CEFEPIME: 5,540 Adverse Event Reports & Safety Profile

Cefepime hydrochloride, USP is a semi-synthetic, broad spectrum, cephalosporin antibacterial for parenteral administration. The chemical name is 1-[[(6 R ,7 R )-7-[2-(2-amino-4-thiazolyl)-glyoxylamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl]-1-methylpyrrolidinium chloride, 7 2 -( Z )-( O -methyloxime), monohydrochloride, monohydrate, which corresponds to the following structural formula: Cefepime hydrochloride (monohydrate) has a molecular mass of 571.50 and a molecular formula of C 19 H 25 ClN 6 O 5 S 2

• HCl•H 2 O. Cefepime hydrochloride is a white to pale yellow powder. Cefepime hydrochloride contains the equivalent of not less than 825 mcg and not more than 911 mcg of cefepime (C 19 H 24 N 6 O 5 S 2 ) per mg, calculated on an anhydrous basis. It is highly soluble in water. Cefepime for Injection USP and Dextrose Injection USP in the DUPLEX® dual chamber container is supplied for intravenous administration in strengths equivalent to 1 g and 2 g of cefepime. Cefepime for Injection USP and Dextrose Injection USP is supplied as a sterile, nonpyrogenic, single-dose packaged combination of cefepime hydrochloride with L-arginine (drug chamber) and 50 mL of 5% dextrose injection (diluent) in the DUPLEX® sterile container. The powder chamber of the DUPLEX® container contains a sterile, dry mixture of cefepime hydrochloride and L-arginine. It contains the equivalent of not less than 90.0 percent and not more than 115.0 percent of the labeled amount of cefepime (C 19 H 24 N 6 O 5 S 2 ). The L-arginine, at an approximate concentration of 725 mg/g of cefepime, is added to control the pH of the reconstituted solution at 4.0 – 6.0. The diluent chamber contains Dextrose Injection USP, an iso-osmotic diluent using Hydrous Dextrose USP in Water for Injection USP.

Dextrose

Injection USP is sterile, nonpyrogenic, and contains no bacteriostatic or antimicrobial agents. Its empirical formula is C 6 H 12 O 6

• H 2 O and its molecular weight is 198.17.

Hydrous

Dextrose USP has the following structural (molecular) formula: The DUPLEX® container is a flexible dual chamber container. After removing the peelable foil strip, activating the seals, and thoroughly mixing, the reconstituted drug product is hyperosmotic and is intended for single intravenous use.

Each

50 mL contains cefepime hydrochloride equivalent to either 1 gram or 2 grams of cefepime. Reconstituted solutions of Cefepime for Injection USP and Dextrose Injection USP range in color from colorless to amber. The DUPLEX® dual chamber container is made from a specially formulated material. The product (diluent and drug) contact layer is a mixture of thermoplastic rubber and a polypropylene ethylene copolymer that contains no plasticizers. The safety of the container is supported by USP biological evaluation procedures.

Chemical Structure Dextrose Formula

Illustration

AND USAGE Cefepime for injection is a cephalosporin antibacterial indicated for the treatment of the following infections caused by susceptible strains of the designated microorganisms: Pneumonia. ( 1.1 ) Empiric therapy for febrile neutropenic patients. ( 1.2 ) Uncomplicated and complicated urinary tract infections (including pyelonephritis). ( 1.3 ) Uncomplicated skin and skin structure infections. ( 1.4 ) Complicated intra-abdominal infections (used in combination with metronidazole) in adults. ( 1.5 )

1.1 Pneumonia Cefepime for injection is indicated in the treatment of pneumonia (moderate to severe) caused by susceptible strains of Streptococcus pneumoniae , including cases associated with concurrent bacteremia, Pseudomonas aeruginosa , Klebsiella pneumoniae , or Enterobacter species .

1.2 Empiric Therapy for Febrile Neutropenic Patients Cefepime for injection as monotherapy is indicated for empiric treatment of febrile neutropenic patients. In patients at high risk for severe infection (including patients with a history of recent bone marrow transplantation, with hypotension at presentation, with an underlying hematologic malignancy, or with severe or prolonged neutropenia), antimicrobial monotherapy may not be appropriate. Insufficient data exist to support the efficacy of cefepime monotherapy in such patients [ see Clinical Studies ( 14.1 ) ].

1.3 Uncomplicated and Complicated Urinary Tract Infections (including pyelonephritis) Cefepime for injection is indicated in the treatment of uncomplicated and complicated urinary tract infections (including pyelonephritis) caused by susceptible isolates of Escherichia coli or Klebsiella pneumoniae , when the infection is severe, or caused by Escherichia coli , Klebsiella pneumoniae , or Proteus mirabilis , when the infection is mild to moderate, including cases associated with concurrent bacteremia with these bacteria.

1.4 Uncomplicated Skin and Skin Structure Infections Cefepime for injection is indicated in the treatment of uncomplicated skin and skin structure infections caused by Staphylococcus aureus (methicillin-susceptible isolates only) or Streptococcus pyogenes .

1.5 Complicated Intra-abdominal Infections (used in combination with metronidazole) Cefepime for injection is indicated in the treatment of complicated intra-abdominal infections (used in combination with metronidazole) in adults caused by susceptible isolates of Escherichia coli , viridans group streptococci, Pseudomonas aeruginosa , Klebsiella pneumoniae, Enterobacter species, or Bacteroides fragilis [ see Clinical Studies ( 14.2 ) ].

1.6 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of cefepime for injection and other antibacterial drugs, cefepime for injection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

1.1 Pneumonia Cefepime for injection is indicated in the treatment of pneumonia (moderate to severe) caused by susceptible strains of Streptococcus pneumoniae , including cases associated with concurrent bacteremia, Pseudomonas aeruginosa , Klebsiella pneumoniae , or Enterobacter species .

1.2 Empiric Therapy for Febrile Neutropenic Patients Cefepime for injection as monotherapy is indicated for empiric treatment of febrile neutropenic patients. In patients at high risk for severe infection (including patients with a history of recent bone marrow transplantation, with hypotension at presentation, with an underlying hematologic malignancy, or with severe or prolonged neutropenia), antimicrobial monotherapy may not be appropriate. Insufficient data exist to support the efficacy of cefepime monotherapy in such patients [ see Clinical Studies ( 14.1 ) ].

1.3 Uncomplicated and Complicated Urinary Tract Infections (including pyelonephritis) Cefepime for injection is indicated in the treatment of uncomplicated and complicated urinary tract infections (including pyelonephritis) caused by susceptible isolates of Escherichia coli or Klebsiella pneumoniae , when the infection is severe, or caused by Escherichia coli , Klebsiella pneumoniae , or Proteus mirabilis , when the infection is mild to moderate, including cases associated with concurrent bacteremia with these bacteria.

1.4 Uncomplicated Skin and Skin Structure Infections Cefepime for injection is indicated in the treatment of uncomplicated skin and skin structure infections caused by Staphylococcus aureus (methicillin-susceptible isolates only) or Streptococcus pyogenes .

1.5 Complicated Intra-abdominal Infections (used in combination with metronidazole) Cefepime for injection is indicated in the treatment of complicated intra-abdominal infections (used in combination with metronidazole) in adults caused by susceptible isolates of Escherichia coli , viridans group streptococci, Pseudomonas aeruginosa , Klebsiella pneumoniae, Enterobacter species, or Bacteroides fragilis [ see Clinical Studies ( 14.2 ) ].

1.6 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of cefepime for injection and other antibacterial drugs, cefepime for injection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

AND ADMINISTRATION Recommended Dosage in Adults with Creatinine Clearance (CrCL)

Greater Than

60 mL/min ( 2.1 ) Site and Type of Infection Dose Frequency Duration (days) Moderate to Severe Pneumonia § 1 to 2 g IV Every 8 to 12 hours 10 Empiric Therapy for Febrile Neutropenic Patients 2 g IV Every 8 hours 7* Mild to Moderate Uncomplicated or Complicated Urinary Tract Infections 0.5 to 1 g IV/IM** Every 12 hours 7 to 10 Severe Uncomplicated or Complicated Urinary Tract Infections 2 g IV Every 12 hours 10 Moderate to Severe Uncomplicated Skin and Skin Structure Infections 2 g IV Every 12 hours 10 Complicated Intra-abdominal Infections § (used in combination with metronidazole) 2 g IV Every 12 hours 7 to 10 § For Pseudomonas aeruginosa , use 2 g IV every 8 hours. ( 2.1 ) *Or until resolution of neutropenia. ( 2.1 ) **Intramuscular route of administration is indicated only for mild to moderate, uncomplicated or complicated UTIs due to E. coli. (2.1 )

Pediatric

Patients (2 months to 16 years) Recommended dosage in pediatric with CrCL greater than 60 mL/min. ( 2.2 ) The usual recommended dosage in pediatric patients is 50 mg per kg per dose administered every 12 hours (every 8 hours for febrile neutropenia). ( 2.2 ) Patients with Renal Impairment: Adjust dose in patients with CrCL less than or equal to 60 mL/min. ( 2.3 )

2.1 Dosage for Adults The recommended adult dosages and routes of administration are outlined in Table 1 below for patients with creatinine clearance greater than 60 mL/min. Administer cefepime for injection intravenously over approximately 30 minutes.

Table

1: Recommended Dosage Schedule for Cefepime for Injection in Adult Patients with Creatinine Clearance (CrCL)

Greater Than

60mL/min Site and Type of Infection Dose Frequency Duration (days)

Adults

Intravenous (IV)/ Intramuscular (IM) Moderate to Severe Pneumonia § 1 to 2 g IV Every 8 to 12hours 10 Empiric therapy for febrile neutropenic patients 2 g IV Every 8 hours 7* Mild to Moderate Uncomplicated or Complicated Urinary Tract Infections, including pyelonephritis 0.5 to 1 g IV/IM** Every 12 hours 7 to 10 Severe Uncomplicated or Complicated Urinary Tract Infections, including pyelonephritis 2 g IV Every 12 hours 10 Moderate to Severe Uncomplicated Skin and Skin Structure Infections 2 g IV Every 12 hours 10 Complicated Intra-abdominal Infections § (used in combination with metronidazole) 2 g IV Every 8 to 12hours 7 to 10 *or until resolution of neutropenia. In patients whose fever resolves but who remain neutropenic for more than 7 days, the need for continued antimicrobial therapy should be re-evaluated frequently. **Intramuscular route of administration is indicated only for mild to moderate, uncomplicated or complicated UTIs due to E. coli . § For P. aeruginosa , use 2 g IV every 8 hours.

2.2 Pediatric Patients (2 months up to 16 years) The maximum dose for pediatric patients should not exceed the recommended adult dose. The usual recommended dosage in pediatric patients up to 40 kg in weight for durations as given above for adults is: 50 mg per kg per dose, administered every 12 hours for uncomplicated and complicated urinary tract infections (including pyelonephritis), uncomplicated skin and skin structure infections, and pneumonia (see below). For moderate to severe pneumonia due to P. aeruginosa give 50 mg per kg per dose, every 8 hours. 50 mg per kg per dose, every 8 hours for febrile neutropenic patients.

2.3 Dosage Adjustments in Patients with Renal Impairment Adult Patients Adjust the dose of cefepime for injection in patients with creatinine clearance less than or equal to 60 mL/min to compensate for the slower rate of renal elimination. In these patients, the recommended initial dose of cefepime for injection should be the same as in patients with CrCL greater than 60 mL/min except in patients undergoing hemodialysis. The recommended doses of cefepime for injection in patients with renal impairment are presented in Table 2. When only serum creatinine is available, the following formula (Cockcroft and Gault 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 × serum creatinine (mg/dL) Females: 0.85 × above value Table 2: Recommended Dosing Schedule for Cefepime for Injection in Adult Patients With Creatinine Clearance Less Than or Equal to 60 mL/min Creatinine Clearance (mL/min)

Recommended Maintenance Schedule

Greater than 60 500 mg every 12hours 1 g every 12 hours 2 g every 12 hours 2 g every 8 hours 30 to 60 500 mg every 24 hours 1 g every 24 hours 2 g every 24 hours 2 g every 12 hours 11 to 29 500 mg every 24 hours 500 mg every 24 hours 1 g every 24 hours 2 g every 24 hours Less than 11 250 mg every 24 hours 250 mg every 24 hours 500 mg every 24 hours 1 g every 24 hours Continuous Ambulatory Peritoneal Dialysis (CAPD) 500 mg every 48 hours 1 g every 48 hours 2 g every 48 hours 2 g every 48 hours Hemodialysis* 1 g on day 1, then 500 mg every 24 hours thereafter 1 g every 24 hours *On hemodialysis days, cefepime should be administered following hemodialysis. Whenever possible, cefepime should be administered at the same time each day. In patients undergoing Continuous Ambulatory Peritoneal Dialysis (CAPD), cefepime for injection may be administered at the recommended doses at a dosage interval of every 48 hours (see Table 2). In patients undergoing hemodialysis, approximately 68% of the total amount of cefepime present in the body at the start of dialysis will be removed during a 3-hour dialysis period. The dosage of cefepime for injection for hemodialysis patients is 1 g on Day 1 followed by 500 mg every 24 hours for the treatment of all infections except febrile neutropenia, which is 1 g every 24 hours. Cefepime for injection should be administered at the same time each day and following the completion of hemodialysis on hemodialysis days (see Table 2).

Pediatric Patients

Data in pediatric patients with impaired renal function are not available; however, since cefepime pharmacokinetics are similar in adults and pediatric patients [ see Clinical Pharmacology (12.3) ], changes in the dosing regimen proportional to those in adults (see Tables 1 and 2) are recommended for pediatric patients.

2.4 Preparation of Cefepime for Injection for Intravenous Infusion Vials Constitute the 1 gram, or 2 grams vial, of cefepime for injection with the one of the following diluents: Sterile Water for Injection 0.9% Sodium Chloride Injection 5% Dextrose Injection 0.5% or 1% Lidocaine Hydrochloride Injection Sterile Bacteriostatic Water for Injection with Parabens or Benzyl Alcohol Dilute the reconstituted solution with one of the following compatible infusion solutions prior to intravenous infusion (Refer to Table 3 below for the amount of diluent to be added to each vial and the amount of the reconstituted solution to be withdrawn): 0.9% Sodium Chloride Injection 5% and 10% Dextrose Injection M/6 Sodium Lactate Injection 5% Dextrose and 0.9% sodium Chloride Injection Lactated Rings and 5% Dextrose Injection Normosol®-R and Normosol®-M in 5% Dextrose Injection Parenteral drugs should be inspected visually for particulate matter before administration. If particulate matter is evident in reconstituted fluids, the drug solution should be discarded. Administer the resulting intravenous infusion over approximately 30 minutes. Intermittent intravenous infusion with a Y-type administration set can be accomplished with compatible solutions. However, during infusion of a solution containing cefepime, it is desirable to discontinue the other solution.

2.5 Preparation of Cefepime for Injection for Intramuscular Administration Constitute cefepime for injection vials 1 gram and 2 grams with one of the following diluents: Sterile Water for Injection, 0.9% Sodium Chloride, 5% Dextrose Injection, 0.5% or 1% Lidocaine Hydrochloride, or Sterile Bacteriostatic Water for Injection with Parabens or Benzyl Alcohol. Refer to Table 3 below for the amount of diluent to be added to each vial and the amount of reconstituted volume to be withdrawn. Parenteral drugs should be inspected visually for particulate matter before administration. If particulate matter is evident in reconstituted fluids, the drug solution should be discarded.

Table

3: Preparation of Reconstituted Solutions of Cefepime for Injection Single-Dose Vials for Intravenous (IV)/Intramuscular (IM)Administration Amount of Diluent to be added (mL)

Approximate Cefepime

Concentration (mg/mL) Amount of Reconstituted Volume to be Withdrawn (mL) Cefepime vial content 1 g (IV) 10 100 10.5 1 g (IM) 2.4 280 3.6 2 g (IV) 10 160 12.5

2.6 Compatibility and Stability Intravenous Cefepime for Injection Intravenous Infusion Compatibility Cefepime for injection vials are compatible at concentrations between 1 mg per mL and 40 mg per mL with the following intravenous infusion fluids: 0.9% Sodium Chloride Injection, 5% and 10% Dextrose Injection, M/6 Sodium Lactate Injection, 5% Dextrose and 0.9% Sodium Chloride Injection, Lactated Ringers and 5% Dextrose Injection, Normosol®-R, and Normosol®-M in 5% Dextrose Injection. These solutions may be stored up to 24 hours at controlled room temperature 20°C to 25°C (68°F to 77°F) or 7 days in a refrigerator 2°C to 8°C (36°F to 46°F).

Admixture Compatibility

Cefepime for injection admixture compatibility information is summarized in Table 4.

Table

4: Cefepime Admixture Stability Cefepime for Injection Concentration Admixture and Concentration Intravenous (IV)

Infusion

Solutions RT/L (20° to 25°C)

Stability

Time for Refrigeration (2° to 8°C) 40 mg/mL Amikacin 6 mg/mL NS or D5W 24 hours 7 days 40 mg/mL Ampicillin 1 mg/mL D5W 8 hours 8 hours 40 mg/mL Ampicillin 10 mg/mL D5W 2 hours 8 hours 40 mg/mL Ampicillin 1 mg/mL NS 24 hours 48 hours 40 mg/mL Ampicillin 10 mg/mL NS 8 hours 48 hours 4 mg/mL Ampicillin 40 mg/mL NS 8 hours 8 hours 4 to 40 mg/mL Clindamycin Phosphate 0.25 to 6 mg/mL NS or D5W 24 hours 7 days 4 mg/mL Heparin 10 to 50 units/mL NS or D5W 24 hours 7 days 4 mg/mL Potassium Chloride 10 to 40 mEq/L NS or D5W 24 hours 7 days 4 mg/mL Theophylline 0.8 mg/mL D5W 24 hours 7 days 1 to 4 mg/mL na Aminosyn™II 4.25% with electrolytes and calcium 8 hours 3 days 0.125 to 0.25 mg/mL na Inpersol™ with 4.25% dextrose 24 hours 7 days NS = 0.9% Sodium Chloride Injection. D5W = 5% Dextrose Injection. na = not applicable. RT/L = Ambient room temperature and light. Cefepime for Injection Admixture Incompatibility Do not add solutions of cefepime for injection, to solutions of ampicillin at a concentration greater than 40 mg per mL, or to metronidazole, vancomycin, gentamicin, tobramycin, netilmicin sulfate, or aminophylline because of potential interaction. However, if concurrent therapy with cefepime for injection is indicated, each of these antibacterial drugs can be administered separately.

Intramuscular

Cefepime for Injection Cefepime for injection constituted as directed is stable for 24 hours at controlled room temperature 20°C to 25°C (68°F to 77°F) or for 7 days in a refrigerator 2°C to 8°C (36°F to 46°F) with the following diluents: Sterile Water for Injection, 0.9% Sodium Chloride Injection, 5% Dextrose Injection, Sterile Bacteriostatic Water for Injection with Parabens or Benzyl Alcohol, or 0.5% or 1% Lidocaine Hydrochloride. Intramuscular and Intravenous Cefepime for Injection As with other cephalosporins, the color of cefepime for injection powder, as well as its solutions tend to darken depending on storage conditions; however, when stored as recommended, the product potency is not adversely affected.

2.1 Dosage for Adults The recommended adult dosages and routes of administration are outlined in Table 1 below for patients with creatinine clearance greater than 60 mL/min. Administer cefepime for injection intravenously over approximately 30 minutes.

Table

1: Recommended Dosage Schedule for Cefepime for Injection in Adult Patients with Creatinine Clearance (CrCL)

Greater Than

60mL/min Site and Type of Infection Dose Frequency Duration (days)

Adults

Intravenous (IV)/ Intramuscular (IM) Moderate to Severe Pneumonia § 1 to 2 g IV Every 8 to 12hours 10 Empiric therapy for febrile neutropenic patients 2 g IV Every 8 hours 7* Mild to Moderate Uncomplicated or Complicated Urinary Tract Infections, including pyelonephritis 0.5 to 1 g IV/IM** Every 12 hours 7 to 10 Severe Uncomplicated or Complicated Urinary Tract Infections, including pyelonephritis 2 g IV Every 12 hours 10 Moderate to Severe Uncomplicated Skin and Skin Structure Infections 2 g IV Every 12 hours 10 Complicated Intra-abdominal Infections § (used in combination with metronidazole) 2 g IV Every 8 to 12hours 7 to 10 *or until resolution of neutropenia. In patients whose fever resolves but who remain neutropenic for more than 7 days, the need for continued antimicrobial therapy should be re-evaluated frequently. **Intramuscular route of administration is indicated only for mild to moderate, uncomplicated or complicated UTIs due to E. coli . § For P. aeruginosa , use 2 g IV every 8 hours.

2.2 Pediatric Patients (2 months up to 16 years) The maximum dose for pediatric patients should not exceed the recommended adult dose. The usual recommended dosage in pediatric patients up to 40 kg in weight for durations as given above for adults is: 50 mg per kg per dose, administered every 12 hours for uncomplicated and complicated urinary tract infections (including pyelonephritis), uncomplicated skin and skin structure infections, and pneumonia (see below). For moderate to severe pneumonia due to P. aeruginosa give 50 mg per kg per dose, every 8 hours. 50 mg per kg per dose, every 8 hours for febrile neutropenic patients.

2.3 Dosage Adjustments in Patients with Renal Impairment Adult Patients Adjust the dose of cefepime for injection in patients with creatinine clearance less than or equal to 60 mL/min to compensate for the slower rate of renal elimination. In these patients, the recommended initial dose of cefepime for injection should be the same as in patients with CrCL greater than 60 mL/min except in patients undergoing hemodialysis. The recommended doses of cefepime for injection in patients with renal impairment are presented in Table 2. When only serum creatinine is available, the following formula (Cockcroft and Gault 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 × serum creatinine (mg/dL) Females: 0.85 × above value Table 2: Recommended Dosing Schedule for Cefepime for Injection in Adult Patients With Creatinine Clearance Less Than or Equal to 60 mL/min Creatinine Clearance (mL/min)

Recommended Maintenance Schedule

Greater than 60 500 mg every 12hours 1 g every 12 hours 2 g every 12 hours 2 g every 8 hours 30 to 60 500 mg every 24 hours 1 g every 24 hours 2 g every 24 hours 2 g every 12 hours 11 to 29 500 mg every 24 hours 500 mg every 24 hours 1 g every 24 hours 2 g every 24 hours Less than 11 250 mg every 24 hours 250 mg every 24 hours 500 mg every 24 hours 1 g every 24 hours Continuous Ambulatory Peritoneal Dialysis (CAPD) 500 mg every 48 hours 1 g every 48 hours 2 g every 48 hours 2 g every 48 hours Hemodialysis* 1 g on day 1, then 500 mg every 24 hours thereafter 1 g every 24 hours *On hemodialysis days, cefepime should be administered following hemodialysis. Whenever possible, cefepime should be administered at the same time each day. In patients undergoing Continuous Ambulatory Peritoneal Dialysis (CAPD), cefepime for injection may be administered at the recommended doses at a dosage interval of every 48 hours (see Table 2). In patients undergoing hemodialysis, approximately 68% of the total amount of cefepime present in the body at the start of dialysis will be removed during a 3-hour dialysis period. The dosage of cefepime for injection for hemodialysis patients is 1 g on Day 1 followed by 500 mg every 24 hours for the treatment of all infections except febrile neutropenia, which is 1 g every 24 hours. Cefepime for injection should be administered at the same time each day and following the completion of hemodialysis on hemodialysis days (see Table 2).

Pediatric Patients

Data in pediatric patients with impaired renal function are not available; however, since cefepime pharmacokinetics are similar in adults and pediatric patients [ see Clinical Pharmacology (12.3) ], changes in the dosing regimen proportional to those in adults (see Tables 1 and 2) are recommended for pediatric patients.

Adult Patients

Adjust the dose of cefepime for injection in patients with creatinine clearance less than or equal to 60 mL/min to compensate for the slower rate of renal elimination. In these patients, the recommended initial dose of cefepime for injection should be the same as in patients with CrCL greater than 60 mL/min except in patients undergoing hemodialysis. The recommended doses of cefepime for injection in patients with renal impairment are presented in Table 2. When only serum creatinine is available, the following formula (Cockcroft and Gault 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 × serum creatinine (mg/dL) Females: 0.85 × above value Table 2: Recommended Dosing Schedule for Cefepime for Injection in Adult Patients With Creatinine Clearance Less Than or Equal to 60 mL/min Creatinine Clearance (mL/min)

Recommended Maintenance Schedule

Greater than 60 500 mg every 12hours 1 g every 12 hours 2 g every 12 hours 2 g every 8 hours 30 to 60 500 mg every 24 hours 1 g every 24 hours 2 g every 24 hours 2 g every 12 hours 11 to 29 500 mg every 24 hours 500 mg every 24 hours 1 g every 24 hours 2 g every 24 hours Less than 11 250 mg every 24 hours 250 mg every 24 hours 500 mg every 24 hours 1 g every 24 hours Continuous Ambulatory Peritoneal Dialysis (CAPD) 500 mg every 48 hours 1 g every 48 hours 2 g every 48 hours 2 g every 48 hours Hemodialysis* 1 g on day 1, then 500 mg every 24 hours thereafter 1 g every 24 hours *On hemodialysis days, cefepime should be administered following hemodialysis. Whenever possible, cefepime should be administered at the same time each day. In patients undergoing Continuous Ambulatory Peritoneal Dialysis (CAPD), cefepime for injection may be administered at the recommended doses at a dosage interval of every 48 hours (see Table 2). In patients undergoing hemodialysis, approximately 68% of the total amount of cefepime present in the body at the start of dialysis will be removed during a 3-hour dialysis period. The dosage of cefepime for injection for hemodialysis patients is 1 g on Day 1 followed by 500 mg every 24 hours for the treatment of all infections except febrile neutropenia, which is 1 g every 24 hours. Cefepime for injection should be administered at the same time each day and following the completion of hemodialysis on hemodialysis days (see Table 2).

Pediatric Patients

Data in pediatric patients with impaired renal function are not available; however, since cefepime pharmacokinetics are similar in adults and pediatric patients [ see Clinical Pharmacology (12.3) ], changes in the dosing regimen proportional to those in adults (see Tables 1 and 2) are recommended for pediatric patients.

2.4 Preparation of Cefepime for Injection for Intravenous Infusion Vials Constitute the 1 gram, or 2 grams vial, of cefepime for injection with the one of the following diluents: Sterile Water for Injection 0.9% Sodium Chloride Injection 5% Dextrose Injection 0.5% or 1% Lidocaine Hydrochloride Injection Sterile Bacteriostatic Water for Injection with Parabens or Benzyl Alcohol Dilute the reconstituted solution with one of the following compatible infusion solutions prior to intravenous infusion (Refer to Table 3 below for the amount of diluent to be added to each vial and the amount of the reconstituted solution to be withdrawn): 0.9% Sodium Chloride Injection 5% and 10% Dextrose Injection M/6 Sodium Lactate Injection 5% Dextrose and 0.9% sodium Chloride Injection Lactated Rings and 5% Dextrose Injection Normosol®-R and Normosol®-M in 5% Dextrose Injection Parenteral drugs should be inspected visually for particulate matter before administration. If particulate matter is evident in reconstituted fluids, the drug solution should be discarded. Administer the resulting intravenous infusion over approximately 30 minutes. Intermittent intravenous infusion with a Y-type administration set can be accomplished with compatible solutions. However, during infusion of a solution containing cefepime, it is desirable to discontinue the other solution.

2.5 Preparation of Cefepime for Injection for Intramuscular Administration Constitute cefepime for injection vials 1 gram and 2 grams with one of the following diluents: Sterile Water for Injection, 0.9% Sodium Chloride, 5% Dextrose Injection, 0.5% or 1% Lidocaine Hydrochloride, or Sterile Bacteriostatic Water for Injection with Parabens or Benzyl Alcohol. Refer to Table 3 below for the amount of diluent to be added to each vial and the amount of reconstituted volume to be withdrawn. Parenteral drugs should be inspected visually for particulate matter before administration. If particulate matter is evident in reconstituted fluids, the drug solution should be discarded.

Table

3: Preparation of Reconstituted Solutions of Cefepime for Injection Single-Dose Vials for Intravenous (IV)/Intramuscular (IM)Administration Amount of Diluent to be added (mL)

Approximate Cefepime

Concentration (mg/mL) Amount of Reconstituted Volume to be Withdrawn (mL) Cefepime vial content 1 g (IV) 10 100 10.5 1 g (IM) 2.4 280 3.6 2 g (IV) 10 160 12.5

2.6 Compatibility and Stability Intravenous Cefepime for Injection Intravenous Infusion Compatibility Cefepime for injection vials are compatible at concentrations between 1 mg per mL and 40 mg per mL with the following intravenous infusion fluids: 0.9% Sodium Chloride Injection, 5% and 10% Dextrose Injection, M/6 Sodium Lactate Injection, 5% Dextrose and 0.9% Sodium Chloride Injection, Lactated Ringers and 5% Dextrose Injection, Normosol®-R, and Normosol®-M in 5% Dextrose Injection. These solutions may be stored up to 24 hours at controlled room temperature 20°C to 25°C (68°F to 77°F) or 7 days in a refrigerator 2°C to 8°C (36°F to 46°F).

Admixture Compatibility

Cefepime for injection admixture compatibility information is summarized in Table 4.

Table

4: Cefepime Admixture Stability Cefepime for Injection Concentration Admixture and Concentration Intravenous (IV)

Infusion

Solutions RT/L (20° to 25°C)

Stability

Time for Refrigeration (2° to 8°C) 40 mg/mL Amikacin 6 mg/mL NS or D5W 24 hours 7 days 40 mg/mL Ampicillin 1 mg/mL D5W 8 hours 8 hours 40 mg/mL Ampicillin 10 mg/mL D5W 2 hours 8 hours 40 mg/mL Ampicillin 1 mg/mL NS 24 hours 48 hours 40 mg/mL Ampicillin 10 mg/mL NS 8 hours 48 hours 4 mg/mL Ampicillin 40 mg/mL NS 8 hours 8 hours 4 to 40 mg/mL Clindamycin Phosphate 0.25 to 6 mg/mL NS or D5W 24 hours 7 days 4 mg/mL Heparin 10 to 50 units/mL NS or D5W 24 hours 7 days 4 mg/mL Potassium Chloride 10 to 40 mEq/L NS or D5W 24 hours 7 days 4 mg/mL Theophylline 0.8 mg/mL D5W 24 hours 7 days 1 to 4 mg/mL na Aminosyn™II 4.25% with electrolytes and calcium 8 hours 3 days 0.125 to 0.25 mg/mL na Inpersol™ with 4.25% dextrose 24 hours 7 days NS = 0.9% Sodium Chloride Injection. D5W = 5% Dextrose Injection. na = not applicable. RT/L = Ambient room temperature and light. Cefepime for Injection Admixture Incompatibility Do not add solutions of cefepime for injection, to solutions of ampicillin at a concentration greater than 40 mg per mL, or to metronidazole, vancomycin, gentamicin, tobramycin, netilmicin sulfate, or aminophylline because of potential interaction. However, if concurrent therapy with cefepime for injection is indicated, each of these antibacterial drugs can be administered separately.

Intramuscular

Cefepime for Injection Cefepime for injection constituted as directed is stable for 24 hours at controlled room temperature 20°C to 25°C (68°F to 77°F) or for 7 days in a refrigerator 2°C to 8°C (36°F to 46°F) with the following diluents: Sterile Water for Injection, 0.9% Sodium Chloride Injection, 5% Dextrose Injection, Sterile Bacteriostatic Water for Injection with Parabens or Benzyl Alcohol, or 0.5% or 1% Lidocaine Hydrochloride. Intramuscular and Intravenous Cefepime for Injection As with other cephalosporins, the color of cefepime for injection powder, as well as its solutions tend to darken depending on storage conditions; however, when stored as recommended, the product potency is not adversely affected.

Patients with known immediate hypersensitivity reactions to cefepime or other cephalosporins, penicillins or other beta-lactam antibacterial drugs. ( 4 )

4.1 Hypersensitivity to Cefepime or the Cephalosporin Class of Antibacterials, Penicillins, or Other Beta-lactam Antibacterials Cefepime for Injection and Dextrose Injection is contraindicated in patients who have shown immediate hypersensitivity reactions to cefepime or the cephalosporin class of antibacterial drugs, penicillins or other beta-lactam antibacterials.

4.2 Hypersensitivity to Corn Products Solutions containing dextrose may be contraindicated in patients with hypersensitivity to corn products.

REACTIONS The following adverse reactions are discussed in the Warnings and Precautions section and below: Hypersensitivity Reactions [ see Warnings and Precautions ( 5.1 ) ] Neurotoxicity [ see Warnings and Precautions ( 5.2) ] Clostridioides difficile -Associated Diarrhea [ see Warnings and Precautions (5.3 ) ] The most common adverse reactions (incidence ≥ 1%) were local reactions, positive Coombs' test, decreased phosphorous, increased ALT and AST, increased PT and PTT and rash. ( 6.1 ) At the highest dose (2 g every 8 hours), incidence of adverse reactions was ≥1% for rash, diarrhea, nausea, vomiting, pruritis, fever, and headache. (6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-877-845-0689, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In clinical trials using multiple doses of cefepime, 4137 patients were treated with the recommended dosages of cefepime (500 mg to 2 g intravenous every 12 hours). There were no deaths or permanent disabilities thought related to drug toxicity. Sixty-four (1.5%) patients discontinued medication due to adverse reactions. Thirty-three (51%) of these 64 patients who discontinued therapy did so because of rash. The percentage of cefepime-treated patients who discontinued study drug because of drug-related adverse reactions was similar at daily doses of 500 mg, 1 g, and 2 g every 12 hours (0.8%, 1.1%, and 2%, respectively). However, the incidence of discontinuation due to rash increased with the higher recommended doses. The following adverse reactions (Table 5) were identified in clinical trials conducted in North America (n=3125 cefepime-treated patients).

Table

5: Adverse Reactions in Cefepime Multiple-Dose Dosing Regimens Clinical Trials in North America Incidence equal to or greater than 1% Local adverse reactions (3%), including phlebitis (1.3%), pain and/or inflammation (0.6%)*; rash (1.1%) Incidence less than 1% but greater than 0.1% Colitis (including pseudomembranous colitis), diarrhea, erythema, fever, headache, nausea, oral moniliasis, pruritus, urticaria, vaginitis, vomiting, anemia At the higher dose of 2 g every 8 hours, the incidence of adverse reactions was higher among the 795 patients who received this dose of cefepime. They consisted of rash (4%), diarrhea (3%), nausea (2%), vomiting (1%), pruritus (1%), fever (1%), and headache (1%). The following (Table 6) adverse laboratory changes, with cefepime, were seen during clinical trials conducted in North America.

Table

6: Adverse Laboratory Changes in Cefepime Multiple-Dose Dosing Regimens Clinical Trials in North America Incidence equal to or greater than 1% Positive Coombs' test (without hemolysis) (16.2%); decreased phosphorus (2.8%); increased Alanine Transaminase (ALT) (2.8%), Aspartate Transaminase (AST) (2.4%), eosinophils (1.7%); abnormal PTT (1.6%), Prothrombin Time (PT)(1.4%) Incidence less than 1% but greater than 0.1% Increased alkaline phosphatase, Blood Urea Nitrogen (BUN), calcium, creatinine, phosphorus, potassium, total bilirubin; decreased calcium*, hematocrit, neutrophils, platelets, White Blood Cells (WBC) * Hypocalcemia was more common among elderly patients. Clinical consequences from changes in either calcium or phosphorus were not reported. A similar safety profile was seen in clinical trials of pediatric patients

6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of cefepime for injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. In addition to the adverse reactions reported during the North American clinical trials with cefepime, the following adverse reactions have been reported during worldwide postmarketing experience. Encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, and coma), aphasia, myoclonus, seizures, and nonconvulsive status epilepticus have been reported [ see Warnings and Precautions (5.2 ) ]. Anaphylaxis including anaphylactic shock, transient leukopenia, neutropenia, agranulocytosis and thrombocytopenia, have been reported.

6.3 Cephalosporin-Class Adverse Reactions In addition to the adverse reactions listed above that have been observed in patients treated with cefepime, the following adverse reactions and altered laboratory tests have been reported for cephalosporin-class antibacterial drugs: Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, renal dysfunction, toxic nephropathy, aplastic anemia, hemolytic anemia, hemorrhage, hepatic dysfunction including cholestasis, and pancytopenia.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In clinical trials using multiple doses of cefepime, 4137 patients were treated with the recommended dosages of cefepime (500 mg to 2 g intravenous every 12 hours). There were no deaths or permanent disabilities thought related to drug toxicity. Sixty-four (1.5%) patients discontinued medication due to adverse reactions. Thirty-three (51%) of these 64 patients who discontinued therapy did so because of rash. The percentage of cefepime-treated patients who discontinued study drug because of drug-related adverse reactions was similar at daily doses of 500 mg, 1 g, and 2 g every 12 hours (0.8%, 1.1%, and 2%, respectively). However, the incidence of discontinuation due to rash increased with the higher recommended doses. The following adverse reactions (Table 5) were identified in clinical trials conducted in North America (n=3125 cefepime-treated patients).

Table

5: Adverse Reactions in Cefepime Multiple-Dose Dosing Regimens Clinical Trials in North America Incidence equal to or greater than 1% Local adverse reactions (3%), including phlebitis (1.3%), pain and/or inflammation (0.6%)*; rash (1.1%) Incidence less than 1% but greater than 0.1% Colitis (including pseudomembranous colitis), diarrhea, erythema, fever, headache, nausea, oral moniliasis, pruritus, urticaria, vaginitis, vomiting, anemia At the higher dose of 2 g every 8 hours, the incidence of adverse reactions was higher among the 795 patients who received this dose of cefepime. They consisted of rash (4%), diarrhea (3%), nausea (2%), vomiting (1%), pruritus (1%), fever (1%), and headache (1%). The following (Table 6) adverse laboratory changes, with cefepime, were seen during clinical trials conducted in North America.

Table

6: Adverse Laboratory Changes in Cefepime Multiple-Dose Dosing Regimens Clinical Trials in North America Incidence equal to or greater than 1% Positive Coombs' test (without hemolysis) (16.2%); decreased phosphorus (2.8%); increased Alanine Transaminase (ALT) (2.8%), Aspartate Transaminase (AST) (2.4%), eosinophils (1.7%); abnormal PTT (1.6%), Prothrombin Time (PT)(1.4%) Incidence less than 1% but greater than 0.1% Increased alkaline phosphatase, Blood Urea Nitrogen (BUN), calcium, creatinine, phosphorus, potassium, total bilirubin; decreased calcium*, hematocrit, neutrophils, platelets, White Blood Cells (WBC) * Hypocalcemia was more common among elderly patients. Clinical consequences from changes in either calcium or phosphorus were not reported. A similar safety profile was seen in clinical trials of pediatric patients

6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of cefepime for injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. In addition to the adverse reactions reported during the North American clinical trials with cefepime, the following adverse reactions have been reported during worldwide postmarketing experience. Encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, and coma), aphasia, myoclonus, seizures, and nonconvulsive status epilepticus have been reported [ see Warnings and Precautions (5.2 ) ]. Anaphylaxis including anaphylactic shock, transient leukopenia, neutropenia, agranulocytosis and thrombocytopenia, have been reported.

6.3 Cephalosporin-Class Adverse Reactions In addition to the adverse reactions listed above that have been observed in patients treated with cefepime, the following adverse reactions and altered laboratory tests have been reported for cephalosporin-class antibacterial drugs: Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, renal dysfunction, toxic nephropathy, aplastic anemia, hemolytic anemia, hemorrhage, hepatic dysfunction including cholestasis, and pancytopenia.

AND PRECAUTIONS Hypersensitivity Reactions: Cross-hypersensitivity among beta-lactam antibacterial drugs may occur in up to 10% of patients with a history of penicillin allergy. If an allergic reaction to Cefepime for Injection occurs, discontinue the drug. ( 5.1 ) Neurotoxicity: May occur especially in patients with renal impairment administered unadjusted doses. If neurotoxicity associated with cefepime for injection therapy occurs, discontinue the drug. ( 5.2 ) Clostridioides difficile Associated Diarrhea (CDAD): Evaluate if diarrhea occurs. ( 5.3 )

5.1 Hypersensitivity Reactions Before therapy with cefepime for injection is instituted, careful inquiry should be made to determine whether the patient has had previous immediate hypersensitivity reactions to cefepime, cephalosporins, penicillins, or other beta-lactams. Exercise caution if this product is to be given to penicillin-sensitive patients 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 cefepime for injection occurs, discontinue the drug and institute appropriate supportive measures.

5.2 Neurotoxicity Serious adverse reactions have been reported including life-threatening or fatal occurrences of the following: encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, and coma), aphasia, myoclonus, seizures, and nonconvulsive status epilepticus [ see Adverse Reactions ( 6.2 ) ]. Most cases occurred in patients with renal impairment who did not receive appropriate dosage adjustment. However, some cases of neurotoxicity occurred in patients receiving a dosage adjustment appropriate for their degree of renal impairment. In the majority of cases, symptoms of neurotoxicity were reversible and resolved after discontinuation of cefepime and/or after hemodialysis. If neurotoxicity associated with cefepime therapy occurs, discontinue cefepime and institute appropriate supportive measures.

5.3 Clostridioides difficile Associated Diarrhea Clostridioides difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including cefepime 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.

5.4 Development of Drug-Resistant Bacteria Prescribing cefepime for injection in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. As with other antimicrobials, prolonged use of cefepime for injection may result in overgrowth of nonsusceptible microorganisms. Repeated evaluation of the patient's condition is essential. Should superinfection occur during therapy, appropriate measures should be taken.

5.5 Drug/Laboratory Test Interactions Urinary Glucose The administration of cefepime may result in a false-positive reaction for glucose in the urine when using some methods (e.g. Clinitest™ tablets) [ see Drug Interactions ( 7.1 ) ] . Coombs' Tests Positive direct Coombs' tests have been reported during treatment with cefepime for injection. In patients who develop hemolytic anemia, discontinue the drug and institute appropriate therapy.

Positive

Coombs' test may be observed in newborns whose mothers have received cephalosporin antibacterial drugs before parturition.

Prothrombin Time

Many cephalosporins, including cefepime, have been associated with a fall in prothrombin activity. Those at risk include patients with renal or hepatic impairment, or poor nutritional state, as well as patients receiving a protracted course of antimicrobial therapy. Prothrombin time should be monitored in patients at risk, and exogenous vitamin K administered as indicated.

5.1 Hypersensitivity Reactions Before therapy with cefepime for injection is instituted, careful inquiry should be made to determine whether the patient has had previous immediate hypersensitivity reactions to cefepime, cephalosporins, penicillins, or other beta-lactams. Exercise caution if this product is to be given to penicillin-sensitive patients 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 cefepime for injection occurs, discontinue the drug and institute appropriate supportive measures.

5.2 Neurotoxicity Serious adverse reactions have been reported including life-threatening or fatal occurrences of the following: encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, and coma), aphasia, myoclonus, seizures, and nonconvulsive status epilepticus [ see Adverse Reactions ( 6.2 ) ]. Most cases occurred in patients with renal impairment who did not receive appropriate dosage adjustment. However, some cases of neurotoxicity occurred in patients receiving a dosage adjustment appropriate for their degree of renal impairment. In the majority of cases, symptoms of neurotoxicity were reversible and resolved after discontinuation of cefepime and/or after hemodialysis. If neurotoxicity associated with cefepime therapy occurs, discontinue cefepime and institute appropriate supportive measures.

5.3 Clostridioides difficile Associated Diarrhea Clostridioides difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including cefepime 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.

5.4 Development of Drug-Resistant Bacteria Prescribing cefepime for injection in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. As with other antimicrobials, prolonged use of cefepime for injection may result in overgrowth of nonsusceptible microorganisms. Repeated evaluation of the patient's condition is essential. Should superinfection occur during therapy, appropriate measures should be taken.

5.5 Drug/Laboratory Test Interactions Urinary Glucose The administration of cefepime may result in a false-positive reaction for glucose in the urine when using some methods (e.g. Clinitest™ tablets) [ see Drug Interactions ( 7.1 ) ] . Coombs' Tests Positive direct Coombs' tests have been reported during treatment with cefepime for injection. In patients who develop hemolytic anemia, discontinue the drug and institute appropriate therapy.

Positive

Coombs' test may be observed in newborns whose mothers have received cephalosporin antibacterial drugs before parturition.

Prothrombin Time

Many cephalosporins, including cefepime, have been associated with a fall in prothrombin activity. Those at risk include patients with renal or hepatic impairment, or poor nutritional state, as well as patients receiving a protracted course of antimicrobial therapy. Prothrombin time should be monitored in patients at risk, and exogenous vitamin K administered as indicated.

INTERACTIONS Aminoglycosides: increased potential of nephrotoxicity and ototoxicity. Monitor renal function. ( 7.2 ) Diuretics: nephrotoxicity has been reported following concomitant administration of other cephalosporins with potent diuretics such as furosemide. Monitor renal function. ( 7.3 )

7.1 Drug/Laboratory Test Interactions The administration of cefepime may result in a false-positive reaction for glucose in the urine with certain methods. It is recommended that glucose tests based on enzymatic glucose oxidase reactions be used.

7.2 Aminoglycosides Monitor renal function if aminoglycosides are to be administered with cefepime for injection because of the increased potential of nephrotoxicity and ototoxicity of aminoglycoside antibacterial drugs.

7.3 Diuretics Nephrotoxicity has been reported following concomitant administration of other cephalosporins with potent diuretics such as furosemide. Monitor renal function when cefepime is concomitantly administered with potent diuretics.

7.1 Drug/Laboratory Test Interactions The administration of cefepime may result in a false-positive reaction for glucose in the urine with certain methods. It is recommended that glucose tests based on enzymatic glucose oxidase reactions be used.

7.2 Aminoglycosides Monitor renal function if aminoglycosides are to be administered with cefepime for injection because of the increased potential of nephrotoxicity and ototoxicity of aminoglycoside antibacterial drugs.

7.3 Diuretics Nephrotoxicity has been reported following concomitant administration of other cephalosporins with potent diuretics such as furosemide. Monitor renal function when cefepime is concomitantly administered with potent diuretics.