NDC 66794-209 Cefepime

Cefepime

NDC Product Code 66794-209

NDC Product Information

Cefepime with NDC 66794-209 is a a human prescription drug product labeled by Piramal Critical Care Inc.. The generic name of Cefepime is cefepime. The product's dosage form is injection, powder, lyophilized, for solution and is administered via intramuscular; intravenous form.

Labeler Name: Piramal Critical Care Inc.

Dosage Form: Injection, Powder, Lyophilized, For Solution - A dosage form intended for the solution prepared by lyophilization ("freeze drying"), a process which involves the removal of water from products in the frozen state at extremely low pressures; this is intended for subsequent addition of liquid to create a solution that conforms in all respects to the requirements for Injections.

Product Type: Human Prescription Drug Additional informationCallout TooltipWhat kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.


Cefepime Active Ingredient(s)

Additional informationCallout TooltipWhat is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • CEFEPIME HYDROCHLORIDE 10 g/10g

Inactive Ingredient(s)

Additional informationCallout TooltipAbout the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • N2-(4-FLUOROBENZOYL)-L-ARGININE (UNII: NN7Q1D14KA)

Administration Route(s)

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The translation of the route code submitted by the firm, indicating route of administration.

  • Intramuscular - Administration within a muscle.
  • Intravenous - Administration within or into a vein or veins.

Pharmacological Class(es)

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These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Cephalosporin Antibacterial - [EPC] (Established Pharmacologic Class)
  • Cephalosporins - [CS]

Product Labeler Information

Additional informationCallout TooltipWhat is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Piramal Critical Care Inc.
Labeler Code: 66794
FDA Application Number: ANDA091048 Additional informationCallout TooltipWhat is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: ANDA - A product marketed under an approved Abbreviated New Drug Application. Additional informationCallout TooltipWhat is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 02-25-2019 Additional informationCallout TooltipWhat is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2020 Additional informationCallout TooltipWhat is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N Additional informationCallout TooltipWhat is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA’s requests for correction to deficient or non-compliant submissions. Values = ‘Y’ or ‘N’.

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Cefepime Product Label Images

Cefepime Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

1 Indications And Usage

1.1 PneumoniaCefepime 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 PatientsCefepime 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 InfectionsCefepime 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 UsageTo 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.

2 Dosage And Administration

  • 2.1 Dosage for AdultsThe 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 60 mL/minSite and Type of InfectionDoseFrequencyDuration (days)AdultsIntravenous (IV)/Intramuscular (IM)Moderate to Severe Pneumonia
  • §1 to 2 g IVEvery 8 to 12 hours10Empiric therapy for febrile neutropenic patients2 g IVEvery 8 hours7*Mild to Moderate Uncomplicated or Complicated Urinary Tract Infections, including pyelonephritis0.5 to 1 g IV/IM**Every 12 hours7 to 10Severe Uncomplicated or Complicated Urinary Tract Infections, including pyelonephritis2 g IVEvery 12 hours10Moderate to Severe Uncomplicated Skin and Skin Structure Infections2 g IVEvery 12 hours10Complicated Intra-abdominal Infections
  • § (used in combination with metronidazole)
  • 2 g IVEvery 8 to 12 hours7 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 Adjustment in Patients with Renal ImpairmentAdult 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 a steady state of renal function:
  • Females: 0.85 x above valueTable 2: Recommended Dosing Schedule for Cefepime for Injection in Adult Patients with Creatinine Clearance Less Than or Equal to 60 mL/minCreatinine Clearance (mL/min)Recommended Maintenance ScheduleGreater than 60500 mg every 12 hours1 g every 12 hours2 g every 12 hours2 g every 8 hours30 to 60500 mg every 24 hours1 g every 24 hours2 g every 24 hours2 g every 12 hours11 to 29500 mg every 24 hours500 mg every 24 hours1 g every 24 hours2 g every 24 hoursLess than 11250 mg every 24 hours250 mg every 24 hours500 mg every 24 hours1 g every 24 hoursContinuous Ambulatory
  • Peritoneal Dialysis (CAPD)
  • 500 mg every 48 hours1 g every 48 hours2 g every 48 hours2 g every 48 hoursHemodialysis*1 g on day 1, then 500 mg every 24 hours thereafter1 g every 24 hours* On hemodialysis days, cefepime should be administered following hemodialysis. Whenever possible, cefepime should be administered at the same time each day.In patients undergoing Continuous Ambulatory Peritoneal Dialysis (CAPD), cefepime for injection may be administered at the recommended doses at a 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 a 3-hour dialysis period. The dosage of cefepime for injection for hemodialysis patients is 1 g on Day 1 followed by 500 mg every 24 hours for the treatment of all infections except febrile neutropenia, which is 1 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 1 and 2) are recommended for pediatric patients.
  • 2.4 Preparation of Cefepime for Injection for Intravenous InfusionVialsConstitute the 1 gram or 2 grams vial, of cefepime for injection with the one of the following diluents:Sterile Water for Injection0.9% Sodium Chloride Injection5% Dextrose Injection0.5% or 1% Lidocaine Hydrochloride InjectionSterile Bacteriostatic Water for Injection with Parabens or Benzyl AlcoholDilute the reconstituted solution with one of the following compatible infusion solutions prior to intravenous infusion (Refer to Table 3 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 Injection5% and 10% Dextrose InjectionM/6 Sodium Lactate Injection5% Dextrose and 0.9% sodium Chloride InjectionLactated Ringers and 5% Dextrose InjectionNormosol™-R and Normosol™-M in 5% Dextrose InjectionParenteral drugs should be inspected visually for particulate matter before administration. If particulate matter is evident in reconstituted fluids, the drug solution should be discarded.Administer the resulting intravenous infusion over approximately 30 minutes.Intermittent intravenous infusion with a Y-type administration set can be accomplished with compatible solutions. However, during infusion of a solution containing cefepime, it is desirable to discontinue the other solution.2.5 Preparation for Intramuscular AdministrationConstitute cefepime for injection vials 1 gram and 2 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 3 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 Diluent to be added (mL)Approximate Cefepime Concentration (mg/mL)Amount of Reconstituted Volume to be Withdrawn (mL)Cefepime vial content1 g (IV)1010010.51 g (IM)2.42803.62 g (IV)1016012.52.6 Compatibility and StabilityIntravenous Cefepime for InjectionIntravenous Infusion CompatibilityCefepime for injection vials are compatible at concentrations between 1 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™-R, and Normosol™-M in 5% Dextrose Injection. These solutions may be stored up to 24 hours at controlled room temperature 20°C to 25°C (68°F to 77°F) or 7 days in a refrigerator 2°C to 8°C (36°F to 46°F).Admixture CompatibilityCefepime for injection admixture compatibility information is summarized in Table 4.Table 4: Cefepime Admixture StabilityCefepime forinjectionConcentrationAdmixture andConcentrationIntravenous (IV)Infusion SolutionsRT/L(20° to 25°C)Stability Time for Refrigeration(2° to 8°C)40 mg/mLAmikacin
  • 6 mg/mL
  • NS or D5W24 hours7 days40 mg/mLAmpicillin
  • 1 mg/mL
  • D5W8 hours8 hours40 mg/mLAmpicillin
  • 10 mg/mL
  • D5W2 hours8 hours40 mg/mLAmpicillin
  • 1 mg/mL
  • NS24 hours48 hours40 mg/mLAmpicillin
  • 10 mg/mL
  • NS8 hours48 hours4 mg/mLAmpicillin
  • 40 mg/mL
  • NS8 hours8 hours4 to 40 mg/mLClindamycinPhosphate 0.25 to 6 mg/mLNS or D5W24 hours7 days4 mg/mLHeparin
  • 10 to 50 units/mL
  • NS or D5W24 hours7 days4 mg/mLPotassium Chloride
  • 10 to 40 mEq/L
  • NS or D5W24 hours7 days4 mg/mLTheophylline0.8
  • Mg/mL
  • D5W24 hours7 days1 to 4 mg/mLnaAminosyn™ II4.25% withelectrolytes and
  • Calcium
  • 8 hours3 days0.125 to 0.25 mg/mLnaInpersol™ with
  • 4.25% dextrose
  • 24 hours7 daysNS = 0.9% Sodium Chloride Injection.D5W = 5% Dextrose Injection.na = not applicable.RT/L = Ambient room temperature and light.Cefepime for Injection Admixture IncompatibilityDo not add solutions of cefepime for injection, to solutions of ampicillin at a 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 20ºC to 25ºC (68ºF to 77ºF) or for 7 days in a refrigerator 2ºC to 8ºC (36ºF to 46ºF) 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.

3 Dosage Forms And Strengths

  • Cefepime for Injection, USP is a sterile white to pale yellow powder of cefepime in single-dose vials and it is available in the following strengths:1 gram per vial2 grams per vial

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.

5 Warnings And Precautions

5.1 Hypersensitivity ReactionsBefore 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 a history of penicillin allergy. If an allergic reaction to cefepime for injection occurs, discontinue the drug and institute appropriate supportive measures.5.2 NeurotoxicitySerious adverse reactions have been reported including life-threatening or fatal occurrences of the following: encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, and coma), aphasia, myoclonus, seizures, and nonconvulsive status epilepticus [see
Adverse Reactions (
6.2)]. Most cases occurred in patients with renal impairment who did not receive appropriate dosage adjustment. However, some cases of neurotoxicity occurred in patients receiving a dosage adjustment appropriate for their degree of renal impairment. In the majority of cases, symptoms of neurotoxicity were reversible and resolved after discontinuation of cefepime and/or after hemodialysis. If neurotoxicity associated with cefepime therapy occurs, discontinue cefepime and institute appropriate supportive measures.
5.3 Clostridium difficile Associated DiarrheaClostridium 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 A and B, which contribute to the development of CDAD. Hypertoxin-producing strains of
C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy.
CDAD must be considered in all patients who present with diarrhea following antibacterial drug use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against
C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of
C. difficile, and surgical evaluation should be instituted as clinically indicated.
5.4 Development of Drug-Resistant BacteriaPrescribing cefepime for injection in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.As with other antimicrobials, prolonged use of cefepime for 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 InteractionsUrinary GlucoseThe administration of cefepime may result in a false-positive reaction for glucose in the urine when using some methods (e.g. Clinitest
TM tablets) [see
Drug Interactions (
7.1)].
Coombs’ 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 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.

6 Adverse Reactions

  • The following adverse reactions are discussed in the Warnings and Precautions section and below:Hypersensitivity Reactions [see
  • Warnings and Precautions (
  • 5.1)]
  • Neurotoxicity [see
  • Warnings and Precautions (
  • 5.2)]
  • Clostridium difficile Associated Diarrhea [see
  • Warnings and Precautions (
  • 5.3)]
  • 6.1 Clinical Trials ExperienceBecause 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 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 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 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 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 ExperienceThe 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 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 ReactionsIn 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.

7 Drug Interactions

7.1 Drug/Laboratory Test InteractionsThe 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 AminoglycosidesMonitor 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 DiureticsNephrotoxicity 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

8.1 PregnancyPregnancy 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 a body surface area basis) or to mice at doses up to 1200 mg/kg (approximately equal to the recommended maximum human dose calculated on a body surface area basis) or to rabbits at a dose level of 100 mg/kg (0.3 times the recommended maximum human dose calculated on a body surface area basis).8.2 Labor and DeliveryCefepime has not been studied for use during labor and delivery. Treatment should only be given if clearly indicated.8.3 Nursing MothersCefepime is excreted in human breast milk. Caution should be exercised when cefepime is administered to a nursing woman
[see Clinical Pharmacology (12.3)].
8.4 Pediatric UseThe 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 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 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 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.
8.5 Geriatric UseOf 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 ImpairmentAdjust 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 Adjustment in Patients with Renal Impairment (2.3)].

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)].

11 Description

Cefepime for Injection, 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-azabyciclo[4.2.0] oct-2-en-3-yl]methyl]-1-methylpyrrolidinum chloride,7
2-(Z)-O-methyloxime), monohydrochloride, monohydrate, which corresponds to the following 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
19H
24N
6O
5S
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 gram and 2 grams 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 707 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.

12 Clinical Pharmacology

12.1 Mechanism of ActionCefepime is a cephalosporin antibacterial drug
[see Microbiology (12.4)].
12.2 PharmacodynamicsSimilar 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 PharmacokineticsPharmacokinetic parameters for cefepime in healthy adult male volunteers (n=9) following single 30­minute infusions (IV) of cefepime 500 mg, 1 g, and 2 g are summarized in Table 7. Elimination of cefepime is principally via renal excretion with an average (±SD) half-life of 2 (±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 2 g. There is no evidence of accumulation in healthy adult male volunteers (n=7) receiving clinically relevant doses for a period of 9 days.Table 7: Mean Pharmacokinetic Parameters for Cefepime (±SD), Intravenous AdministrationCefepime for InjectionParameter500 mg IV1 g IV2 g IVC
max, mcg/mL
39.1 (3.5)81.7 (5.1)163.9 (25.3)AUC, h•mcg/mL70.8 (6.7)148.5 (15.1)284.8 (30.6)Number of subjects (male)999Pharmacokinetic parameters for cefepime following a single intramuscular injection are summarized in Table 8. The pharmacokinetics of cefepime are linear over the range of 500 mg to 2 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 g IM2 g IMC
max, mcg/mL
13.9 (3.4)29.6 (4.4)57.5 (9.5)T
max, h
1.4 (0.9)1.6 (0.4)1.5 (0.4)AUC, h•mcg/mL60 (8)137 (11)262 (23)Number of subjects (male)6612AbsorptionFollowing 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 a concentration of 0.5 mcg/mL. A 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 g IV61.581.4 mcg/mLBronchial Mucosa2 g IV204.824.1 mcg/gSputum2 g IV547.4 mcg/mLUrine500 mg IV80 to 4292 mcg/mL1 g IV120 to 4926 mcg/mL2 g IV120 to 43120 mcg/mLBile2 g IV269.417.8 mcg/mLPeritoneal Fluid2 g IV194.418.3 mcg/mLAppendix2 g IV315.75.2 mcg/gGallbladder2 g IV388.911.9 mcg/gProstate2 g 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 a 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 a single 1 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 a decrease in cefepime total body clearance as a function of creatinine clearance. Therefore, dosage administration of cefepime in the elderly should be adjusted as appropriate if the patient’s creatinine clearance is 60 mL/min or less
[see Dosage and Administration (2.3)].
Pediatric patientsCefepime pharmacokinetics have been evaluated in pediatric patients from 2 months to 11 years of age following single and multiple doses on every 8 hours (n=29) and every 12 hours (n=13) schedules. Following a 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 2 (±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 C
max, AUC, and t½ were increased about 15% at steady state after 50 mg per kg every 8 hours. The exposure to cefepime following a 50 mg per kg intravenous dose in a pediatric patient is comparable to that in an adult treated with a 2 g 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 MicrobiologyMechanism of ActionCefepime is a bactericidal drug that acts by inhibition of bacterial cell wall synthesis. Cefepime has a broad spectrum of
in vitro activity that encompasses a 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 BacteriaEnterobacter spp
.Escherichia coli Klebsiella pneumoniaeProteus mirabilisPseudomonas aeruginosaGram-positive BacteriaStaphylococcus aureus (methicillin-susceptible isolates only)
Streptococcus pneumoniaeStreptococcus 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 BacteriaStaphylococcus epidermidis (methicillin-susceptible isolates only)
Staphylococcus saprophyticusStreptococcus agalactiaeNOTE: Most isolates of enterococci, e.g.,
Enterococcus faecalis, and methicillin-resistant
staphylococci are resistant to cefepime.
Gram-negative BacteriaAcinetobacter calcoaceticus subsp.
lwoffiiCitrobacter diversus Citrobacter freundii Enterobacter agglomerans Haemophilus influenzaeHafnia alveiKlebsiella oxytocaMoraxella catarrhalisMorganella morganiiProteus vulgarisProvidencia rettgeriProvidencia stuartiiSerratia marcescensNOTE: 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.

13 Nonclinical Toxicology

13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityNo 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 2 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 a body surface area basis).

14 Clinical Studies

14.1 Febrile Neutropenic PatientsThe safety and efficacy of empiric cefepime monotherapy of febrile neutropenic patients have been assessed in two multicenter, randomized trials comparing cefepime monotherapy (at a dose of 2 g intravenously every 8 hours) to ceftazidime monotherapy (at a dose of 2 g intravenously every 8 hours). These studies comprised 317 evaluable patients. Table 12 describes the characteristics of the evaluable patient population.Table 12: Demographics of Evaluable Patients (First Episodes Only)CefepimeCeftazidimeTotal 164153Median age (yr)56 (range, 18 to 82)55 (range, 16 to 84)Male86 (52%)85 (56%)Female78 (48%)68 (44%)Leukopenia65 (40%)52 (34%)Other hematologic malignancies43 (26%)36 (24%)Solid tumor54 (33%)56 (37%)Median ANC nadir (cells/microliter)20 (range, 0 to 500)20 (range, 0 to 500)Median duration of neutropenia (days)6 (range, 0 to 39)6 (range, 0 to 32)Indwelling venous catheter97 (59%)86 (56%)Prophylactic antibiotics62 (38%)64 (42%)Bone marrow graft9 (5%)7 (5%)SBP less than 90 mm Hg at entry7 (4%)2 (1%)ANC = absolute neutrophil count; SBP = systolic blood pressureTable 13 describes the clinical response rates observed. For all outcome measures, cefepime was therapeutically equivalent to ceftazidime.Table 13: Pooled Response Rates for Empiric Therapy of Febrile Neutropenic Patients% Response CefepimeCeftazidimeOutcome Measures(n=164)(n=153)Primary episode resolved with no treatment modification, no new febrile episodes or infection, and oral antibiotics allowed for completion of treatment5155Primary episode resolved with no treatment modification, no new febrile episodes or infection and no post-treatment oral antibiotics3439Survival, any treatment modification allowed9397Primary episode resolved with no treatment modification and oral antibiotics allowed for completion of treatment6267Primary episode resolved with no treatment modification and no post-treatment oral antibiotics4651Insufficient data exist to support the efficacy of cefepime monotherapy 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). No data are available in patients with septic shock.14.2 Complicated Intra-abdominal InfectionsPatients hospitalized with complicated intra-abdominal infections participated in a randomized, double-blind, multicenter trial comparing the combination of cefepime (2 g every 12 hours) plus intravenous metronidazole (500 mg every 6 hours) versus imipenem/cilastatin (500 mg every 6 hours) for a 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 a surgically confirmed complicated infection, at least one pathogen isolated pretreatment, at least 5 days of treatment, and a 4 to 6 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 a greater proportion of patients with high APACHE II scores in the imipenem/cilastatin group.

15 References

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

16 How Supplied/Storage And Handling

How SuppliedCefepime for Injection, USP is supplied as follows:NDCCefepime for Injection, USPPackage Factor66794-209-021 gram* Single-Dose Vial1 vial66794-209-411 gram* Single-Dose Vial10 vials per carton66794-210-022 gram* Single-Dose Vial1 vial66794-210-412 gram* Single-Dose Vial10 vials per carton*Based on cefepime activity.Cefepime for Injection, USP in the dry state, is a white to pale yellow powder. Constituted solutions of Cefepime for Injection, USP can range in color from pale yellow to amber.Storage and HandlingIn the dry state store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F). [See USP Controlled Room Temperature.]Protect from light. Retain in carton until time of use.
Discard unused portion.Sterile, Nonpyrogenic, Preservative-free.The container closure is not made with natural rubber latex.

17 Patient Counseling Information

  • Counsel 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 a 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. • Diarrhea is a 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.Advise 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.Brands listed are the trademarks of their respective owners.Mfd. for: Piramal Critical CareBethlehem, PA 18017, USAMade in India©2019 Piramal Critical Care

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