CEFEPIME

1 INDICATIONS AND USAGE 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.

2 DOSAGE AND ADMINISTRATION 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…

5 WARNINGS 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 occurs, discontinue the drug. ( 5.2 ) Clostridium difficile Associated Diarrhea (CDAD) : Evaluate if diarrhea occurs. ( 5.3 ) 5.1 Hypersensitivity Reactions Before therapy with Cefepime for Injection, USP 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 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 Clostridium difficile Associated Diarrhea Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including cefepime, 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, antibiotic treatment of C. difficile , and surgical evaluation should be instituted as clinically indicated. 5.4 Development of Drug-Resistant Bacteria Prescribing cefepime in the absence of a proven or strongly suspected bacterial infection 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 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 ​TM tablets) [see Drug Interactions (7.1) ] . Coombs’ Tests Positive direct Coombs’ tests have been reported…

4 CONTRAINDICATIONS 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 )

7 DRUG 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 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.

6 ADVERSE 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) ] 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 reliab…