1.1 Lower Respiratory Tract Infections

Ceftazidime for Injection and Dextrose Injection is indicated for the treatment of lower respiratory tract infections, including pneumonia, caused by Pseudomonas aeruginosa and other Pseudomonas spp.; Haemophilus influenzae, including ampicillin-resistant isolates; Klebsiella spp.; Enterobacter spp.; Proteus mirabilis; Escherichia coli; Serratia spp.; Citrobacter spp.; Streptococcus pneumoniae; and Staphylococcus aureus (methicillin-susceptible isolates).

1.2 Skin and Skin-structure Infections

Ceftazidime for Injection and Dextrose Injection is indicated for the treatment of 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 isolates); and Streptococcus pyogenes (group A beta-hemolytic streptococci).

1.3 Bacterial Septicemia

Ceftazidime for Injection and Dextrose Injection is indicated for the treatment of bacterial septicemia caused by Pseudomonas aeruginosa, Klebsiella spp., Haemophilus influenzae, Escherichia coli, Serratia spp., Streptococcus pneumoniae, and Staphylococcus aureus (methicillin-susceptible isolates).

1.4 Bone and Joint Infections

Ceftazidime for Injection and Dextrose Injection is indicated for the treatment of bone and joint infections caused by Pseudomonas aeruginosa, Klebsiella spp., Enterobacter spp., and Staphylococcus aureus (methicillin-susceptible isolates).

1.5 Gynecologic Infections

Ceftazidime for Injection and Dextrose Injection is indicated for the treatment of gynecologic infections, including endometritis, pelvic cellulitis, and other infections of the female genital tract caused by Escherichia coli.

1.6 Intra-abdominal Infections

Ceftazidime for Injection and Dextrose Injection is indicated for the treatment of intra-abdominal infections, including peritonitis caused by Escherichia coli, Klebsiella spp., and Staphylococcus aureus (methicillin-susceptible isolates) and polymicrobial infections caused by aerobic and anaerobic organisms and Bacteroides spp. (many isolates of Bacteroides fragilis are resistant).

1.7 Central Nervous System Infections

Ceftazidime for Injection and Dextrose Injection is indicated for the treatment of 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.

1.8 Usage

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Ceftazidime for Injection and Dextrose Injection and other antibacterial drugs, Ceftazidime for Injection and Dextrose Injection 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.

2.1 Adult and Pediatric Patients (Who Require the Full Adult Dose)

Ceftazidime for Injection and Dextrose Injection in the DUPLEX® Container should be used only in patients who require the entire 1 or 2 gram dose and not any fraction thereof. Ceftazidime for Injection and Dextrose Injection should be administered intravenously (IV) over approximately 30 minutes.

The guidelines for dosage of Ceftazidime for Injection and Dextrose Injection are listed in Table 1. The following dosage schedule is recommended.

*  Use this formulation of ceftazidime only in patients who require the entire 1 or 2 gram dose and not any fraction thereof.

2.2 Pediatric Patients

Ceftazidime for Injection and Dextrose Injection in the DUPLEX® Container is designed to deliver a 1 g or 2 g dose of ceftazidime. To prevent unintentional overdose, this product should not be used in pediatric patients who require less than the full adult dose of ceftazidime [see Use in Specific Populations (8.4)] 

2.3 Patients with Renal Impairment

Ceftazidime for Injection and Dextrose Injection in the DUPLEX® Container is designed to deliver a 1 g or 2 g dose of ceftazidime. To prevent unintentional overdose, this product should not be used in patients with creatinine clearance less than or equal to 15 mL/min who require less than a  1 g dose of ceftazidime.

In patients with impaired renal function (creatinine clearance less than or equal to 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 for Injection and Dextrose Injection may be given. An estimate of creatinine clearance should be made to determine the appropriate maintenance dosage. The recommended dosage is presented in Table 2.

NOTE: IF THE DOSE RECOMMENDED IN TABLE 1 ABOVE IS LOWER THAN THAT RECOMMENDED FOR PATIENTS WITH RENAL INSUFFICIENCY AS OUTLINED IN TABLE 2, THE LOWER DOSE SHOULD BE USED.

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:

In patients with severe infections who would normally receive 2 grams IV every 8hr of Ceftazidime for Injection and Dextrose Injection 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.

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.

2.4 Preparation for Use of Ceftazidime for Injection and Dextrose Injection in DUPLEX® Container

This reconstituted solution is for intravenous use only.

Do not use plastic containers in series connections. Such use would 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. If administration is controlled by a pumping device, care must be taken to discontinue pumping action before the container runs dry or air embolism may result.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Use only if solution is clear and container and seals are intact.

Patient Labeling and Drug Powder/Diluent Inspection

• Apply patient-specific label on foil side of container. Use care to avoid activation. Do not cover any portion of foil strip with patient label.
• Unlatch side tab and unfold DUPLEX® Container (see Diagram 1).

• Visually inspect diluent chamber for particulate matter.
• Use only if container and seals are intact.
• To inspect the drug powder for foreign matter or discoloration, peel foil strip from drug chamber (see Diagram 2).

• Protect from light after removal of foil strip.
  
  Note: If foil strip is removed, the container should be re-folded and the side tab latched until ready to activate. The product must then be used within 7 days, but not beyond the labeled expiration date.

Reconstitution (Activation)

• Do not use directly after storage by refrigeration, allow the product to equilibrate to room temperature before patient use.
• Unfold the DUPLEX® Container and point the set port in a downward direction. Starting at the hanger tab end, fold the DUPLEX® Container just below the diluent meniscus trapping all air above the fold. To activate, squeeze the folded diluent chamber until the seal between the diluent and powder opens, releasing diluent into the drug powder chamber (see Diagram 3).

• Agitate the liquid-powder mixture until the drug powder is completely dissolved.
  
  Note: Following reconstitution (activation), product must be used within 12 hours if stored at room temperature or within 3 days if stored under refrigeration.

Administration

• Visually inspect the reconstituted solution for particulate matter.
• Point the set port in a downwards direction. Starting at the hanger tab end, fold the DUPLEX® Container just below the solution meniscus trapping all air above the fold. Squeeze the folded DUPLEX® Container until the seal between reconstituted drug solution and set port opens, releasing liquid to set port (see Diagram 4).

• Prior to attaching the IV set, check for minute leaks by squeezing container firmly. If leaks are found, discard container and solution as sterility may be compromised.
• Using aseptic technique, peel foil cover from the set port and attach sterile administration set (see Diagram 5).

• Refer to directions for use accompanying the administration set.

5.1 Hypersensitivity Reactions to Ceftazidime, Cephalosporins, Penicillins, or Other Drugs

Immediate hypersensitivity reactions to ceftazidime have been reported. Careful inquiry should be made to determine whether the patient has had previous hypersensitivity reactions with cephalosporins or penicillins. Exercise caution if this product is to be given to penicillin-sensitive patients because cross-hypersensitivity among beta-lactam antibacterials has been clearly documented and may occur in up to 10% of patients with a history of penicillin allergy. If an allergic reaction to Ceftazidime for Injection and Dextrose Injection occurs, discontinue the drug.

5.2 Hemolytic Anemia

An immune mediated hemolytic anemia has been observed in patients receiving cephalosporin class antibacterials including ceftazidime. Severe cases of hemolytic anemia, including fatalities, have been reported during treatment with cephalosporin class antibacterials in both adults and children. If a patient develops anemia while on ceftazidime, the diagnosis of a cephalosporin associated anemia should be considered and ceftazidime stopped until the etiology is determined.

5.3 Clostridioides difficile-associated Diarrhea           

Clostridioides difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including ceftazidime products, 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 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 use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial  treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

5.4 Neurological Adverse Reactions

Seizures, nonconvulsive status epilepticus (NCSE), encephalopathy, coma, asterixis, neuromuscular excitability, and myoclonus have been reported in patients treated with ceftazidime, including Ceftazidime for Injection and Dextrose Injection particularly in the setting of renal impairment. Adjust dosing based on creatinine clearance in patients with renal impairment [see Dosage and Administration (2.3)].

5.5 Hypersensitivity to Dextrose-containing Products

Hypersensitivity reactions, including anaphylaxis, have been reported with administration of dextrose containing products. These reactions have been reported in patients receiving high concentrations of dextrose (i.e. 50% dextrose). The reactions have also been reported when corn-derived dextrose solutions were administered to patients with or without a history of hypersensitivity to corn products.

5.6 Risk of Development of Drug-resistant Bacteria

Prescribing Ceftazidime for Injection and Dextrose Injection in the absence of 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.

As with other antimicrobials, prolonged use of Ceftazidime for Injection and Dextrose Injection may result in overgrowth of nonsusceptible microorganisms. Repeated evaluation of the patient's condition is essential. Should superinfection occur during therapy, appropriate measures should be taken.

5.7 Drug/Laboratory Test Interactions

5.8 Inadvertent Intra-arterial Administration

Distal necrosis can occur after inadvertent intra-arterial administration of ceftazidime.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The following adverse reactions were reported in less than or equal to 2% of patients from clinical trials:

• Local reactions including phlebitis and inflammation at the site of injection.

• Hypersensitivity reactions including pruritus, rash, fever and immediate reactions, generally manifested by rash and/or pruritus. 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.

• Gastrointestinal reactions including diarrhea, nausea, vomiting, and abdominal pain. The onset of pseudomembranous colitis symptoms may occur during or after treatment. [see Warnings and Precautions (5.3)]

• Central nervous system adverse reactions included headache, dizziness, and paresthesia. Seizures have been reported with several cephalosporins, including ceftazidime. In addition, encephalopathy, coma, asterixis, neuromuscular excitability, and myoclonus have been reported in patients with renal impairment treated with unadjusted dosing regimens of ceftazidime [see Warnings and Precautions (5.4)]

• Hematologic reactions including cases of hemolytic anemia have been reported. [see Warnings and Precautions (5.2)]

• Other adverse reactions include candidiasis (including oral thrush) and vaginitis.

6.2 Postmarketing Experience

The following adverse reactions have been reported during postapproval use of ceftazidime. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to readily estimate their frequency or establish a causal relationship to drug exposure.

•  Anaphylaxis, allergic reactions, which, in rare instances, were severe (e.g., cardiopulmonary arrest), urticaria. 

•  Nephropathy, which may be severe (e.g., renal failure).

•  Hyperbilirubinemia, jaundice.

•  Pain at the injection site.

6.3 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 antibacterials:

• Adverse Reactions: hepatic dysfunction including cholestasis, aplastic anemia, hemorrhage, and pancytopenia.

• Altered Laboratory Tests: Prolonged prothrombin time, false-positive test for urinary glucose. [see Warnings and Precautions (5.7)]

7.1 Aminoglycosides

Renal function should be monitored carefully if high doses of aminoglycosides are to be administered with Ceftazidime for Injection and Dextrose Injection because of the increased potential of nephrotoxicity and ototoxicity of aminoglycoside antibacterials. Nephrotoxicity and ototoxicity were not noted when ceftazidime was given alone in clinical trials.

7.2 Chloramphenicol

Chloramphenicol has been shown to be antagonistic to beta-lactam antibacterials, 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.

7.3 Drug/Laboratory Test Interactions

The administration of ceftazidime may result in a false-positive reaction for glucose in the urine with certain methods. It is recommended that glucose tests based on enzymatic glucose oxidase reactions be used [see Warnings and Precautions (5.7)].

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

Ceftazidime for injection and Dextrose injection is indicated for the treatment of lower respiratory tract infections, skin and skin structure infections, bacterial septicemia, bone and joint infections, gynecological infections,  intra-abdominal infections and central nervous system infections in pediatric patients for whom appropriate dosing with this formulation can be achieved [see Indications and Usage (1.1-1.7)] and Dosage and Administration (2.3)].

Because of the limitations of the available strengths and administration requirements (i.e., administration of fractional doses is not recommended) of Ceftazidime for Injection and Dextrose Injection, and to avoid unintentional overdose, this is not recommended for use if a dose of Ceftazidime for Injection and Dextrose Injection that does not equal 1 gram or 2 grams is required and an alternative formulation of ceftazidime should be considered [see Dosage and Administration (2)].

8.5 Geriatric Use

Of the 2,221 subjects who received ceftazidime in 11 clinical studies, 824 (37%) were 65 and older while 391 (18%) were 75 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 adverse 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. (2.3)]

8.6 Patients with Renal Impairment

Ceftazidime is substantially eliminated by the kidneys, and the risk of adverse reactions to ceftazidime may be greater in patients with renal impairment due to slower elimination by the kidneys. Consequently, dosage adjustment of Ceftazidime for Injection and Dextrose Injection is required in patients with moderate (CrCl 30 to 50 mL/min) and severe (CrCl 16 to 29 mL/min) renal impairment [see Dosage and Administration (2.3) Warnings and Precautions (5.4) and Clinical Pharmacology (12.3)]

12.1 Mechanism of Action

Ceftazidime is an antibacterial drug. [see Clinical Pharmacology (12.4)]

12.2 Pharmacodynamics

Similar to other beta-lactam antimicrobial agents, the time that the unbound plasma concentration of ceftazidime exceeds the MIC of the infecting organisms has been shown to best correlate with efficacy in animal models of infection. However, the pharmacokinetic/pharmacodynamic relationship for ceftazidime has not been evaluated in patients.

12.3 Pharmacokinetics

After 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 3.

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. 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.

12.4 Microbiology

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Long-term studies in animals have not been performed to evaluate carcinogenic potential.

Mutagenesis

A mouse micronucleus test and an Ames test were both negative for mutagenic effects. 

Impairment of Fertility

Adult male rats administered ceftazidime for 11 consecutive days by intraperitoneal injection at 50 or 250 mg/kg/day (approximatley 8 and 40 times the MRHD based on body surface area comparison) resulted in a similar reduction in sperm motility of > 80% compared to controls.

Store the unactivated unit at 20-25°C (68-77°F).  Excursions permitted to 15-30°C (59-86°F) [See USP Controlled Room Temperature.] Protect from light. Freezing solutions of Ceftazidime for Injection USP and Dextrose Injection USP is not recommended.

Not made with natural rubber latex, PVC, or DEHP. 

As with other cephalosporins, Ceftazidime for Injection USP and Dextrose Injection USP powder, as well as solutions, tend to darken depending on storage conditions; within the stated recommendations, however, product potency is not adversely affected.

Use only if prepared solution is clear and free from particulate matter.