ADVERSE REACTIONS SECTION.

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 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 FORTAZ 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.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

Carcinogenesis, Mutagenesis, Impairment of Fertility. Long-term studies in animals have not been performed to evaluate carcinogenic potential. However, mouse micronucleus test and an Ames test were both negative for mutagenic effects.

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. After IV administration of 500-mg and 1-g doses of ceftazidime over 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 Average Serum Concentrations of CeftazidimeCeftazidimeSerum Concentrations (mcg/mL)IV Dose0.5 hr1 hr2 hr4 hr8 hr500 mg422512621 g6039231132 g1297542135The absorption and elimination of ceftazidime were directly proportional to the size of the dose. The half-life following IV administration was approximately 1.9 hours. Less than 10% of ceftazidime was protein bound. The degree of protein binding was independent of concentration. There was no evidence of accumulation of ceftazidime in the serum in individuals with normal renal function following multiple IV doses of and g every 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 hour. Serum concentrations remained above mcg/mL for and hours after the IM administration of 500-mg and 1-g doses, respectively. The half-life of ceftazidime in these volunteers was approximately hours.The presence of hepatic dysfunction had no effect on the pharmacokinetics of ceftazidime in individuals administered g intravenously every hours for days. Therefore, 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 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 hours. An additional 20% was excreted between and hours after dosing, and approximately another 12% of the dose appeared in the urine between and hours later. The elimination of ceftazidime by the kidneys resulted in high therapeutic concentrations in the urine.The mean renal clearance of ceftazidime was approximately 100 mL/min. The calculated plasma clearance of approximately 115 mL/min indicated nearly complete elimination of ceftazidime by the renal route. Administration of probenecid before dosing had no effect on the elimination kinetics of ceftazidime. This suggested that ceftazidime is eliminated by glomerular filtration and is not actively secreted by renal tubular mechanisms.Since ceftazidime is eliminated almost solely by the kidneys, its serum half-life is significantly prolonged in patients with impaired renal function. Consequently, dosage adjustments in such patients as described in the DOSAGE AND ADMINISTRATION section are suggested.Therapeutic concentrations of ceftazidime are achieved in the following body tissues and fluids.Table 2. Ceftazidime Concentrations in Body Tissues and FluidsTissue or FluidDose/RouteNo. of PatientsTime of Sample PostdoseAverage Tissueor Fluid Level(mcg/mL or mcg/g)Urine500 mg IM60-2 hr2,100.02 IV60-2 hr12,000.0Bile2 IV390 min36.4Synovial fluid2 IV132 hr25.6Peritoneal fluid2 IV82 hr48.6Sputum1 IV81 hr9.0Cerebrospinal fluid2 q8hr IV5120 min9.8(inflamed meninges)2 q8hr IV6180 min9.4Aqueous humor2 IV131-3 hr11.0Blister fluid1 IV72-3 hr19.7Lymphatic fluid1 IV72-3 hr23.4Bone2 IV80.67 hr31.1Heart muscle2 IV3530-280 min12.7Skin2 IV2230-180 min6.6Skeletal muscle2 IV3530-280 min9.4Myometrium2 IV311-2 hr18.7. Microbiology. Mechanism of Action. Ceftazidime is bactericidal agent that acts by inhibition of bacterial cell wall synthesis. Ceftazidime has activity in the presence of some beta-lactamases, both penicillinases and cephalosporinases, of Gram-negative and Gram-positive bacteria.. Mechanism of Resistance. Resistance to ceftazidime is primarily through hydrolysis by beta-lactamase, alteration of penicillin-binding proteins (PBPs), and decreased permeability.Interaction with Other AntimicrobialsIn an in vitro study antagonistic effects have been observed with the combination of chloramphenicol and ceftazidime.Ceftazidime has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections as described in the Indications and Usage section:Gram-negative bacteriaoCitrobacter speciesoEnterobacter speciesoEscherichia colioKlebsiella speciesoHaemophilus influenzaeoNeisseria meningitidisoProteus mirabilisoProteus vulgarisoPseudomonas aeruginosaoSerratia speciesGram-positive bacteriaoStaphylococcus aureus oStreptococcus pneumoniaeoStreptococcus pyogenesoStreptococcus agalactiaeAnaerobic bacteriaoBacteroides species(Note: many isolates of Bacteroides species are resistant)The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for ceftazidime. However, the efficacy of ceftazidime in treating clinical infections due to these microorganisms has not been established in adequate and well-controlled clinical trials.Gram-negative bacteriaoAcinetobacter speciesoCitrobacter diversusoCitrobacter freundiioProvidencia species (including Providencia rettgeri)oSalmonella speciesoShigella speciesoHaemophilus parainfluenzae oMorganella morganiioNeisseria gonorrhoeaeoYersinia enterocolitica Gram-positive bacteriaoStaphylococcus epidermidisAnaerobic bacteriaoClostridium species (Not including Clostridium difficile)oPeptostreptococcus species. oCitrobacter species. oEnterobacter species. oEscherichia coli. oKlebsiella species. oHaemophilus influenzae. oNeisseria meningitidis. oProteus mirabilis. oProteus vulgaris. oPseudomonas aeruginosa. oSerratia species. oStaphylococcus aureus oStreptococcus pneumoniae. oStreptococcus pyogenes. oStreptococcus agalactiae. oBacteroides species(Note: many isolates of Bacteroides species are resistant). oAcinetobacter species. oCitrobacter diversus. oCitrobacter freundii. oProvidencia species (including Providencia rettgeri). oSalmonella species. oShigella species. oHaemophilus parainfluenzae oMorganella morganii. oNeisseria gonorrhoeae. oYersinia enterocolitica oStaphylococcus epidermidis. oClostridium species (Not including Clostridium difficile). oPeptostreptococcus species. Susceptibility Testing. For specific information regarding susceptibility test interpretive criteria, and associated test methods and quality control standards recognized by FDA for this drug, please see: http://www.fda.gov/STIC.

CONTRAINDICATIONS SECTION.

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

DESCRIPTION SECTION.

DESCRIPTION. Ceftazidime is semisynthetic, broad-spectrum, beta-lactam antibacterial drug for parenteral administration. It is the pentahydrate of pyridinium, 1-[[7-[[(2-amino-4-thiazolyl)[(1-carboxy-1-methylethoxy)imino]acetyl]amino]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl]-, hydroxide, inner salt, [6R-[6,7(Z)]]. It has the following structure:The molecular formula is C22H32N6O12S2, representing molecular weight of 636.6.FORTAZ is sterile, dry-powdered mixture of ceftazidime pentahydrate and sodium carbonate. The sodium carbonate at 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. The Pharmacy Bulk Package vial contains 709 mg of sodium carbonate. The sodium content is approximately 54 mg (2.3mEq) per gram of ceftazidime.FORTAZ in sterile crystalline form is supplied in Pharmacy Bulk Packages equivalent to 6g of anhydrous ceftazidime. The Pharmacy Bulk Package bottle is container of sterile preparation for parenteral use that contains many single doses. The contents are intended for use in pharmacy admixture program and are restricted to the preparation of admixtures for intravenous use. THE PHARMACY BULK PACKAGE IS NOT FOR DIRECT INFUSION, FURTHER DILUTION IS REQUIRED BEFORE USE. (See DOSAGE AND ADMINISTRATION-Directions for Proper Use of Pharmacy Bulk Package). Solutions of FORTAZ range in color from light yellow to amber, depending on the diluent and volume used. The pH of freshly constituted solutions usually ranges from to 8.

DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION. Dosage. The usual adult dosage is gram administered intravenously or intramuscularly every to 12 hours. The dosage and route should be determined by the susceptibility of the causative organisms, the severity of infection, and the condition and renal function of the patient.The guidelines for dosage of FORTAZ are listed in Table 3. The following dosage schedule is recommended.Table 3. Recommended Dosage Schedule DoseFrequencyAdultsUsual recommended dosage1 gram intravenous or intramuscularevery to 12 hoursUncomplicated urinary tract infections250 mg intravenous or intramuscularevery 12 hoursBone and joint infections2 grams intravenousevery 12 hoursComplicated urinary tract infections500 mg intravenous or intramuscularevery to 12 hoursUncomplicated pneumonia; mild skin and skin-structure infections500 mg to gram intravenous or intramuscularevery hoursSerious gynecologic and intra-abdominal infections2 grams intravenousevery hoursMeningitis2 grams intravenousevery hoursVery severe life-threatening infections, especially in immunocompromised patients2 grams intravenousevery hoursLung infections caused by Pseudomonas spp. in patients with cystic fibrosis with normal renal functionAlthough 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 maximum of grams per dayevery hoursNeonates (0-4 weeks)30 mg/kg intravenousevery 12 hoursInfants and children(1 month-12 years)30 to 50 mg/kg intravenous to maximum of grams per dayThe higher dose should be reserved for immunocompromised pediatric patients or pediatric patients with cystic fibrosis or meningitis. every hoursImpaired Hepatic FunctionNo adjustment in dosage is required for patients with hepatic dysfunction.Impaired Renal FunctionCeftazidime 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 gram of FORTAZ may be given. An estimate of GFR should be made to determine the appropriate maintenance dosage. The recommended dosage is presented in Table 6.Table 4. Recommended Maintenance Dosages of FORTAZ in Renal Insufficiency NOTE: IF THE DOSE RECOMMENDED IN Table ABOVE IS LOWER THAN THAT RECOMMENDED FOR PATIENTS WITH RENAL INSUFFICIENCY AS OUTLINED IN Table 5, THE LOWER DOSE SHOULD BE USED.Creatinine Clearance (mL/min)Recommended Unit Dose of FORTAZFrequency of Dosing50-311 gramevery 12 hours30-161 gramevery 24 hours15-6500 mgevery 24 hoursless than 5500 mgevery 48 hoursWhen only serum creatinine is available, the following formula (Cockcrofts equation)5 may be used to estimate creatinine clearance. The serum creatinine should represent steady state of renal function:Males: Creatinine clearance (mL/min) =Weight (kg) (140 age) 72 serum creatinine (mg/dL)Females: 0.85 male valueIn patients with severe infections who would normally receive grams of FORTAZ 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, loading dose of gram is recommended, followed by gram after each hemodialysis period.FORTAZ can also be used in patients undergoing intraperitoneal dialysis and continuous ambulatory peritoneal dialysis. In such patients, loading dose of gram of FORTAZ may be given, followed by 500 mg every 24 hours. In addition to IV use, FORTAZ can be incorporated in the dialysis fluid at concentration of 250 mg for L of dialysis fluid.Note: Generally FORTAZ should be continued for days after the signs and symptoms of infection have disappeared, but in complicated infections longer therapy may be required.. Administration. Intravenous AdministrationThe 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. Directions for Proper Use of Pharmacy Bulk PackageNot for direct infusion. This Pharmacy Bulk Package is for use in hospital pharmacy admixture service, only in suitable work area, such as laminar flow hood. Using aseptic technique, the container closure may be penetrated only one time using suitable sterile dispensing set or transfer device that allows measured dispensing of the contents. Use of syringe and needle is not recommended as it may cause leakage. The withdrawal of container contents should be accomplished without delay. However, should this not be possible, maximum time of hours from initial closure entry is permitted to complete fluid transfer operations. This time limit should begin with the introduction of the solvent or diluent into the Pharmacy Bulk Package. DISCARD ANY UNUSED PORTION AFTER HOURS. NOT FOR DIRECT INFUSION. THIS PHARMACY BULK PACKAGE IS NOT INTENDED TO BE DISPENSED AS UNIT. Freezing solutions of FORTAZ is not recommended.Table 5. Preparation of Solutions of FORTAZ (Pharmacy Bulk Package)SizeAmount of Diluent to be Added(mL)Approximate Available Volume(mL)Approximate Ceftazidime Concentration(mg/mL)Pharmacy bulk package6-gram vial 26 30200 Fortaz (Pharmacy bulk package), when constituted as directed with Sterile Water for Injection, should have the contents withdrawn within 12 hours. After constitution, 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. All vials of FORTAZ as supplied are under reduced pressure. When FORTAZ is dissolved, carbon dioxide is released and 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 FORTAZ, 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 FORTAZ and an aminoglycoside is indicated, each of these antibacterial drugs can be administered separately to the same patient.

DRUG & OR LABORATORY TEST INTERACTIONS SECTION.

Drug/Laboratory Test Interactions. The administration of ceftazidime may result in false-positive reaction for glucose in the urine when using CLINITEST(R) tablets, Benedicts solution, or Fehlings solution. It is recommended that glucose tests based on enzymatic glucose oxidase reactions (such as CLINISTIX(R)) be used.

DRUG INTERACTIONS SECTION.

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

GENERAL PRECAUTIONS SECTION.

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, nonconvulsive status epilepticus 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 antibacterial drugs, prolonged use of FORTAZ may result in overgrowth of nonsusceptible organisms. Repeated evaluation of the patients condition is essential. If superinfection occurs during therapy, appropriate measures should be taken.Inducible type 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 antibacterial drugs, 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 fall in prothrombin activity. Those at risk include patients with renal and hepatic impairment, or poor nutritional state, as well as patients receiving protracted course of antimicrobial therapy. Prothrombin time should be monitored in patients at risk and exogenous vitamin administered as indicated.FORTAZ should be prescribed with caution in individuals with history of gastrointestinal disease, particularly colitis.Distal necrosis can occur after inadvertent intra-arterial administration of ceftazidime.Prescribing FORTAZ in the absence of proven or strongly suspected bacterial infection or prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

GERIATRIC USE SECTION.

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 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).

HOW SUPPLIED SECTION.

HOW SUPPLIED. FORTAZ in the dry state should be stored between 15 and 30C (59 and 86F) and protected from light. FORTAZ is dry, white to off-white powder supplied in vials as follows:NDC 52565-109-06 6-g Pharmacy Bulk Package (Tray of 6)Equivalent to anhydrous ceftazidime.. NDC 52565-109-06 6-g Pharmacy Bulk Package (Tray of 6).

INDICATIONS & USAGE SECTION.

INDICATIONS AND USAGE. FORTAZ 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 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 limited number of cases of meningitis due to Pseudomonas aeruginosa and Streptococcus pneumoniae. FORTAZ 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.FORTAZ 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 patients condition.To reduce the development of drug-resistant bacteria and maintain the effectiveness of FORTAZ and other antibacterial drugs, FORTAZ 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.. 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 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 limited number of cases of meningitis due to Pseudomonas aeruginosa and Streptococcus pneumoniae.

INFORMATION FOR PATIENTS SECTION.

Information for Patients. Patients should be counseled that antibacterial drugs, including FORTAZ, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When FORTAZ is prescribed to treat 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 FORTAZ or other antibacterial drugs in the future.Diarrhea is common problem caused by antibacterial drugs which usually ends when the antibacterial drug is discontinued. Sometimes after starting treatment with antibacterial drugs, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as or more months after having taken the last dose of the antibacterial drug. If this occurs, patients should contact their physician as soon as possible.

MECHANISM OF ACTION SECTION.

Mechanism of Action. Ceftazidime is bactericidal agent that acts by inhibition of bacterial cell wall synthesis. Ceftazidime has activity in the presence of some beta-lactamases, both penicillinases and cephalosporinases, of Gram-negative and Gram-positive bacteria.

MICROBIOLOGY SECTION.

Microbiology. Mechanism of Action. Ceftazidime is bactericidal agent that acts by inhibition of bacterial cell wall synthesis. Ceftazidime has activity in the presence of some beta-lactamases, both penicillinases and cephalosporinases, of Gram-negative and Gram-positive bacteria.. Mechanism of Resistance. Resistance to ceftazidime is primarily through hydrolysis by beta-lactamase, alteration of penicillin-binding proteins (PBPs), and decreased permeability.Interaction with Other AntimicrobialsIn an in vitro study antagonistic effects have been observed with the combination of chloramphenicol and ceftazidime.Ceftazidime has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections as described in the Indications and Usage section:Gram-negative bacteriaoCitrobacter speciesoEnterobacter speciesoEscherichia colioKlebsiella speciesoHaemophilus influenzaeoNeisseria meningitidisoProteus mirabilisoProteus vulgarisoPseudomonas aeruginosaoSerratia speciesGram-positive bacteriaoStaphylococcus aureus oStreptococcus pneumoniaeoStreptococcus pyogenesoStreptococcus agalactiaeAnaerobic bacteriaoBacteroides species(Note: many isolates of Bacteroides species are resistant)The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for ceftazidime. However, the efficacy of ceftazidime in treating clinical infections due to these microorganisms has not been established in adequate and well-controlled clinical trials.Gram-negative bacteriaoAcinetobacter speciesoCitrobacter diversusoCitrobacter freundiioProvidencia species (including Providencia rettgeri)oSalmonella speciesoShigella speciesoHaemophilus parainfluenzae oMorganella morganiioNeisseria gonorrhoeaeoYersinia enterocolitica Gram-positive bacteriaoStaphylococcus epidermidisAnaerobic bacteriaoClostridium species (Not including Clostridium difficile)oPeptostreptococcus species. oCitrobacter species. oEnterobacter species. oEscherichia coli. oKlebsiella species. oHaemophilus influenzae. oNeisseria meningitidis. oProteus mirabilis. oProteus vulgaris. oPseudomonas aeruginosa. oSerratia species. oStaphylococcus aureus oStreptococcus pneumoniae. oStreptococcus pyogenes. oStreptococcus agalactiae. oBacteroides species(Note: many isolates of Bacteroides species are resistant). oAcinetobacter species. oCitrobacter diversus. oCitrobacter freundii. oProvidencia species (including Providencia rettgeri). oSalmonella species. oShigella species. oHaemophilus parainfluenzae oMorganella morganii. oNeisseria gonorrhoeae. oYersinia enterocolitica oStaphylococcus epidermidis. oClostridium species (Not including Clostridium difficile). oPeptostreptococcus species. Susceptibility Testing. For specific information regarding susceptibility test interpretive criteria, and associated test methods and quality control standards recognized by FDA for this drug, please see: http://www.fda.gov/STIC.

NURSING MOTHERS SECTION.

Nursing Mothers. Ceftazidime is excreted in human milk in low concentrations. Caution should be exercised when FORTAZ is administered to nursing woman.

OVERDOSAGE SECTION.

OVERDOSAGE. 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.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

Principal Display Panel 6 gram Pharmacy Bulk Package. NDC 52565-109-01Fortaz(R) (ceftazidime for injection)6 g/vialEquivalent to g of ceftazidime. Pharmacy Bulk Package-Not for Direct InfusionFor Intravenous use.Further Dilution Required. Rx onlySee package insert for Dosage and Administration. Before constitution, store between 15o and 30oC (59o and 86oF) and protect from light.IMPORTANT: This Pharmacy Bulk Package vial is under reduced pressure. Addition of diluent generates positive pressure. Before constituting, see Instructions for Constitution.Under laminar flow hood, penetrate one time using sterile transfer device. USE PROMPTLY. DISCARD UNUSED PORTION WITHIN 12 HOURS AFTER INITIAL ENTRY. To prepare solution, add 26 mL of Sterile Water for Injection. Shake well to dissolve. The constituted solution occupies volume of about 31.5 mL and contains approximately g of ceftazidime activity per mL.This vial contains 709 mg of sodium carbonate. The sodium content is approximately 54mg (2.3 mEq) per gram of ceftazidime. Dist. by Teligent Pharma, Inc.Buena, NJ 08310Made in Italy.

PEDIATRIC USE SECTION.

Pediatric Use. See DOSAGE AND ADMINISTRATION.

PRECAUTIONS SECTION.

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, nonconvulsive status epilepticus 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 antibacterial drugs, prolonged use of FORTAZ may result in overgrowth of nonsusceptible organisms. Repeated evaluation of the patients condition is essential. If superinfection occurs during therapy, appropriate measures should be taken.Inducible type 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 antibacterial drugs, 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 fall in prothrombin activity. Those at risk include patients with renal and hepatic impairment, or poor nutritional state, as well as patients receiving protracted course of antimicrobial therapy. Prothrombin time should be monitored in patients at risk and exogenous vitamin administered as indicated.FORTAZ should be prescribed with caution in individuals with history of gastrointestinal disease, particularly colitis.Distal necrosis can occur after inadvertent intra-arterial administration of ceftazidime.Prescribing FORTAZ in the absence of proven or strongly suspected bacterial infection or prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.. Information for Patients. Patients should be counseled that antibacterial drugs, including FORTAZ, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When FORTAZ is prescribed to treat 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 FORTAZ or other antibacterial drugs in the future.Diarrhea is common problem caused by antibacterial drugs which usually ends when the antibacterial drug is discontinued. Sometimes after starting treatment with antibacterial drugs, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as or more months after having taken the last dose of the antibacterial drug. If this occurs, patients should contact their physician as soon as possible.. 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.In common with other antibacterial drugs, ceftazidime may affect the gut flora, leading to lower estrogen reabsorption and reduced efficacy of combined oral estrogen/progesterone contraceptives.. Drug/Laboratory Test Interactions. The administration of ceftazidime may result in false-positive reaction for glucose in the urine when using CLINITEST(R) tablets, Benedicts solution, or Fehlings solution. It is recommended that glucose tests based on enzymatic glucose oxidase reactions (such as CLINISTIX(R)) be used.. Carcinogenesis, Mutagenesis, Impairment of Fertility. Long-term studies in animals have not been performed to evaluate carcinogenic potential. However, 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 FORTAZ. 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. Caution should be exercised when FORTAZ is administered to nursing woman.. Pediatric Use. See DOSAGE AND ADMINISTRATION.. 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 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).

PREGNANCY SECTION.

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 FORTAZ. 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.

REFERENCES SECTION.

REFERENCES Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16:31-41.FORTAZ(R) (ceftazidime for injection): Distributed by: Teligent Pharma, Inc., Buena, NJ 08310 FORTAZ and ZINACEF are registered trademarks of Teligent, Inc.CLINITEST and CLINISTIX are registered trademarks of Ames Division, Miles Laboratories, Inc.Distributed by:Teligent Pharma, Inc.Buena, NJ 08310Rev: 08/2018 TEAR AWAYFORTAZ(R) (ceftazidime for injection)Instructions for Constitution Pharmacy Bulk Package: g1. Insert the syringe needle through the vial closure and inject 26 mL of diluent. The vacuum may assist entry of the diluent. Remove the syringe needle.2. Shake to dissolve; clear solution containing approximately g of ceftazidime activity per mL will be obtained in to minutes.3. Insert gas-relief needle through the vial closure to relieve the internal pressure. Remove the gas-relief needle before extracting any solution.Note: To preserve product sterility, it is important that gas-relief needle is not inserted through the vial closure before the product has dissolved. Distributed by:Teligent Pharma, Inc.Buena, NJ 08310 Rev: 08/2018 Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16:31-41.

SPL UNCLASSIFIED SECTION.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of FORTAZ and other antibacterial drugs, FORTAZ should be used only to treat infections that are proven or strongly suspected to be caused by bacteria.

TERATOGENIC EFFECTS SECTION.

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 FORTAZ. 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.

WARNINGS SECTION.

WARNINGS. BEFORE THERAPY WITH FORTAZ 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 HISTORY OF PENICILLIN ALLERGY. IF AN ALLERGIC REACTION TO FORTAZ 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 FORTAZ, 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 and 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).