Cefepime Hydrochloride

1 INDICATIONS AND USAGE Cefepime for injection 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 ) 1.1 Pneumonia Cefepime for injection 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 for 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 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 for injection 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 for injection 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 and other antibacterial drugs, cefepime for 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.

1.1 Pneumonia Cefepime for injection 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 for 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 pat …

2 DOSAGE AND ADMINISTRATION 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 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 0.5 to 1 g IV/IM** Every 12 hours 7 to 10 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 to 10 § 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 ) 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 ) 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 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 intravenously over approximately 30 minutes. Table 1: Recommended Dosage Schedule for Cefepime for Injection in Adult Patients with Creatinine Clearance (CrCL) Greater Than 60mL/min Site and Type of Infection Dose Frequency Duration (days) Adults Intravenous (IV)/ Intramuscular (IM) Moderate to Severe Pneumonia § 1 to 2 g IV Every 8 to 12hours 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 12hours 7 to 10 *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. 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. 2.3 Dosage Adjustments in Patients with Renal Impairment Adult Patients Adjust the dose of cefepime for 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 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 in patients with renal impairment are presented in Table 2. When only serum cre …

3 DOSAGE FORMS AND STRENGTHS Cefepime for Injection, USP is a sterile white to pale yellow powder of cefepime in single-dose vials for reconstitution and it is available in the following strengths: 1 gram per vial 2 grams per vial Cefepime for injection is a sterile powder of cefepime in single-dose vials for reconstitution, available in the following strengths: 1 gram per vial and 2 grams per vial. ( 3 )

4 CONTRAINDICATIONS Cefepime for 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 antibacterial drugs. Patients with known immediate hypersensitivity reactions to cefepime or other cephalosporins, penicillins or other beta-lactam antibacterial drugs. ( 4 )

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) ] 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 Hikma Pharmaceuticals USA Inc. at 1-877-845-0689, 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 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 5) were identified in clinical trials conducted in North America (n=3125 cefepime-treated patients). Table 5: 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%)*; 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 6) adverse laboratory changes, with cefepime, were seen during clinical trials conducted in North America. Table 6: 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*, hematocrit, neutrophils, platelets, White Blood Cells (WBC) * Hypocalcemia was more common among elderly patients. Clinical consequences from changes in either calcium or phosphorus were not reported. 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 for 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 th …

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 for 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. Monitor renal function when cefepime is concomitantly administered with potent diuretics.

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 for 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. 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. ( 8.5 ) 8.1 Pregnancy Risk Summary There are no cases of cefepime for injection 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 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 (rats), approximately equal to (mice), and 0.3 times (rabbits) the recommended maximum 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 breast milk at low concentrations (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 the 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 any potential adverse effects on the breastfed child from cefepime for injection or from the underlying maternal condition. Data A pharmacokinetic study was conducted in 9 healthy lactating women to evaluate the concentrations of cefepime in plasma and breast milk following a single intravenous dose of 1000 mg. The mean breast milk concentrations of cefepime during the first 8 hours post-dose were approximately 0.5 mcg/mL and then declined and became undetectable between 12- and 24-hours post-dose. The mean cumulative breast milk excretion of cefepime over 24 hours was 0.01% of the administered dose. The pharmacokinetics of cefepime are similar between lactating and non-lactating women. 8.4 Pediatric Use The safety and effectiveness of cefepime 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 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 …

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

11 DESCRIPTION Cefepime for Injection, USP (cefepime hydrochloride, 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,72-(Z)-(O-methyloxime), monohydrochloride, monohydrate, which corresponds to the following structural formula: Structural formula 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 for intramuscular or intravenous administration in strengths equivalent to 1 g and 2 g of cefepime. Cefepime for Injection, USP is a sterile, dry mixture of cefepime hydrochloride and L-arginine. The L-arginine, at an approximate concentration of 725 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, USP will range in color from pale yellow to amber. Structural formula

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

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Cefepime for injection is supplied as follows: Cefepime for Injection, USP in the dry state, is a white to pale yellow powder. Constituted solution of Cefepime for Injection, USP can range in color from pale yellow to amber. Unit of Sale Strength NDC 0143-9477-10 Carton containing 10 Single-dose Vials 1 gram* NDC 0143-9478-10 Carton containing 10 Single-dose Vials 2 grams* *Based on cefepime activity. Storage and Handling Cefepime for Injection, USP in the dry state should be stored at 20 to 25° C (68 to 77°F) [see USP controlled room temperature] and protected from light.