Cefepime Hydrochloride

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.

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 )

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.

Hypersensitivity reactions : Cross-hypersensitivity may occur in up to 10% of patients with a history of penicillin allergy. If an allergic reaction occurs, discontinue the drug. ( 5.1 ) Neurotoxicity : May occur especially in patients with renal impairment administered unadjusted doses. If neurotoxicity associated with Cefepime for Injection and Dextrose Injection occurs, discontinue the drug. ( 5.2 ) Clostridio ides difficile- associated diarrhea (CDAD): Evaluate if diarrhea occurs. ( 5.3 )

5.1 Hypersensitivity Reactions Before therapy with Cefepime for Injection and Dextrose Injection is instituted, careful inquiry should be made to determine whether the patient has had previous immediate hypersensitivity reactions to cefepime, cephalosporins, penicillins, or other drugs. Exercise caution if this product is to be given to penicillin-sensitive patients because cross-hypersensitivity among beta-lactam antibacterials 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 for Injection and Dextrose Injection 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 Clostridioides difficile -Associated Diarrhea Clostridioides 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 use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial drug treatment of C. difficile , and surgical evaluation should be instituted as clinically indicated.

5.4 Risk of Development of Drug-resistant Bacteria Prescribing Cefepime for Injection and Dextrose Injection in the absence of proven or strongly suspected bacterial infection or a prophylactic indication 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 for Injection and Dextrose Injection 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 with glucose in the urine when using glucose tests based on Benedict’s copper reduction reaction that determine the amount of reducing substances like glucose in the urine. It is recommended that glucose tests based on enzymatic glucose oxidase be used. Coombs’ Test Positive direct Coombs' tests have been reported during treatment with cefepime. In patients who develop hemolytic anemia, discontinue the drug and institute appropriate therapy. Positive Coombs' test may be observed in newborns whose mothers have received cephalosporin antibacterial drugs before parturition. Prothrombin Time Many cephalosporins, including cefepime, have been associated with a fall in prothrombin activity. Those at risk include patients with renal or hepatic impairment, or poor nutritional state, as well as patients receiving a protracted course of antimicrobial therapy. Prothrombin time should be monitored in patients at risk, and exogenous vitamin K administered as indicated.

5.6 Patients with a History of Gastrointestinal Disease Cefepime for Injection and Dextrose Injection should be prescribed with caution in individuals with a history of gastrointestinal disease, particularly colitis.

5.7 Possible Effects of Arginine on Glucose Metabolism Cefepime for Injection and Dextrose Injection contains arginine. Arginine has been shown to alter glucose metabolism and elevate serum potassium transiently when administered at 33 times the amount provided by the maximum recommended human dose of cefepime. The effect of lower doses is not presently known.

5.8 Patients with Overt or Known Subclinical Diabetes Mellitus or Carbohydrate Intolerance As with other dextrose-containing solutions, Cefepime for Injection and Dextrose Injection should be prescribed with caution in patients with overt or known subclinical diabetes mellitus or carbohydrate intolerance for any reason.

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 postapproval use of cefepime. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to readily estimate their frequency or establish a causal relationship to drug exposure. In addition to the adverse reactions reported during the 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) has 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 antibacterials: Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, renal impairment, toxic nephropathy, aplastic anemia, hemolytic anemia, hemorrhage, fall in prothrombin activity, hepatic impairment including cholestasis, and pancytopenia.

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.

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 treatment of serious infections in the pediatric population where the suspected or proven pathogen is Haemophilus influenzae type b. In those patients in whom meningeal seeding from a distant infection site or in whom meningitis is suspected or documented, an alternate agent with demonstrated clinical efficacy in this setting should be used. Cefepime for Injection and Dextrose Injection in the DUPLEX® Container should be used only in pediatric patients who require the entire 1 or 2 gram dose and not any fraction thereof.

8.5 Geriatric Use Of the more than 6400 adults treated with cefepime in clinical studies, 35% were 65 years or older while 16% were 75 years or older. When geriatric patients received the usual recommended adult dose, clinical efficacy and safety were comparable to clinical efficacy and safety in nongeriatric adult patients. Serious adverse reactions have occurred in geriatric patients with renal impairment given unadjusted doses of cefepime, including life-threatening or fatal occurrences of the following: encephalopathy, myoclonus, and seizures [ see Warnings and Precautions (5.2) , Adverse Reactions (6.2) ]. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and renal function should be monitored [see Clinical Pharmacology (12.3) , Warnings and Precautions (5.2) , and Dosage and Administration (2.3) ].

8.6 Renal Impairment 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 [see Dosage Adjustments in Patients with Renal Impairment (2.3) ].

Cefepime is a cephalosporin antibacterial drug [see Microbiology (12.4) ].