Cefepime Hydrochloride

1 INDICATIONS AND USAGE Cefepime for Injection and Dextrose Injection is a cephalosporin antibacterial indicated in 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 ( 1.3 ) Uncomplicated skin and skin structure infections ( 1.4 ) Complicated intra-abdominal infections (used in combination with metronidazole) ( 1.5 ) To reduce the development of drug-resistant bacteria and maintain the effectiveness of Cefepime for Injection and Dextrose Injection and other antibacterial drugs, Cefepime for Injection and Dextrose Injection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. ( 1.6 ) 1.1 Pneumonia Cefepime for Injection and Dextrose Injection is indicated for the treatment of pneumonia (moderate to severe) caused by 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 and Dextrose 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 and Dextrose Injection is indicated for uncomplicated and complicated urinary tract infections (including pyelonephritis) caused by 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 microorganisms. 1.4 Uncomplicated Skin and Skin Structure Infections Cefepime for Injection and Dextrose Injection is indicated in the treatment of uncomplicated skin and skin structure infections caused by Staphylococcus aureus (methicillin-susceptible strains only) or Streptococcus pyogenes . 1.5 Complicated Intra-abdominal Infections Cefepime for Injection and Dextrose Injection is indicated for complicated intra-abdominal infections (used in combination with metronidazole) caused by 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 Dextrose Injection and other antibacterial drugs, Cefepime for Injection and Dextrose 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.

2 DOSAGE AND ADMINISTRATION For intravenous use only administered over approximately 30 minutes. ( 2 ) Use this formulation of cefepime only in adult and pediatric patients who require the entire 1 or 2 gram dose and not any fraction thereof. ( 2.1 , 2.2 ) Recommended Dosing Schedule in Adult Patients with CrCL Greater than 60 mL/min ( 2.1 ) * Site and Type of Infection Dose Frequency Duration (days) Moderate to severe pneumonia For Pseudomonas aeruginosa , use 2 g IV every 8 hours ( 2.1 ) 1 or 2 g IV Every 8-12 hours 10 days Empiric therapy for febrile neutropenic patients 2 g IV Every 8 hours 7 days Or until resolution of neutropenia. ( 2.1 ) Mild to moderate uncomplicated or complicated urinary tract infections 0.5 or 1 g IV Every 12 hours 7–10 days Severe uncomplicated or complicated urinary tract infections 2 g IV Every 12 hours 10 days Moderate to severe uncomplicated skin and skin structure infections 2 g IV Every 12 hours 10 days Complicated intra-abdominal infections (used in combination with metronidazole) 2 g IV Every 8-12 hours 7–10 days Pediatric Patients (2 months to 16 years): Recommended Dosage in pediatric patients 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 ) Patient with Renal Impairment: Adjust dose in patients with CrCl less than or equal to 60 mL/min ( 2.3 ) 2.1 Dosage for Adults Cefepime for Injection and Dextrose Injection in the DUPLEX® Container should be used only in patients who require the entire 1 or 2 gram dose and not any fraction thereof. 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 and Dextrose Injection intravenously over approximately 30 minutes. Table 1: Recommended Dosing Schedule for Cefepime for Injection and Dextrose Injection in Adult Patients with CrCL Greater Than 60 mL/min Site and Type of Infection Dose Frequency Duration (days) Adults Intravenous (IV) Moderate to Severe Pneumonia due to S. pneumoniae , P. aeruginosa For P. aeruginosa , use 2 g IV every 8 hours. , K. pneumoniae , or Enterobacter species 1-2 g IV Every 8 to 12 hours 10 Empiric therapy for febrile neutropenic patients [see Indications and Usage (1) and Clinical Studies (14) ] 2 g IV Every 8 hours 7 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. Mild to Moderate Uncomplicated or Complicated Urinary Tract Infections, including pyelonephritis, due to E. coli , K. pneumoniae , or P. mirabilis 0.5-1 g IV Every 12 hours 7 to 10 Severe Uncomplicated or Complicated Urinary Tract Infections, including pyelonephritis, due to E. coli or K. pneumoniae 2 g IV Every 12 hours 10 Moderate to Severe Uncomplicated Skin and Skin Structure Infections due to S. aureus or S. pyogenes 2 g IV Every 12 hours 10 Complicated Intra-abdominal Infections (used in combination with metronidazole) caused by E. coli , viridans group streptococci, P. aeruginosa , K. pneumoniae , Enterobacter species, or B. fragilis. [see Clinical Studies (14) ] 2 g IV Every 8 to 12 hours 7 to 10 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 for febrile neutropenic patients. 50 mg per kg per dose, every 8 hours for febrile neutropenic patients. Cefepime for Injection and Dextrose Injection in the DUPLEX® Container is designed to deliver a 1 g or 2 g dose of cefepime. To prevent unintentional overdose, this product should not be used in pediatric patients who require less than the full adult dose of cefepime. 2.3 Dosage Adjustments in Patients with Renal Impairment Adult Patients Adjust the dose of Cefepime for Injection and Dextrose 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 and Dextrose 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 and Dextrose Injection in patients with renal impairment are presented in Table 2 . Cefepime for Injection and Dextrose Injection in the DUPLEX® Container should be used only in patients who require the entire 1 or 2 gram dose and not any fraction thereof. When only serum creatinine is available, the following formula (Cockcroft and Gault equation) 1 may be used to estimate creatinine clearance [see References (15) ]. The serum creatinine should represent a steady state of renal function: Males: Creatinine Clearance (mL/min) = Weight (kg) × (140-age) 72 × serum creatinine (mg/dL) Females: 0.85 × above value Table 2: Recommended Dosing Schedule for Cefepime for Injection and Dextrose 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 12 hours 1 g every 12 hours 2 g every 12 hours 2 g every 8 hours 30–60 500 mg every 24 hours 1 g every 24 hours 2 g every 24 hours 2 g every 12 hours 11–29 500 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 On hemodialysis days, Cefepime for Injection and Dextrose Injection should be administered following hemodialysis. Whenever possible, Cefepime for Injection and Dextrose Injection should be administered at the same time each day. 1 g on day 1, then 500 mg every 24 hours thereafter 1 g every 24 hours In patients undergoing Continuous Ambulatory Peritoneal Dialysis (CAPD), Cefepime for Injection and Dextrose Injection may be administered at normally 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 and Dextrose 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 and Dextrose 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 for Use of Cefepime for Injection and Dextrose Injection in DUPLEX® Container This reconstituted solution is for intravenous use only. Do not use plastic containers in series connections. Such use would result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is complete. If administration is controlled by a pumping device, care must be taken to discontinue pumping action before the container runs dry or air embolism may result. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Use only if solution is clear and container and seals are intact. DUPLEX® Container Storage To avoid inadvertent activation, the DUPLEX® Container should remain in the folded position until activation is intended. Patient Labeling and Drug Powder/Diluent Inspection Apply patient-specific label on foil side of container. Use care to avoid activation. Do not cover any portion of foil strip with patient label. Unlatch side tab and unfold DUPLEX® Container (see Diagram 1 ). Visually inspect diluent chamber for particulate matter. Use only if container and seals are intact. To inspect the drug powder for foreign matter or discoloration, peel foil strip from drug chamber (see Diagram 2 ). Protect from light after removal of foil strip. Note: If foil strip is removed, the container should be re-folded and the side tab latched until ready to activate. The product must then be used within 7 days, but not beyond the labeled expiration date. Diagram 1 Diagram 2 Reconstitution (Activation) Do not use directly after storage by refrigeration, allow the product to equilibrate to room temperature before patient use. Unfold the DUPLEX® container and point the set port in a downward direction. Starting at the hanger tab end, fold the DUPLEX® Container just below the diluent meniscus trapping all air above the fold. To activate, squeeze the folded diluent chamber until the seal between the diluent and powder opens, releasing diluent into the drug powder chamber (see Diagram 3 ). Agitate the liquid-powder mixture until the drug powder is completely dissolved. Note: Following reconstitution (activation), product must be used within 12 hours if stored at room temperature or within 5 days if stored under refrigeration. Diagram 3 Administration Visually inspect the reconstituted solution for particulate matter. Point the set port in a downwards direction. Starting at the hanger tab end, fold the DUPLEX® Container just below the solution meniscus trapping all air above the fold. Squeeze the folded DUPLEX® Container until the seal between reconstituted drug solution and set port opens, releasing liquid to set port (see Diagram 4 ). Prior to attaching the IV set, check for minute leaks by squeezing container firmly. If leaks are found, discard container and solution as sterility may be compromised. Using aseptic technique, peel foil cover from the set port and attach sterile administration set (see Diagram 5 ). Refer to directions for use accompanying the administration set. Diagram 4 Diagram 5 Important Administration Instructions Do not use in series connections. Do not introduce additives into the DUPLEX® Container. Administer Cefepime for Injection and Dextrose Injection intravenously over approximately 30 minutes. Discard unused portions of solutions. Intermittent intravenous infusion with a Y-type administration set can be accomplished with compatible solutions. However, during infusion of Cefepime for Injection and Dextrose Injection, it is advisable to discontinue the other solution. Solutions of cefepime should not be added to solutions of ampicillin at a concentration greater than 40 mg/mL, and should not be added to metronidazole, vancomycin, gentamicin, tobramycin, netilimicin sulfate or aminophylline because of potential interaction. However, if concurrent therapy with cefepime is indicated, each of these antibacterials can be administered separately.

6 ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: 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 B. Braun Medical Inc. at 1-800-854-6851 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 the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In clinical trials using multiple doses of cefepime, 4137 patients were treated with the recommended dosages of cefepime (500 mg to 2 g intravenously 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 thought by the investigators to be possibly, probably, or almost certainly related to drug toxicity. Thirty-three (51%) of these sixty-four 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 2.0%, respectively). However, the incidence of discontinuation due to rash increased with the higher recommended doses. The following adverse reactions ( Table 3 ) were identified in clinical trials conducted in North America (n=3125 cefepime-treated patients). Table 3: Adverse Clinical Reactions Cefepime Multiple-dose Dosing Regimens Clinical Trials – North America Incidence equal to or greater than 1% Local adverse reactions (3%), including phlebitis (1.3%), pain and/or inflammation (0.6%) Local reactions, irrespective of relationship to cefepime in those patients who received intravenous infusion (n=3048). ; 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 probably-related adverse reactions was higher among the 795 patients who received this dose of cefepime. Reactions included rash (4%), diarrhea (3%), nausea (2%), vomiting (1%), pruritus (1%), fever (1%), and headache (1%). The following ( Table 4 ) adverse laboratory changes, irrespective of relationship to therapy with cefepime, were seen during clinical trials conducted in North America. Table 4: Adverse Laboratory Changes Cefepime Multiple-dose Dosing Regimens Clinical Trials – 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 Hypocalcemia was more common among elderly patients. Clinical consequences from changes in either calcium or phosphorus were not reported. , hematocrit, neutrophils, platelets, White Blood Cells (WBC) A similar safety profile was seen in clinical trials of pediatric patients. 6.2 Postmarketing Experience The following adverse reactions have been reported during postapproval use of cefepime. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to readily estimate their frequency or establish a causal relationship to drug exposure. 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) has 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 antibacterials: Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, renal impairment, toxic nephropathy, aplastic anemia, hemolytic anemia, hemorrhage, hepatic impairment including cholestasis, and pancytopenia.

12.3 Pharmacokinetics Pharmacokinetic parameters for cefepime in healthy adult male volunteers (n=9) following single 30-minute IV infusions of cefepime 500 mg, 1 g, and 2 g are summarized in Table 5. Elimination of cefepime is principally via renal excretion with an average (±SD) half-life of 2 (±0.3) hours and total body clearance of 120 (±8) mL/min in healthy volunteers. Cefepime pharmacokinetics are linear over the range 250 mg to 2 g. There is no evidence of accumulation in healthy adult male volunteers (n=7) receiving clinically relevant doses for a period of 9 days. Table 5: Mean Pharmacokinetic Parameters for Cefepime (±SD), Intravenous Administration Parameter 500 mg IV 1 g IV 2 g IV C max , mcg/mL 39.1 (3.5) 81.7 (5.1) 163.9 (25.3) AUC, h∙mcg/mL 70.8 (6.7) 148.5 (15.1) 284.8 (30.6) Number of subjects (male) 9 9 9 Distribution The average steady-state volume of distribution of cefepime is 18.0 (±2.0) L. The serum protein binding of cefepime is approximately 20% and is independent of its concentration in serum. Concentrations of cefepime achieved in specific tissues and body fluids are listed in Table 6 . Table 6: Mean Concentrations of Cefepime in Specific Body Fluids (mcg/mL) or Tissues (mcg/g) Tissue or Fluid Dose/Route # of Patients Average Time of Sample Post-Dose (h) Average Concentration Blister Fluid 2 g IV 6 1.5 81.4 mcg/mL Bronchial Mucosa 2 g IV 20 4.8 24.1 mcg/g Sputum 2 g IV 5 4 7.4 mcg/mL Urine 500 mg IV 8 0–4 292 mcg/mL 1 g IV 12 0–4 926 mcg/mL 2 g IV 12 0–4 3120 mcg/mL Bile 2 g IV 26 9.4 17.8 mcg/mL Peritoneal Fluid 2 g IV 19 4.4 18.3 mcg/mL Appendix 2 g IV 31 5.7 5.2 mcg/g Gallbladder 2 g IV 38 8.9 11.9 mcg/g Prostate 2 g IV 5 1 31.5 mcg/g Data suggest that cefepime does cross the inflamed blood-brain barrier. The clinical relevance of these data are uncertain at this time. Metabolism and Excretion Cefepime is metabolized to N-methylpyrrolidine (NMP), which is rapidly converted to the N-oxide (NMP-N-oxide). Urinary recovery of unchanged cefepime accounts for approximately 85% of the administered dose. Less than 1% of the administered dose is recovered from urine as NMP, 6.8% as NMP-N-oxide, and 2.5% as an epimer of cefepime. Because renal excretion is a significant pathway of elimination, patients with renal dysfunction and patients undergoing hemodialysis require dosage adjustment [see Dosage and Administration (2.3) ]. Specific Populations Patients with Renal Impairment Cefepime pharmacokinetics have been investigated in patients with various degrees of renal impairment (n=30). The average half-life in patients requiring hemodialysis was 13.5 (±2.7) hours and in patients requiring continuous peritoneal dialysis was 19 (±2.0) hours. Cefepime total body clearance decreased proportionally with creatinine clearance in patients with abnormal renal function, which serves as the basis for dosage adjustment recommendations in this group of patients [see Dosage and Administration (2.3) ]. Patients with Hepatic Impairment The pharmacokinetics of cefepime were unaltered in patients with hepatic impairment who received a single 1 g dose (n=11). Geriatric Patients Cefepime pharmacokinetics have been investigated in elderly (65 years of age and older) men (n=12) and women (n=12) whose mean (SD) creatinine clearance was 74.0 (±15) mL/min. There appeared to be a decrease in cefepime total body clearance as a function of creatinine clearance. Therefore, dosage administration of cefepime in the elderly should be adjusted as appropriate if the patient's creatinine clearance is 60 mL/min or less [see Dosage and Administration (2.3) ]. Pediatric Patients Cefepime pharmacokinetics have been evaluated in pediatric patients from 2 months to 11 years of age following single and multiple doses on every 8 hours (n=29) and every 12 hours (n=13) schedules. Following a single intravenous dose, total body clearance and the steady-state volume of distribution averaged 3.3 (±1) mL/min/kg and 0.3 (±0.1) L/kg, respectively. The urinary recovery of unchanged cefepime was 60.4 (±30.4)% of the administered dose, and the average renal clearance was 2 (±1.1) mL/min/kg. There were no significant effects of age or gender (25 male vs. 17 female) on total body clearance or volume of distribution, corrected for body weight. No accumulation was seen when cefepime was given at 50 mg per kg every 12 hours (n=13), while C max , AUC, and t 1/2 were increased about 15% at steady state after 50 mg per kg every 8 hours. The exposure to cefepime following a 50 mg per kg intravenous dose in a pediatric patient is comparable to that in an adult treated with a 2 g intravenous dose. The absolute bioavailability of cefepime after an intramuscular dose of 50 mg per kg was 82.3 (±15)% in eight patients.