CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. Cefepime for Injection 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).

PREGNANCY SECTION.

8.1 Pregnancy. Pregnancy Category BThere are no adequate and well-controlled studies of cefepime use in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.Cefepime was not teratogenic or embryocidal when administered during the period of organogenesis to rats at doses up to 1000 mg/kg/day (1.6 times the recommended maximum human dose calculated on body surface area basis) or to mice at doses up to 1200 mg/kg (approximately equal to the recommended maximum human dose calculated on body surface area basis) or to rabbits at dose level of 100 mg/kg (0.3 times the recommended maximum human dose calculated on body surface area basis).

REFERENCES SECTION.

15 REFERENCES. 1.Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976; 16:31-41.. 1.Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976; 16:31-41.

SPL UNCLASSIFIED SECTION.

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.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. No animal carcinogenicity studies have been conducted with cefepime. In chromosomal aberration studies, cefepime was positive for clastogenicity in primary human lymphocytes, but negative in Chinese hamster ovary cells. In other in vitro assays (bacterial and mammalian cell mutation, DNA repair in primary rat hepatocytes, and sister chromatid exchange in human lymphocytes), cefepime was negative for genotoxic effects. Moreover, in vivo assessments of cefepime in mice (2 chromosomal aberration and micronucleus studies) were negative for clastogenicity. No untoward effects on fertility were observed in rats when cefepime was administered subcutaneously at doses up to 1000 mg/kg/day (1.6 times the recommended maximum human dose calculated on body surface area basis).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Cefepime is cephalosporin antibacterial drug [See Microbiology (12.4) ].. 12.2 Pharmacodynamics. Similar to other beta-lactam antimicrobial agents, the time that the unbound plasma concentration of cefepime exceeds the MIC of the infecting organism has been shown to best correlate with efficacy in animal models of infection. However, the pharmacokinetic/pharmacodynamics relationship for cefepime has not been evaluated in patients.. 12.3 Pharmacokinetics. Pharmacokinetic parameters for cefepime in healthy adult male volunteers (n=9) following single 30-minute infusions (IV) of cefepime 500 mg, g, and g are summarized in Table 7. Elimination of cefepime is principally via renal excretion with an average (+-SD) half-life of (+-0.3) hours and total body clearance of 120 (+-8) mL/min in healthy volunteers. Cefepime pharmacokinetics are linear over the range 250 mg to g. There is no evidence of accumulation in healthy adult male volunteers (n=7) receiving clinically relevant doses for period of days.Table 7: Mean Pharmacokinetic Parameters for Cefepime (+-SD), Intravenous AdministrationCefepime for InjectionParameter500 mg IV1 IV2 IVCmax, mcg/mL39.1 (3.5)81.7 (5.1)163.9 (25.3)AUC, homcg/mL70.8 (6.7)148.5 (15.1)284.8 (30.6)Number of subjects999(male)Pharmacokinetic parameters for cefepime following single intramuscular injection are summarized in Table 8. The pharmacokinetics of cefepime are linear over the range of 500 mg to g intramuscularly and do not vary with respect to treatment duration.Table 8: Mean Pharmacokinetic Parameters for Cefepime (+-SD), Intramuscular AdministrationCefepime for InjectionParameter500 mg IM1 IM2 IMCmax, mcg/mL13.9 (3.4)29.6 (4.4)57.5 (9.5)Tmax, h1.4 (0.9)1.6 (0.4)1.5 (0.4)AUC, homcg/mL60 (8)137 (11)262 (23)Number of subjects6612(male)AbsorptionFollowing intramuscular (IM) administration, cefepime is completely absorbed.DistributionThe average steady-state volume of distribution of cefepime is 18 (+-2) L. The serum protein binding of cefepime is approximately 20% and is independent of its concentration in serum.Cefepime is excreted in human milk at concentration of 0.5 mcg/mL. nursing infant consuming approximately 1000 mL of human milk per day would receive approximately 0.5 mg of cefepime per day [see Use in Specific Populations (8.3) ].Concentrations of cefepime achieved in specific tissues and body fluids are listed in Table 9.Table 9: Mean Concentrations of Cefepime in Specific Body Fluids (mcg/mL) or Tissues (mcg/g)Tissue or FluidDose/Route of PatientsMean Time of Sample Post-Dose(h)Mean ConcentrationBlister Fluid2 IV61.581.4 mcg/mLBronchial Mucosa2 IV204.824.1 mcg/gSputum2 IV547.4 mcg/mLUrine500 mg IV80 to 4292 mcg/mL1 IV120 to 4926 mcg/mL2 IV120 to 43120 mcg/mLBile2 IV269.417.8 mcg/mLPeritoneal Fluid2 IV194.418.3 mcg/mLAppendix2 IV315.75.2 mcg/gGallbladder2 IV388.911.9 mcg/gProstate2 IV5131.5 mcg/gData suggest that cefepime does cross the inflamed blood-brain barrier. The clinical relevance of these data is uncertain at this time.Metabolism and ExcretionCefepime is metabolized to N-methylpyrrolidine (NMP) which is rapidly converted to the N-oxide (NMP-N-oxide). Urinary recovery of unchanged cefepime accounts for approximately 85% of the administered dose. Less than 1% of the administered dose is recovered from urine as NMP, 6.8% as NMP-N-oxide, and 2.5% as an epimer of cefepime. Because renal excretion is significant pathway of elimination, patients with renal dysfunction and patients undergoing hemodialysis require dosage adjustment [see Dosage and Administration (2.3) ].Specific PopulationsPatients with Renal impairmentCefepime pharmacokinetics have been investigated in patients with various degrees of renal impairment (n=30). The average half-life in patients requiring hemodialysis was 13.5 (+-2.7) hours and in patients requiring continuous peritoneal dialysis was 19 (+-2) hours. Cefepime total body clearance decreased proportionally with creatinine clearance in patients with abnormal renal function, which serves as the basis for dosage adjustment recommendations in this group of patients [see Dosage and Administration (2.3) ]. Patients with Hepatic impairmentThe pharmacokinetics of cefepime were unaltered in patients with hepatic impairment who received single g dose (n=11).Geriatric patientsCefepime pharmacokinetics have been investigated in elderly (65 years of age and older) men (n=12) and women (n=12) whose mean (SD) creatinine clearance was 74 (+-15) mL/min. There appeared to be decrease in cefepime total body clearance as function of creatinine clearance. Therefore, dosage administration of cefepime in the elderly should be adjusted as appropriate if the patients creatinine clearance is 60 mL/min or less [see Dosage and Administration (2.3) ].Pediatric patientsCefepime pharmacokinetics have been evaluated in pediatric patients from months to 11 years of age following single and multiple doses on every hours (n=29) and every 12 hours (n=13) schedules. Following single intravenous dose, total body clearance and the steady-state volume of distribution averaged 3.3 (+-1) mL/min/kg and 0.3 (+-0.1) L/kg, respectively. The urinary recovery of unchanged cefepime was 60.4 (+-30.4)% of the administered dose, and the average renal clearance was (+-1.1) mL/min/kg. There were no significant effects of age or gender (25 male vs. 17 female) on total body clearance or volume of distribution, corrected for body weight. No accumulation was seen when cefepime was given at 50 mg per kg every 12 hours (n=13), while Cmax, AUC, and 1/2 were increased about 15% at steady state after 50 mg per kg every hours. The exposure to cefepime following 50 mg per kg intravenous dose in pediatric patient is comparable to that in an adult treated with 2 intravenous dose. The absolute bioavailability of cefepime after an intramuscular dose of 50 mg per kg was 82.3 (+-15)% in eight patients.. 12.4 Microbiology. Mechanism of ActionCefepime is bactericidal drug that acts by inhibition of bacterial cell wall synthesis. Cefepime has broad spectrum of in vitro activity that encompasses wide range of Gram-positive and Gram-negative bacteria. Within bacterial cells, the molecular targets of cefepime are the penicillin binding proteins (PBP).Antimicrobial ActivityCefepime has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections as described in the Indications and Usage section (1).Gram-negative Bacteria Enterobacter spp. Escherichia coli Klebsiella pneumoniae Proteus mirabilis Pseudomonas aeruginosa Gram-positive Bacteria Staphylococcus aureus (methicillin-susceptible isolates only) Streptococcus pneumoniae Streptococcus pyogenes Viridans group streptococciThe following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for cefepime against isolates of similar genus or organism group. However, the efficacy of cefepime in treating clinical infections due to these bacteria has not been established in adequate and well-controlled clinical trials.Gram-positive Bacteria Staphylococcus epidermidis (methicillin-susceptible isolates only) Staphylococcus saprophyticus Streptococcus agalactiae NOTE: Most isolates of enterococci, e.g., Enterococcus faecalis, and methicillin-resistant staphylococci are resistant to cefepime.Gram-negative Bacteria Acinetobacter calcoaceticus subsp. lwoffii Citrobacter diversus Citrobacter freundii Enterobacter agglomerans Haemophilus influenzae Hafnia alvei Klebsiella oxytoca Moraxella catarrhalis Morganella morganii Proteus vulgaris Providencia rettgeri Providencia stuartii Serratia marcescens NOTE: Cefepime is inactive against many isolates of Stenotrophomonas maltophilia. Susceptibility TestingFor specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Febrile Neutropenic Patients. The safety and efficacy of empiric cefepime monotherapy of febrile neutropenic patients have been assessed in two multicenter, randomized trials comparing cefepime monotherapy (at dose of g intravenously every hours) to ceftazidime monotherapy (at dose of g intravenously every hours). These studies comprised 317 evaluable patients. Table 10 describes the characteristics of the evaluable patient population.Table 10: Demographics of Evaluable Patients (First Episodes Only)ANC absolute neutrophil count; SBP systolic blood pressureCefepimeCeftazidimeTotal 164153Median age (yr) 56 (range, 18 to 82)55 (range, 16 to 84)Male 86 (52%)85 (56%)Female 78 (48%)68 (44%)Leukemia 65 (40%)52 (34%)Other hematologic malignancies 43 (26%)36 (24%)Solid tumor 54 (33%)56 (37%)Median ANC nadir (cells/microliter) 20 (range, to 500)20 (range, to 500)Median duration of neutropenia (days) (range, to 39)6 (range, to 32)Indwelling venous catheter 97 (59%)86 (56%)Prophylactic antibiotics 62 (38%)64 (42%)Bone marrow graft (5%)7 (5%)SBP less than 90 mm Hg at entry (4%)2 (1%)Table 11 describes the clinical response rates observed. For all outcome measures, cefepime was therapeutically equivalent to ceftazidime.Table 11: Pooled Response Rates for Empiric Therapy of Febrile Neutropenic Patients% ResponseCefepimeCeftazidimeOutcome Measures (n=164)(n=153)Primary episode resolved with no treatment modification, nonew febrile episodes or infection, and oral antibiotics allowedfor completion of treatment5155Primary episode resolved with no treatment modification, nonew febrile episodes or infection and no post-treatment oralantibiotics3439Survival, any treatment modification allowed9397Primary episode resolved with no treatment modification andoral antibiotics allowed for completion of treatment6267Primary episode resolved with no treatment modification and nopost-treatment oral antibiotics4651Insufficient data exist to support the efficacy of cefepime monotherapy in patients at high risk for severe infection (including patients with history of recent bone marrow transplantation, with hypotension at presentation, with an underlying hematologic malignancy, or with severe or prolonged neutropenia). No data are available in patients with septic shock.. 14.2 Complicated Intra-abdominal Infections. Patients hospitalized with complicated intra-abdominal infections participated in randomized, double-blind, multicenter trial comparing the combination of cefepime (2 every 12 hours) plus intravenous metronidazole (500 mg every hours) versus imipenem/cilastatin (500 mg every hours) for maximum duration of 14 days of therapy. The study was designed to demonstrate equivalence of the two therapies. The primary analyses were conducted on the population consisting of those with surgically confirmed complicated infection, at least one pathogen isolated pretreatment, at least days of treatment, and 4 to week follow-up assessment for cured patients. Subjects in the imipenem/cilastatin arm had higher APACHE II scores at baseline. The treatment groups were otherwise generally comparable with regard to their pretreatment characteristics. The overall clinical cure rate among the primary analysis patients was 81% (51 cured/63 evaluable patients) in the cefepime plus metronidazole group and 66% (62/94) in the imipenem/cilastatin group. The observed differences in efficacy may have been due to greater proportion of patients with high APACHE II scores in the imipenem/cilastatin group.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. oGeriatric Use: Serious neurologic adverse reactions have occurred in geriatric patients with renal insufficiency given unadjusted doses of cefepime. (8.5). oGeriatric Use: Serious neurologic adverse reactions have occurred in geriatric patients with renal insufficiency given unadjusted doses of cefepime. (8.5). 8.1 Pregnancy. Pregnancy Category BThere are no adequate and well-controlled studies of cefepime use in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.Cefepime was not teratogenic or embryocidal when administered during the period of organogenesis to rats at doses up to 1000 mg/kg/day (1.6 times the recommended maximum human dose calculated on body surface area basis) or to mice at doses up to 1200 mg/kg (approximately equal to the recommended maximum human dose calculated on body surface area basis) or to rabbits at dose level of 100 mg/kg (0.3 times the recommended maximum human dose calculated on body surface area basis).. 8.2 Labor and Delivery. Cefepime has not been studied for use during labor and delivery. Treatment should only be given if clearly indicated.. 8.3 Nursing Mothers. Cefepime is excreted in human breast milk. Caution should be exercised when cefepime is administered to nursing woman [see Clinical Pharmacology (12.3) ].. 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 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 Pharmacology (12.3) ].Safety and effectiveness in pediatric patients below the age of months have not been established. There are insufficient clinical data to support the use of Cefepime for Injection in pediatric patients for the treatment of serious infections in the pediatric population where the suspected or proven pathogen is H. influenzae type b. In those patients in whom meningeal seeding from distant infection site or in whom meningitis is suspected or documented, an alternate agent with demonstrated clinical efficacy in this setting should be used.. 8.5 Geriatric Use. Of the more than 6400 adults treated with Cefepime for Injection 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 non-geriatric adult patients.Serious adverse events have occurred in geriatric patients with renal insufficiency 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), Dosage and Administration (2.3) ].. 8.6 Renal Impairment 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. [See Dosage Adjustments in Patients with Renal Impairment (2.3).

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. oHypersensitivity Reactions: Cross-hypersensitivity among beta-lactam antibacterial drugs may occur in up to 10% of patients with history of penicillin allergy. If an allergic reaction to Cefepime for Injection occurs, discontinue the drug. (5.1)oNeurotoxicity: May occur especially in patients with renal impairment administered unadjusted doses. If neurotoxicity associated with Cefepime for Injection therapy occurs, discontinue the drug. (5.2)oClostridium difficile Associated Diarrhea (CDAD): Evaluate if diarrhea occurs. (5.3). 5.1 Hypersensitivity Reactions. Before therapy with Cefepime for 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 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 history of penicillin allergy. If an allergic reaction to Cefepime for 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 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 for Injection, 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 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 for Injection in the absence of 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 for Injection may result in overgrowth of nonsusceptible microorganisms. Repeated evaluation of the patients condition is essential. Should superinfection occur during therapy, appropriate measures should be taken.. 5.5 Drug/Laboratory Test Interactions. Urinary GlucoseThe administration of cefepime may result in false-positive reaction for glucose in the urine when using some methods (e.g. Clinitest(TM) tablets) [see Drug Interactions (7.1)]. Coombs TestsPositive direct Coombs tests have been reported during treatment with Cefepime for Injection. 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 antibiotics before parturition.Prothrombin TimeMany cephalosporins, including cefepime, have been associated with fall in prothrombin activity. Those at risk include patients with renal or hepatic impairment, or poor nutritional state, as well as patients receiving protracted course of antimicrobial therapy. Prothrombin time should be monitored in patients at risk, and exogenous vitamin administered as indicated.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following adverse reactions are discussed in the Warnings and Precautions section and below:oHypersensitivity Reactions [see Warnings and Precautions (5.1) ]oNeurotoxicity [see Warnings and Precautions (5.2) ]oClostridium difficile-Associated Diarrhea [see Warnings and Precautions (5.3) ]. oHypersensitivity Reactions [see Warnings and Precautions (5.1) ]. oNeurotoxicity [see Warnings and Precautions (5.2) ]. oClostridium difficile-Associated Diarrhea [see Warnings and Precautions (5.3) ]. oThe 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)oAt the highest dose (2 every hours), incidence of adverse reactions was >=1% for rash, diarrhea, nausea, vomiting, pruritis, fever, and headache. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Apotex Corp. at 1-800-706-5575, 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 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 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, g, and 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 AmericaIncidence 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, anemiaAt the higher dose of g every 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 AmericaIncidence 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 calciumHypocalcemia 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 for Injection. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish 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, 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.

DESCRIPTION SECTION.

11 DESCRIPTION. Cefepime for Injection (cefepime hydrochloride, USP) is 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:Cefepime hydrochloride is white to pale yellow powder. Cefepime hydrochloride contains the equivalent of not less than 825 mcg and not more than 911 mcg of cefepime (C19H24N6O5S2) per mg, calculated on an anhydrous basis. It is highly soluble in water.Cefepime for Injection is supplied for intramuscular or intravenous administration in strengths equivalent to 500 mg, g, and g of cefepime. Cefepime for Injection is 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 to 6. Freshly constituted solutions of Cefepime for Injection will range in color from pale yellow to amber. cefepime-structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. For Pseudomonas aeruginosa, use g IV every 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 InfectionDoseFrequencyDuration (days)Moderate to Severe Pneumonia 1-2 IVEvery 8-12 hours10Empiric Therapy for Febrile Neutropenic Patients2 IVEvery hours7Mild to Moderate Uncomplicated or Complicated Urinary Tract Infections0.5-1 IV/IMEvery 12 hours7-10Severe Uncomplicated or Complicated Urinary Tract Infections2 IVEvery 12 hours10Moderate to Severe Uncomplicated Skin and Skin Structure Infections2 IVEvery 12 hours10Complicated Intra-abdominal Infections (used in combination with metronidazole)2 IVEvery 12 hours7-10Pediatric Patients (2 months to 16 years)Recommended dosage in pediatric with CrCL greater than 60 mL/min. (2.2)oThe usual recommended dosage in pediatric patients is 50 mg per kg per dose administered every 12 hours (every hours for febrile neutropenia). (2.2)oPatients with Renal Impairment: Adjust dose in patients with CrCL less than or equal to 60 mL/min. (2.3). oThe usual recommended dosage in pediatric patients is 50 mg per kg per dose administered every 12 hours (every hours for febrile neutropenia). (2.2). oPatients 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 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 60 mL/minor until resolution of neutropenia. In patients whose fever resolves but who remain neutropenic for more than 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 g IV every hours.Site and Type of InfectionDoseFrequencyDuration(days)AdultsIntravenous (IV)/Intramuscular (IM)Moderate to Severe Pneumonia to g IVEvery to12 hours10Empiric therapy for febrile neutropenic patients2 IVEvery hours7Mild to Moderate Uncomplicated or Complicated Urinary Tract Infections, including pyelonephritis0.5 to gIV/IMEvery 12 hours7 to 10Severe Uncomplicated or Complicated Urinary Tract Infections, including pyelonephritis2 IVEvery 12 hours10Moderate to Severe Uncomplicated Skin and Skin Structure Infections2 IVEvery 12 hours10Complicated Intra-abdominal Infections (used in combination with metronidazole)2 IVEvery to12 hours7 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: o50 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). oFor moderate to severe pneumonia due to P. aeruginosa give 50 mg per kg per dose, every hours.o50 mg per kg per dose, every hours for febrile neutropenic patients.. o50 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). oFor moderate to severe pneumonia due to P. aeruginosa give 50 mg per kg per dose, every hours.. o50 mg per kg per dose, every hours for febrile neutropenic patients.. 2.3 Dosage Adjustments in Patients with Renal Impairment. Adult PatientsAdjust 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 creatinine is available, the following formula (Cockcroft and Gault equation)1 may be used to estimate creatinine clearance. The serum creatinine should represent steady state of renal function:Males: Creatinine Clearance (mL/min) Weight (kg) (140 age) 72 serum creatinine (mg/dL)Females: 0.85 above valueTable 2: Recommended Dosing Schedule for Cefepime for Injection in Adult Patients With Creatinine Clearance Less Than or Equal to 60 mL/minCreatinineClearance (mL/min)Recommended Maintenance ScheduleGreater than 60 500 mg every12 hours1 every12 hours2 every12 hours2 every hours30 to 60500 mgevery 24 hours1 gevery 24 hours2 gevery 24 hours2 gevery 12 hours11 to 29500 mgevery 24 hours500 mgevery 24 hours1 gevery 24 hours2 gevery 24 hoursLess than 11250 mgevery 24 hours250 mgevery 24 hours500 mgevery 24 hours1 gevery 24 hoursContinuous Ambulatory Peritoneal Dialysis (CAPD)500 mgevery 48 hours1 gevery 48 hours2 gevery 48 hours2 gevery 48 hoursHemodialysisOn hemodialysis days, cefepime should be administered following hemodialysis. Whenever possible, cefepime should be administered at the same time each day. g on day 1, then 500 mg every 24 hours thereafter1 gevery 24 hoursIn patients undergoing Continuous Ambulatory Peritoneal Dialysis (CAPD), Cefepime for Injection may be administered at the recommended doses at 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 3-hour dialysis period. The dosage of Cefepime for Injection for hemodialysis patients is g on Day followed by 500 mg every 24 hours for the treatment of all infections except febrile neutropenia, which is g every 24 hours.Cefepime for Injection should be administered at the same time each day and following the completion of hemodialysis on hemodialysis days (see Table 2).Pediatric PatientsData 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 and 2) are recommended for pediatric patients.. 2.4 Preparation of Cefepime for Injection for Intravenous Infusion. oConstitute the 0.5 gram, gram, or grams vial, of Cefepime for Injection with the one of the following diluents: Sterile Water for Injection 0.9% Sodium Chloride Injection 5% Dextrose Injection 0.5% or 1% Lidocaine Hydrochloride Injection Sterile Bacteriostatic Water for Injection with Parabens or Benzyl AlcoholoDilute the reconstituted solution with one of the following compatible infusion solutions prior to intravenous infusion (Refer to Table below for the amount of diluent to be added to each vial and the amount of the reconstituted solution to be withdrawn): 0.9% Sodium Chloride Injection 5% and 10% Dextrose Injection M/6 Sodium Lactate Injection 5% Dextrose and 0.9% sodium Chloride Injection Lactated Rings and 5% Dextrose Injection Normosol(TM)-R and Normosol(TM)-M in 5% Dextrose InjectionoParenteral drugs should be inspected visually for particulate matter before administration. If particulate matter is evident in reconstituted fluids, the drug solution should be discarded.oAdminister the resulting intravenous infusion over approximately 30 minutes.oIntermittent intravenous infusion with Y-type administration set can be accomplished with compatible solutions. However, during infusion of solution containing cefepime, it is desirable to discontinue the other solution.. 2.5 Preparation for Intramuscular Administration. Constitute Cefepime for Injection vials 0.5 gram, gram and grams with one of the following diluents: Sterile Water for Injection, 0.9% Sodium Chloride, 5% Dextrose Injection, 0.5% or 1% Lidocaine Hydrochloride, or Sterile Bacteriostatic Water for Injection with Parabens or Benzyl Alcohol. Refer to Table below for the amount of diluent to be added to each vial and the amount of reconstituted volume to be withdrawn.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.Table 3: Preparation of Reconstituted Solutions of Cefepime for InjectionSingle-Dose Vials for Intravenous (IV)/Intramuscular (IM)AdministrationAmount of Diluentto be added(mL)Approximate Cefepime Concentration (mg/mL)Amount of Reconstituted Volume to be Withdrawn (mL)500 mg (IV)51005500 mg (IM)1.32801.81 (IV)1010010.51 (IM)2.42803.62 (IV)1016012.5. 2.6 Compatibility and Stability. Intravenous Cefepime for InjectionIntravenous Infusion CompatibilityCefepime for Injection vials are compatible at concentrations between mg per mL and 40 mg per mL with the following intravenous infusion fluids: 0.9% Sodium Chloride Injection, 5% and 10% Dextrose Injection, M/6 Sodium Lactate Injection, 5% Dextrose and 0.9% Sodium Chloride Injection, Lactated Ringers and 5% Dextrose Injection, Normosol(TM)-R, and Normosol(TM)-M in 5% Dextrose Injection. These solutions may be stored up to 24 hours at controlled room temperature 20C to 25C (68F to 77F) or days in refrigerator 2C to 8C (36F to 46F).Admixture CompatibilityCefepime for Injection admixture compatibility information is summarized in Table 4.Table 4: Cefepime Admixture StabilityNS 0.9% Sodium Chloride Injection.D5W 5% Dextrose Injection.na not applicable.RT/L Ambient room temperature and light.Stability Time forCefepime for InjectionConcentrationAdmixture andConcentrationIntravenous (IV) InfusionSolutionsRT/L (20 to 25C)Refrigeration(2 to 8C)40 mg/mLAmikacin6 mg/mLNS or D5W24 hours7 days40 mg/mLAmpicillin1 mg/mLD5W8 hours8 hours40 mg/mLAmpicillin10 mg/mLD5W2 hours8 hours40 mg/mLAmpicillin1 mg/mLNS24 hours48 hours40 mg/mLAmpicillin10 mg/mLNS8 hours48 hours4 mg/mLAmpicillin40 mg/mLNS8 hours8 hours4 to 40 mg/mLClindamycinPhosphate0.25 to mg/mLNS or D5W24 hours7 days4 mg/mLHeparin10 to 50 units/mLNS or D5W24 hours7 days4 mg/mLPotassium Chloride10 to 40 mEq/LNS or D5W24 hours7 days4 mg/mLTheophylline0.8 mg/mLD5W24 hours7 days1 to mg/mLnaAminosyn(TM) II4.25% withelectrolytes and calcium8 hours3 days0.125 to0.25 mg/mLnaInpersol(TM)with 4.25% dextrose24 hours7 daysCefepime for Injection Admixture IncompatibilityDo not add solutions of Cefepime for Injection, to solutions of ampicillin at 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 for Injection is indicated, each of these antibiotics can be administered separately.Intramuscular Cefepime for InjectionCefepime for Injection constituted as directed is stable for 24 hours at controlled room temperature 20C to 25C (68F to 77F) or for days in refrigerator 2C to 8C (36F to 46F) with the following diluents: Sterile Water for Injection, 0.9% Sodium Chloride Injection, 5% Dextrose Injection, Sterile Bacteriostatic Water for Injection with Parabens or Benzyl Alcohol, or 0.5% or 1% Lidocaine Hydrochloride.Intramuscular and Intravenous Cefepime for InjectionAs with other cephalosporins, the color of Cefepime for Injection powder, as well as its solutions tend to darken depending on storage conditions; however, when stored as recommended, the product potency is not adversely affected.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Cefepime for Injection is sterile white to pale yellow powder of cefepime in single-dose vials for reconstitution and it is available in the following strengths:o 0.5 gram per vialo g per vialo g per vial. Cefepime for Injection is sterile powder of cefepime in vials for reconstitution, available in the following strengths:o0.5 gram per vial, gram per vial and grams per vial. (3). o0.5 gram per vial, gram per vial and grams per vial. (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. oAminoglycosides: increased potential of nephrotoxicity and ototoxicity. Monitor renal function. (7.2)oDiuretics: nephrotoxicity has been reported following concomitant administration of other cephalosporins with potent diuretics such as furosemide. Monitor renal function. (7.3). oAminoglycosides: increased potential of nephrotoxicity and ototoxicity. Monitor renal function. (7.2). oDiuretics: nephrotoxicity has been reported following concomitant administration of other cephalosporins with potent diuretics such as furosemide. Monitor renal function. (7.3). 7.1Drug/Laboratory Test Interactions The administration of cefepime may result in 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.. 7.2Aminoglycosides 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.. 7.3Diuretics 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.

GERIATRIC USE SECTION.

8.5 Geriatric Use. Of the more than 6400 adults treated with Cefepime for Injection 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 non-geriatric adult patients.Serious adverse events have occurred in geriatric patients with renal insufficiency 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), Dosage and Administration (2.3) ].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. How SuppliedCefepime for injection is supplied as follows: Cefepime for Injection in the dry state, is white to pale yellow powder. Constituted solution of Cefepime for Injection can range in color from pale yellow to amber.Unit of SaleStrengthEachNDC 60505-6144-4 Carton containing 101 gramBased on cefepime activity. NDC 60505-6144-0 VialNDC 60505-6145-4 Carton containing 102 grams NDC 60505-6145-0 VialStorage and HandlingCefepime for injection in the dry state should be stored at 20 to 25 (68 to 77 F) [see USP controlled room temperature.] and protected from light.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Cefepime for Injection is cephalosporin antibacterial indicated for the treatment of the following infections caused by susceptible strains of the designated microorganisms:oPneumonia. (1.1)oEmpiric therapy for febrile neutropenic patients. (1.2)oUncomplicated and complicated urinary tract infections (including pyelonephritis). (1.3)oUncomplicated skin and skin structure infections. (1.4)oComplicated 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 for Injection and other antibacterial drugs, Cefepime for Injection should be used only to treat infections that are proven or strongly suspected to be caused by bacteria. (1.6). oPneumonia. (1.1). oEmpiric therapy for febrile neutropenic patients. (1.2). oUncomplicated and complicated urinary tract infections (including pyelonephritis). (1.3). oUncomplicated skin and skin structure infections. (1.4). oComplicated 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 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 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.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. oCounsel patients that antibacterial drugs including Cefepime for Injection should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Cefepime for Injection is prescribed to treat bacterial infection, tell patients that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Cefepime for Injection or other antibacterial drugs in the future.oDiarrhea is common problem caused by antibacterial drugs, which usually ends when the antibiotic is discontinued. Inform patient that they may develop watery and bloody stools (with or without stomach cramps and fever) during treatment and as late as two or more months after having taken the last dose of the antibiotic. Inform patients that they should contact their physician as soon as possible if this occurs.oAdvise patients of neurological adverse events that could occur with Cefepime for Injection use. Instruct patients or their caregivers to inform their healthcare provider at once of any neurological signs and symptoms, including encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, and coma), aphasia (disturbance of speaking and understanding spoken and written language), myoclonus, seizures and nonconvulsive status epilepticus, for immediate treatment, dosage adjustment, or discontinuation of Cefepime for Injection.Manufactured by:Qilu Pharmaceutical Co., Ltd. High Tech ZoneJinan, 250101, ChinaManufactured for:Apotex Corp.Weston, Florida, USA 33326Code number: 34040006111DNOVAPLUS(R).

LABOR & DELIVERY SECTION.

8.2 Labor and Delivery. Cefepime has not been studied for use during labor and delivery. Treatment should only be given if clearly indicated.

MECHANISM OF ACTION SECTION.

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

MICROBIOLOGY SECTION.

12.4 Microbiology. Mechanism of ActionCefepime is bactericidal drug that acts by inhibition of bacterial cell wall synthesis. Cefepime has broad spectrum of in vitro activity that encompasses wide range of Gram-positive and Gram-negative bacteria. Within bacterial cells, the molecular targets of cefepime are the penicillin binding proteins (PBP).Antimicrobial ActivityCefepime has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections as described in the Indications and Usage section (1).Gram-negative Bacteria Enterobacter spp. Escherichia coli Klebsiella pneumoniae Proteus mirabilis Pseudomonas aeruginosa Gram-positive Bacteria Staphylococcus aureus (methicillin-susceptible isolates only) Streptococcus pneumoniae Streptococcus pyogenes Viridans group streptococciThe following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for cefepime against isolates of similar genus or organism group. However, the efficacy of cefepime in treating clinical infections due to these bacteria has not been established in adequate and well-controlled clinical trials.Gram-positive Bacteria Staphylococcus epidermidis (methicillin-susceptible isolates only) Staphylococcus saprophyticus Streptococcus agalactiae NOTE: Most isolates of enterococci, e.g., Enterococcus faecalis, and methicillin-resistant staphylococci are resistant to cefepime.Gram-negative Bacteria Acinetobacter calcoaceticus subsp. lwoffii Citrobacter diversus Citrobacter freundii Enterobacter agglomerans Haemophilus influenzae Hafnia alvei Klebsiella oxytoca Moraxella catarrhalis Morganella morganii Proteus vulgaris Providencia rettgeri Providencia stuartii Serratia marcescens NOTE: Cefepime is inactive against many isolates of Stenotrophomonas maltophilia. Susceptibility TestingFor specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. No animal carcinogenicity studies have been conducted with cefepime. In chromosomal aberration studies, cefepime was positive for clastogenicity in primary human lymphocytes, but negative in Chinese hamster ovary cells. In other in vitro assays (bacterial and mammalian cell mutation, DNA repair in primary rat hepatocytes, and sister chromatid exchange in human lymphocytes), cefepime was negative for genotoxic effects. Moreover, in vivo assessments of cefepime in mice (2 chromosomal aberration and micronucleus studies) were negative for clastogenicity. No untoward effects on fertility were observed in rats when cefepime was administered subcutaneously at doses up to 1000 mg/kg/day (1.6 times the recommended maximum human dose calculated on body surface area basis).

NURSING MOTHERS SECTION.

8.3 Nursing Mothers. Cefepime is excreted in human breast milk. Caution should be exercised when cefepime is administered to nursing woman [see Clinical Pharmacology (12.3) ].

OVERDOSAGE SECTION.

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) ].

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 1 gram Vial Single-Dose Vial NDC 60505-6144-0Cefepime for Injection, USP1 gram per vialReconstitute before Intramuscular Use.Dilute before Intravenous Infusion.Rx OnlyNOVAPLUS(R) vial-1-gram.

PEDIATRIC USE SECTION.

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 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 Pharmacology (12.3) ].Safety and effectiveness in pediatric patients below the age of months have not been established. There are insufficient clinical data to support the use of Cefepime for Injection in pediatric patients for the treatment of serious infections in the pediatric population where the suspected or proven pathogen is H. influenzae type b. In those patients in whom meningeal seeding from distant infection site or in whom meningitis is suspected or documented, an alternate agent with demonstrated clinical efficacy in this setting should be used.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Similar to other beta-lactam antimicrobial agents, the time that the unbound plasma concentration of cefepime exceeds the MIC of the infecting organism has been shown to best correlate with efficacy in animal models of infection. However, the pharmacokinetic/pharmacodynamics relationship for cefepime has not been evaluated in patients.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Pharmacokinetic parameters for cefepime in healthy adult male volunteers (n=9) following single 30-minute infusions (IV) of cefepime 500 mg, g, and g are summarized in Table 7. Elimination of cefepime is principally via renal excretion with an average (+-SD) half-life of (+-0.3) hours and total body clearance of 120 (+-8) mL/min in healthy volunteers. Cefepime pharmacokinetics are linear over the range 250 mg to g. There is no evidence of accumulation in healthy adult male volunteers (n=7) receiving clinically relevant doses for period of days.Table 7: Mean Pharmacokinetic Parameters for Cefepime (+-SD), Intravenous AdministrationCefepime for InjectionParameter500 mg IV1 IV2 IVCmax, mcg/mL39.1 (3.5)81.7 (5.1)163.9 (25.3)AUC, homcg/mL70.8 (6.7)148.5 (15.1)284.8 (30.6)Number of subjects999(male)Pharmacokinetic parameters for cefepime following single intramuscular injection are summarized in Table 8. The pharmacokinetics of cefepime are linear over the range of 500 mg to g intramuscularly and do not vary with respect to treatment duration.Table 8: Mean Pharmacokinetic Parameters for Cefepime (+-SD), Intramuscular AdministrationCefepime for InjectionParameter500 mg IM1 IM2 IMCmax, mcg/mL13.9 (3.4)29.6 (4.4)57.5 (9.5)Tmax, h1.4 (0.9)1.6 (0.4)1.5 (0.4)AUC, homcg/mL60 (8)137 (11)262 (23)Number of subjects6612(male)AbsorptionFollowing intramuscular (IM) administration, cefepime is completely absorbed.DistributionThe average steady-state volume of distribution of cefepime is 18 (+-2) L. The serum protein binding of cefepime is approximately 20% and is independent of its concentration in serum.Cefepime is excreted in human milk at concentration of 0.5 mcg/mL. nursing infant consuming approximately 1000 mL of human milk per day would receive approximately 0.5 mg of cefepime per day [see Use in Specific Populations (8.3) ].Concentrations of cefepime achieved in specific tissues and body fluids are listed in Table 9.Table 9: Mean Concentrations of Cefepime in Specific Body Fluids (mcg/mL) or Tissues (mcg/g)Tissue or FluidDose/Route of PatientsMean Time of Sample Post-Dose(h)Mean ConcentrationBlister Fluid2 IV61.581.4 mcg/mLBronchial Mucosa2 IV204.824.1 mcg/gSputum2 IV547.4 mcg/mLUrine500 mg IV80 to 4292 mcg/mL1 IV120 to 4926 mcg/mL2 IV120 to 43120 mcg/mLBile2 IV269.417.8 mcg/mLPeritoneal Fluid2 IV194.418.3 mcg/mLAppendix2 IV315.75.2 mcg/gGallbladder2 IV388.911.9 mcg/gProstate2 IV5131.5 mcg/gData suggest that cefepime does cross the inflamed blood-brain barrier. The clinical relevance of these data is uncertain at this time.Metabolism and ExcretionCefepime is metabolized to N-methylpyrrolidine (NMP) which is rapidly converted to the N-oxide (NMP-N-oxide). Urinary recovery of unchanged cefepime accounts for approximately 85% of the administered dose. Less than 1% of the administered dose is recovered from urine as NMP, 6.8% as NMP-N-oxide, and 2.5% as an epimer of cefepime. Because renal excretion is significant pathway of elimination, patients with renal dysfunction and patients undergoing hemodialysis require dosage adjustment [see Dosage and Administration (2.3) ].Specific PopulationsPatients with Renal impairmentCefepime pharmacokinetics have been investigated in patients with various degrees of renal impairment (n=30). The average half-life in patients requiring hemodialysis was 13.5 (+-2.7) hours and in patients requiring continuous peritoneal dialysis was 19 (+-2) hours. Cefepime total body clearance decreased proportionally with creatinine clearance in patients with abnormal renal function, which serves as the basis for dosage adjustment recommendations in this group of patients [see Dosage and Administration (2.3) ]. Patients with Hepatic impairmentThe pharmacokinetics of cefepime were unaltered in patients with hepatic impairment who received single g dose (n=11).Geriatric patientsCefepime pharmacokinetics have been investigated in elderly (65 years of age and older) men (n=12) and women (n=12) whose mean (SD) creatinine clearance was 74 (+-15) mL/min. There appeared to be decrease in cefepime total body clearance as function of creatinine clearance. Therefore, dosage administration of cefepime in the elderly should be adjusted as appropriate if the patients creatinine clearance is 60 mL/min or less [see Dosage and Administration (2.3) ].Pediatric patientsCefepime pharmacokinetics have been evaluated in pediatric patients from months to 11 years of age following single and multiple doses on every hours (n=29) and every 12 hours (n=13) schedules. Following single intravenous dose, total body clearance and the steady-state volume of distribution averaged 3.3 (+-1) mL/min/kg and 0.3 (+-0.1) L/kg, respectively. The urinary recovery of unchanged cefepime was 60.4 (+-30.4)% of the administered dose, and the average renal clearance was (+-1.1) mL/min/kg. There were no significant effects of age or gender (25 male vs. 17 female) on total body clearance or volume of distribution, corrected for body weight. No accumulation was seen when cefepime was given at 50 mg per kg every 12 hours (n=13), while Cmax, AUC, and 1/2 were increased about 15% at steady state after 50 mg per kg every hours. The exposure to cefepime following 50 mg per kg intravenous dose in pediatric patient is comparable to that in an adult treated with 2 intravenous dose. The absolute bioavailability of cefepime after an intramuscular dose of 50 mg per kg was 82.3 (+-15)% in eight patients.