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Cefepime

Pronunciation

Generic Name: Cefepime hydrochloride
Dosage Form: injection, solution

Indications and Usage for Cefepime

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.

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)].

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.

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.

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)].

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.

Cefepime Dosage and Administration

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

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.

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.

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.

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

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.

Warnings and Precautions

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.

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.

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.

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.

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' Test

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

Adverse Reactions

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

Hypersensitivity reactions [see Warnings and Precautions (5.1)]
Neurotoxicity [see Warnings and Precautions (5.2)]
Clostridium difficile-associated diarrhea [see Warnings and Precautions (5.3)]

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.

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.

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.

Drug Interactions

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)].

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.

Diuretics

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

USE IN SPECIFIC POPULATIONS

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.

Labor and Delivery

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

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.

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.

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)].

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)].

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)].

Cefepime 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:

Cefepime hydrochloride (monohydrate) has a molecular mass of 571.50 and a molecular formula of C19H25ClN6O5S2•HCl•H2O.

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* Function Dosage Formulations
1 g in 50 mL 2 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.

Cefepime - Clinical Pharmacology

Mechanism of Action

Cefepime is an antibacterial drug. [See Microbiology (12.4)]

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.

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
Parameter 500 mg IV 1 g IV 2 g IV

Cmax, mcg/mL

39.1 (3.5)

81.7 (5.1)

163.9 (25.3)

AUC, h•mcg/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 Fluid Dose/Route # of Patients Mean 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.

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

When available, the clinical microbiology laboratory should provide cumulative reports of in vitro susceptibility test results for antimicrobial drug products used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug product for treatment.

Dilution techniques

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method2 (broth and/or agar). The MIC should be interpreted according to criteria provided in Table 8.

Diffusion techniques

Quantitative methods that require the measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method.2,3 This procedure uses paper discs impregnated with 30 mcg Cefepime to test the susceptibility of microorganisms to Cefepime. The disk diffusion interpretive criteria are provided in Table 8.

Table 8: Susceptibility Test Interpretive Criteria for Cefepime*
*
For patients with renal impairment see Table 2 in Dosage and Administration (2.2).
For isolates of Enterobacteriaceae with intermediate susceptibility, use a dose of 2g every 8 hours in patients with normal renal function.
For Pseudomonas aeruginosa, use 2 g IV every 8 hours in patients with normal renal function.
§
For non-meningitis isolates, a penicillin MIC of < 0.06 mcg/ml (or oxacillin zone > 20mm) can predict susceptibility to Cefepime.

Pathogen

Minimum Inhibitory Concentrations

(mcg/mL)

Disk Diffusion Zone Diameters

(mm)

(S)
Susceptible

(I)
Intermediate

(R)
Resistant

(S)
Susceptible

(I)
Intermediate

(R)

Resistant

Enterobacteriaceae

≤2

4-8

≥16

≥25

19-24

≤18

Pseudomonas aeruginosa

≤8

-

≥16

≥18

-

≤17

Streptococcus pneumoniae§

non-meningitis isolates

≤1

2

≥4

-

-

-

Streptococcus pyogenes

≤0.5

-

-

≥24

-

-

Viridans group streptococci

≤1

2

≥4

≥24

22-23

≤21

Susceptibility of staphylococci to Cefepime may be deduced from testing only penicillin and either cefoxitin or oxacillin.

A report of Susceptible (S) indicates that the antimicrobial drug is likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentration usually achievable at the site of infection.

A report of Intermediate(I) indicates that the results should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where a high dosage of the drug can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation.

A report of Resistant(R) indicates that the antimicrobial drug is not likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentration usually achievable at the infection site; other therapy should be selected.

Quality Control

Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individual performing the test. 2,3 Standard Cefepime powder should provide the following range of MIC values noted in Table 8. For the diffusion technique using the 30 mcg disc, the criteria in Table 9 should be achieved.

Table 9: Acceptable Quality Control Ranges for Cefepime

QC Strain

Minimum Inhibitory

Disk Diffusion

Concentrations (mcg/mL)

(zone diameters in mm)

Escherichia coli ATCC 25922

0.015 - 0.12

31 - 37

Staphylococcus aureus ATCC 29213

1 - 4

-

Staphylococcus aureus ATCC 25923

-

23 - 29

Pseudomonas aeruginosa ATCC 27853

0.5 - 4

24 - 30

Streptococcus pneumoniae ATCC 49619

0.03 - 0.25

28 - 35

Neisseria gonorrhoeae ATCC 49226

0.015 - 0.06

37 - 46

Haemophilus influenzae ATCC 49247

0.5 - 2

25 - 31

Nonclinical Toxicology

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).

Clinical Studies

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 10 describes the characteristics of the evaluable patient population.

Table 10: Demographics of Evaluable Patients (First Episodes Only)
Cefepime Ceftazidime
Total 164 153

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 11 describes the clinical response rates observed. For all outcome measures, Cefepime was therapeutically equivalent to ceftazidime.

Table 11: Pooled Response Rates for Empiric Therapy of Febrile Neutropenic Patients
% Response
Cefepime Ceftazidime
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.

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.

REFERENCES

1.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976; 16:31-41.
2.
Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard - Tenth Edition. CLSI document M07-A10, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2015.
3.
Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty-sixth Informational Supplement, CLSI document M100-S26. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2016.
4.
Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests; Approved Standard – Twelfth Edition. CLSI document M02-A12, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2015.

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 Cntainers (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)].

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.

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 Bayer Healthcare LLC.

07-19-75-358

PACKAGE LABEL - PRINCIPLE DISPLAY PANEL

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

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

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

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.

Cefepime 
Cefepime injection, solution
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0338-1301
Route of Administration INTRAVENOUS DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
Cefepime HYDROCHLORIDE (Cefepime) Cefepime 1 g  in 50 mL
Inactive Ingredients
Ingredient Name Strength
ANHYDROUS DEXTROSE 1.03 g  in 50 mL
ARGININE 725 mg  in 50 mL
HYDROCHLORIC ACID  
WATER  
Packaging
# Item Code Package Description
1 NDC:0338-1301-41 24 BAG in 1 BOX
1 50 mL in 1 BAG
2 NDC:0338-1301-48 12 BAG in 1 BOX
2 100 mL in 1 BAG
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA050817 08/05/2008
Labeler - Baxter Healthcare Corporation (005083209)
Establishment
Name Address ID/FEI Operations
Baxter Healthcare Corporation 194684502 MANUFACTURE(0338-1301), LABEL(0338-1301), PACK(0338-1301), STERILIZE(0338-1301), ANALYSIS(0338-1301)
Establishment
Name Address ID/FEI Operations
Baxter Healthcare Corporation 059140764 ANALYSIS(0338-1301)
Revised: 05/2016
 
Baxter Healthcare Corporation
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