CEFTAZIDIME
DESCRIPTION:
FOR INTRAVENOUS OR INTRAMUSCULAR USE
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)acetyl)amino)-2-carboxy- 8-
oxo-5-thia-1-azabicyclo(4.2.0)oct-2-en- 3-yl)methyl)-, hydroxide, inner salt,
(6R- (6alpha,7beta(Z))).
The empirical formula is C22H32N6O12S2, representing a molecular weight of
636.6.
CEFIZOX is a sterile, dry mixture of ceftazidime pentahydrate and L-arginine. The
L-arginine is at a concentration of 349 mg/g of ceftazidime activity. CEFIZOX
dissolves without the evolution of gas. The product contains no sodium ion.
Solutions of CEFIZOX range in color from light yellow to amber, depending on the
diluent and volume used. The pH of freshly constituted solutions usually ranges
from 5 to 7.5.
ACTIONS/CLINICAL PHARMACOLOGY:
After intravenous (IV) administration of 500-mg and 1-g doses of ceftazidime
over 5 minutes to normal adult male volunteers, mean peak serum concentrations
of 45 and 90 mcg/mL, respectively, were achieved. After IV infusion of 500-mg,
1-g, and 2-g doses of ceftazidime over 20 to 30 minutes to normal adult male
volunteers, mean peak serum concentrations of 42, 69, and 170 mcg/mL,
respectively, were achieved. The average serum concentrations following IV
infusion of 500-mg, 1-g, and 2-g doses to these volunteers over an 8-hour
interval are given in Table 1.
TABLE 1
-------------------------------------------------
Serum Concentrations
Ceftazidime (mcg/mL)
IV Dose ----------------------------------------------------------
0.5 h 1 h 2 h 4 h 8 h
-------------------------------------------------
500 mg 42 25 12 6 2
1 g 60 39 23 11 3
2 g 129 75 42 13 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 and 2 g every 8 hours for 10 days.
Following intramuscular (IM) administration of 500-mg and 1-g doses of
ceftazidime to normal adult volunteers, the mean peak serum concentrations were
17 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-g 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 g 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-g 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.
Ceftazidime concentrations achieved in specific body tissues and fluids are
depicted in Table 2.
TABLE 2: CEFTAZIDIME CONCENTRATIONS IN BODY TISSUES AND FLUIDS
-----------------------------------------------------------------------------
Average
Tissue or
Time of Fluid Level
No. of Sample (mcg/mL or
Tissue or Fluid Dose/Route Patients Postdose mcg/g)
---------------------------------------------------------------------------------------------------------------------------------------------------------
Urine 500 mg IM 6 0-2 h 2,100.0
2 g IV 6 0-2 h 12,000.0
Bile 2 g IV 3 90 min 36.4
Synovial fluid 2 g IV 13 2 h 25.6
Peritoneal fluid 2 g IV 8 2 h 48.6
Sputum 1 g IV 8 1 h 9.0
Cerebrospinal fluid 2 g q8h IV 5 120 min 9.8
(inflamed meninges) 2 g q8h IV 6 180 min 9.4
Aqueous humor 2 g IV 13 1-3 h 11.0
Blister fluid 1 g IV 7 2-3 h 19.7
Lymphatic fluid 1 g IV 7 2-3 h 23.4
Bone 2 g IV 8 0.67 h 31.1
Heart muscle 2 g IV 35 30-280 min 12.7
Skin 2 g IV 22 30-180 min 6.6
Skeletal muscle 2 g IV 35 30-280 min 9.4
Myometrium 2 g IV 31 1-2 h 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 this activity is
unknown: Acinetobacter spp.; Clostridium spp. (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 procedure (REF. 1-3) 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 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 and 32 mm for
Escherichia Coli ATCC 25922. For Pseudomonas Aeruginosa ATCC 27853, the zone
diameters should be between 22 and 29 mm. For Staphylococcus Aureus ATCC 25923,
the zone diameters should be between 16 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 to 16 mcg/mL for Staphylococcus Aureus ATCC 25923. For
Escherichia Coli ATCC 25922, the MIC range should be between 0.125 and 0.5
mcg/mL. For Pseudomonas Aeruginosa ATCC 27853, the MIC range should be between
0.5 and 2 mcg/mL.
INDICATIONS AND USAGE:
CEFIZOX is indicated for the treatment of patients with infections caused by
susceptible strains of the designated organisms in the following diseases:
1. 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).
2. 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).
3. 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.
4. BACTERIAL SEPTICEMIA caused by Pseudomonas Aeruginosa, Klebsiella spp.,
Haemophilus Influenzae, Escherichia Coli, Serratia spp., Streptococcus
Pneumoniae, and Staphylococcus Aureus (methicillin-susceptible strains).
5. BONE AND JOINT INFECTIONS caused by Pseudomonas Aeruginosa, Klebsiella spp.,
Enterobacter spp., and Staphylococcus Aureus (methicillin-susceptible strains).
6. GYNECOLOGIC INFECTIONS, including endometritis, pelvic cellulitis, and other
infections of the female genital tract caused by Escherichia Coli.
7. 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).
8. 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.
As with other extended-spectrum cephalosporins and penicillins, some strains of
Enterobacter spp. can develop resistance during ceftazidime therapy due to
induced type-1 beta-lactamase production. When clinically appropriate during
therapy of Enterobacter spp. infections, periodic susceptibility testing should
be considered.
CEFIZOX 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.
CEFIZOX 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 (see COMPATIBILITY AND
STABILITY). When such concomitant treatment is appropriate, prescribing
information in the labeling for the other antibiotics should be followed. The
dosage depends on the severity of the infection and the patient's condition.
CONTRAINDICATIONS:
CEFIZOX is contraindicated in patients who have shown hypersensitivity to
ceftazidime or the cephalosporin group of antibiotics.
WARNINGS:
BEFORE THERAPY WITH CEFIZOX 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
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 CEFIZOX OCCURS, DISCONTINUE 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 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 one 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 discontinuation of the drug alone.
In moderate to severe cases, consideration should be given to management with
fluids and electrolytes, protein supplementation, and treatment with an
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 CEFIZOX 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.
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.
CEFIZOX should be prescribed with caution in individuals with a history of
gastrointestinal disease, particularly colitis.
Arginine has been shown to alter glucose metabolism and elevate serum potassium
transiently when administered at 50 times the recommended dose. The effect of
lower dosing is not known.
Distal necrosis can occur after inadvertent intra-arterial administration of
ceftazidime.
Inducible type I 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.
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
aminoglycosidic 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(R)
tablets, Benedict's solution, or Fehling's solution. It is recommended that
glucose tests based on enzymatic glucose oxidase reactions (such as CLINISTIX(R)
or TES-TAPE(R)) 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
ceftazidime. CEFIZOX at 23 times the human dose was not teratogenic or
embryotoxic in a rat reproduction study. 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. It
is not known whether the arginine component of this product is excreted in human
milk. Because many drugs are excreted in human milk and because safety of the
arginine component of CEFIZOX in nursing infants has not been established, a
decision should be made whether to discontinue nursing or to discontinue the
drug, taking into account the importance of the drug to the mother.
PEDIATRIC USE: Safety of the arginine component of CEFIZOX in neonates, infants,
and children has not been established. This product is for use in patients 12
years and older. If treatment with ceftazidime is indicated for neonates,
infants, or children, a sodium carbonate formulation should be used.
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
aminoglycosidic 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.
(See Also PRECAUTIONS)
ADVERSE REACTIONS:
The following adverse effects from clinical trials were considered to be either
related to ceftazidime therapy or were of uncertain etiology. The most common
were local reactions following IV injection and allergic and gastrointestinal
reactions. No disulfiramlike reactions were reported.
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. Immediate reactions, generally manifested by rash and/or pruritus,
occurred in 1 in 285 patients. Toxic epidermal necrolysis, Stevens-Johnson
syndrome, and erythema multiforme have also been reported with cephalosporin
antibiotics, including ceftazidime. 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%) included headache, dizziness,
and paresthesia. Seizures have been reported with several cephalosporins,
including ceftazidime. In addition, encephalopathy, asterixis, and neuromuscular
excitability have been reported in renally impaired patients treated with
unadjusted dosing 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 ceftazidime 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.
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 to 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 CEFIZOX are listed in Table 3. The following dosage
schedule is recommended.
TABLE 3: RECOMMENDED DOSAGE SCHEDULE
------------------------------------------------------------------------------------------------------------------------------------------------------
Dose Frequency
------------------------------------------------------------------------------------------------------------------------------------------------------
PATIENTS 12 YEARS AND OLDER*
USUAL RECOMMENDED DOSAGE 1 GRAM IV OR IM Q8-12H
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 q8-12h
Uncomplicated pneumonia; mild 500 mg-1 gram IV
skin and skin-structure infections or IM q8h
Serious gynecologic 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. 30-50 mg/kg IV
in patients with cystic fibrosis with to a maximum
normal renal function** of 6 grams per day q8h
---------------------------------------------------------------------------------------------------------------------------------------------------------------------
* This product is for use in patients 12 years and older. If treatment with
ceftazidime is indicated for patients less than 12 years old, a sodium
carbonate formulation should be used.
** Although clinical improvement has been shown, bacteriologic cures cannot be
expected in patients with chronic respiratory disease and cystic fibrosis.
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 CEFIZOX may be given. An estimate of GFR should be made to determine the
appropriate maintenance dosage. The recommended dosage is presented in Table 4.
TABLE 4: RECOMMENDED MAINTENANCE DOSAGES OF CEFIZOX
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 Recommended
Clearance Unit Dose of Frequency
(mL/min) CEFIZOX 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) (REF. 4) may be used to estimate creatinine clearance. The serum
creatinine should represent a steady state of renal function:
Males: Weight (kg) X
Creatinine clearance (140-age)
(mL/min) = --------------------
72 X serum creatinine
(mg/dL)
Females: 0.85 X male value
In patients with severe infections who would normally receive 6 grams of CEFIZOX
daily were it not for renal insufficiency, the unit dose given in the table
above may be increased by 50% or the dosing frequency may be increased
appropriately. Further dosing should be determined by therapeutic monitoring,
severity of the infection, and susceptibility of the causative organism.
In patients undergoing hemodialysis, a loading dose of 1 gram is recommended,
followed by 1 gram after each hemodialysis period.
CEFIZOX can also be used in patients undergoing intraperitoneal dialysis and
continuous ambulatory peritoneal dialysis. In such patients, a loading dose of 1
gram of CEFIZOX may be given, followed by 500 mg every 24 hours. It is not known
whether or not CEFIZOX can be safely incorporated into dialysis fluid.
NOTE: Generally CEFIZOX 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: CEFIZOX 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.)
INTRAMUSCULAR ADMINISTRATION: For IM administration, CEFIZOX should be
constituted with one of the following diluents: sterile water for injection,
bacteriostatic water for injection, or 0.5% or 1% lidocaine hydrochloride
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, constitute CEFIZOX as directed in
Table 5 with sterile water for injection, 5% dextrose injection, or 0.9% sodium
chloride 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, constitute the 1- or 2-gram infusion pack with 100 mL of
sterile water for injection or one of the compatible IV fluids listed under the
COMPATIBILITY AND STABILITY section. Alternatively, constitute the 1- 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 IV 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.
TABLE 5: PREPARATION OF CEFIZOX SOLUTIONS
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Amount of Volume Approximate
Diluent to Be Ceftazidime
to Be Added Withdrawn Concentration
Size (mL) (mL) (mg/mL)
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Intramuscular
1-gram vial 3.0 Total 250
Intravenous
1-gram vial 10.0 Total 90
2-gram vial 10.0 Total 170
Infusion pack
1-gram vial 100 -- 10
2-gram vial 100 -- 20
Pharmacy bulk package
10-gram vial 40 Amount needed 200
Solutions of CEFIZOX, 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 CEFIZOX and an aminoglycoside is indicated,
each of these antibiotics can be administered separately to the same patient.
INSTRUCTIONS FOR CONSTITUTION: Vials of CEFIZOX as supplied are under a slightly
reduced pressure. This may assist entry of the diluent. No gas- relief needle is
required when adding the diluent, except for the infusion pack where it is
required during the latter stages of addition (in order to preserve product
sterility, a gas-relief needle should not be inserted until an overpressure is
produced in the vial). No evolution of gas occurs on constitution. When the vial
contents are dissolved, vials other than infusion packs may still be under a
reduced pressure. This reduced pressure is particularly noticeable for the 10-g
pharmacy bulk package.
COMPATIBILITY AND STABILITY
INTRAMUSCULAR: CEFIZOX, when constituted as directed with sterile water for
injection, bacteriostatic water for injection, or 0.5% or 1% lidocaine
hydrochloride injection, maintains satisfactory potency for 18 hours at room
temperature or for 7 days under refrigeration. Solutions in sterile water for
injection that are frozen immediately after constitution in the original
container are stable for 6 months when stored at -20 deg C. Components of the
solution may precipitate in the frozen state and will dissolve on reaching room
temperature with little or no agitation. Potency is not affected. Frozen
solutions should only be thawed at room temperature. 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 12 hours at
room temperature or for 7 days in a refrigerator.
INTRAVENOUS: CEFTAZIDIME CONCENTRATION GREATER THAN 100 MG/ML (2-G VIAL OR 10-G
PHARMACY BULK PACKAGE): CEFIZOX, when constituted as directed with sterile water
for injection, 0.9% sodium chloride injection, or 5% dextrose injection,
maintains satisfactory potency for 18 hours at room temperature or for 7 days
under refrigeration. Solutions of a similar concentration in sterile water for
injection that are frozen immediately after constitution in the original
container are stable for 6 months when stored at -20 deg C. Components of the
solution may precipitate in the frozen state and will dissolve on reaching room
temperature with little or no agitation. Potency is not affected. Frozen
solutions should only be thawed at room temperature. 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 12 hours at
room temperature or for 7 days in a refrigerator.
CEFTAZIDIME CONCENTRATION OF 100 MG/ML OR LESS (1-G VIAL OR INFUSION PACKS):
CEFIZOX, when constituted as directed with sterile water for injection, 0.9%
sodium chloride injection, or 5% dextrose injection, maintains satisfactory
potency for 24 hours at room temperature or for 7 days under refrigeration.
Solutions, prepared by a pharmacist, of the approved arginine formulation of
ceftazidime of a similar concentration in sterile water for injection, 0.9%
sodium chloride injection, or 5% dextrose injection in the original container or
in 0.9% sodium chloride injection in VIRAFLEX(R) (PL 146(R) Plastic) small-
volume containers that are frozen immediately after constitution by the
pharmacist are stable for 6 months when stored at -20 deg C. Solutions in the PL
146 Plastic small- volume containers are in contact with the polyvinyl chloride
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.
Stability of the frozen solution in other containers has not been confirmed.
Frozen solutions should only be thawed at room temperature. Do not force thaw by
immersion in water baths or by microwave irradiation. For the larger volumes of
IV infusion solutions where it may be necessary to warm the frozen product, care
should be taken to avoid heating after thawing is complete. Once thawed,
solutions should not be refrozen. Thawed solutions may be stored for up to 18
hours at room temperature or for 7 days in a refrigerator.
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. Check for minute leaks in plastic containers by squeezing bag firmly.
Discard bag if leaks are found as sterility may be impaired. Do not add
supplementary medication to bags. 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:
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
CEFIZOX is compatible with the more commonly used IV infusion fluids. Solutions
at concentrations between 1 and 40 mg/mL in 0.9% sodium chloride injection; 1/6
M sodium lactate injection; 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; ringer's injection,
USP; lactated ringer's injection, USP; 10% invert sugar in sterile water for
injection; and NORMOSOL(R)-M in 5% dextrose injection may be stored for up to 24
hours at room temperature or for 7 days if refrigerated.
CEFIZOX is less stable in sodium bicarbonate injection than in other IV fluids.
It is not recommended as a diluent. Solutions of CEFIZOX in 5% dextrose injection
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 4 mg/mL has been found compatible for 24 hours
at room temperature or for 7 days under refrigeration in 0.9% sodium chloride
injection or 5% dextrose injection when admixed with: cefuroxime sodium
(ZINACEF(R)) 3 mg/mL; heparin sodium in concentrations up to 50 U/mL; or
potassium chloride in concentrations up to 40 mEq/L. Ceftazidime may be
constituted at a concentration of 20 mg/mL with metronidazole injection 5 mg/mL,
and the resultant solution may be stored for 24 hours at room temperature or for
7 days under refrigeration. Ceftazidime at a concentration of 20 mg/mL has been
found compatible for 24 hours at room temperature or for 7 days under
refrigeration in 0.9% sodium chloride injection or 5% dextrose injection when
admixed with 6 mg/mL clindamycin (as clindamycin phosphate).
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.
NOTE: Parenteral drug products should be inspected visually for particulate
matter before administration whenever solution and container permit.
As with other cephalosporins, CEFIZOX powder as well as solutions tend to darken,
depending on storage conditions; within the stated recommendations, however,
product potency is not adversely affected.
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). GOOD PHARMACY PRACTICE DICTATES
THAT THE CLOSURE BE PENETRATED ONLY ONE TIME AFTER CONSTITUTION. AFTER INITIAL
PENETRATION OF THE CLOSURE, USE ENTIRE CONTENTS OF VIAL PROMPTLY. ANY UNUSED
PORTION MUST BE DISCARDED WITHIN 18 HOURS OF CONSTITUTION.
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