CEFEPIME

Cefepime Injection in Galaxy Container is a sterile, injectable product consisting of Cefepime Hydrochloride, USP, a semi-synthetic, broad spectrum, cephalosporin antibacterial for parenteral administration. The chemical name is 1-[[(6R,7R)-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 Injection in Galaxy Container is a frozen, iso-osmotic, sterile, non-pyrogenic premixed solution supplied for intravenous administration in strengths equivalent to 1 g and 2 g of cefepime [see Dosage and Administration (2) ]. It contains the equivalent of not less than 90 percent and not more than 115 percent of the labeled amount of cefepime (C 19 H 24 N 6 O 5 S 2 ). The solution is intended for intravenous use after thawing to room temperature. The components and dosage formulations are given in the table below: Table 5: Cefepime Injection in Galaxy Containers Premixed Frozen Solution Component Cefepime is present in the formulation as Cefepime Hydrochloride, USP. The amounts of Dextrose Hydrous, USP and L-Arginine, USP are approximate. Function Dosage Formulations 1 g in 50 mL 2 g in 100 mL Cefepime active ingredient 1 g 2 g Dextrose Hydrous, USP osmolality adjuster 1.03 g 2.06 g L-Arginine, USP The pH may have been adjusted with hydrochloric acid and/or additional L-Arginine, USP. The pH is 4.0 – 6.0. pH adjuster 725 mg 1.45 g Hydrochloric Acid pH adjuster As needed As needed Water for Injection, USP vehicle q.s. This is an abbreviation for sufficient quantity. 50 mL q.s. 100 mL Cefepime Injection will range in color from colorless to amber. The plastic container is fabricated from a specially designed multilayer plastic. Solutions are in contact with the polyethylene layer of this container and can leach out certain chemical components of the plastic in very small amounts within the expiration period. The suitability of the plastic has been confirmed in tests in animals according to the USP biological tests for plastic containers, as well as by tissue culture toxicity studies. Structural Formula

Cefepime Injection is a cephalosporin antibacterial indicated in the treatment of the following infections caused by susceptible isolates 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 ); and 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 Injection and other antibacterial drugs, Cefepime 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 Injection is indicated for 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 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) ]. 1.3 Uncomplicated and Complicated Urinary Tract Infections (including pyelonephritis) Cefepime 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 Injection is indicated for uncomplicated skin and skin structure infections caused by Staphylococcus aureus (methicillin-susceptible isolates only) or Streptococcus pyogenes . 1.5 Complicated Intra-abdominal Infections Cefepime 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) ]. 1.6 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of Cefepime Injection and other antibacterial drugs, Cefepime 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.

Recommended Dosage in Adults With Creatinine Clearance (CrCL) Greater Than 60 mL/min ( 2.1 ) Site and Type of Infection (Adults) Dose (IV) Frequency Duration (Days) Moderate to Severe Pneumonia For Pseudomonas aeruginosa , use 2 g IV every 8 hours ( 2.1 ) 1-2 g Every 8-12 hours 10 Empiric therapy for febrile neutropenic patients 2 g Every 8 hours 7 Or until resolution of neutropenia ( 2.1 ) Mild to Moderate Uncomplicated or Complicated Urinary Tract Infections 0.5-1 g Every 12 hours 7-10 Severe Uncomplicated or Complicated Urinary Tract Infections 2 g Every 12 hours 10 Moderate to Severe Uncomplicated Skin and Skin Structure Infections 2 g Every 12 hours 10 Complicated Intra-abdominal Infections (used in combination with metronidazole) 2 g Every 8-12 hours 7-10 • 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 ) • Cefepime Injection in Galaxy Container should be used only in pediatric patients who require the entire 1 gram or 2 gram dose and not any fraction thereof. ( 2.2 ) • Patients with Renal Impairment: Adjust dose in patients with CrCL less than or equal to 60 mL/min. ( 2.3 ) • Administer intravenously over approximately 30 minutes. ( 2.1 ) • Do not force thaw frozen container by immersion in water baths or by microwave irradiation. ( 2.4 ) 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 Injection intravenously over approximately 30 minutes. Table 1: Recommended Dosage Schedule for Cefepime Injection in Adult Patients with Creatinine Clearance (CrCL) Greater Than 60 mL/min Site and Type of Infection Dose Frequency Duration (days) Adults Moderate to Severe Pneumonia due to S. pneumoniae , P. aeruginosa For Pseudomonas aeruginosa , use 2 g IV every 8 hours , K. pneumoniae, or Enterobacter species 1-2 g IV Every 8-12 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 7-10 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 8-12 hours 7-10 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. • 50 mg per kg per dose, every 8 hours for febrile neutropenic patients. Cefepime Injection in Galaxy Container should be used only in pediatric patients who require the entire 1 or 2 g dose and not any fraction thereof. 2.3 Dosage Adjustments in Patients with Renal Impairment Adult Patients Adjust the dose of Cefepime 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 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 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 x serum creatinine (mg/dL) Females: 0.85 x above value Table 2: Recommended Dosing Schedule for Cefepime 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 Injection should be administered following hemodialysis. Whenever possible, Cefepime 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 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 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 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 Table 1 and Table 2 ) are recommended for pediatric patients. 2.4 Directions for Use of Cefepime Injection in Galaxy Container Cefepime Injection in Galaxy Container is for intravenous administration using sterile equipment after thawing to room temperature. Thawing of Plastic Container Thaw frozen container at room temperature 25°C (77°F) or under refrigeration 5°C (41°F). Do not force thaw by immersion in water baths or by microwave irradiation. [See How Supplied/Storage and Handling (16) .] Check for minute leaks by squeezing container firmly. If leaks are detected, discard solution as sterility may be impaired. Do not add supplementary medication. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Visually inspect the container. If the outlet port protector is damaged, detached, or not present, discard container as solution path sterility may be impaired. Components of the solution may precipitate in the frozen state and will dissolve upon reaching room temperature with little or no agitation. Potency is not affected. Agitate after solution has reached room temperature. If after visual inspection the solution remains cloudy or if an insoluble precipitate is noted or if any seals are not intact, the container should be discarded. Caution: Do not use plastic containers in series connections. Such use could 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. Preparation for intravenous administration. 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. Cefepime Injection should be administered intravenously over approximately 30 minutes. Intermittent intravenous infusion with a Y-type administration set can be accomplished with compatible solutions. However, during infusion of Cefepime Injection, it is desirable to discontinue the other solution. Solutions of cefepime, like those of most beta-lactam antibacterial drugs, should not be added to solutions of ampicillin at a concentration greater than 40 mg per mL, and should not be added to metronidazole, vancomycin, gentamicin, tobramycin, netilmicin sulfate or aminophylline because of potential interaction. However, if concurrent therapy with cefepime is indicated, each of these antibacterials can be administered separately. As with other cephalosporins, the color of Cefepime Injection tend to darken depending on storage conditions; however, when stored as recommended, the product potency is not adversely affected.

Cefepime Injection is contraindicated in patients who have shown immediate hypersensitivity reactions to cefepime or the cephalosporin class of antibacterials, penicillins or other beta-lactam antibacterial drugs. Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products. • Prior immediate hypersensitivity reactions to cefepime or the cephalosporin class of antibacterial drugs, penicillins, and other beta-lactam antibacterial drugs. ( 4 )

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 Baxter at 1-866-888-2472 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. 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 3 ) were identified in clinical trials conducted in North America (n=3125 cefepime-treated patients). Table 3: 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%) 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 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 4 ) adverse laboratory changes with cefepime, were seen during clinical trials conducted in North America. Table 4: 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 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 identified during post-approval use of Cefepime 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 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: Kounis syndrome, Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, renal dysfunction, toxic nephropathy, aplastic anemia, hemolytic anemia, hemorrhage, fall in prothrombin activity, hepatic dysfunction including cholestasis, and pancytopenia.

• Aminoglycosides -- increased potential of nephrotoxicity and ototoxicity. ( 7.2 ) • Diuretics -- nephrotoxicity has been reported following concomitant administration of other cephalosporins with potent diuretics such as furosemide. ( 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 [see Warning and Precautions (5.5)] . 7.2 Aminoglycosides Renal function should be monitored carefully if high doses of aminoglycosides are to be administered with Cefepime 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.