CEFEPIME HYDROCHLORIDE AND DEXTROSE

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 neutro …

3 DOSAGE FORMS AND STRENGTHS Dual-chamber, single-dose container: 1 g cefepime for injection USP and 50 mL of 5% dextrose injection USP 2 g cefepime for injection USP and 50 mL of 5% dextrose injection USP Injection: 1 g in 50 mL and 2 g in 50 mL in a DUPLEX® Container ( 3 )

4 CONTRAINDICATIONS 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.

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 1-833-425-1464 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 pos …

7 DRUG INTERACTIONS Aminoglycosides: Increased potential of nephrotoxicity and ototoxicity. ( 7.2 ) Diuretics: Nephrotoxicity has been reported with concomitant administration of cephalosporins with potent diuretics such as furosemide. Monitor renal function. ( 7.3 ) 7.1 Drug/Laboratory Test Interactions The administration of Cefepime for Injection and Dextrose Injection 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 and Dextrose Injection because of the increased potential of nephrotoxicity and ototoxicity of aminoglycoside antibacterials. 7.3 Diuretics Nephrotoxicity has been reported following concomitant administration of cephalosporins with potent diuretics such as furosemide. Monitor renal function when cefepime is concomitantly administered with potent diuretics.

8 USE IN SPECIFIC POPULATIONS Geriatric Use: Serious neurologic adverse reactions have occurred in geriatric patients with renal insufficiency given unadjusted doses of cefepime ( 5.2 , 8.5 ) Pediatric use: Safety and efficacy have not been established in patients less than 2 months of age or for use in any pediatric patients with complicated intra-abdominal infections. ( 8.4 ) 8.1 Pregnancy Risk Summary There are no cases of cefepime exposure during pregnancy reported from postmarketing experience or from clinical trials. Available data from published observational studies and case reports over several decades with cephalosporin use in pregnant women have not established drug-associated risks of major birth defects, miscarriage or adverse maternal or fetal outcomes (see Data ). Cefepime crosses the placenta. Cefepime was not associated with adverse developmental outcomes in rats, mice, or rabbits when administered parenterally during organogenesis. The doses used in these studies were 1.6 times (rats), approximately equal to (mice) and 0.3 times (rabbits) the maximum recommended human dose ( see Data ). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Human Data While available studies cannot definitively establish the absence of risk, published data from case-control studies and case reports over several decades have not identified an association with cephalosporin use during pregnancy and major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Available studies have methodologic limitations, including small sample size, retrospective data collection, and inconsistent comparator groups. Animal Data Cefepime was not embryocidal and did not cause fetal malformations when administered parenterally during the period of organogenesis to rats at doses up to 1000 mg/kg/day, to mice at doses up to 1200 mg/kg/day, or to rabbits at doses up to 100 mg/kg/day. These doses are 1.6 times (rats), approximately equal to (mice), and 0.3 times (rabbits) the maximum recommended clinical dose based on body surface area. 8.2 Lactation Risk Summary Cefepime is present in human milk at low concentration (approximately 0.5 mcg/mL), following a single intravenous dose of 1000 mg. A nursing infant consuming approximately 1000 mL of human milk per day would receive approximately 0.5 mg of cefepime per day ( see Data) . There is no information regarding effects of cefepime on the breastfed infant or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for cefepime for injection and dextrose injection and any potential adverse effects on the breastfed child from cefepime for injection and dextrose injection or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of Cefepime for Injection and Dextrose Injection in the treatment of uncomplicated and complicated urinary tract infections (including pyelonephritis), uncomplicated skin and skin structure infections, pneumonia, and as empiric therapy for febrile neutropenic patients have been established in the age groups 2 months up to 16 years. Use of Cefepime for Injection and Dextrose Injection in these age groups is supported by evidence from adequate and well-controlled studies of cefepime in adults with additional pharmacokinetic and safety data from pediatric trials [see Clinical Pharmacology (12.3) ]. Safety and effectiveness in pediatric patients below the age of 2 months have not been established. There are insufficient clinical data to support the use of Cefepime for Injection and Dextrose Injection in pediatric patients for the treatme …

12.1 Mechanism of Action Cefepime is a cephalosporin antibacterial drug [see Microbiology (12.4) ].

11 DESCRIPTION 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. Structural Formula Structural Formula

10 OVERDOSAGE Patients who receive an overdose should be carefully observed and given supportive treatment. In the presence of renal impairment, hemodialysis, not peritoneal dialysis, is recommended to aid in the removal of cefepime from the body. Accidental overdosing has occurred when large doses were given to patients with impaired renal function. Symptoms of overdose include encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, and coma), myoclonus, seizures, nonconvulsive status epilepticus, and neuromuscular excitability [see Warnings and Precautions (5.2) , Adverse Reactions (6.2) , and Dosage and Administration (2.3 )].

16 HOW SUPPLIED/STORAGE AND HANDLING Cefepime for Injection USP and Dextrose Injection USP in the DUPLEX® Container is a flexible dual chamber container supplied in two strengths, 1 and 2 g cefepime. The diluent chamber contains approximately 50 mL of 5% Dextrose Injection. Cefepime for Injection USP and Dextrose Injection USP is supplied sterile and nonpyrogenic in the DUPLEX Container packaged 24 single-dose units per case. NDC REF Dose Volume 0264-3193-11 3193-11 1 g 50 mL 0264-3195-11 3195-11 2 g 50 mL Store the unactivated unit at 20–25°C (68–77°F). Excursions permitted to 15–30°C (59–86°F). [See USP Controlled Room Temperature.] Do not freeze. Not made with natural rubber latex, PVC or Di(2-ethylhexyl)phthalate (DEHP). As with other cephalosporins, reconstituted Cefepime for Injection USP and Dextrose Injection USP tends to darken depending on storage conditions, within the stated recommendations. However, product potency is not adversely affected. Use only if prepared solution is clear and free from particulate matter.