Ceftazidime and Dextrose

B. Braun Medical Inc.

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use Ceftazidime for Injection USP and Dextrose Injection USP safely and effectively. See full prescribing information for Ceftazidime for Injection USP and Dextrose Injection USP. CEFTAZIDIME FOR INJECTION USP AND DEXTROSE INJECTION USP IN DUPLEX® CONTAINER, for intravenous useInitial U.S. Approval: 1985MicrobiologyTo reduce the development of drug-resistant bacteria and maintain the effectiveness of Ceftazidime for Injection USP and Dextrose Injection USP and other antibacterial drugs, Ceftazidime for Injection USP and Dextrose Injection USP should be used only to treat infections that are proven or strongly suspected to be caused by bacteria.INDICATIONS AND USAGECeftazidime for Injection USP and Dextrose Injection USP is a cephalosporin antibacterial indicated in the treatment of the following infections caused by susceptible isolates of the designated microorganisms: Lower respiratory tract infections (1.1); skin and skin-structure infections (1.2); bacterial septicemia (1.3); bone and joint infections (1.4); gynecologic infections (1.5); intra-abdominal infections (1.6); central nervous system infections (1.7).DOSAGE AND ADMINISTRATIONFor intravenous use only over approximately 30 minutes. (2) Recommended Dosage Schedule for Creatinine Clearance greater than 50 mL/min  Adults  Dose  Frequency  Bone and joint infections  2 grams IV  every 12hr  Uncomplicated pneumonia; mild skin and skin-structure infections  500 mg*–1 gram IV  every 8hr  Serious gynecologic and intra-abdominal infections  2 grams IV every 8hr  Meningitis  2 grams IV every 8hr  Very severe life-threatening infections, especially in immunocompromised patients  2 grams IV every 8hr * Use this formulation of ceftazidime only in patients who require the entire 1 or 2 gram dose and not any fraction thereof. (2.1)DOSAGE FORMS AND STRENGTHS 1 g in 50 mL and 2 g in 50 mL (3) CONTRAINDICATIONS Hypersensitivity to ceftazidime or other cephalosporin class antibiotics, penicillins, or other beta-lactam antibiotics (4.1) WARNINGS AND PRECAUTIONS Hypersensitivity reactions: Include anaphylaxis and serious skin reactions. Cross-hypersensitivity may occur in up to 10% of patients with a history of penicillin allergy. If an allergic reaction occurs, discontinue the drug. (5.1) Clostridium difficile-associated diarrhea: May range from mild diarrhea to fatal colitis. Evaluate if diarrhea occurs. (5.3) Use in patients with renal impairment: Dose adjustment required for patients with CrCL less than or equal to 50 mL/min. Increased risk of serious neurologic adverse reactions, including life-threatening or fatal occurrences of encephalopathy, myoclonus, or seizures. (5.4) Side Effects The most common adverse reactions occurring in less than 2% of patients include: hypersensitivity reactions, gastrointestinal symptoms, and central nervous system reactions. (6) To report SUSPECTED ADVERSE REACTIONS, contact B. Braun Medical Inc. at 1-800-227-2862 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS Aminoglycosides: Increased potential of nephrotoxicity and ototoxicity. (7.1) Chloramphenicol: Has been shown to be antagonistic to beta-lactam antibiotics, including ceftazidime. (7.2) Contraceptives: Reduces efficacy of combined oral estrogen/progesterone contraceptives. (7.3) USE IN SPECIFIC POPULATIONS Pediatric Use: To prevent unintentional overdose, this product should not be used in pediatric patients who require less than the full adult dose of ceftazidime. (2.2, 8.4)

FULL PRESCRIBING INFORMATION: CONTENTS*

• 1 CEFTAZIDIME AND DEXTROSE INDICATIONS AND USAGE
  • 1.1 Lower Respiratory Tract Infections
  • 1.2 Skin and Skin-structure Infections
  • 1.3 Bacterial Septicemia
  • 1.4 Bone and Joint Infections
  • 1.5 Gynocologic Infections
  • 1.6 Intra-abdominal Infections
  • 1.7 Central Nervous System Infections
• 2 CEFTAZIDIME AND DEXTROSE DOSAGE AND ADMINISTRATION
  • 2.1 Adult Population
  • 2.2 Pediatric Population
  • 2.3 Patients with Renal Impairment
  • 2.4 Preparation for Use of Ceftazidime for Injection USP and Dextrose Injection USP in DUPLEX® Container
• 3 DOSAGE FORMS AND STRENGTHS
• 4 CEFTAZIDIME AND DEXTROSE CONTRAINDICATIONS
  • 4.1 Hypersensitivity Reactions to Ceftazidime or the Cephalosporin Class of Antibiotics, Penicillins, or Other Beta-lactam Antibiotics
• 5 WARNINGS AND PRECAUTIONS
  • 5.1 Hypersensitivity Reactions to Ceftazidime, Cephalosporins, Penicillins, or Other Drugs
  • 5.2 Hemolytic Anemia
  • 5.3 -associated Diarrhea
  • 5.4 Neurologic Adverse Events in Patients with Renal Impairment
  • 5.5 Hypersensitivity to Dextrose-Containing Products
  • 5.6 Risk of Development of Drug-Resistant Bacteria
  • 5.7 Drug/Laboratory Test Interactions
  • 5.8 Inadvertent Intra-arterial Administration
  • 5.9 Patients with a History of Gastrointestinal Disease
  • 5.10 Patients with Overt or Known Subclinical Diabetes Mellitus or Carbohydrate Intolerance
• 6 CEFTAZIDIME AND DEXTROSE ADVERSE REACTIONS
  • 6.1 Clinical Trials Experience
  • 6.2 Postmarketing Experience
  • 6.3 Cephalosporin-class Adverse Reactions
• 7 DRUG INTERACTIONS
  • 7.1 Aminoglycosides
  • 7.2 Chloramphenicol
  • 7.3 Contraceptives
• 8 USE IN SPECIFIC POPULATIONS
  • 8.1 Pregnancy
  • 8.2 Labor and Delivery
  • 8.3 Nursing Mothers
  • 8.4 Pediatric Use
  • 8.5 Geriatric Use
• 10 OVERDOSAGE
• 11 CEFTAZIDIME AND DEXTROSE DESCRIPTION
• 12 CLINICAL PHARMACOLOGY
  • 12.1 Mechanism of Action
  • 12.2 Pharmacodynamics
  • 12.3 Pharmacokinetics
  • 12.4 Microbiology
• 13 NONCLINICAL TOXICOLOGY
  • 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
• 15 REFERENCES
• 16 HOW SUPPLIED/STORAGE AND HANDLING
• 17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

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

Ceftazidime for Injection and Dextrose Injection is indicated for the treatment of the following infections when caused by susceptible bacteria.

1.1 Lower Respiratory Tract Infections

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

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

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

Bone and joint infections caused by Pseudomonas aeruginosa, Klebsiella spp., Enterobacter spp., and Staphylococcus aureus (methicillin-susceptible isolates).

1.5 Gynocologic Infections

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

1.6 Intra-abdominal Infections

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

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.

2 DOSAGE AND ADMINISTRATION

2.1 Adult Population

Ceftazidime for Injection USP and Dextrose Injection USP 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 USP and Dextrose Injection USP should be administered intravenously (IV) over approximately 30 minutes.

The guidelines for dosage of Ceftazidime for Injection USP and Dextrose Injection USP 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 Population

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 ≤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 USP and Dextrose Injection USP 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)⁵ 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 USP and Dextrose Injection USP 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 USP and Dextrose Injection USP 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.

DUPLEX® Drug Delivery System Storage

• To avoid inadvertent activation, the DUPLEX® Container should remain in the folded position until activation is intended.

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.

Important Administration Instructions

• Do not use in series connections.
• Do not introduce additives into the DUPLEX® Container.
• Administer Ceftazidime for Injection USP and Dextrose Injection USP intravenously over approximately 30 minutes.
• Intermittent intravenous infusion with a Y-type administration set can be accomplished with compatible solutions. However, during infusion of Ceftazidime for Injection USP and Dextrose Injection USP, it is advisable to discontinue the other solution.
• 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 1 of the compatible IV fluids) between the administration of these 2 agents.
  Note: Parenteral drug products should be inspected visually for particulate matter before administration whenever solution and container permit.
  Solutions of Ceftazidime for Injection USP and Dextrose Injection USP should not be added to solutions of aminoglycoside antibacterials because of potential inactivation. If concurrent therapy with Ceftazidime for Injection USP and Dextrose Injection USP and an aminoglycoside is indicated, each of these antibacterials should be administered separately to the same patient.
• 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.

3 DOSAGE FORMS AND STRENGTHS

Dual-chamber, single-use container:

• 1 g ceftazidime for injection USP and 50 mL of 5% dextrose injection USP
• 2 g ceftazidime for injection USP and 50 mL of 5% dextrose injection USP

4 CONTRAINDICATIONS

4.1 Hypersensitivity Reactions to Ceftazidime or the Cephalosporin Class of Antibiotics, Penicillins, or Other Beta-lactam Antibiotics

Ceftazidime for Injection USP and Dextrose Injection USP is contraindicated in patients who have a history of immediate hypersensitivity reactions (e.g., anaphylaxis, serious skin reactions) to ceftazidime or the cephalosporin class of antibiotics, penicillins, or other beta-lactam antibiotics. [see Warnings and Precautions (5.1) ].

5 WARNINGS AND PRECAUTIONS

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 USP and Dextrose Injection USP 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 antibiotics 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 -associated Diarrhea

Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including ceftazidime, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B, which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

5.4 Neurologic Adverse Events in Patients with Renal Impairment

Elevated levels of ceftazidime in patients with renal impairment can lead to seizures, encephalopathy, coma, asterixis, neuromuscular excitability, and myoclonus. Continued dosage should be determined by degree of renal impairment, severity of infection, and susceptibility of the causative organisms. [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)¹. The reactions have also been reported when corn-derived dextrose solutions were administered to patients with or without a history of hypersensitivity to corn products².

5.6 Risk of Development of Drug-Resistant Bacteria

Prescribing Ceftazidime for Injection USP and Dextrose Injection USP in the absence of proven or strongly suspected bacterial infection 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 USP and Dextrose Injection USP 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

Prothrombin Time

Many cephalosporins, including ceftazidime, have been 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.

Urinary Glucose

The administration of ceftazidime may result in a false-positive reaction with glucose in the urine when using CLINITEST® tablets. It is recommended that glucose tests based on enzymatic glucose oxidase reactions (e.g., CLINISTIX®) be used.

5.8 Inadvertent Intra-arterial Administration

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

5.9 Patients with a History of Gastrointestinal Disease

Ceftazidime for Injection USP and Dextrose Injection USP should be prescribed with caution in individuals with a history of gastrointestinal disease, particularly colitis.

5.10 Patients with Overt or Known Subclinical Diabetes Mellitus or Carbohydrate Intolerance

As with other dextrose-containing solutions, Ceftazidime for Injection USP and Dextrose Injection USP should be prescribed with caution in patients with overt or known subclinical diabetes mellitus or carbohydrate intolerance for any reason.

6 ADVERSE REACTIONS

The following serious adverse reactions to ceftazidime are described below and elsewhere in the labeling:

• Hypersensitivity reactions [see Warnings and Precautions (5.1) ]
• Hemolytic anemia [see Warnings and Precautions (5.2) ]
• Clostridium difficile-associated diarrhea [see Warnings and Precautions (5.3) ]
• Neurologic adverse events in patients with renal impairment [see  Warnings and Precautions (5.4) ]

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.
• Hypersensitivty 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 antibiotics, 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 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 Side Effects

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: 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 DRUG INTERACTIONS

7.1 Aminoglycosides

Renal function should be monitored carefully if high doses of aminoglycosides are to be administered with Ceftazidime for Injection USP and Dextrose Injection USP 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 Contraceptives

In common with other antibacterials, ceftazidime may affect the gut flora, leading to lower estrogen reabsorption and reduced efficacy of combined oral estrogen/progesterone contraceptives.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

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. 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.

8.2 Labor and Delivery

Ceftazidime has not been studied for use during labor and delivery. Treatment should only be given if clearly indicated.

8.3 Nursing Mothers

Ceftazidime is excreted in human milk in low concentrations. Caution should be exercised when Ceftazidime for Injection USP and Dextrose Injection USP is administered to a nursing woman.

8.4 Pediatric Use

Ceftazidime for Injection USP and Dextrose Injection USP 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  Dosage and Administration (2.2) ]

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) ]

10 OVERDOSAGE

Ceftazidime overdosage has occurred in patients with renal failure. Reactions have included seizure activity, encephalopathy, asterixis, neuromuscular excitability, and coma [see Warnings and Precautions (5.4) ]. 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.

11 DESCRIPTION

The molecular formula is C₂₂H₂₂N₆O₇S₂•5H₂O, representing a molecular weight of 636.6.

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 the DUPLEX® Container equivalent to 1 g or 2 g of anhydrous ceftazidime. The pH of freshly constituted solutions usually ranges from 5 to 7.5.

The diluent chamber contains 50 mL of 5% Dextrose Injection USP.

Solutions of Ceftazidime for Injection USP and Dextrose Injection USP range in color from light yellow to amber. The solution is intended for intravenous (IV) use only. The pH of solutions ranges from 5 to 7.5. Dextrose Injection USP is sterile, nonpyrogenic, and contains no bacteriostatic or antimicrobial agents.

Hydrous Dextrose USP has the following structural (molecular) formula:

After removing the peelable foil strip, activating the seals, and thoroughly mixing, the reconstituted drug product is intended for single intravenous use. When reconstituted, the osmolality of the reconstituted solution of Ceftazidime for Injection USP and Dextrose Injection USP is approximately 340 mOsmol/kg for the 1 g dose and approximately 400 mOsmol/kg for the 2 g dose.

The DUPLEX® Container is not manufactured with Latex, PVC, or DEHP.

The DUPLEX® dual chamber container is made from a specially formulated material. The product (diluent and drug) contact layer is a mixture of thermoplastic rubber and a polypropylene ethylene copolymer that contains no plasticizers. The safety of the container system is supported by USP biological evaluation procedures.

12 CLINICAL PHARMACOLOGY

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 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.

Distribution

Less than 10% of ceftazidime was protein bound. The degree of protein binding was independent of concentration. Therapeutic concentrations of ceftazidime are achieved in the body tissues and fluids outlined in Table 4.

Excretion

Approximately 80% to 90% of an 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 (Table 4).

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.

Specific Populations

Patients with Hepatic Impairment

 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.

Patients with Renal Impairment

 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 are suggested. [see  Dosage and Administration (2.3) ]

12.4 Microbiology

Mechanism of Action

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 isolates 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 isolates resistant to ampicillin and other cephalosporins.

Mechanism of Resistance

Resistance to ceftazidime is primarily through hydrolysis of ceftazidime by extended-spectrum beta-lactamases and through active efflux. 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.

Interaction with Other Antimicrobials

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 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 (1):

Gram-negative bacteria

• Citrobacter spp.
• Enterobacter spp.
• Escherichia coli
• Haemophilus influenzae
• Klebsiella spp.
• Neisseria meningitidis
• Proteus mirabilis
• Proteus vulgaris
• Pseudomonas spp.
• Serratia spp.

Gram-positive bacteria

• Staphylococcus aureus
• Streptococcus agalactiae (group B streptococcus)
• Streptococcus pneumoniae
• Streptococcus pyogenes (group A beta-hemolytic streptococcus)

Anaerobic bacteria

• Bacteroides spp.

There are no established interpretive criteria for anaerobic bacteria

The following in vitro data are available, but their clinical significance is unknown . At least 90 percent of the following bacteria 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 bacteria has not been established in adequate and well-controlled clinical trials.

Gram-positive bacteria

• Staphylococcus epidermidis

Gram-negative bacteria

• Acinetobacter spp.
• Haemophilus parainfluenzae
• Morganella morganii
• Neisseria gonorrhoeae
• Providencia spp.
• Salmonella spp.
• Shigella spp.
• Yersinia enterocolitica.

Anaerobic bacteria

• Clostridium spp. (not including Clostridium difficile)
• Peptococcus spp.
• Peptostreptococcus spp.
  
  
  

Susceptibility Test Methods

 When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drug products used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug product for treatment.

Dilution Techniques

 Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method ^3,4 (broth and/or agar). The MIC values should be interpreted according to criteria provided in Table 5.

Diffusion Techniques

Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method.^4,5 This procedure uses paper disks impregnated with 30 mcg ceftazidime to test the susceptibility of microorganisms to ceftazidime. The disk diffusion interpretive criteria are provided in Table 5.

A report of Susceptible indicates that the antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations at the infection site necessary to inhibit growth of the pathogen. A report of Intermediate indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug product is physiologically concentrated or in situations where a high dosage of the drug product can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of Resistant indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations usually achievable at the infection site; other therapy should be selected.

Quality Control

Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individual performing the test. ^4,5,6 Standard ceftazidime powder should provide the following MIC values noted in Table 6. For the diffusion technique using the 30-mcg disk, the criteria in Table 6 should be achieved.

13 NONCLINICAL TOXICOLOGY

13.1 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.

15 REFERENCES

• Czarny D, Prichard PJ, Fennessy M, Lewis S. Anaphylactoid reaction to 50% solution of dextrose. Med J Aust 1980;2:255-258.
• Guharoy, SR, Barajas M. Probably Anaphylactic Reaction to Corn-Derived Dextrose Solution. Vet Hum Toxicol 1991;33:609-610.
• Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically. CLSI document M07-A8. CLSI, 940 West Valley Road, Suite 1400, Wayne, PA 19087-1898, 2009.
• CLSI. Performance Standards for Antimicrobial Disk Susceptibility Tests. CLSI document M02-A10. CLSI, 940 West Valley Road, Suite 1400, Wayne, PA 19087-1898, 2009.
• CLSI. Performance Standards for Antimicrobial Susceptibility Testing; Twenty-First Informational Supplement. CLSI Document M100-S21. CLSI, 940 West Valley Road, Suite 1400, Wayne, PA 19087-1898, 2011.
• CLSI. Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard-Seventh Edition. CLSI documents M11-A7 2007, and M11-S1E 2009.

16 HOW SUPPLIED/STORAGE AND HANDLING

Ceftazidime for Injection USP and Dextrose Injection USP in the DUPLEX® Drug Delivery System is a flexible dual chamber container supplied in two concentrations. The diluent chamber contains approximately 50 mL of 5% Dextrose Injection. After reconstitution, the concentrations are equivalent to 1* g and 2* g ceftazidime.

Ceftazidime for Injection USP and Dextrose Injection USP is supplied sterile and nonpyrogenic in the DUPLEX® Drug Delivery System containers packaged 24 units per case.

*Anhydrous basis.

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.

17 PATIENT COUNSELING INFORMATION

Patients should be advised that allergic reactions, including serious allergic reactions could occur and that serious reactions require immediate treatment and discontinuation of ceftazidime. Patients should report to their health care provider any previous allergic reactions to ceftazidime, cephalosporins, penicillins, or other similar antibacterials.

Advise patients of neurological adverse reactions that could occur with Ceftazidime for Injection USP and Dextrose Injection USP use. Instruct patients to inform a healthcare provider at once of any neurological signs and symptoms, including encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, and coma), myoclonus, and seizures, for immediate treatment, dosage adjustment, or discontinuation of Ceftazidime for Injection USP and Dextrose Injection USP.

Patients should be advised that diarrhea is a common problem caused by antibacterials which usually ends when the antibacterial is discontinued. Sometimes after starting treatment with antibacterials, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as 2 or more months after having taken the last dose of the antibacterial. If this occurs, patients should contact their physician as soon as possible.

Patients should be counseled that antibacterial drugs, including Ceftazidime for Injection USP and Dextrose Injection USP, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Ceftazidime for Injection USP and Dextrose Injection USP 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 Ceftazidime for Injection USP and Dextrose Injection USP or other antibacterial drugs in the future.

Rx only

DUPLEX is a registered trademark of B. Braun Medical Inc.
ATCC is a registered trademark of the American Type Culture Collection
Clinitest is a registered trademark of Siemens Healthcare Diagnostics Inc.
Clinistix is a registered trademark of Bayer HealthCare LLC.

U.S. Patent Nos. 5,944,709, 6,165,161, 6,203,535, 6,846,305, and 6,996,951.

B. Braun Medical Inc.
Irvine, CA 92614-5895 USA
1-800-227-2862
www.bbraun.com
Made in USA.

Y36-002-783
LD-101-2

PRINCIPAL DISPLAY PANEL - 1 g Container Label

Ceftazidime for Injection USP
and Dextrose Injection USP

1 g*

REF 3143-11
NDC 0264-3143-11

DUPLEX^®
DRUG DELIVERY SYSTEM

50 mL

Use only after mixing contents of both chambers.

For IV Use Only     Hyperosmotic     Single Dose     Sterile/Nonpyrogenic

* Contains sterile ceftazidime pentahydrate USP equivalent to 1 g of ceftazidime
and sodium carbonate to facilitate dissolution.

Reconstitution: Hold container with set port in a downward direction and fold the
diluent chamber just below the solution meniscus. To activate seal, squeeze folded diluent
chamber until seal between diluent and drug chamber opens, releasing diluent into drug
chamber. Agitate the reconstituted solution until the drug powder is completely dissolved.
Fold the container a second time and squeeze until seal between drug chamber and set
port opens.

Drug chamber contains 118 mg of sodium carbonate. The sodium content is approximately
54 mg (2.3 mEq). After reconstitution each 50 mL single dose unit contains: Ceftazidime
for Injection (equivalent to 1 g ceftazidime) with approximately 2.83 g (5% w/v) Hydrous
Dextrose USP in Water for Injection USP. Approximate osmolality: 340 mOsmol/kg

Prior to Reconstitution: Store between 15° and 30°C (59° and 86°F). Use only if
container and seals are intact. Do not peel foil strip until ready for use. After foil strip
removal, product must be used within 7 days, but not beyond the labeled expiration date.
Protect from light after removal of foil strip. Color changes do not affect potency.

After Reconstitution: Use only if prepared solution is clear and free from particulate
matter. Use within 12 hours if stored at room temperature or within 3 days if stored under
refrigeration. Do not use in a series connection. Do not introduce additives into this
container. Prior to administration check for minute leaks by squeezing container firmly. If
leaks are found, discard container and solution as sterility may be impaired. Do not freeze.

The DUPLEX Container is not manufactured with Latex, PVC or DEHP

Rx only

Y37-002-356
LD-102-1

B. Braun Medical Inc.

Made in USA

LOT
EXP

PRINCIPAL DISPLAY PANEL - 2 g Container Label

Ceftazidime for Injection USP
and Dextrose Injection USP

2 g*

REF 3145-11
NDC 0264-3145-11

DUPLEX^®
DRUG DELIVERY SYSTEM

50 mL

Use only after mixing contents of both chambers.

For IV Use Only     Hyperosmotic     Single Dose     Sterile/Nonpyrogenic

* Contains sterile ceftazidime pentahydrate USP equivalent to 2 g of ceftazidime
and sodium carbonate to facilitate dissolution.

Reconstitution: Hold container with set port in a downward direction and fold the
diluent chamber just below the solution meniscus. To activate seal, squeeze folded diluent
chamber until seal between diluent and drug chamber opens, releasing diluent into drug
chamber. Agitate the reconstituted solution until the drug powder is completely dissolved.
Fold the container a second time and squeeze until seal between drug chamber and set
port opens.

Drug chamber contains 236 mg of sodium carbonate. The sodium content is approximately
108 mg (4.7 mEq). After reconstitution each 50 mL single dose unit contains: Ceftazidime
for Injection (equivalent to 2 g ceftazidime) with approximately 2.83 g (5% w/v) Hydrous
Dextrose USP in Water for Injection USP. Approximate osmolality: 400 mOsmol/kg

Prior to Reconstitution: Store between 15° and 30°C (59° and 86°F). Use only if
container and seals are intact. Do not peel foil strip until ready for use. After foil strip
removal, product must be used within 7 days, but not beyond the labeled expiration date.
Protect from light after removal of foil strip. Color changes do not affect potency.

After Reconstitution: Use only if prepared solution is clear and free from particulate
matter. Use within 12 hours if stored at room temperature or within 3 days if stored under
refrigeration. Do not use in a series connection. Do not introduce additives into this
container. Prior to administration check for minute leaks by squeezing container firmly. If
leaks are found, discard container and solution as sterility may be impaired. Do not freeze.

The DUPLEX Container is not manufactured with Latex, PVC or DEHP

Rx only

Y37-002-357
LD-103-1

B. Braun Medical Inc.

Made in USA

LOT
EXP

Display Panel - Drug Chamber Barrier

PEEL HERE

Drug Chamber

Discard unit if foil strip is damaged. Peel foil strip only when
ready for use. Visually inspect drug prior to reconstitution.

See package insert for complete directions for reconstitution
and administration.

LD-336-1  X27-001-485