CEFAZIDIME HUP

Ceftazidime is a semisynthetic, broad-spectrum, beta-lactam antibacterial drug 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-[6α,7β(Z)].

It has the following structural formula

The molecular formula is C 22 H 22 N 6 O 7 S 2 •5H 2 O, representing a molecular weight of 636.65.

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/g of ceftazidime activity has been admixed to facilitate dissolution.

The total sodium content of the mixture is approximately 54 mg (2.3 mEq)/g of ceftazidime activity.

Ceftazidime for injection, USP in sterile crystalline form is supplied in single-dose vials equivalent to 1 g or 2 g of anhydrous ceftazidime.

Ceftazidime for injection, USP is a white to cream-colored crystalline powder.

Solutions of ceftazidime for injection, USP range in color from light yellow to amber, depending on the diluent and volume used.

The pH of freshly constituted solutions usually ranges from to 8.

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

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).

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

Infections caused by Pseudomonas aeruginosa, Klebsiella spp., Enterobacter spp., and Staphylococcus aureus (methicillin-susceptible strains).

Infections, including endometritis, pelvic cellulitis, and other infections of the female genital tract caused by Escherichia coli.

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).

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.

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 antibacterial drugs have been used.

Ceftazidime for injection, USP may also be used concomitantly with other antibacterial drugs, 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 antibacterial drugs 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 ceftazidime for injection, USP and other antibacterial drugs, ceftazidime for injection, USP should be used only to treat 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.

IV administration of 500 mg and 1 g doses of ceftazidime over 5 minutes to normal adult male volunteers, mean peak serum concentrations of and 90 mcg/mL, respectively, were achieved.

IV infusion of 500 mg, 1 g, and 2 g doses of ceftazidime over 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.

Average Serum Concentrations of Ceftazidime Ceftazidime IV Dose Serum Concentrations (mcg/mL) 0.5 hr 1 hr 2 hr 4 hr 8 hr 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 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 and 39 mcg/mL, respectively, at approximately 1 hour.

Serum concentrations remained above 4 mcg/mL for 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 and 4 hours after dosing, and approximately another 12% of the dose appeared in the urine between 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. of Patients Time of Sample Post Dose Average Tissue or Fluid Level (mcg/mL or mcg/g) Urine 500 mg IM 6 0 to 2 hr 2,100 2 g IV 6 0 to 2 hr 12,000 Bile 2 g IV 3 90 min 36.4 Synovial fluid 2 g IV 13 2 hr 25.6 Peritoneal fluid 2 g IV 8 2 hr 48.6 Sputum 1 g IV 8 1 hr 9 Cerebrospinal fluid 2 g q8hr IV 5 120 min 9.8 (inflamed meninges) 2 g q8hr IV 6 180 min 9.4 Aqueous humor 2 g IV 13 1 to 3 hr 11 Blister fluid 1 g IV 7 2 to 3 hr 19.7 Lymphatic fluid 1 g IV 7 2 to 3 hr 23.4 Bone 2 g IV 8 0.67 hr 31.1 Heart muscle 2 g IV 35 30 to 280 min 12.7 Skin 2 g IV 22 30 to 180 min 6.6 Skeletal muscle 2 g IV 35 30 to 280 min 9.4 Myometrium 2 g IV 31 1 to 2 hr 18.7 Microbiology Mechanism of Action Ceftazidime is a bactericidal agent that acts by inhibition of bacterial cell wall synthesis.

Ceftazidime has activity in the presence of some beta-lactamases, both penicillinases and cephalosporinases, of Gram-negative and Gram-positive bacteria.

Resistance to ceftazidime is primarily through hydrolysis by beta-lactamase, alteration of penicillin-binding proteins (PBPs), and decreased permeability.

In an in vitro study, antagonistic effects have been observed with the combination of chloramphenicol and ceftazidime.

Ceftazidime has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section: Gram-negative bacteria Citrobacter species Enterobacter species Escherichia coli Klebsiella species Haemophilus influenzae Neisseria meningitidis Proteus mirabilis Proteus vulgaris Pseudomonas aeruginosa Serratia species Gram-positive bacteria Staphylococcus aureus Streptococcus pneumoniae Streptococcus pyogenes Streptococcus agalactiae Anaerobic bacteria Bacteroides species (Note: many isolates of Bacteroides species are resistant) The following in vitro data are available, but their clinical significance is unknown.

At least 90 percent of the following microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for ceftazidime.

However, the efficacy of ceftazidime in treating clinical infections due to these microorganisms has not been established in adequate and well-controlled clinical trials.

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).

Reactions, reported in 2% of patients, were pruritus, rash, and fever.

Immediate reactions, generally manifested by rash and/or pruritus, occurred in in 285 patients.

Toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme have also been reported with cephalosporin antibacterial drugs, including ceftazidime.

Angioedema and anaphylaxis (bronchospasm and/or hypotension) have been reported very rarely.

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.

Reactions (fewer than 1%) included headache, dizziness, and paresthesia.

Seizures have been reported with several cephalosporins, including ceftazidime.

In addition, encephalopathy, coma, asterixis, neuromuscular excitability, and myoclonia have been reported in renally impaired patients treated with unadjusted dosing regimens of ceftazidime.

Events (fewer than 1%) were candidiasis (including oral thrush) and vaginitis.

Rare cases of hemolytic anemia have been reported.

Changes noted during clinical trials with ceftazidime 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.

Postmarketing Experience with Ceftazidime Products

In addition to the adverse events reported during clinical trials, the following events have been observed during clinical practice in patients treated with ceftazidime and were reported spontaneously.

For some of these events, data are insufficient to allow an estimate of incidence or to establish causation.

Anaphylaxis; allergic reactions, which, in rare instances, were severe (e.g., cardiopulmonary arrest); urticaria; pain at injection site.

Hyperbilirubinemia, jaundice.

Renal impairment.

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 antibacterial drugs: Adverse Reactions Colitis, toxic nephropathy, hepatic dysfunction including cholestasis, aplastic anemia, hemorrhage.

Prolonged prothrombin time, false-positive test for urinary glucose, pancytopenia.

To report SUSPECTED ADVERSE

REACTIONS, contact Sagent Pharmaceuticals, Inc.fda.gov/medwatch.

Ceftazidime overdosage has occurred in patients with renal failure.

Reactions have included seizure activity, encephalopathy, asterixis, neuromuscular excitability, and coma.

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.

10% OF PATIENTS WITH A HISTORY OF PENICILLIN ALLERGY.

IF AN ALLERGIC REACTION TO CEFTAZIDIME FOR INJECTION 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.

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including ceftazidime for injection, 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 antibacterial drug 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 antibacterial drug use not directed against C. difficile may need to be discontinued.

Appropriate fluid and electrolyte management, protein supplementation, antibacterial drug treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Elevated levels of ceftazidime in patients with renal insufficiency can lead to seizures, nonconvulsive status epilepticus (NCSE), encephalopathy, coma, asterixis, neuromuscular excitability, and myoclonia.

Ceftazidime for injection is contraindicated in patients who have shown hypersensitivity to ceftazidime or the cephalosporin group of antibacterial drugs.

The usual adult dosage is 1 gram administered intravenously or intramuscularly every 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 ceftazidime for injection are listed in Table 3.

The following dosage schedule is recommended.

Table 3.

Schedule Although clinical improvement has been shown, bacteriologic 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.

Usual recommended dosage 1 gram intravenous or intramuscular every to 12 hours Uncomplicated urinary tract infection 250 mg intravenous or intramuscular every 12 hours Bone and joint infections 2 grams intravenous every 12 hours Complicated urinary tract infections 500 mg intravenous or intramuscular every to 12 hours Uncomplicated pneumonia; mild skin and skin-structure infections 500 mg to 1 gram intravenous or intramuscular every 8 hours Serious gynecological and intra-abdominal infections 2 grams intravenous every 8 hours Meningitis 2 grams intravenous every 8 hours Very severe life-threatening infections, especially in immunocompromised patients 2 grams intravenous every 8 hours Lung infections caused by Pseudomonas spp. in patients with cystic fibrosis with normal renal function 30 to 50 mg/kg intravenous to a maximum of 6 grams per day every 8 hours Neonates (0 to 4 weeks) 30 mg/kg intravenous every 12 hours Infants and children (1 month to 12 years) 30 to 50 mg/kg intravenous to a maximum of 6 grams per day* every 8 hours Impaired Hepatic Function No adjustment in dosage is required for patients with hepatic dysfunction.

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 dosage.

The recommended dosage is presented in

Table 4.

Recommended Maintenance Dosages of Ceftazidime for Injection 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.

Clearance (mL/min) Recommended Unit Dose of Ceftazidime for Injection Frequency of Dosing to 31 1 gram every 12 hours to 16 1 gram every 24 hours to 6 500 mg every 24 hours less than 5 500 mg every 48 hours When only serum creatinine is available, the following formula (Cockcroft's equation) 1 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 ceftazidime for injection 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 pediatric patients as for adults, the creatinine clearance should be adjusted for body surface area or lean body mass, and the dosing frequency should be 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.

Ceftazidime for injection can also be used in patients undergoing intraperitoneal dialysis and continuous ambulatory peritoneal dialysis.

In such patients, a loading dose of 1 gram of ceftazidime for injection may be given, followed by 500 mg every 24 hours.

In addition to

IV use, ceftazidime for injection can be incorporated in the dialysis fluid at a concentration of 250 mg for 2 L of dialysis fluid.

Generally, ceftazidime for injection should be continued for 2 days after the signs and symptoms of infection have disappeared, but in complicated infections longer therapy may be required.

Ceftazidime for injection 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.

IM administration, ceftazidime for injection 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.

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 ceftazidime for injection as directed in Table with Sterile Water for Injection.

Slowly inject directly into the vein over a period of to 5 minutes or give through the tubing of an administration set while the patient is also receiving one of the compatible IV fluids.

IV infusion, constitute 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 listed under the COMPATIBILITY AND STABILITY section.

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.

Preparation of Solutions of Ceftazidime for

Injection To obtain a dose of 1 g, withdraw 10 mL from the vial following reconstitution. * To obtain a dose of 2 g, withdraw 11.5 mL from the vial following reconstitution.

Size Amount of Diluent to be

Added (mL) Approximate Available Volume (mL) Approximate Ceftazidime Concentration (mg/mL) Intramuscular 1 gram vial 3 3.6 280 Intravenous 1 gram vial 10 10.8 100 2 gram vial 10 11.5* 170 Discard unused portion.

All vials of ceftazidime for injection as supplied are under reduced pressure.

When ceftazidime for injection is dissolved, carbon dioxide is released and a positive pressure develops.

For ease of use please follow the recommended techniques of constitution described on the detachable Instructions for Constitution section of this insert.

Solutions of ceftazidime for injection, like those of most beta-lactam antibacterial drugs, should not be added to solutions of aminoglycoside antibacterial drugs because of potential interaction.

However, if concurrent therapy with ceftazidime for injection and an aminoglycoside is indicated, each of these antibacterial drugs can be administered separately to the same patient.

Ceftazidime for injection, USP in the dry state should be stored at 20°C to 25°C (68°F to 77°F) and protected from light.

Ceftazidime for injection, USP is a white to cream-colored crystalline powder supplied in vials as follows: NDC Ceftazidime for Injection, USP Package Factor 25021-127-20 1 g Single-Dose Vial 25 vials per carton 25021-128-50 2 g Single-Dose Vial 10 vials per carton *Equivalent to anhydrous ceftazidime.

The container closure is not made with natural rubber latex.

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 for injection.

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.

Ceftazidime is excreted in human milk in low concentrations.

Caution should be exercised when ceftazidime is administered to a nursing woman.

Of the 2,221 subjects who received ceftazidime in 11 clinical studies, 824 (37%) were and older while 391 (18%) were and older.

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.