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CLINICAL PHARMACOLOGY After intravenous (IV) administration of 500-mg and 1-g doses of ceftazidime over 5 minutes to normal adult male volunteers, mean peak serum concentrations of 45 and 90 mcg/mL, respectively, were achieved. After IV infusion of 500-mg, 1-g, and 2-g doses of ceftazidime over 20 to 30 minutes to normal adult male volunteers, mean peak serum concentrations of 42, 69, and 170 mcg/mL, respectively, were achieved. The average serum concentrations following IV infusion of 500-mg, 1-g, and 2-g doses to these volunteers over an 8-hour interval are given in Table 1. Table 1. Average Serum Concentrations of Ceftazidime Ceftazidime Serum Concentrations (mcg/mL) IV Dose 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 1 and 2 g every 8 hours for 10 days. Following intramuscular (IM) administration of 500-mg and 1-g doses of ceftazidime to normal adult volunteers, the mean peak serum concentrations were 17 and 39 mcg/mL, respectively, at approximately 1 hour. Serum concentrations remained above 4 mcg/mL for 6 and 8 hours after the IM administration of 500-mg and 1-g doses, respectively. The half-life of ceftazidime in these volunteers was approximately 2 hours. The presence of hepatic dysfunction had no effect on the pharmacokinetics of ceftazidime in individuals administered 2 g intravenously every 8 hours for 5 days. Therefore, a dosage adjustment from the normal recommended dosage is not required for patients with hepatic dysfunction, provided renal function is not impaired. Approximately 80% to 90% of an IM or IV dose of ceftazidime is excreted unchanged by the kidneys over a 24-hour period. After the IV administration of single 500-mg or 1-g doses, approximately 50% of the dose appeared in the urine in the first 2 hours. An additional 20% was excreted between 2 and 4 hours after dosing, and approximately another 12% of the dose appeared in the urine between 4 and 8 hours later. The elimination of ceftazidime by the kidneys resulted in high therapeutic concentrations in the urine. The mean renal clearance of ceftazidime was approximately 100 mL/min. The calculated plasma clearance of approximately 115 mL/min indicated nearly complete elimination of ceftazidime by the renal route. Administration of probenecid before dosing had no effect on the elimination kinetics of ceftazidime. This suggested that ceftazidime is eliminated by glomerular filtration and is not actively secreted by renal tubular mechanisms. Since ceftazidime is eliminated almost solely by the kidneys, its serum half-life is significantly prolonged in patients with impaired renal function. Consequently, dosage adjustments in such patients as described in the DOSAGE AND ADMINISTRATION section are suggested. Ceftazidime concentrations achieved in specific body tissues and fluids are depicted in Table 2. Table 2. Ceftazidime Concentrations in Body Tissues and Fluids Tissue or Fluid Dose/ Route No. of Patients Time of Sample Postdose Average Tissue or Fluid Level (mcg/mL or mcg/g) Urine 500 mg IM 6 0-2 hr 2,100.0 2 g IV 6 0-2 hr 12,000.0 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 9.0 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 1-3 hr 11.0 Blister fluid 1 g IV 7 2-3 hr 19.7 Lymphatic fluid 1 g IV 7 2-3 hr 23.4 Bone 2 g IV 8 0.67 hr 31.1 Heart muscle 2 g IV 35 30-280 min 12.7 Skin 2 g IV 22 30-180 min 6.6 Skeletal muscle 2 g IV 35 30-280 min 9.4 Myometrium 2 g IV 31 1-2 hr 18.7 Microbiology: Ceftazidime is bactericidal in action, exerting its effect by inhibition of enzymes responsible for cell-wall synthesis. A wide range of gram-negative organisms is susceptible to ceftazidime in vitro, including strains resistant to gentamicin and other aminoglycosides. In addition, ceftazidime has been shown to be active against gram-positive organisms. It is highly stable to most clinically important beta-lactamases, plasmid or chromosomal, which are produced by both gram-negative and gram-positive organisms and, consequently, is active against many strains resistant to ampicillin and other cephalosporins. Ceftazidime has been shown to be active against the following organisms both in vitro and in clinical infections (see INDICATIONS). Aerobes, Gram-negative: Citrobacter spp., including Citrobacter freundii and Citrobacter diversus; Enterobacter spp., including Enterobacter cloacae and Enterobacter aerogenes; Escherichia coli; Haemophilus influenzae, including ampicillin-resistant strains; Klebsiella spp. (including Klebsiella pneumoniae); Neisseria meningitidis; Proteus mirabilis; Proteus vulgaris; Pseudomonas spp. (including Pseudomonas aeruginosa); and Serratia spp. Aerobes, Gram-positive: Staphylococcus aureus, including penicillinase- and non penicillinase-producing strains; Streptococcus agalactiae (group B streptococci); Streptococcus pneumoniae; and Streptococcus pyogenes (group A beta-hemolytic streptococci). Anaerobes: Bacteroides spp. (NOTE: many strains of Bacteroides fragilis are resistant). Ceftazidime has been shown to be active in vitro against most strains of the following organisms; however, the clinical significance of this activity is unknown: Acinetobacter spp., Clostridium spp. (not including Clostridium difficile), Haemophilus parainfluenzae, Morganella morganii (formerly Proteus morganii), Neisseria gonorrhoeae, Peptococcus spp., Peptostreptococcus spp., Providencia spp. (including Providencia rettgeri, formerly Proteus rettgeri), Salmonella spp., Shigella spp., Staphylococcus epidermidis, and Yersinia enterocolitica. Ceftazidime and the aminoglycosides have been shown to be synergistic in vitro against Pseudomonas aeruginosa and the enterobacteriaceae. Ceftazidime and carbenicillin have also been shown to be synergistic in vitro against Pseudomonas aeruginosa. Ceftazidime is not active in vitro against methicillin-resistant staphylococci, Streptococcus faecalis and many other enterococci, Listeria monocytogenes, Campylobacter spp., or Clostridium difficile. Susceptibility Tests: Diffusion Techniques: Quantitative methods that require measurement of zone diameters give an estimate of antibiotic susceptibility. One such procedure1-3 has been recommended for use with disks to test susceptibility to ceftazidime. Reports from the laboratory giving results of the standard single-disk susceptibility test with a 30-mcg ceftazidime disk should be interpreted according to the following criteria: Susceptible organisms produce zones of 18 mm or greater, indicating that the test organism is likely to respond to therapy. Organisms that produce zones of 15 to 17 mm are expected to be susceptible if high dosage is used or if the infection is confined to tissues and fluids (e.g., urine) in which high antibiotic levels are attained. Resistant organisms produce zones of 14 mm or less, indicating that other therapy should be selected. Organisms should be tested with the ceftazidime disk since ceftazidime has been shown by in vitro tests to be active against certain strains found resistant when other beta-lactam disks are used. Standardized procedures require the use of laboratory control organisms. The 30-mcg ceftazidime disk should give zone diameters between 25 and 32 mm for Escherichia coli ATCC 25922. For Pseudomonas aeruginosa ATCC 27853, the zone diameters should be between 22 and 29 mm. For Staphylococcus aureus ATCC 25923, the zone diameters should be between 16 and 20 mm. Dilution Techniques: In other susceptibility testing procedures, e.g., ICS agar dilution or the equivalent, a bacterial isolate may be considered susceptible if the minimum inhibitory concentration (MIC) value for ceftazidime is not more than 16 mcg/mL. Organisms are considered resistant to ceftazidime if the MIC is ≥ 64 mcg/mL. Organisms having an MIC value of < 64 mcg/mL but > 16 mcg/mL are expected to be susceptible if high dosage is used or if the infection is confined to tissues and fluids (e.g., urine) in which high antibiotic levels are attained. As with standard diffusion methods, dilution procedures require the use of laboratory control organisms. Standard ceftazidime powder should give MIC values in the range of 4 to 16 mcg/mL for Staphylococcus aureus ATCC 25923. For Escherichia coli ATCC 25922, the MIC range should be between 0.125 and 0.5 mcg/mL. For Pseudomonas aeruginosa ATCC 27853, the MIC range should be between 0.5 and 2 mcg/mL. REFERENCES 1. Bauer AW, Kirby WMM, Sherris JC, Turck M. Antibiotic susceptibility testing by a standardized single disk method. Am J Clin Pathol. 1966;45:493-496. 2. National Committee for Clinical Laboratory Standards. Approved Standard: Performance Standards for Antimicrobial Disc Susceptibility Tests. (M2-A3). December 1984. 3. Certification procedure for antibiotic sensitivity discs (21 CFR 460.1). Federal Register. May 30, 1974;39:19182-19184.

CEPTAZ® (ceftazidime) Injection L-arginine formulation For Intravenous or Intramuscular Use DESCRIPTION Ceftazidime is a semisynthetic, broad-spectrum, beta-lactam antibiotic for parenteral administration. It is the pentahydrate of pyridinium, 1-[[7-[[(2-amino-4-thiazolyl)[(1-carboxy-1-methylethoxy)imino]acetyl]amino]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl]-, hydroxide, inner salt, [6R-[6α,7β (Z)]]. It has the following structure: The empirical formula is C22H32N6O12S2, representing a molecular weight of 636.6. CEPTAZ is a sterile, dry mixture of ceftazidime pentahydrate and L-arginine. The L-arginine is at a concentration of 349 mg/g of ceftazidime activity. CEPTAZ (ceftazidime) dissolves without the evolution of gas. The product contains no sodium ion. Solutions of CEPTAZ (ceftazidime) range in color from light yellow to amber, depending on the diluent and volume used. The pH of freshly constituted solutions usually ranges from 5 to 7.5.

INDICATIONS CEPTAZ (ceftazidime) 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 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). 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. Bacterial Septicemia caused by Pseudomonas aeruginosa, Klebsiella spp., Haemophilus influenzae, Escherichia coli, Serratia spp., Streptococcus pneumoniae, and Staphylococcus aureus (methicillin-susceptible strains). Bone and Joint Infections caused by Pseudomonas aeruginosa, Klebsiella spp., Enterobacter spp., and Staphylococcus aureus (methicillin-susceptible strains). Gynecologic Infections, including endometritis, pelvic cellulitis, and other infections of the female genital tract caused by Escherichia coli. 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). Central Nervous System Infections, including meningitis, caused by Haemophilus influenzae and Neisseria meningitidis. Ceftazidime has also been used successfully in a limited number of cases of meningitis due to Pseudomonas aeruginosa and Streptococcus pneumoniae. Specimens for bacterial cultures should be obtained before therapy in order to isolate and identify causative organisms and to determine their susceptibility to ceftazidime. Therapy may be instituted before results of susceptibility studies are known; however, once these results become available, the antibiotic treatment should be adjusted accordingly. CEPTAZ (ceftazidime) may be used alone in cases of confirmed or suspected sepsis. Ceftazidime has been used successfully in clinical trials as empiric therapy in cases where various concomitant therapies with other antibiotics have been used. CEPTAZ (ceftazidime) may also be used concomitantly with other antibiotics, such as aminoglycosides, vancomycin, and clindamycin; in severe and life-threatening infections; and in the immunocompromised patient (see Compatibility And Stability). When such concomitant treatment is appropriate, prescribing information in the labeling for the other antibiotics should be followed. The dosage depends on the severity of the infection and the patient's condition. 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 CEPTAZ (ceftazidime) are listed in Table 3. The following dosage schedule is recommended. Table 3. Recommended Dosage Schedule Dose Frequency Patients 12 years and older* Usual recommended dosage 1 gram IV or IM q8-12hr Uncomplicated urinary tract infections 250 mg IV or IM q12hr Bone and joint infections 2 grams IV q12hr Complicated urinary tract infections 500 mg IV or IM q8-12hr Uncomplicated pneumonia; mild skin and skin-structure infections 500 mg-1 gram IV or IM q8hr Serious gynecologic and intra-abdominal infections 2 grams IV q8hr Meningitis 2 grams IV q8hr Very severe life-threatening infections, especially in immunocompromised patients 2 grams IV q8hr Lung infections caused by Pseudomonas spp. in patients with cystic fibrosis with normal renal function† 30-50 mg/kg IV to a maximum of 6 grams per day q8hr * This product is for use in patients 12 years and older. If treatment with ceftazidime is indicated for patients less than 12 years old, a sodium carbonate formulation should be used. †Although clinical improvement has been shown, bacteriologic cures cannot be expected in patients with chronic respiratory disease and cystic fibrosis. Impaired Hepatic Function: No adjustment in dosage is required for patients with hepatic dysfunction. Impaired Renal Function: Ceftazidime is excreted by the kidneys, almost exclusively by glomerular filtration. Therefore, in patients with impaired renal function (glomerular filtration rate [GFR] < 50 mL/min), it is recommended that the dosage of ceftazidime be reduced to compensate for its slower excretion. In patients with suspected renal insufficiency, an initial loading dose of 1 gram of CEPTAZ (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 CEPTAZ (ceftazidime) 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 CEPTAZ Frequency of Dosing 50-31 1 gram q12hr 30-16 1 gram q24hr 15-6 500 mg q24hr

PATIENT INFORMATION No information provided. Please refer to the WARNINGS and PRECAUTIONS sections.

OVERDOSE 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. CONTRAINDICATIONS CEPTAZ (ceftazidime) is contraindicated in patients who have shown hypersensitivity to ceftazidime or the cephalosporin group of antibiotics.

SIDE EFFECTS The following adverse effects from clinical trials were considered to be either related to ceftazidime therapy or were of uncertain etiology. The most common were local reactions following IV injection and allergic and gastrointestinal reactions. No disulfiramlike reactions were reported. Local Effects, reported in fewer than 2% of patients, were phlebitis and inflammation at the site of injection (1 in 69 patients). Hypersensitivity Reactions, reported in 2% of patients, were pruritus, rash, and fever. Immediate reactions, generally manifested by rash and/or pruritus, occurred in 1 in 285 patients. Toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme have also been reported with cephalosporin antibiotics, including ceftazidime. Angioedema and anaphylaxis (bronchospasm and/or hypotension) have been reported very rarely. Gastrointestinal Symptoms, reported in fewer than 2% of patients, were diarrhea (1 in 78), nausea (1 in 156), vomiting (1 in 500), and abdominal pain (1 in 416). The onset of pseudomembranous colitis symptoms may occur during or after treatment (see WARNINGS). Central Nervous System Reactions (fewer than 1%) included headache, dizziness, and paresthesia. Seizures have been reported with several cephalosporins, including ceftazidime. In addition, encephalopathy, coma, asterixis, neuromuscular excitability, and myoclonia have been reported in renally impaired patients treated with unadjusted dosage regimens of ceftazidime (see PRECAUTIONS: General). Less Frequent Adverse Events (fewer than 1%) were candidiasis (including oral thrush) and vaginitis. Hematologic: Rare cases of hemolytic anemia have been reported. Laboratory Test Changes noted during ceftazidime clinical trials were transient and included: eosinophilia (1 in 13), positive Coombs' test without hemolysis (1 in 23), thrombocytosis (1 in 45), and slight elevations in one or more of the hepatic enzymes, aspartate aminotransferase (AST, SGOT) (1 in 16), alanine aminotransferase (ALT, SGPT) (1 in 15), LDH (1 in 18), GGT (1 in 19), and alkaline phosphatase (1 in 23). As with some other cephalosporins, transient elevations of blood urea, blood urea nitrogen, and/or serum creatinine were observed occasionally. Transient leukopenia, neutropenia, agranulocytosis, thrombocytopenia, and lymphocytosis were seen very rarely. Postmarketing Experience With Ceptaz (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 CEPTAZ (ceftazidime) and were reported spontaneously. For some of these events, data are insufficient to allow an estimate of incidence or to establish causation. General: Anaphylaxis; allergic reactions, which, in rare instances, were severe (e.g., cardiopulmonary arrest); urticaria; pain at injection site. Hepatobiliary Tract: Hyperbilirubinemia, jaundice. Renal and Genitourinary: Renal impairment. 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 antibiotics: Adverse Reactions: Colitis, toxic nephropathy, hepatic dysfunction including cholestasis, aplastic anemia, hemorrhage. Altered Laboratory Tests: Prolonged prothrombin time, false-positive test for urinary glucose, pancytopenia. DRUG INTERACTIONS Nephrotoxicity has been reported following concomitant administration of cephalosporins with aminoglycoside antibiotics or potent diuretics such as furosemide. Renal function should be carefully monitored, especially if higher dosages of the aminoglycosides are to be administered or if therapy is prolonged, because of the potential nephrotoxicity and ototoxicity of aminoglycosidic antibiotics. Nephrotoxicity and ototoxicity were not noted when ceftazidime was given alone in clinical trials. Chloramphenicol has been shown to be antagonistic to beta-lactam antibiotics, including ceftazidime, based on in vitro studies and time kill curves with enteric gram-negative bacilli. Due to the possibility of antagonism in vivo, particularly when bactericidal activity is desired, this drug combination should be avoided. Drug/Laboratory Test Interactions: The administration of ceftazidime may result in a false-positive reaction for glucose in the urine when using CLINITEST® tablets, Benedict's solution, or Fehling's solution. It is recommended that glucose tests based on enzymatic glucose oxidase reactions (such as CLINISTIX®) be used.

WARNINGS BEFORE THERAPY WITH CEPTAZ (ceftazidime) 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 ANTIBIOTICS HAS BEEN CLEARLY DOCUMENTED AND MAY OCCUR IN UP TO 10% OF PATIENTS WITH A HISTORY OF PENICILLIN ALLERGY. IF AN ALLERGIC REACTION TO CEPTAZ (ceftazidime) OCCURS, DISCONTINUE THE DRUG. SERIOUS ACUTE HYPERSENSITIVITY REACTIONS MAY REQUIRE TREATMENT WITH EPINEPHRINE AND OTHER EMERGENCY MEASURES, INCLUDING OXYGEN, IV FLUIDS, IV ANTIHISTAMINES, CORTICOSTEROIDS, PRESSOR AMINES, AND AIRWAY MANAGEMENT, AS CLINICALLY INDICATED. Pseudomembranous colitis has been reported with nearly all antibacterial agents, including ceftazidime, and may range in severity from mild to life threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents. Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is one primary cause of "antibiotic-associated colitis." After the diagnosis of pseudomembranous colitis has been established, appropriate therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against Clostridium difficile colitis. Elevated levels of ceftazidime in patients with renal insufficiency can lead to seizures, encephalopathy, coma, asterixis, neuromuscular excitability, and myoclonia (see PRECAUTIONS). PRECAUTIONS General: High and prolonged serum ceftazidime concentrations can occur from usual dosages in patients with transient or persistent reduction of urinary output because of renal insufficiency. The total daily dosage should be reduced when ceftazidime is administered to patients with renal insufficiency (see DOSAGE AND ADMINISTRATION). Elevated levels of ceftazidime in these patients can lead to seizures, encephalopathy, coma, asterixis, neuromuscular excitability, and myoclonia. Continued dosage should be determined by degree of renal impairment, severity of infection, and susceptibility of the causative organisms. As with other antibiotics, prolonged use of CEPTAZ (ceftazidime) may result in overgrowth of nonsusceptible organisms. Repeated evaluation of the patient's condition is essential. If superinfection occurs during therapy, appropriate measures should be taken. Inducible type I beta-lactamase resistance has been noted with some organisms (e.g., Enterobacter spp., Pseudomonas spp., and Serratia spp.). As with other extended-spectrum beta-lactam antibiotics, resistance can develop during therapy, leading to clinical failure in some cases. When treating infections caused by these organisms, periodic susceptibility testing should be performed when clinically appropriate. If patients fail to respond to monotherapy, an aminoglycoside or similar agent should be considered. Cephalosporins may be associated with a fall in prothrombin activity. Those at risk include patients with renal or hepatic impairment, or poor nutritional state, as well as patients receiving a protracted course of antimicrobial therapy. Prothrombin time should be monitored in patients at risk and exogenous vitamin K administered as indicated. CEPTAZ (ceftazidime) should be prescribed with caution in individuals with a history of gastrointestinal disease, particularly colitis. Arginine has been shown to alter glucose metabolism and elevate serum potassium transiently when administered at 50 times the recommended dose. The effect of lower dosing is not known. Distal necrosis can occur after inadvertent intra-arterial administration of ceftazidime. Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term studies in animals have not been performed to evaluate carcinogenic potential. However, a mouse Micronucleus test and an Ames test were both negative for mutagenic effects. Pregnancy: Teratogenic Effects: Pregnancy Category B. Reproduction studies have been performed in mice and rats at doses up to 40 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to ceftazidime. CEPTAZ (ceftazidime) at 23 times the human dose was not teratogenic or embryotoxic in a rat reproduction study. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nursing Mothers: Ceftazidime is excreted in human milk in low concentrations. It is not known whether the arginine component of this product is excreted in human milk. Because many drugs are excreted in human milk and because safety of the arginine component of CEPTAZ (ceftazidime) in nursing infants has not been established, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: Safety of the arginine component of CEPTAZ (ceftazidime) in neonates, infants, and children has not been established. This product is for use in patients 12 years and older. If treatment with ceftazidime is indicated for neonates, infants, or children, a sodium carbonate formulation should be used. Geriatric Use: Clinical studies of CEPTAZ (L-arginine formulation of ceftazidime) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. However, of the 2,221 subjects who received ceftazidime as FORTAZ in 11 clinical studies, 824 (37%) were 65 and over while 391 (18%) were 75 and over. 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).