CEFEPIME

Cefepime for Injection, Pharmacy Bulk Package bag SmartPak® should not be used in patients who require less than a 500 mg dose of cefepime. Cefepime for Injection, USP is a semi-synthetic, 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: BEFORE ADMINISTRATION, THIS PHARMACY BULK PACKAGE REQUIRES CONSTITUTION USING STERILE WATER FOR INJECTION, USP TO A CONCENTRATION OF 100 MG PER ML AND FURTHER DILUTION IN 50 ML OF A COMPATIBLE SOLUTION AND INFUSED INTRAVENOUSLY. 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 is supplied in a SmartPak ® pharmacy bulk package containing the equivalent of 100 grams of cefepime. Cefepime for Injection is a sterile, dry mixture of cefepime hydrochloride and L-arginine. The L-arginine, at an approximate concentration of 707 mg/g of cefepime, is added to control the pH of the constituted solution at 4 to 6. Freshly constituted solutions of Cefepime for Injection will range in color from pale yellow to amber. Each SmartPak ® Pharmacy Bulk Package contains sterile Cefepime Hydrochloride, USP, equivalent to 100 grams of cefepime and is intended for intravenous infusion only. Its L-arginine content is approximately 70.7 grams. A Pharmacy Bulk Package is a container of a sterile preparation for parenteral use that contains many single doses. The contents are intended for use in a pharmacy admixture service and are restricted to the preparation of admixtures for intravenous infusion. FURTHER DILUTION IS REQUIRED BEFORE USE. CONSTITUTED BULK SOLUTION SHOULD NOT BE USED FOR DIRECT INFUSION.

Cefepime for Injection, USP 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 ) To reduce the development of drug-resistant bacteria and maintain the effectiveness of cefepime and other antibacterial drugs, cefepime should be used only to treat infections that are proven or strongly suspected to be caused by bacteria. ( 1.6 ) 1.1 Pneumonia Cefepime 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 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 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 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 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, USP and other antibacterial drugs, Cefepime for Injection, USP should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

THE INTENT OF THIS PHARMACY BULK PACKAGE IS FOR THE PREPARATION OF SOLUTIONS FOR INTRAVENOUS INFUSION ONLY. BEFORE ADMINISTRATION, THIS PHARMACY BULK PACKAGE REQUIRES RECONSTITUTION TO A CONCENTRATION OF 100 mg/mL AND FURTHER DILUTION IN 50 mL OF A COMPATIBLE SOLUTION. THIS IS A PHARMACY BULK PACKAGE – NOT FOR DIRECT INJECTION For intravenous use only over approximately 30 minutes ( 2 ) THIS IS A PHARMACY BULK PACKAGE - NOT FOR DIRECT INJECTION. Cefepime for Injection, Pharmacy Bulk Package bag SmartPak should not be used in patients who require less than a 500 mg dose of cefepime. § 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 ) 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 to12 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 to10 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 to10 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 ) 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 Cefepime for Injection, Pharmacy Bulk Package bag SmartPak® should not be used in patients who require less than a 500 mg dose of cefepime. The recommended adult dosages and routes of administration are outlined Table 1 below for patients with creatinine clearance greater than 60 mL/min. Administer Cefepime for Injection, USP intravenously over approximately 30 minutes. Table 1: Recommended Dosage Schedule for Cefepime for Injection, USP in Adult Patients with Creatinine Clearance (CrCL) Greater Than 60 mL/minute *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. Site and Type of Infection Dose Frequency Duration (days) Adults Intravenous (IV) 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, 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 12 hours 7 to 10 Cefepime for Injection, Pharmacy Bulk Package bag SmartPak® should not be used in patients who require less than a 500 mg dose of cefepime. 2.2 Pediatric Patients (2 months up to 16 years) Cefepime for Injection, Pharmacy Bulk Package bag SmartPak® should not be used in patients who require less than a 500 mg dose of cefepime. 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 Cefepime for Injection, Pharmacy Bulk Package bag SmartPak® should not be used in patients who require less than a 500 mg dose of cefepime. Adult Patients Adjust the dose of cefepime 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 should be the same as in patients with CrCL greater than 60 mL/min except in patients undergoing hemodialysis. The recommended doses of cefepime 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, USP 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 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 On hemodialysis days, cefepime should be administered following hemodialysis. Whenever possible, cefepime 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 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 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 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, USP, Pharmacy Bulk Package bags, SmartPak ® Cefepime for Injection, Pharmacy Bulk Package bag SmartPak® should not be used in patients who require less than a 500 mg dose of cefepime. Directions for Proper Use of a Pharmacy Bulk Package NOT FOR DIRECT INFUSION . The Pharmacy Bulk Package is for use in the hospital pharmacy admixture service only in a suitable work area, such as a laminar flow hood. Using aseptic technique, the container closure may be penetrated only one time after constitution using a suitable sterile dispensing set or transfer device that allows measured dispensing of the contents. Use of a syringe and needle is not recommended as it may cause leakage. The withdrawal of the container contents should be accomplished without delay. However, should this not be possible, a maximum time of 4 HOURS from initial reconstitution port closure entry is permitted to complete fluid transfer operations. This time limit should begin with the introduction of the solvent or diluent into the Pharmacy Bulk Package. Discard any unused portion after 4 HOURS . This pharmacy bulk package is not intended to be dispensed as a unit. PRIOR TO CONSTITUTION: DO NOT USE THE INNER BAG IF PARTICULATE OR FOREIGN MATTER IS PRESENT, IF THE SEALS ARE NOT INTACT, OR IF THERE IS ANY OTHER DAMAGE TO THE BAG. IN SUCH CASE, DISCARD THE BAG IMMEDIATELY. After initial reconstitution port entry, use entire contents of the Pharmacy Bulk Package promptly. Any unused portion must be discarded after 4 HOURS . INSTRUCTION FOR CONSTITUTION OF THE PHARMACY BULK PACKAGE BAG SmartPak ® The entire contents of the bag and the preparation process (constitution and dilution) should be completed within 4 hours of initial entry. Document the date and time constitution starts in the designated place on the container label. The entire contents of the bag must be used within 4 hours from the time of initial entry. Remove the translucent unthreaded cap from the reconstitution (smaller) port, and discard it. Constitute the powder through the reconstitution (smaller) port, using Sterile Water for Injection according to Table 3 below. Table 3: Constitution Table SmartPak ® Bag Size Amount of Sterile Water Approximate Concentration 100 grams 875 mL 100 mg/mL ( 1gram/10 mL) After constitution is complete, remove the transfer needle from the reconstitution port. Place the bag on a flat surface of a laminar flow hood and mix for at least 15 minutes by rocking gently from side to side. CAUTION: To avoid possible leakage caused by the heavy weight of the added water, do not shake vigorously or pull strongly on the bag. When foam dissipates, visually inspect the bag to verify the solution is clear, pale yellow to amber and free of particulate matter. DO NOT USE THE INNER BAG IF PARTICULATE OR FOREIGN MATTER IS PRESENT. Unscrew the clear threaded cap from the transfer (larger) port and discard it. Attach sterile tubing and filling adapter unit to the transfer port. Constituted solution can now be transferred using the transfer port and the filling adapter. It should be noted that the spike placed into the transfer port of the Pharmacy Bulk Package SmartPak ® is NEVER removed during this procedure and that the reconstitution port is self-sealing. Dilution Hang the bag from two eyelets. Following constitution, transfer 10 mL of the constituted solution into transfusion bags, each containing 50 mL of one of the compatible solutions below. Compatible solutions for dilution are the following: Sodium Chloride Injection, USP 5% Dextrose Injection, USP Dilution should be completed within the 4 hour preparation process. When diluted according to the instructions above, cefepime is stable for 24 hours at 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). Important Administration Instructions 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 diluted 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. Do not add solutions of cefepime, 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 is indicated, each of these antibiotics can be administered separately.

Cefepime for Injection, USP is contraindicated in patients who have shown immediate hypersensitivity reactions to cefepime or the cephalosporin class of antibiotics, penicillins or other beta-lactam antibiotics. Patients with known immediate hypersensitivity reactions to cefepime or other cephalosporins, penicillins or other beta-lactam antibacterial drugs. ( 4 )

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) ] Clostridium 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, pruritus, fever, and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Samson Medical Technologies, L.L.C. at 1-877-418-3600 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 very 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 events ( Table 4 ) were identified in clinical trials conducted in North America (n=3125 cefepime-treated patients). Table 4: Adverse Reactions 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 events 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 5 ) adverse laboratory changes, with cefepime, were seen during clinical trials conducted in North America. Table 5: 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. 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 in 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.

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 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.