Ceftazidime

INDICATIONS AND USAGE 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: 1. Lower Respiratory Tract Infections, including pneumonia, caused by Pseudomonas aeruginosa and other Pseudomonas spp.; Haemophilus influenzae, including ampicillin-resistant strains; Klebsiella spp.; Enterobacter spp.; Proteus mirabilis; Escherichia coli; Serratia spp.; Citrobacter spp.; Streptococcus pneumoniae; and Staphylococcus aureus (methicillin-susceptible strains). 2. Skin and Skin-Structure Infections caused by Pseudomonas aeruginosa; Klebsiella spp.; Escherichia coli; Proteus spp., including Proteus mirabilis and indole-positive Proteus; Enterobacter spp.; Serratia spp.; Staphylococcus aureus (methicillin-susceptible strains); and Streptococcus pyogenes (group A beta-hemolytic streptococci). 3. Urinary Tract Infections, both complicated and uncomplicated, caused by Pseudomonas aeruginosa; Enterobacter spp.; Proteus spp., including Proteus mirabilis and indole-positive Proteus; Klebsiella spp.; and Escherichia coli. 4. Bacterial Septicemia caused by Pseudomonas aeruginosa, Klebsiella spp., Haemophilus influenzae, Escherichia coli, Serratia spp., Streptococcus pneumoniae, and Staphylococcus aureus (methicillin-susceptible strains). 5. Bone and Joint Infections caused by Pseudomonas aeruginosa, Klebsiella spp., Enterobacter spp., and Staphylococcus aureus (methicillin-susceptible strains). 6. Gynecologic Infections, including endometritis, pelvic cellulitis, and other infections of the female genital tract caused by Escherichia coli. 7. Intra-abdominal Infections, including peritonitis caused by Escherichia coli, Klebsiella spp., and Staphylococcus aureus (methicillin-susceptible strains) and polymicrobial infections caused by aerobic and anaerobic organisms and Bacteroides spp. (many strains of Bacteroides fragilis are resistant). 8. Central Nervous System Infections, including meningitis, caused by Haemophilus influenzae and Neisseria meningitidis. Ceftazidime has also been used successfully in a limited number of cases of meningitis due to Pseudomonas aeruginosa and Streptococcus pneumoniae. 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.

DOSAGE AND ADMINISTRATION Dosage The usual adult dosage is 1 gram administered intravenously or intramuscularly every 8 to 12 hours. The dosage and route should be determined by the susceptibility of the causative organisms, the severity of infection, and the condition and renal function of the patient. The guidelines for dosage of ceftazidime for injection are listed in Table 3 . The following dosage schedule is recommended. Table 3. Recommended Dosage Schedule Dose Frequency Adult Usual recommended dosage 1 gram intravenous or intramuscular every 8 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 8 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 Although clinical improvement has been shown, bacteriologic cures cannot be expected in patients with chronic respiratory disease and cystic fibrosis. 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 The higher dose should be reserved for immunocompromised pediatric patients or pediatric patients with cystic fibrosis or meningitis. every 8 hours Impaired Hepatic Function No adjustment in dosage is required for patients with hepatic dysfunction. Impaired Renal Function Ceftazidime is excreted by the kidneys, almost exclusively by glomerular filtration. Therefore, in patients with impaired renal function (glomerular filtration rate [GFR] <50 mL/min), it is recommended that the dosage of ceftazidime be reduced to compensate for its slower excretion. In patients with suspected renal insufficiency, an initial loading dose of 1 gram of ceftazidime may be given. An estimate of GFR should be made to determine the appropriate maintenance dosage. The recommended dosage is presented in Table 4 . 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. Creatinine Clearance (mL/min) Recommended Unit Dose of Ceftazidime for Injection Frequency of Dosing 50 to 31 1 gram every 12 hours 30 to 16 1 gram every 24 hours 15 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. Note: 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. Administration 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 (see PRECAUTIONS ). Intramuscular Administration: For 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. Intravenous Administration: The IV route is preferable for patients with bacterial septicemia, bacterial meningitis, peritonitis, or other severe or life-threatening infections, or for patients who may be poor risks because of lowered resistance resulting from such debilitating conditions as malnutrition, trauma, surgery, diabetes, heart failure, or malignancy, particularly if shock is present or pending. For direct intermittent IV administration, constitute ceftazidime for injection as directed in Table 5 with Sterile Water for Injection. Slowly inject directly into the vein over a period of 3 to 5 minutes or give through the tubing of an administration set while the patient is also receiving one of the compatible IV fluids (see COMPATIBILITY AND STABILITY ). For IV infusion, 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. Table 5. Preparation of Solutions of Ceftazidime for Injection 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 2 gram vial 10 10 10.8 To obtain a dose of 1 g, withdraw 10 mL from the vial following reconstitution. 11.5 To obtain a dose of 2 g, withdraw 11.5 mL from the vial following reconstitution. 100 170 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.

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

WARNINGS BEFORE THERAPY WITH CEFTAZIDIME FOR INJECTION IS INSTITUTED, CAREFUL INQUIRY SHOULD BE MADE TO DETERMINE WHETHER THE PATIENT HAS HAD PREVIOUS HYPERSENSITIVITY REACTIONS TO CEFTAZIDIME, CEPHALOSPORINS, PENICILLINS, OR OTHER DRUGS. IF THIS PRODUCT IS TO BE GIVEN TO PENICILLIN-SENSITIVE PATIENTS, CAUTION SHOULD BE EXERCISED BECAUSE CROSS-HYPERSENSITIVITY AMONG BETA-LACTAM ANTIBACTERIAL DRUGS 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 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 (see PRECAUTIONS ).

Drug Interactions Nephrotoxicity has been reported following concomitant administration of cephalosporins with aminoglycoside antibacterial drugs or potent diuretics such as furosemide. Renal function should be carefully monitored, especially if higher dosages of the aminoglycosides are to be administered or if therapy is prolonged, because of the potential nephrotoxicity and ototoxicity of aminoglycoside antibacterial drugs. Nephrotoxicity and ototoxicity were not noted when ceftazidime was given alone in clinical trials. Chloramphenicol has been shown to be antagonistic to beta-lactam antibacterial drugs, 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.

ADVERSE REACTIONS Ceftazidime is generally well tolerated. The incidence of adverse reactions associated with the administration of ceftazidime was low in clinical trials. The most common were local reactions following IV injection and allergic and gastrointestinal reactions. Other adverse reactions were encountered infrequently. No disulfiram-like reactions were reported. The following adverse effects from clinical trials were considered to be either related to ceftazidime therapy or were of uncertain etiology: Local Effects, reported in fewer than 2% of patients, were phlebitis and inflammation at the site of injection (1 in 69 patients). Hypersensitivity Reactions, reported in 2% of patients, were pruritus, rash, and fever. Immediate reactions, generally manifested by rash and/or pruritus, occurred in 1 in 285 patients. Toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme have also been reported with cephalosporin antibacterial drugs, including ceftazidime. Angioedema and anaphylaxis (bronchospasm and/or hypotension) have been reported very rarely. Gastrointestinal Symptoms, reported in fewer than 2% of patients, were diarrhea (1 in 78), nausea (1 in 156), vomiting (1 in 500), and abdominal pain (1 in 416). The onset of pseudomembranous colitis symptoms may occur during or after treatment (see WARNINGS ). Central Nervous System Reactions (fewer than 1%) included headache, dizziness, and paresthesia. Seizures have been reported with several cephalosporins, including ceftazidime. In addition, encephalopathy, coma, asterixis, neuromuscular excitability, and myoclonia have been reported in renally impaired patients treated with unadjusted dosing regimens of ceftazidime (see PRECAUTIONS, General ). Less Frequent Adverse Events (fewer than 1%) were candidiasis (including oral thrush) and vaginitis. Hematologic: Rare cases of hemolytic anemia have been reported. Laboratory Test Changes noted during 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.

Pregnancy Teratogenic Effects 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.