrous ceftazidime.
Solutions of Tazicef range
in color from light yellow to amber, depending on the diluent and
volume used. The pH of freshly reconstituted solutions usually ranges
from 5.0 to 7.5.
CLINICAL PHARMACOLOGY
After IV administration of 500-mg and 1-gram doses
of ceftazidime over 5 minutes to normal adult male volunteers, mean
peak serum concentrations of 45 mcg/mL and 90 mcg/mL, respectively,
were achieved. After IV infusion of 500-mg, 1-gram and 2-gram doses
of ceftazidime over 20 to 30 minutes to normal adult male volunteers,
mean peak serum concentrations of 42 mcg/mL, 69 mcg/mL and 170 mcg/mL,
respectively, were achieved. The average serum concentrations following
IV infusion of 500-mg, 1-gram and 2-gram doses to these volunteers
over an 8-hour interval are given in Table 1.
|
Table 1
|
|
Ceftazidime IV Dosage
|
Serum Concentrations (mcg/mL)
|
|
0.5 hr.
|
1 hr.
|
2 hr.
|
4 hr.
|
8 hr.
|
|
500 mg
1 gram
2 grams
|
42
60
129
|
25
39
75
|
12
23
42
|
6
11
13
|
2
3
5
|
The absorption and elimination of ceftazidime
were directly proportional to the size of the dose. The half-life
following IV administration was approximately 1.9 hours. Less than
10% of ceftazidime was protein bound. The degree of protein binding
was independent of concentration. There was no evidence of accumulation
of ceftazidime in the serum in individuals with normal renal function
following multiple IV doses of 1 gram and 2 grams every 8 hours for
10 days.
Following IM administration of 500-mg
and 1-gram doses of ceftazidime to normal adult volunteers, the mean
peak serum concentrations were 17 mcg/mL and 39 mcg/mL, respectively,
at approximately 1 hour. Serum concentrations remained above 4 mcg/mL
for 6 and 8 hours after the IM administration of 500-mg and 1-gram
doses, respectively. The half-life of ceftazidime in these volunteers
was approximately 2 hours.
The presence of
hepatic dysfunction had no effect on the pharmacokinetics of ceftazidime
in individuals administered 2 grams intravenously every 8 hours for
5 days. Therefore, a dosage adjustment from the normal recommended
dosage is not required for patients with hepatic dysfunction, provided
renal function is not impaired.
Approximately
80% to 90% of an IM or IV dose of ceftazidime is excreted unchanged
by the kidneys over a 24-hour period. After the IV administration
of single 500-mg or 1-gram doses, approximately 50% of the dose appeared
in the urine in the first 2 hours. An additional 20% was excreted
between 2 and 4 hours after dosing, and approximately another 12%
of the dose appeared in the urine between 4 and 8 hours later. The
elimination of ceftazidime by the kidneys resulted in high therapeutic
concentrations in the urine.
The mean renal
clearance of ceftazidime was approximately 100 mL/min. The calculated
plasma clearance of approximately 115 mL/min. indicated nearly complete
elimination of ceftazidime by the renal route. Administration of probenecid
before dosing had no effect on the elimination kinetics of ceftazidime.
This suggested that ceftazidime is eliminated by glomerular filtration
and is not actively secreted by renal tubular mechanisms.
Since ceftazidime is eliminated almost solely by the
kidneys, its serum half-life is significantly prolonged in patients
with impaired renal function. Consequently, dosage adjustments in
such patients as described in the DOSAGE AND ADMINISTRATION section
are suggested.
Therapeutic concentrations
of ceftazidime are achieved in the following body tissues and fluids.
|
Table 2. Ceftazidime Concentrations in Body Tissues
and Fluids
|
|
Tissue or
Fluid
|
Dose/
Route
|
No.
Patients
|
Time of
Sample
Post-Dose
|
Average
Tissue
or
Fluid
Level
(mcg/mL or mcg/g)
|
|
Urine
|
500 mg IM
|
6
|
0 to 2 hours
|
2,100.0
|
|
|
2 grams IV
|
6
|
0 to 2 hours
|
12,000.0
|
|
Bile
|
2 grams IV
|
3
|
90 min.
|
36.4
|
|
Synovial fluid
|
2 grams IV
|
13
|
2 hours
|
25.6
|
|
Peritoneal fluid
|
2 grams IV
|
8
|
2 hours
|
48.6
|
|
Sputum
|
1 gram IV
|
8
|
1 hour
|
9.0
|
|
Cerebrospinal fluid (inflamed meninges)
|
2 grams q8h IV
2
grams q8h IV
|
5
6
|
120 min.
180 min.
|
9.8
9.4
|
|
Aqueous humor
|
2 grams IV
|
13
|
1 to 3 hours
|
11.0
|
|
Blister fluid
|
1 gram IV
|
7
|
2 to 3 hours
|
19.7
|
|
Lymphatic fluid
|
1 gram IV
|
7
|
2 to 3 hours
|
23.4
|
|
Bone
|
2 grams IV
|
8
|
0.67 hour
|
31.1
|
|
Heart muscle
|
2 grams IV
|
35
|
30 to 280 min.
|
12.7
|
|
Skin
|
2 grams IV
|
22
|
30 to 180 min.
|
6.6
|
|
Skeletal muscle
|
2 grams IV
|
35
|
30 to 280 min.
|
9.4
|
|
Myometrium
|
2 grams IV
|
31
|
1 to 2 hours
|
18.7
|
Microbiology: Ceftazidime is bactericidal in action, exerting its effect by inhibition
of enzymes responsible for cell-wall synthesis. A wide range of gram-negative
organisms is susceptible to ceftazidime in vitro, including strains resistant to gentamicin and
other aminoglycosides. In addition, ceftazidime has been shown to
be active against gram-positive organisms. It is highly stable to
most clinically important beta-lactamases, plasmid or chromosomal,
which are produced by both gram-negative and gram-positive organisms
and, consequently, is active against many strains resistant to ampicillin
and other cephalosporins.
Ceftazidime has
been shown to be active against the following organisms both in vitro and in clinical infections
(see INDICATIONS AND USAGE).
Aerobes, Gram-Negative: Citrobacter spp. (including Citrobacter freundii and Citrobacter diversus); Enterobacter spp. (including Enterobacter cloacae and Enterobacter aerogenes ); Escherichia coli; Haemophilus influenzae, including ampicillin-resistant
strains; Klebsiella spp. (including Klebsiella pneumoniae); Neisseria meningitidis; Proteus mirabilis; Proteus vulgaris; Pseudomonas spp.
(including Pseudomonas aeruginosa); and Serratia spp.
Aerobes, Gram-Positive: Staphylococcus aureus, including
penicillinase- and non-penicillinase-producing strains; Streptococcus agalactiae (group B streptococci); Streptococcus pneumoniae; and Streptococcus pyogenes (group A beta-hemolytic
streptococci).
Anaerobes: Bacteroides spp. (NOTE: Many strains of Bacteroides
fragilis are resistant).
Ceftazidime
has been shown to be active in vitro against most strains of the following organisms; however, the clinical
significance of these data is unknown: Acinetobacter spp.; Clostridiumspp. (not including Clostridium
difficile ); Haemophilus parainfluenzae; Morganella morganii (formerly Proteus morganii ); Neisseria gonorrhoeae; Peptococcus spp.; Peptostreptococcus spp.; Providencia spp. (including Providencia rettgeri, formerly Proteus rettgeri); Salmonella spp.; Shigella spp.; Staphylococcus epidermidis; and Yersinia enterocolitica .
Ceftazidime
and the aminoglycosides have been shown to be synergistic in vitro against Pseudomonas aeruginosa and the enterobacteriaceae.
Ceftazidime and carbenicillin have also been shown to be synergistic in vitro against Pseudomonas aeruginosa.
Ceftazidime is not active in vitro against: methicillin-resistant staphylococci, Streptococcus faecalis and many other
enterococci, Listeria monocytogenes, Campylobacter spp., or Clostridium difficile.
Susceptibility Tests: Diffusion Techniques: Quantitative
methods that require measurement of zone diameters give an estimate
of antibiotic susceptibility. One such procedure1-3 has
been recommended for use with disks to test susceptibility to ceftazidime.
Reports from the laboratory giving results of the standard
single-disk susceptibility test with a 30 mcg ceftazidime disk should
be interpreted according to the following criteria:
Susceptible organisms produce zones of 18 mm or greater, indicating
that the test organism is likely to respond to therapy.
Organisms that produce zones of 15 mm to 17 mm are
expected to be susceptible if high dosage is used or if the infection
is confined to tissues and fluids (e.g., urine) in which high antibiotic
levels are attained. Resistant organisms produce zones of 14 mm or
less, indicating that other therapy should be selected. Organisms
should be tested with the ceftazidime disk, since ceftazidime has
been shown by in vitro tests
to be active against certain strains found resistant when other beta-lactam
disks are used.
Standardized procedures require
the use of laboratory control organisms. The 30 mcg ceftazidime disk
should give zone diameters between 25 mm and 32 mm for Escherichia coli ATCC 25922. For Pseudomonas aeruginosa ATCC 27853,
the zone diameters should be between 22 mm and 29 mm. For Staphylococcus aureus ATCC 25923, the
zone diameters should be between 16 mm and 20 mm.
Dilution Techniques: In other susceptibility testing procedures, e.g., ICS agar dilution
or the equivalent, a bacterial isolate may be considered susceptible
if the minimum inhibitory concentration (MIC) value for ceftazidime
is not more than 16 mcg/mL. Organisms are considered resistant to
ceftazidime if the MIC is =64 mcg/mL. Organisms having an MIC
value of <64 mcg/mL but >16 mcg/mL are expected to be susceptible
if high dosage is used or if the infection is confined to tissues
and fluids (e.g., urine) in which high antibiotic levels are attained.
As with standard diffusion methods, dilution procedures
require the use of laboratory control organisms. Standard ceftazidime
powder should give MIC values in the range of 4 mcg/mL to 16 mcg/mL
for Staphylococcus aureus ATCC
25923. For Escherichia coli ATCC 25922, the MIC range should be between 0.125 mcg/mL and 0.5
mcg/mL. For Pseudomonas aeruginosa ATCC 27853, the MIC range should be between 0.5 mcg/mL and 2 mcg/mL.
INDICATIONS AND USAGE
Tazicef (ceftazidime for injection, USP) 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 Pseudomonas aeruginosa and other Pseudomonas spp.; Haemophilus influenzae, including ampicillin-resistant
strains; Klebsiella spp.; Enterobacter spp.; Proteus mirabilis; Escherichia coli ; Serratia spp.; Citrobacter spp.; Streptococcus
pneumoniae; and Staphylococcus
aureus (methicillin-susceptible strains).
-
Skin and Skin-Structure
Infections caused by Pseudomonas
aeruginosa; Klebsiella spp.; Escherichia coli ; Proteus spp.; including Proteus mirabilis and indole-positive Proteus; Enterobacter spp.; Serratia spp.; Staphylococcus aureus (methicillin-susceptible strains); and Streptococcus pyogenes (group A beta-hemolytic streptococci).
-
Urinary Tract Infections, both complicated and uncomplicated, caused by Pseudomonas aeruginosa; Enterobacter spp.; Proteus spp., including Proteus mirabilis and indole-positive Proteus ; Klebsiella spp.; and Escherichia
coli.
-
Bacterial Septicemia caused by Pseudomonas aeruginosa, Klebsiella spp., Haemophilus influenzae, Escherichia coli, Serratia spp., Streptococcus pneumoniae, and Staphylococcus aureus (methicillin-susceptible strains).
-
Bone and Joint Infections caused by Pseudomonas aeruginosa; Klebsiella spp.; Enterobacter spp., and Staphylococcus aureus (methicillin-susceptible
strains).
-
Gynecologic Infections, including endometritis, pelvic cellulitis, and other infections of
the female genital tract caused by Escherichia
coli.
-
Intra-abdominal Infections, including peritonitis caused by Escherichia
coli, Klebsiella spp., and Staphylococcus aureus (methicillin-susceptible strains) and polymicrobial infections caused
by aerobic and anaerobic organisms and Bacteroides spp. (many strains of Bacteroides fragilis are resistant).
-
Central Nervous System
Infections, including meningitis, caused by Haemophilus influenzae and Neisseria meningitidis . Ceftazidime
has also been used successfully in a limited number of cases of meningitis
due to Pseudomonas aeruginosa and Streptococcus pneumoniae.
Specimens for bacterial cultures should be obtained
before therapy in order to isolate and identify causative organisms
and to determine their susceptibility to ceftazidime. Therapy may
be instituted before results of susceptibility studies are known;
however, once these results become available, the antibiotic treatment
should be adjusted accordingly.
Tazicef (ceftazidime
for injection, USP) may be used alone in cases of confirmed or suspected
sepsis. Ceftazidime has been used successfully in clinical trials
as empiric therapy in cases where various concomitant therapies with
other antibiotics have been used.
Tazicef may also be used concomitantly
with other antibiotics, such as aminoglycosides, vancomycin and clindamycin,
in severe and life-threatening infections and in the immunocompromised
patient. When such concomitant treatment is appropriate, prescribing
information in the labeling for the other antibiotics should be followed.
The dose depends on the severity of the infection and the patient’s
condition.
To reduce the development of drug-resistant
bacteria and maintain the effectiveness of Tazicef (ceftazidime) and
other antibacterial drugs, Tazicef (ceftazidime) 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.
CONTRAINDICATIONS
Tazicef is
contraindicated in patients who have shown hypersensitivity to ceftazidime
or the cephalosporin group of antibiotics.
WARNINGS
BEFORE THERAPY WITH TAZICEF IS INSTITUTED, CAREFUL INQUIRY SHOULD BE MADE
TO DETERMINE WHETHER THE PATIENT HAS HAD PREVIOUS HYPERSENSITIVITY
REACTIONS TO CEFTAZIDIME, CEPHALOSPORINS, PENICILLINS, OR OTHER DRUGS.
IF THIS PRODUCT IS TO BE GIVEN TO PENICILLIN-SENSITIVE PATIENTS, CAUTION
SHOULD BE EXERCISED BECAUSE CROSS-HYPERSENSITIVITY AMONG BETA-LACTAM
ANTIBIOTICS HAS BEEN CLEARLY DOCUMENTED AND MAY OCCUR IN UP TO 10%
OF PATIENTS WITH A HISTORY OF PENICILLIN ALLERGY. IF AN ALLERGIC REACTION
TO TAZICEF OCCURS, DISCONTINUE
TREATMENT WITH THE DRUG. SERIOUS ACUTE HYPERSENSITIVITY REACTIONS
MAY REQUIRE TREATMENT WITH EPINEPHRINE AND OTHER EMERGENCY MEASURES,
INCLUDING OXYGEN, IV FLUIDS, IV ANTIHISTAMINES, CORTICOSTEROIDS, PRESSOR
AMINES AND AIRWAY MANAGEMENT, AS CLINICALLY INDICATED.
Pseudomembranous colitis
has been reported with nearly all antibacterial agents, including
ceftazidime, and may range in severity from mild to life-threatening.
Therefore, it is important to consider this diagnosis in patients
who present with diarrhea subsequent to the administration of antibacterial
agents.
Treatment with antibacterial
agents alters the normal flora of the colon and may permit overgrowth
of clostridia. Studies indicate that a toxin produced by Clostridium difficile is a primary cause
of “antibiotic-associated colitis.”
After the diagnosis of pseudomembranous colitis has been established,
appropriate therapeutic measures should be initiated. Mild cases of
pseudomembranous colitis usually respond to drug discontinuation alone.
In moderate to severe cases, consideration should be given to management
with fluids and electrolytes, protein supplementation and treatment
with an oral antibacterial drug clinically effective against Clostridium difficile colitis.
Elevated levels of ceftazidime in patients with renal
insufficiency can lead to seizures, encephalopathy, asterixis and
neuromuscular excitability (see PRECAUTIONS).
PRECAUTIONS
General:
Ceftazidime has not been shown to be nephrotoxic;
however, high and prolonged serum antibiotic concentrations can occur
from usual dosages in patients with transient or persistent reduction
of urinary output because of renal insufficiency. The total daily
dosage should be reduced when ceftazidime is administered to patients
with renal insufficiency (see DOSAGE AND ADMINISTRATION). Elevated
levels of ceftazidime in these patients can lead to seizures, encephalopathy,
asterixis and neuromuscular excitability. Continued dosage should
be determined by degree of renal impairment, severity of infection
and susceptibility of the causative organisms.
As with other antibiotics, prolonged use of Tazicef (ceftazidime
for injection, USP) may result in overgrowth of nonsusceptible organisms.
Repeated evaluation of the patient’s condition is essential.
If superinfection occurs during therapy, appropriate measures should
be taken.
Inducible type-1 beta-lactamase
resistance has been noted with some organisms (e.g., Enterobacter spp., Pseudomonas spp., and Serratia spp.). As with other extended-spectrum
beta-lactam antibiotics, resistance can develop during therapy, leading
to clinical failure in some cases. When treating infections caused
by these organisms, periodic susceptibility testing should be performed
when clinically appropriate. If patients fail to respond to monotherapy,
an aminoglycoside or similar agent should be considered.
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. Prothrombin time should be monitored
in patients at risk and exogenous vitamin K administered as indicated.
Tazicef should
be prescribed with caution in individuals with a history of gastrointestinal
disease, particularly colitis.
Distal necrosis
can occur after inadvertent intra-arterial administration of ceftazidime.
Prescribing Tazicef (ceftazidime) 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.
Drug Interactions:
Nephrotoxicity has been reported following concomitant
administration of cephalosporins with aminoglycoside, antibiotics
or potent diuretics, such as furosemide. Renal function should be
carefully monitored, especially if higher dosages of the aminoglycosides
are to be administered or if therapy is prolonged, because of the
potential nephrotoxicity and ototoxicity of aminoglycoside antibiotics.
Nephrotoxicity and ototoxicity were not noted when ceftazidime was
given alone in clinical trials.
Chloramphenicol
has been shown to be antagonistic to beta-lactam antibiotics, including
ceftazidime, based on in vitro studies and time kill curves with enteric gram-negative bacilli.
Due to the possibility of antagonism in vivo, particularly when bactericidal activity is desired,
this drug combination should be avoided.
Drug/Laboratory Test Interactions:
The administration of ceftazidime may result in a
false-positive reaction for glucose in the urine when using Clinitest® tablets, Benedict’s solution or Fehling’s
solution. It is recommended that glucose tests based on enzymatic
glucose oxidase reactions (such as Clinistix® or Tes-Tape®) be used.
Carcinogenesis, Mutagenesis, Impairment of Fertility:
Long-term studies in animals have not been performed
to evaluate carcinogenic potential. However, a mouse micronucleus
test and an Ames test were both negative for mutagenic effects.
Pregnancy:
Teratogenic Effects: Pregnancy Category B. Reproduction studies have been performed in
mice and rats at doses up to 40 times the human dose and have revealed
no evidence of impaired fertility or harm to the fetus due to Tazicef. 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:
Ceftazidime is excreted in human milk in low concentrations.
Caution should be exercised when Tazicef is administered to a nursing woman.
Pediatric Use:
(See DOSAGE AND ADMINISTRATION).
Information for Patients:
Patients should be counseled that antibacterial drugs
including Tazicef (ceftazidime) should only be used to treat bacterial
infections. They do not treat viral infections (e.g., the common cold).
When Tazicef (ceftazidime) 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 Tazicef (ceftazidime) or other antibacterial
drugs in the future.
ADVERSE REACTIONS
Ceftazidime is generally well-tolerated. The incidence
of adverse reactions associated with the administration of ceftazidime
was low in clinical trials. The most common were local reactions following
IV injection and allergic and gastrointestinal reactions. Other adverse
reactions were encountered infrequently. No disulfiram-like reactions
were reported.
The following adverse effects
from clinical trials were considered to be either related to ceftazidime
therapy or were of uncertain etiology:
Local Effects, reported in fewer than 2%
of patients, were phlebitis and inflammation at the site of injection
(1 in 69 patients).
Hypersensitivity Reactions, reported in 2% of patients,
were pruritus, rash and fever. Toxic epidermal necrolysis, Stevens-Johnson
syndrome, and erythema multiforme have also been reported with cephalosporin
antibiotics, including ceftazidime. Immediate reactions, generally
manifested by rash and/or pruritus, occurred in 1 in 285 patients.
Angioedema and anaphylaxis (bronchospasm and/or hypotension) have
been reported very rarely.
Gastrointestinal Symptoms, reported in
fewer than 2% of patients, were diarrhea (1 in 78), nausea (1 in 156),
vomiting (1 in 500) and abdominal pain (1 in 416). The onset of pseudomembranous
colitis symptoms may occur during or after treatment (see WARNINGS).
Central Nervous System Reactions (fewer than 1%) include headache, dizziness and paresthesia. Seizures
have been reported with several cephalosporins, including ceftazidime.
In addition, encephalopathy, asterixis and neuromuscular excitabiIity
have been reported in renally impaired patients treated with unadjusted
dosage regimens of ceftazidime (see PRECAUTIONS: General).
Less Frequent Adverse Events (fewer than 1%) were candidiasis (including oral thrush) and vaginitis.
Hematologic: Rare
cases of hemolytic anemia have been reported.
Laboratory Test Changes noted
during Tazicef (ceftazidime for injection, USP) clinical trials were
transient and included: eosinophilia (1 in 13), positive Coombs’
test without hemolysis (1 in 23), thrombocytosis (1 in 45), and slight
elevations in one or more of the hepatic enzymes, aspartate aminotransferase
(AST, SGOT) (1 in 16), alanine aminotransferase (ALT, SGPT) (1 in
15), LDH (1 in 18), GGT (1 in 19) and alkaline phosphatase (1 in 23).
As with some other cephalosporins, transient elevations of blood urea,
blood urea nitrogen and/or serum creatinine were observed occasionally.
Transient leukopenia, neutropenia, agranulocytosis, thrombocytopenia
and lymphocytosis were seen very rarely.
Observed During Clinical Practice: In addition
to the adverse events reported from clinical trials, the following
events have been identified during post-approval use of ceftazidime.
Because they are reported voluntarily from a population of unknown
size, estimates of frequency cannot be made. These events have been
chosen for inclusion due to a combination of their seriousness, frequency
of reporting, or potential causal connection to ceftazidime.
General: Anaphylactic
or anaphylactoid reactions, which, in rare instances, were severe
(e.g., cardiopulmonary arrest), including laryngeal edema, stridor,
and urticaria; pain at injection site.
Hepatobiliary Tract and Pancreas: Hyperbilirubinemia.
Renal and Genitourinary: Renal
impairment.
Cephalosporin-Class
Adverse Reactions: In addition to the adverse reactions
listed above that have been observed in patients treated with ceftazidime,
the following adverse reactions and altered laboratory tests have
been reported for cephalosporin-class antibiotics:
Adverse Reactions: Urticaria, colitis, renal dysfunction, toxic nephropathy, hepatic
dysfunction
including cholestasis, aplastic
anemia, hemorrhage.
Altered Laboratory Tests: Prolonged
prothrombin time, false-positive test for urinary glucose,
elevated bilirubin, pancytopenia.
OVERDOSAGE
Ceftazidime overdosage has occurred in patients with
renal failure. Reactions have included seizure activity, encephalopathy,
asterixis and neuromuscular excitability. Patients who receive an
acute overdosage should be carefully observed and given supportive
treatment. In the presence of renal insufficiency, hemodialysis or
peritoneal dialysis may aid in the removal of ceftazidime from the
body.
DOSAGE AND ADMINISTRATION
Dosage: The usual
adult dosage is 1 gram administered intravenously or intramuscularly
every 8 or 12 hours. The dosage and route should be determined by
the susceptibility of the causative organisms, the severity of infection
and the condition and renal function of the patient.
The guidelines for dosage of Tazicef (ceftazidime for injection,
USP) are listed in Table 3. The following dosage schedule is recommended.
|
Table 3. Recommended Dosage Schedule
|
|
|
Dose
|
Frequency
|
|
Adults
|
|
|
|
Usual recommended
dose
|
1 gram IV or
IM
|
q8 or 12h
|
|
Uncomplicated urinary tract infections
|
250 mg IV or IM
|
q12h
|
|
Bone and joint infections
|
2 grams IV
|
q12h
|
|
Complicated urinary tract infections
|
500 mg IV or IM
|
q8 or 12h
|
|
Uncomplicated pneumonia; mild skin and
skin structure infections
|
500 mg to 1 gram IV or IM
|
q8h
|
|
Serious gynecological and intra-abdominal
infections
|
2 grams IV
|
q8h
|
|
Meningitis
|
2 grams IV
|
q8h
|
|
Very severe life-threatening
infections, especially in immunocompromised patients
|
2 grams IV
|
q8h
|
|
|
|
|
Lung infections caused by Pseudomonas spp. in patients with cystic
fibrosis with normal renal function*
|
30 to 50 mg/kg IV to a maximum of 6 grams/day
|
q8h
|
|
Neonates (0 - 4 weeks)
|
30 mg/kg IV
|
q12h
|
|
Infants and
children
(1 month - 12 years)
|
30 to 50 mg/kg IV to a maximum of 6 grams/day†
|
q8h
|
|
*Although clinical improvement
has been shown, bacteriological cures cannot be expected in patients
with chronic respiratory disease and cystic fibrosis.
†The higher dose should be reserved for immunocompromised
pediatric patients or pediatric patients with cystic fibrosis
or meningitis.
|
Impaired Hepatic
Function : No adjustment
in dosage is required for patients with hepatic dysfunction.
Impaired Renal Function : Ceftazidime is excreted by
the kidneys, almost exclusively by glomerular filtration. Therefore,
in patients with impaired renal function (glomerular filtration rate
[GFR]<50 mL/min.), it is recommended that the dosage of ceftazidime
be reduced to compensate for its slower excretion. In patients with
suspected renal insufficiency, an initial loading dose of 1 gram of
ceftazidime may be given. An estimate of GFR should be made to determine
the appropriate maintenance dose. The recommended dosage is presented
in Table 4.
|
Table 4. Recommended Maintenance Doses of Tazicef
(ceftazidime for injection, USP) in Renal Insufficiency
|
|
NOTE: IF THE DOSE RECOMMENDED IN TABLE 3 ABOVE IS LOWER THAN THAT
RECOMMENDED FOR PATIENTS WITH RENAL INSUFFICIENCY AS OUTLINED IN TABLE
4, THE LOWER DOSE SHOULD BE USED.
|
|
Creatinine
Clearance
(mL/min.)
|
Recommended
Unit Dose of
Tazicef
|
Frequency
of Dosing
|
|
50 - 31
|
1 gram
|
q12h
|
|
30 - 16
|
1 gram
|
q24h
|
|
15 - 6
|
500 mg
|
q24h
|
|
<5
|
500 mg
|
q48h
|
When only serum creatinine is available, the
following formula (Cockcroft’s equation)4 may be
used to estimate 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
|
In patients with severe infections who would
normally receive 6 grams of Tazicef daily were it not for renal insufficiency, the unit dose given in
the table above may be increased by 50% or the dosing frequency increased
appropriately. Further dosing should be determined by therapeutic
monitoring, severity of the infection and susceptibility of the causative
organism.
In pediatric patients as for adults,
the creatinine clearance should be adjusted for body surface area
or lean body mass and the dosing frequency reduced in cases of renal
insufficiency.
In patients undergoing hemodialysis,
a loading dose of 1 gram is recommended, followed by 1 gram after
each hemodialysis period.
Tazicef (ceftazidime
for injection, USP) can also be used in patients undergoing intra-peritoneal
dialysis and continuous ambulatory peritoneal dialysis. In such patients,
a loading dose of 1 gram of Tazicef may be given, followed by 500 mg every 24 hours. In addition to IV
use, Tazicef can be incorporated
in the dialysis fluid at a concentration of 250 mg for 2 liters of
dialysis fluid.
Note:Generally Tazicef should be continued for 2 days after the signs and symptoms of infection
have disappeared, but in complicated infections longer therapy may
be required.
Administration: Tazicef may be given intravenously
or by deep IM injection into a large muscle mass such as the upper
outer quadrant of the gluteus maximus or lateral part of the thigh.
Intra-arterial administration should be avoided (see PRECAUTIONS).
Note: Tazicef in ADD-Vantage® vials is not intended for direct IV or IM injection.
Intramuscular Administration: For IM administration, Tazicef should be reconstituted with Sterile Water for Injection. Refer to
Table 5.
Intravenous
Administration: The IV route is preferable for patients
with bacterial septicemia, bacterial meningitis, peritonitis, or other
severe or life-threatening infections, or for patients who may be
poor risks because of lowered resistance resulting from such debilitating
conditions as malnutrition,
trauma, surgery,
diabetes, heart failure or malignancy, particularly if shock is present
or pending.
For direct intermittent IV administration, reconstitute Tazicef as directed in Table 5 with
Sterile Water for Injection. Slowly inject directly into the vein
over a period of 3 to 5 minutes or give through the tubing of an administration
set while the patient is also receiving one of the compatible IV fluids
(see COMPATIBILITY AND STABILITY).
For IV infusion, reconstitute the
1- or 2-gram piggyback vial with 100 mL of Sodium Chloride Injection
or one of the compatible IV fluids listed under the COMPATIBILITY
AND STABILITY section. Alternatively, reconstitute the 1-gram or 2-gram
vial and add an appropriate quantity of the resulting solution to
an IV container with one of the compatible IV fluids.
Intermittent intravenous infusion
with a Y-type administration set can be accomplished with
compatible solutions. However, during infusion of a solution containing
ceftazidime it is desirable to discontinue the other solution.
All vials of Tazicef as supplied are under reduced pressure. When Tazicef is dissolved, carbon dioxide
is released and a positive pressure develops. See RECONSTITUTION.
Solutions of Tazicef , 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 Tazicef and an aminoglycoside is indicated,
each of these antibiotics can be administered separately to the same
patient.
TAZICEF INJECTION IN ADD-VANTAGE® VIALS
Note: Tazicef (ceftazidime for injection, USP) in the
ADD-Vantage® vial is intended to be administered as
a single-dose intravenous infusion with the ADD-Vantage® flexible diluent container.
Tazicef in single-dose ADD-Vantage® vials should be prepared as directed (see RECONSTITUTION,
for ADD-Vantage® Vials) with either 0.9% Sodium Chloride
Injection in the 50 mL or 100 mL flexible diluent containers, 0.45%
Sodium Chloride Injection in the 50 mL container or 5% Dextrose Injection
in the 50 mL or 100 mL containers.
RECONSTITUTION
Single-Dose Vials:
For IM injection, IV direct (bolus) injection or IV infusion, reconstitute
with Sterile Water for Injection according to the following table.
The vacuum may assist entry of the diluent. SHAKE WELL.
|
Table 5
|
|
Vial
Size
|
Amount of
Diluent
to
Be Added
|
Approx. Avail.
Volume
|
Approximate
Ceftazidime
Concentration
|
|
Intramuscular or Intravenous Direct (bolus) Injection
|
|
1 gram
|
3.0 mL
|
3.6 mL
|
280 mg/mL
|
|
Intravenous Infusion
|
|
1 gram
|
10 mL
|
10.6 mL
|
95 mg/mL
|
|
2 gram
|
10 mL
|
11.2 mL
|
180 mg/mL
|
Withdraw the total volume of solution into the
syringe (the pressure in the vial may aid withdrawal).
The withdrawn solution may contain some bubbles of carbon
dioxide.
Note: As
with the administration of all parenteral products, accumulated gases
should be expressed from the syringe immediately before injection
of Tazicef.
These solutions
of Tazicef are stable for 24
hours at room temperature or 7 days if refrigerated (5°C). Slight
yellowing does not affect potency.
For IV
infusion, dilute reconstituted solution in 50 to 100 mL of one of
the parenteral fluids listed under COMPATIBILITY AND STABILITY.
“Piggyback” Vials:
For IV infusion, reconstitute with 10 mL of
Sodium Chloride Injection according to the following table.
The vacuum may assist entry of the diluent. SHAKE WELL.
|
Table 6
|
|
Vial
|
Diluent to
|
Approx. Avail.
|
Approx. Avg.
|
|
Size
|
Be Added
|
Volume
|
Concentration
|
|
1 gram
|
100 mL*
|
100 mL
|
10 mg/mL
|
|
2 gram
|
100 mL*
|
100 mL
|
20 mg/mL
|
|
*Addition should
be in two stages.
|
Insert a gas relief needle through the vial
closure to relieve the internal pressure. With the gas relief needle
in position, add the remaining 90 mL of Sodium Chloride Injection.
Remove the gas relief needle and syringe needle; shake the vial and
set up for infusion in the normal way.
Note: To preserve product sterility, it is important
that a gas relief needle is not inserted through the vial closure
before the product has dissolved.
These solutions of Tazicef (ceftazidime for injection, USP) are
stable for 24 hours at room temperature or 7 days if refrigerated
(5°C). Slight yellowing does not affect potency.
ADD-Vantage ® Vials: ADD-Vantage® vials of Tazicef
(ceftazidime for injection, USP) are to be reconstituted only with
0.9% Sodium Chloride Injection or 5% Dextrose Injection in the 50
mL or 100 mL flexible diluent containers, or with 0.45% Sodium Chloride
Injection in the 50 mL container.
DIRECTIONS FOR USE OF TAZICEF® (CEFTAZIDIME FOR INJECTION, USP) IN ADD-VANTAGE® VIALS
To Open Diluent Container:
Peel overwrap
at corner and remove solution container. Some opacity of the plastic
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)
-
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: 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 three tie strings,
then pull back to remove the cover. (SEE FIGURE 3.)
-
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 1/2 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 sealed,
do not attempt to remove. (SEE FIGURE 4.)
-
Recheck the vial to assure that it is tight by trying
to turn it further in the direction of assembly.
-
Label appropriately.
To Reconstitute the Drug:
-
Squeeze the bottom of the diluent container gently
to inflate the portion of the container surrounding the end of the
drug vial.
-
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.)
-
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.
-
Mix container contents thoroughly and use within
the specified time.
Preparation for Administration:
(Use Aseptic Technique)
-
Confirm the activation and admixture of vial contents.
-
Check for leaks by squeezing container firmly. If
leaks are found discard unit as sterility may be impaired.
-
Close flow control clamp of administration set.
-
Remove cover from outlet port at bottom of container.
-
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.
-
Lift the free end of the hanger loop on the bottom
of the vial, breaking the two tie strings. Bend the loop outward to
lock it in the upright position, then suspend container from hanger.
-
Squeeze and release drip chamber to establish proper
fluid level in chamber.
-
Open flow control clamp and clear air from set. Close
clamp.
-
Attach set to venipuncture device. If device is not
in-dwelling, prime and make venipuncture.
-
Regulate rate of administration with flow control
clamp.
WARNING: Do
not use flexible container in series connections.
COMPATIBILITY AND STABILITY
Intramuscular: Tazicef
(ceftazidime for injection, USP) when reconstituted as directed withSterile Water for Injection, maintains satisfactory potency for 24
hours at room temperature or for 7 days under refrigeration (5°C).
Solutions in Sterile Water for Injection that are frozen immediately
after reconstitution in the original container are stable for 3 months
when stored at -20°C. Once thawed, solutions should not be refrozen.
Thawed solutions may be stored for up to 8 hours at room temperature
or for 4 days in a refrigerator (5°C).
Intravenous: Tazicef (ceftazidime
for injection, USP) when reconstituted as directed with Sterile Water
for Injection, maintains satisfactory potency for 24 hours at room
temperature or for 7 days under refrigeration. Solutions in Sterile
Water for Injection in the original container or in 0.9% Sodium Chloride
Injection in Viaflex® small volume containers that
are frozen immediately after reconstitution are stable for 3 months
when stored at -20°C. For larger volumes where it may be necessary
to warm the frozen product (to a maximum of 40°C), care should
be taken to avoid heating after thawing is complete. Do not force
thaw by immersion in water baths or by microwave irradiation. Once
thawed, solutions should not be refrozen. Thawed solutions may be
stored for up to 8 hours at room temperature or for 4 days in a refrigerator
(5°C).
Tazicef is compatible with the more commonly used IV infusion
fluids. Solutions at concentrations between 1 mg/mL and 40 mg/mL in
the following infusion fluids may be stored for up to 24 hours at
room temperature or 7 days if refrigerated: 0.9% Sodium Chloride Injection;
Ringer’s Injection USP; Lactated Ringer’s Injection
USP; 5% Dextrose Injection; 5% Dextrose and 0.225% Sodium Chloride
Injection; 5% Dextrose and 0.45% Sodium Chloride Injection; 5% Dextrose
and 0.9% Sodium Chloride Injection; 10% Dextrose Injection.
Tazicef is less
stable in Sodium Bicarbonate Injection than in other IV fluids. It
is not recommended as a diluent. Solutions of Tazicef in 5% Dextrose and 0.9% Sodium
Chloride Injection are stable for at least 6 hours at room temperature
in plastic tubing, drip chambers and volume control devices of common
IV infusion sets.
Ceftazidime at a concentration
of 20 mg/mL has been found physically compatible for 24 hours at room
temperature or 7 days under refrigeration in Sterile Water for Injection
when admixed with: cefazolin sodium 330 mg/mL; heparin 1000 units/mL;
and cimetidine HCI 150 mg/mL.
Ceftazidime
at a concentration of 20 mg/mL has been found physically compatible
for 24 hours at room temperature or 7 days under refrigeration in
5% Dextrose Injection when admixed with potassium chloride 40 mEq/L.
Vancomycin solution exhibits a physical incompatibility
when mixed with a number of drugs, including ceftazidime. The likelihood
of precipitation with ceftazidime is dependent on the concentrations
of vancomycin and ceftazidime present. It is therefore recommended,
when both drugs are to be administered by intermittent IV infusion,
that they be given separately, flushing the IV lines (with one of
the compatible IV fluids) between the administration of these two
agents.
ADD-Vantage ® Vials: Ordinarily, ADD-Vantage® vials should be reconstituted only when it is certain that the patient
is ready to receive the drug. However, Tazicef in ADD-Vantage® vials is stable
for 24 hours at room temperature when reconstituted as directed (see
RECONSTITUTION, ADD-Vantage®Vials, and DIRECTIONS
FOR USE OF TAZICEF® INJECTION IN ADD-VANTAGE® VIALS).
Note: Parenteral drug products should be inspected visually for particulate
matter prior to administration whenever solution and container permit.
As with other cephalosporins, Tazicef powder, as well as solutions, tends to darken depending
on storage conditions; within the stated recommendations, however,
product potency is not adversely affected.
HOW SUPPLIED
Tazicef in
the dry state should be stored at 20° to 25°C (68°
to 77°F) [See USP Controlled Room Temperature] and protected
from light. Tazicef (ceftazidime for injection, USP) is a dry, white
to off-white powder supplied in vials as follows:
Vials: equivalent to 1 gram and 2 grams of ceftazidime.
1 gram (tray of 25): NDC 0409-5082-16
2 gram (tray of 10): NDC 0409-5084-11
“Piggyback”
Vials for IV admixture: equivalent to 1 gram of ceftazidime.
1 gram (tray of 10): NDC 0409-5083-11
ADD-Vantage® Vials: equivalent to 1 gram and 2 grams
of ceftazidime.
1 gram: NDC 0409-5092-16
2 gram: NDC 0409-5093-11
Also available
as:
Pharmacy Bulk Vials: equivalent to 6 grams
of ceftazidime.
6 gram (tray of 10): NDC 0409-5086-11
Clinical Studies
N/A
REFERENCES
-
Bauer AW, Kirby WMM, Sherris JC, Turck M. Antibiotic
susceptibility testing by a standardized single disk method. Am J Clin Pathol. 1966;45:493-496.
-
National Committee for Clinical Laboratory Standards. Approved Standard: Performance Standards for Antimicrobial
Disk Susceptibility Tests. (M2-A3), December, 1984.
-
Certification procedure for antibiotic sensitivity
discs (21 CFR 460.1). Federal Register. May 30, 1974;39:19182-19184.
-
Cockcroft DW, Gault MH. Prediction of creatinine
clearance from serum creatinine. Nephron. 1976;16:31-41.
Rev: September, 2005
Manufactured
by Sandoz GmbH for Hospira Worldwide, Inc.,
Lake Forest, IL 60045, USA.
Made in Kundl, Austria.
©Hospira 2005
EN-1039 Printed in Austria
Revised: 01/2007Hospira Worldwide, Inc.