CEFEPIME injection, solution

Cefepime by

Drug Labeling and Warnings

Cefepime by is a Prescription medication manufactured, distributed, or labeled by Baxter Healthcare Corporation. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

  • 1 INDICATIONS AND USAGE

    1.1 Pneumonia

    Cefepime Injection is indicated for pneumonia (moderate to severe) caused by Streptococcus pneumoniae, including cases associated with concurrent bacteremia, Pseudomonas aeruginosa, Klebsiella pneumoniae, or Enterobacter species.

    1.2 Empiric Therapy for Febrile Neutropenic Patients

    Cefepime 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)].

    1.3 Uncomplicated and Complicated Urinary Tract Infections (including pyelonephritis)

    Cefepime Injection is indicated for uncomplicated and complicated urinary tract infections (including pyelonephritis) caused by Escherichia coli or Klebsiella pneumoniae, when the infection is severe, or caused by Escherichia coli, Klebsiella pneumoniae, or Proteus mirabilis, when the infection is mild to moderate, including cases associated with concurrent bacteremia with these microorganisms.

    1.4 Uncomplicated Skin and Skin Structure Infections

    Cefepime Injection is indicated for uncomplicated skin and skin structure infections caused by Staphylococcus aureus (methicillin-susceptible isolates only) or Streptococcus pyogenes.

    1.5 Complicated Intra-abdominal Infections

    Cefepime Injection is indicated for complicated intra-abdominal infections (used in combination with metronidazole) caused by Escherichia coli, viridans group streptococci, Pseudomonas aeruginosa, Klebsiella pneumoniae, Enterobacter species, or Bacteroides fragilis [see Clinical Studies (14)].

    1.6 Usage

    To reduce the development of drug-resistant bacteria and maintain the effectiveness of Cefepime Injection and other antibacterial drugs, Cefepime Injection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

  • 2 DOSAGE AND ADMINISTRATION

    2.1 Dosage for Adults

    The recommended adult dosages and routes of administration are outlined in Table 1 below for patients with creatinine clearance greater than 60 mL/min. Administer Cefepime Injection intravenously over approximately 30 minutes.

    Table 1: Recommended Dosage Schedule for Cefepime Injection in Adult Patients with Creatinine Clearance (CrCL) Greater Than 60 mL/min

    Site and Type of Infection
    Dose
    Frequency    		Duration
    (days)
  • * For Pseudomonas aeruginosa, use 2 g IV every 8 hours
  • † 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.
    		•

    Adults

    Moderate to Severe Pneumonia due to S. pneumoniae, P. aeruginosa*, K. pneumoniae, or Enterobacter species

    1-2 g IV

    Every 8-12 hours

    10

    Empiric therapy for febrile neutropenic patients [see Indications and Usage (1) and Clinical Studies (14)]

    2 g IV

    Every 8 hours

    7†

    Mild to Moderate Uncomplicated or Complicated Urinary Tract Infections, including pyelonephritis, due to E. coli, K. pneumoniae, or P. mirabilis

    0.5-1 g IV

    Every 12 hours

    7-10

    Severe Uncomplicated or Complicated Urinary Tract Infections, including pyelonephritis, due to E. coli or K. pneumoniae

    2 g IV

    Every 12 hours

    10

    Moderate to Severe Uncomplicated Skin and Skin Structure Infections due to S. aureus or S. pyogenes

    2 g IV

    Every 12 hours

    10

    Complicated Intra-abdominal Infections (used in combination with metronidazole) caused by E. coli, viridans group streptococci, P. aeruginosa*, K. pneumoniae, Enterobacter species, or B. fragilis. [see Clinical Studies (14)]

    2 g IV

    Every 8-12 hours

    7-10

    2.2 Pediatric Patients (2 months up to 16 years)

    The maximum dose for pediatric patients should not exceed the recommended adult dose. The usual recommended dosage in pediatric patients up to 40 kg in weight for durations as given above for adults is:

    • 50 mg per kg per dose, administered every 12 hours for uncomplicated and complicated urinary tract infections (including pyelonephritis), uncomplicated skin and skin structure infections, and pneumonia (see below).
    • For moderate to severe pneumonia due to P. aeruginosa give 50 mg per kg per dose, every 8 hours.
    • 50 mg per kg per dose, every 8 hours for febrile neutropenic patients.

    Cefepime Injection in GALAXY Container should be used only in pediatric patients who require the entire 1 or 2 g dose and not any fraction thereof.

    2.3 Dosage Adjustments in Patients with Renal Impairment

    Adult Patients

    Adjust the dose of Cefepime Injection in patients with creatinine clearance less than or equal to 60 mL/min to compensate for the slower rate of renal elimination. In these patients, the recommended initial dose of Cefepime 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 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:

    Males: Creatinine Clearance (mL/min) =

         

    Weight (kg) x (140 – age)

         

    72 x serum creatinine (mg/dL)

    Females: 0.85 x above value
    Table 2: Recommended Dosing Schedule for Cefepime Injection in Adult Patients With Creatinine Clearance Less Than or Equal to 60 mL/min
    Creatinine Clearance
    (mL/min)    		Recommended Maintenance Schedule
  • * On hemodialysis days, Cefepime Injection should be administered following hemodialysis. Whenever possible, Cefepime Injection should be administered at the same time each day.
    		•

    Greater than 60

    500 mg every
    12 hours

    1 g every
    12 hours

    2 g every
    12 hours

    2 g every
    8 hours

    30–60

    500 mg every
    24 hours

    1 g every
    24 hours

    2 g every
    24 hours

    2 g every
    12 hours

    11–29

    500 mg every
    24 hours

    500 mg every
    24 hours

    1 g every
    24 hours

    2 g every
    24 hours

    Less than 11

    250 mg every
    24 hours

    250 mg every
    24 hours

    500 mg every
    24 hours

    1 g every
    24 hours

    Continuous
    Ambulatory
    Peritoneal Dialysis
    CAPD

    500 mg every
    48 hours

    1 g every
    48 hours

    2 g every
    48 hours

    2 g every
    48 hours

    Hemodialysis*

    1 g on day 1, then 500 mg every 24 hours thereafter

    1 g every
    24 hours

    In patients undergoing Continuous Ambulatory Peritoneal Dialysis (CAPD), Cefepime 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 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 Injection should be administered at the same time each day and following the completion of hemodialysis on hemodialysis days (see Table 2).

    Pediatric Patients

    Data 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 Table 1 and Table 2) are recommended for pediatric patients.

    2.4 Directions for Use of Cefepime Injection in GALAXY Container

    Cefepime Injection in GALAXY Container (PL 2040 Plastic) is for intravenous administration using sterile equipment after thawing to room temperature.

    Thawing of Plastic Container

    Thaw frozen container at room temperature 25°C (77°F) or under refrigeration 5°C (41°F). Do not force thaw by immersion in water baths or by microwave irradiation. [See How Supplied/Storage and Handling (16).]

    Check for minute leaks by squeezing container firmly. If leaks are detected, discard solution as sterility may be impaired.

    Do not add supplementary medication.

    Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

    Visually inspect the container. If the outlet port protector is damaged, detached, or not present, discard container as solution path sterility may be impaired. Components of the solution may precipitate in the frozen state and will dissolve upon reaching room temperature with little or no agitation. Potency is not affected. Agitate after solution has reached room temperature. If after visual inspection the solution remains cloudy or if an insoluble precipitate is noted or if any seals are not intact, the container should be discarded.

    Caution: Do not use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is complete.

    Preparation for intravenous administration.

    • 1. Suspend container from eyelet support.
    • 2. Remove protector from outlet port at bottom of container.
    • 3. Attach administration set. Refer to complete directions accompanying set.

    Cefepime Injection should be administered intravenously over approximately 30 minutes.

    Intermittent intravenous infusion with a Y-type administration set can be accomplished with compatible solutions. However, during infusion of Cefepime Injection, it is desirable to discontinue the other solution.

    Solutions of cefepime, like those of most beta-lactam antibiotics, should not be added to solutions of ampicillin at a concentration greater than 40 mg per mL, and should not be added to metronidazole, vancomycin, gentamicin, tobramycin, netilmicin sulfate or aminophylline because of potential interaction. However, if concurrent therapy with cefepime is indicated, each of these antibiotics can be administered separately.

    As with other cephalosporins, the color of Cefepime Injection 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 Injection is available in the following strengths:

    • 1 g in 50 mL (contains 1 g of cefepime as Cefepime Hydrochloride, USP) single-dose GALAXY Container
    • 2 g in 100 mL (contains 2 g of cefepime as Cefepime Hydrochloride, USP) single-dose GALAXY Container
  • 4 CONTRAINDICATIONS

    Cefepime 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.

    Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products.

  • 5 WARNINGS AND PRECAUTIONS

    5.1 Hypersensitivity Reactions

    Before therapy with Cefepime 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 Injection occurs, discontinue the drug and institute appropriate supportive measures.

    5.2 Neurotoxicity

    Serious adverse reactions have been reported including life-threatening or fatal occurrences of the following: encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, and coma), aphasia, myoclonus, seizures, and nonconvulsive status epilepticus [see Adverse Reactions (6.2)]. Most cases occurred in patients with renal impairment who did not receive appropriate dosage adjustment. However, some cases of neurotoxicity occurred in patients receiving a dosage adjustment appropriate for their degree of renal impairment.

    In the majority of cases, symptoms of neurotoxicity were reversible and resolved after discontinuation of cefepime and/or after hemodialysis. If neurotoxicity associated with cefepime therapy occurs, discontinue cefepime and institute appropriate supportive measures.

    5.3 Clostridium difficile Associated Diarrhea

    Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Cefepime 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 Bacteria

    Prescribing cefepime 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 may result in overgrowth of nonsusceptible microorganisms. Repeated evaluation of the patient’s condition is essential. Should superinfection occur during therapy, appropriate measures should be taken.

    5.5 Drug/Laboratory Test Interactions

    Urinary Glucose

    The administration of cefepime may result in a false-positive reaction for glucose in the urine when using some methods (e.g. CLINITEST tablets) [see Drug Interactions (7.1)].

    Coombs' Tests

    Positive direct Coombs’ tests have been reported during treatment with cefepime. In patients who develop hemolytic anemia, discontinue the drug and institute appropriate therapy. Positive Coombs’ test may be observed in newborns whose mothers have received cephalosporin antibiotics before parturition.

    Prothrombin Time

    Many cephalosporins, including cefepime, have been associated with a fall in prothrombin activity. Those at risk include patients with renal or hepatic impairment, or poor nutritional state, as well as patients receiving a protracted course of antimicrobial therapy. Prothrombin time should be monitored in patients at risk, and exogenous vitamin K administered as indicated.

  • 6 ADVERSE REACTIONS

    The following adverse reactions are discussed in other sections of the labeling:

    6.1 Clinical Trials Experience

    Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

    In clinical trials using multiple doses of cefepime, 4137 patients were treated with the recommended dosages of cefepime (500 mg to 2 g intravenously every 12 hours). There were no deaths or permanent disabilities thought related to drug toxicity. Sixty‑four (1.5%) patients discontinued medication due to adverse reactions. 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 3) were identified in clinical trials conducted in North America (n=3125 cefepime-treated patients).

    Table 3: Adverse Reactions in Cefepime Multiple-Dose Dosing Regimens Clinical Trials in North America
  • * Local reactions, irrespective of relationship to cefepime in those patients who received intravenous infusion (n=3048).
    		•

    INCIDENCE EQUAL TO OR GREATER THAN 1%

    Local adverse reactions (3%), including phlebitis (1.3%), pain and/or inflammation (0.6%)*; rash (1.1%)

    INCIDENCE LESS THAN 1% BUT GREATER THAN 0.1%

    Colitis (including pseudomembranous colitis), diarrhea, erythema, fever, headache, nausea, oral moniliasis, pruritus, urticaria, vaginitis, vomiting, anemia

    At the higher dose of 2 g every 8 hours, the incidence of adverse reactions was higher among the 795 patients who received this dose of cefepime. They consisted of rash (4%), diarrhea (3%), nausea (2%), vomiting (1%), pruritus (1%), fever (1%), and headache (1%).

    The following (Table 4) adverse laboratory changes with cefepime, were seen during clinical trials conducted in North America.

    Table 4: Adverse Laboratory Changes in Cefepime Multiple-Dose Dosing Regimens Clinical Trials in North America
  • * Hypocalcemia was more common among elderly patients. Clinical consequences from changes in either calcium or phosphorus were not reported.
    		•

    INCIDENCE EQUAL TO OR GREATER THAN 1%

    Positive Coombs’ test (without hemolysis) (16.2%); decreased phosphorus (2.8%); increased Alanine Transaminase (ALT) (2.8%), Aspartate Transaminase (AST) (2.4%), eosinophils (1.7%); abnormal PTT (1.6%), Prothrombin Time (PT) (1.4%)

    INCIDENCE LESS THAN 1% BUT GREATER THAN 0.1%

    Increased alkaline phosphatase, Blood Urea Nitrogen (BUN), calcium, creatinine, phosphorus, potassium, total bilirubin; decreased calcium*, hematocrit, neutrophils, platelets, White Blood Cells (WBC)

    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 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 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.

  • 7 DRUG INTERACTIONS

    7.1 Drug/Laboratory Test Interactions

    The administration of cefepime may result in a false-positive reaction for glucose in the urine with certain methods. It is recommended that glucose tests based on enzymatic glucose oxidase reactions be used [see Warning and Precautions (5.5)].

    7.2 Aminoglycosides

    Renal function should be monitored carefully if high doses of aminoglycosides are to be administered with Cefepime Injection because of the increased potential of nephrotoxicity and ototoxicity of aminoglycoside antibiotics.

    7.3 Diuretics

    Nephrotoxicity has been reported following concomitant administration of other cephalosporins with potent diuretics such as furosemide.

  • 8 USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy

    Pregnancy Category B. 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 mg/m2 basis) or to mice at doses up to 1200 mg/kg (approximately equal to the recommended maximum human dose calculated on a mg/m2 basis) or to rabbits at a dose level of 100 mg/kg (0.3 times the recommended maximum human dose calculated on a mg/m2 basis).

    There are, however, 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.

    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 in very low concentrations (0.5 mcg/mL). Caution should be exercised when Cefepime Injection is administered to a nursing woman.

    8.4 Pediatric Use

    The safety and effectiveness of cefepime in the treatment of uncomplicated and complicated urinary tract infections (including pyelonephritis), uncomplicated skin and skin structure infections, pneumonia, and as empiric therapy for febrile neutropenic patients have been established in the age groups 2 months up to 16 years. Use of Cefepime 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)].

    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 Injection in pediatric patients under 2 months of age or for the treatment of serious infections in the pediatric population where the suspected or proven pathogen is Haemophilus influenzae type b. In those patients in whom meningeal seeding from a distant infection site or in whom meningitis is suspected or documented, an alternate agent with demonstrated clinical efficacy in this setting should be used.

    Cefepime Injection in GALAXY Container should be used only in pediatric patients who require the entire 1 or 2 g dose and not any fraction thereof.

    8.5 Geriatric Use

    Of the more than 6400 adults treated with cefepime in clinical studies, 35% were 65 years or older while 16% were 75 years or older. When geriatric patients received the usual recommended adult dose, clinical efficacy and safety were comparable to clinical efficacy and safety in nongeriatric adult patients.

    Serious adverse events have occurred in geriatric patients with renal impairment given unadjusted doses of cefepime, including life-threatening or fatal occurrences of the following: encephalopathy, myoclonus, and seizures [see Warnings and Precautions (5) and Adverse Reactions (6)].

    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), Warnings and Precautions (5), and Dosage and Administration (2)].

    8.6 Renal Impairment

    Adjust the dose of Cefepime Injection in patients with creatinine clearance less than or equal to 60 mL/min to compensate for the slower rate of renal elimination [see Dosage and Administration (2.3)].

  • 10 OVERDOSAGE

    Patients who receive an overdose should be carefully observed and given supportive treatment. In the presence of renal impairment, hemodialysis, not peritoneal dialysis, is recommended to aid in the removal of cefepime from the body. Accidental overdosing has occurred when large doses were given to patients with impaired renal function. Symptoms of overdose include encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, and coma), myoclonus, seizures, and neuromuscular excitability [see Warnings and Precautions (5), Adverse Reactions (6), and Dosage and Administration (2)].

  • 11 DESCRIPTION

    Cefepime Injection in GALAXY Containers (PL 2040 Plastic) is a sterile, injectable product consisting of Cefepime Hydrochloride, USP, a semi-synthetic, broad spectrum, cephalosporin antibiotic for parenteral administration. The chemical name is 1-[[(6R,7R)-7-[2-(2-Amino-4-thiazolyl) glyoxylamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0] oct-2-en-3-yl]methyl]-1-methylpyrrolidinium chloride, 72-(Z)-(O-methyloxime), monohydrochloride, monohydrate, which corresponds to the following structural formula:

    Structural Formula

    Cefepime hydrochloride (monohydrate) has a molecular mass of 571.50 and a molecular formula of C19H25ClN6O5S2HClH2O.

    Cefepime Injection in GALAXY Container (PL 2040 Plastic) is a frozen, iso-osmotic, sterile, non-pyrogenic premixed solution supplied for intravenous administration in strengths equivalent to 1 g and 2 g of cefepime [see Dosage and Administration (2)]. It contains the equivalent of not less than 90 percent and not more than 115 percent of the labeled amount of cefepime (C19H24N6O5S2).

    The solution is intended for intravenous use after thawing to room temperature. The components and dosage formulations are given in the table below:

    Table 5: Cefepime Injection in GALAXY Containers (PL 2040 Plastic) Premixed Frozen Solution
    Component*FunctionDosage Formulations
    1 g in 50 mL2 g in 100 mL
  • * Cefepime is present in the formulation as Cefepime Hydrochloride, USP. The amounts of Dextrose Hydrous, USP and L-Arginine, USP are approximate.
  • † The pH may have been adjusted with hydrochloric acid and/or additional L-Arginine, USP. The pH is 4.0 – 6.0.
  • ‡ This is an abbreviation for sufficient quantity.
    		•

    Cefepime

    active ingredient

    1 g

    2 g

    Dextrose Hydrous, USP

    osmolality adjuster

    1.03 g

    2.06 g

    L-Arginine, USP†

    pH adjuster

    725 mg

    1.45 g

    Hydrochloric Acid†

    pH adjuster

    As needed

    As needed

    Water for Injection, USP

    vehicle

    q.s.‡ 50 mL

    q.s.‡ 100 mL

    Cefepime Injection will range in color from colorless to amber.

    The plastic container is fabricated from a specially designed multilayer plastic (PL 2040). Solutions are in contact with the polyethylene layer of this container and can leach out certain chemical components of the plastic in very small amounts within the expiration period. The suitability of the plastic has been confirmed in tests in animals according to the USP biological tests for plastic containers, as well as by tissue culture toxicity studies.

  • 12 CLINICAL PHARMACOLOGY

    12.1 Mechanism of Action

    Cefepime is an 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/pharmacodynamic 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 intravenous infusions of cefepime 500 mg, 1 g, and 2 g are summarized in Table 6. 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 6: Mean Pharmacokinetic Parameters for Cefepime (±SD), Intravenous Administration
    CEFEPIME
    Parameter500 mg IV1 g IV2 g IV

    Cmax, mcg/mL

    39.1 (3.5)

    81.7 (5.1)

    163.9 (25.3)

    AUC, hmcg/mL

    70.8 (6.7)

    148.5 (15.1)

    284.8 (30.6)

    Number of subjects (male)

    9

    9

    9

    Distribution

    The average steady-state volume of distribution of cefepime is 18.0 (±2.0) 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 7.

    Table 7: 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
    Concentration

    Blister Fluid

    2 g IV

    6

    1.5

    81.4 mcg/mL

    Bronchial Mucosa

    2 g IV

    20

    4.8

    24.1 mcg/g

    Sputum

    2 g IV

    5

    4

    7.4 mcg/mL

    Urine

    500 mg IV

    8

    0-4

    292 mcg/mL

    1 g IV

    12

    0-4

    926 mcg/mL

    2 g IV

    12

    0-4

    3120 mcg/mL

    Bile

    2 g IV

    26

    9.4

    17.8 mcg/mL

    Peritoneal Fluid

    2 g IV

    19

    4.4

    18.3 mcg/mL

    Appendix

    2 g IV

    31

    5.7

    5.2 mcg/g

    Gall Bladder

    2 g IV

    38

    8.9

    11.9 mcg/g

    Prostate

    2 g IV

    5

    1

    31.5 mcg/g

    Data suggest that cefepime does cross the inflamed blood-brain barrier. The clinical relevance of these data is uncertain at this time.

    Metabolism and Excretion

    Cefepime 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)].

    Specific Populations

    Patients with Renal Impairment

    Cefepime 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 (±2.0) 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)].

    Patients with Hepatic Impairment

    The pharmacokinetics of cefepime were unaltered in patients with hepatic impairment who received a single 1 g dose (n=11).

    Geriatric Patients

    Cefepime 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 74.0 (±15.0) 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)].

    Pediatric Patients

    Cefepime 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 (±1.0) 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 2.0 (±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 t1/2 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.

    12.4 Microbiology

    Mechanism of Action

    Cefepime is a bactericidal agent 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. Cefepime has a low affinity for chromosomally-encoded beta-lactamases. Cefepime is highly resistant to hydrolysis by most beta-lactamases and exhibits rapid penetration into Gram-negative bacterial cells. Within bacterial cells, the molecular targets of cefepime are the penicillin binding proteins (PBP).

    Antimicrobial Activity

    Cefepime has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections [see INDICATIONS AND USAGE (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 (Lancefield’s Group A streptococci)
    •    Viridans group streptococci

    The 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 (Lancefield’s Group B streptococci)

    NOTE: Most isolates of enterococci, eg, 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 (formerly Xanthomonas maltophilia and Pseudomonas maltophilia).

    Susceptibility Test Methods

    For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: http://www.fda.gov/STIC.

  • 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 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 mg/m2 basis).

  • 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 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 8 describes the characteristics of the evaluable patient population.

    Table 8: Demographics of Evaluable Patients (First Episodes Only)
    CefepimeCeftazidime
    Total164153

    Median age (yr)

    56 (range, 18-82)

    55 (range, 16-84)

    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 per microliter)

    20 (range, 0-500)

    20 (range, 0-500)

    Median duration of neutropenia (days)

    6 (range, 0-39)

    6 (range, 0-32)

    Indwelling venous catheter

    97 (59%)

    86 (56%)

    Prophylactic antibiotics

    62 (38%)

    64 (42%)

    Bone marrow graft

    9 (5%)

    7 (5%)

    SBP less than 90 mm Hg at entry

    7 (4%)

    2 (1%)

    ANC = absolute neutrophil count; SBP = systolic blood pressure

    Table 9 describes the clinical response rates observed. For all outcome measures, cefepime was therapeutically equivalent to ceftazidime.

    Table 9: Pooled Response Rates for Empiric Therapy of Febrile Neutropenic Patients
    % Response
    CefepimeCeftazidime
    Outcome 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 treatment

    51

    55

    Primary episode resolved with no treatment modification, no new febrile episodes or infection, and no post-treatment oral antibiotics

    34

    39

    Survival, any treatment modification allowed

    93

    97

    Primary episode resolved with no treatment modification and oral antibiotics allowed for completion of treatment

    62

    67

    Primary episode resolved with no treatment modification and no post-treatment oral antibiotics

    46

    51

    Insufficient 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 Infections

    Patients 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 protocol-valid population, which consisted 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 protocol-valid 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

    Cefepime Injection is supplied as a frozen, iso-osmotic, sterile, nonpyrogenic solution in 50 mL and 100 mL single-dose GALAXY Containers (PL 2040 Plastic) as follows:

  • * Based on cefepime activity
    		•

     2G3578 

     NDC: 0338-1301-41 

    1 g* in 50 mL 

     Supplied 24/box 

     2G3579 

     NDC: 0338-1301-48 

     2 g* in 100 mL 

     Supplied 12/box 

    Store at or below –20°C (-4°F).

    Handle frozen product containers with care. Product containers may be fragile in the frozen state.

    Thaw frozen container at room temperature 25°C (77°F) or under refrigeration 5°C (41°F). Do not force thaw by immersion in water baths or by microwave irradiation.

    The thawed solution remains stable for 7 days under refrigeration 5°C (41°F) or 24 hours at room temperature 25°C (77°F). Do not refreeze.

    [See Dosage and Administration (2.4)].

  • 17 PATIENT COUNSELING INFORMATION

    • Patients should be counseled that antibacterial drugs including Cefepime Injection should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Cefepime Injection is prescribed to treat a bacterial infection, patients should be told 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 Injection or other antibacterial drugs in the future.
    • Diarrhea is a common problem caused by antibiotics, which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should be instructed to contact their physician as soon as possible.
    • Advise patients of neurological adverse events that could occur with Cefepime 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 Injection.
  • SPL UNCLASSIFIED SECTION

    Manufactured by:
    Baxter Healthcare Corporation
    Deerfield, IL 60015

    Baxter and Galaxy are registered trademarks of Baxter International Inc.

    Clinitest is a registered trademark of Siemens Healthcare Diagnostics Inc.

    Clinistix is a registered trademark of Ascensia Diabetes Care Holdings AG

    07-19-00-468

  • PACKAGE LABEL - PRINCIPLE DISPLAY PANEL

    Representative Cefepime Container Label

    Container Label

    Baxter 1 g

    Cefepime Injection

    GALAXY
    Single-Dose
    Container

    50 mL
    Iso-osmotic

    NDC: 0338-1301-41
    Code 2G3578

    Each 50 mL contains: Cefepime Hydrochloride, USP equivalent to 1 g of

    cefepime with approx. 1.03 g of Dextrose Hydrous, USP added to adjust

    osmolality. Approx. 725 mg of L-Arginine, USP added per g of cefepime to

    adjust the pH. The pH may have been adjusted with hydrochloric acid and/or

    additional L-Arginine, USP. The pH is 4.0 - 6.0.

    Dosage: Intravenously as directed by a physician. See insert.

    Cautions: Do not add supplementary medication. Must not be used in series

    connections. Check for minute leaks and solution clarity.

    Store at or below -20°C/-4°F. Thaw at room temperature (25°C/77°F) or under

    refrigeration (5°C/41°F). DO NOT FORCE THAW BY IMMERSION IN WATER BATHS OR BY MICROWAVE IRRADIATION. Thawed solution remains stable for

    7 days under refrigeration (5°C/41°F) or 24 hours at room temperature (25°C/77°F). Do not

    refreeze.

    Rx Only

    Baxter and GALAXY are registered trademarks of Baxter International Inc.

    Baxter Healthcare Corporation

    Deerfield, IL 60015 USA
    PL 2040 Plastic

    Made in USA
    07-34-63-744

    Representative Cefepime Carton Label_panel 1 of 3

    Carton Label_panel 1 of 3

    Thaw at room temperature (25°C/77°F) or under refrigeration (5°C/41°F). DO NOT FORCE THAW BY IMMERSION IN WATER BATHS OR BY MICROWAVE IRRADIATION. Thawed solution remains stable for 7 days under refrigeration (5°C/41°F) or 24 hours at room
    temperature (25°C/77°F). Do not refreeze.

    Handle frozen product containers with care. Product containers may be fragile in the frozen state.

    Baxter and Galaxy are registered trademarks of Baxter International Inc.

    Baxter Healthcare Corporation, Deerfield, IL 60015 USA

    07-04-65-195

    Made in USA

    PL 2040 Plastic

    Baxter Logo

    1 g

    Cefepime Injection

    Rx Only

    Representative Cefepime Carton Label_panel 2 of 3

    Carton Label_panel 2 of 3

    12 - 50 mL Single-Dose Containers. Iso-osmotic. NDC: 0338-1301-41

    Store at or below -20°C/-4°F. Do not refreeze. Code 2G3578

    *BAR CODE POSITION ONLY
    (01) 20303381301419

    Representative Cefepime Carton Label_panel 3 of 3

    Carton Label_panel 3 of 3

    GALAXY Container
    Sterile Nonpyrogenic

    Each 50 mL contains: Cefepime Hydrochloride, USP equivalent to 1 g of cefepime with approx. 1.03 g of Dextrose Hydrous, USP added to adjust osmolality. Approx. 725 mg of L-Arginine, USP added per g of cefepime to adjust the pH. The pH may have been adjusted with hydrochloric acid and/or additional L-Arginine, USP. The pH is 4.0 - 6.0.

    Dosage: Intravenously as directed by a physician. See insert.

    Cautions: Do not add supplementary medication. Must not be used in series connections. Check for minute leaks and solution clarity. Check for minute leaks by squeezing thawed bag firmly. If leaks are found, discard bag as sterility may be impaired. Do not use unless solution is clear.

  • INGREDIENTS AND APPEARANCE
    CEFEPIME 
    cefepime injection, solution
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 0338-1301
    Route of AdministrationINTRAVENOUS
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    CEFEPIME HYDROCHLORIDE (UNII: I8X1O0607P) (CEFEPIME - UNII:807PW4VQE3) CEFEPIME1 g  in 50 mL
    Inactive Ingredients
    Ingredient NameStrength
    ANHYDROUS DEXTROSE (UNII: 5SL0G7R0OK) 1.03 g  in 50 mL
    ARGININE (UNII: 94ZLA3W45F) 725 mg  in 50 mL
    HYDROCHLORIC ACID (UNII: QTT17582CB)  
    WATER (UNII: 059QF0KO0R)  
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 0338-1301-4124 in 1 BOX08/05/2008
    150 mL in 1 BAG; Type 0: Not a Combination Product
    2NDC: 0338-1301-4812 in 1 BOX08/05/2008
    2100 mL in 1 BAG; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    NDANDA05081708/05/2008
    Labeler - Baxter Healthcare Corporation (005083209)
    Establishment
    NameAddressID/FEIBusiness Operations
    Baxter Healthcare Corporation194684502MANUFACTURE(0338-1301) , LABEL(0338-1301) , PACK(0338-1301) , STERILIZE(0338-1301) , ANALYSIS(0338-1301)
    Establishment
    NameAddressID/FEIBusiness Operations
    Baxter Healthcare Corporation059140764ANALYSIS(0338-1301)
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