PRODUCT MONOGRAPH

Cefepime for Injection

(cefepime hydrochloride)
1 g and 2 g cefepime per vial
Orchid Standard
Antibiotic

Manufactured by:
Orchid Healthcare
(A Division of Orchid Chemicals & Pharmaceuticals Ltd.)
Plot No: B3-B6 & B11-B14, SIPCOT Industrial Park,
Irungattukottai- 602 105, Sriperumbudur P.O.,
Kancheepuram District, INDIA.

Manufactured for: DATE OF PREPARATION

Apotex Inc. April 20, 2020
150 Signet Drive
Weston, ON, M9L 1T9

Control #: 234594
 Table of Contents
PART I: HEALTH PROFESSIONAL INFORMATION .................................................. 3
SUMMARY PRODUCT INFORMATION ............................................................................. 3
INDICATIONS AND CLINICAL USE................................................................................... 3
CONTRAINDICATIONS ........................................................................................................ 5
WARNINGS AND PRECAUTIONS ...................................................................................... 5
ADVERSE REACTIONS ........................................................................................................ 8
DRUG INTERACTIONS ....................................................................................................... 10
DOSAGE AND ADMINISTRATION ................................................................................... 10
OVERDOSAGE ..................................................................................................................... 15
ACTION AND CLINICAL PHARMACOLOGY ................................................................. 15
STORAGE AND STABILITY .............................................................................................. 19
SPECIAL HANDLING INSTRUCTIONS ............................................................................ 19
DOSAGE FORMS, COMPOSITION AND PACKAGING .................................................. 19
PART II: SCIENTIFIC INFORMATION ......................................................................... 20
PHARMACEUTICAL INFORMATION .............................................................................. 20
CLINICAL TRIALS............................................................................................................... 20
MICROBIOLOGY ................................................................................................................. 21
PHARMACOLOGY .............................................................................................................. 27
TOXICOLOGY ...................................................................................................................... 29
REFERENCES ....................................................................................................................... 35
PART III: CONSUMER INFORMATION ....................................................................... 36
 CEFEPIME FOR INJECTION
(cefepime hydrochloride)

PART I: HEALTH PROFESSIONAL INFORMATION

SUMMARY PRODUCT INFORMATION

Route of Dosage Form / Strength AllNonmedicinal Ingredients

Administration
Parenteral Powder for injection Contains 725 mg of L-arginine per
(1 g - I.M/I.V) 1 g and 2 g cefepime gram of Cefepime. The L-arginine is
(2 g – I.V) per vial added to control the pH of the
reconstituted solution at 4.0 – 6.0.

INDICATIONS AND CLINICAL USE

Treatment

Cefepime for injection (cefepime hydrochloride) is indicated in the treatment of the

following infections when caused by susceptible strains of the designated microorganisms:

ADULTS

Lower respiratory tract infections: Nosocomial and community acquired pneumonia

caused by Pseudomonas aeruginosa, Staphylococcus aureus (methicillin-susceptible
strains), Streptococcus pneumoniae, Escherichia coli, and Haemophilus influenzae.

Acute exacerbations of chronic bronchitis caused by Streptococcus pneumoniae and

Haemophilus influenzae.

Uncomplicated and complicated urinary tract infections, including pyelonephritis

caused by Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, and
Proteus mirabills.

Due to the nature of the underlying conditions which usually predispose patients to
Pseudomonas infections of the lower respiratory and urinary tracts, a good clinical
response accompanied by bacterial eradication may not be achieved despite evidence of in
vitro sensitivity.

Skin and skin structure infections caused by Staphylococcus aureus (methicillin-

susceptible strains), Streptococcus pyogenes (Group A streptococci), and Pseudomonas
aeruginosa.

Peritonitis due to gangrenous and perforated appendicitis caused by Escherichia coli.

Bacterial septicemia caused by Escherichia coli, Streptococcus pneumoniae and

Klebsiella pneumoniae.
Empiric therapy in febrile neutropenic patients: Cefepime 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.

Specimens for bacteriologic culture should be obtained prior to therapy in order to identify
the causative organisms and to determine their susceptibilities to cefepime.

Treatment with cefepime for injection may be instituted empirically before results of
susceptibility studies are known; however, modification of the antibiotic treatment may be
required once these results become available.

In patients who are at risk of injection due to an anaerobic organism, concurrent initial
therapy with an anti-anaerobic agent such as metronidazole or clindamycin is
recommended before the causative organism(s) is (are) known. When such concomitant
treatment is appropriate, the recommended doses of both antibiotics should be given
according to the severity of the infection and the patient’s condition.

PEDIATRICS
Cefepime for injection is indicated in pediatric patients for the treatment of infections
listed below when caused by susceptible bacteria:
Lower respiratory tract infections: Nosocomial and community acquired pneumonia
caused by Pseudomonas aeruginosa, Staphylococcus aureus (methicillin-susceptible
strains), Streptococcus pneumoniae, Escherichia coli, and Haemophilus influenzae.
Uncomplicated and complicated urinary tract infections, including pyelonephritis
caused by Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, and
Proteus mirabilis.
Skin and skin structure infections caused by Staphylococcus aureus (methicillin-
susceptible strains), Streptococccus pyogenes (Group A streptococci), and Pseudomonas
aeruginosa.
Empiric therapy in febrile neutropenic patients: Cefepime 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.

Specimens of bacteriologic culture should be obtained prior to therapy in order to identify

the causative organisms and to determine their susceptibilities to cefepime.

Treatment with cefepime for injection may be instituted empirically before results of
susceptibility studies are known; however, modification of the antibiotic treatment may be
required once these results become available.
To reduce the development of drug-resistant bacteria and maintain the effectiveness of
Cefepime for Injection and other antibacterial drugs, Cefepime for Injection should be used
only to treat infections that are proven or strongly suspected to be caused by susceptible
bacteria. When culture and susceptibility information are available, they should be
considered in selecting or modifying antibacterial therapy. In the absence of such data,
local epidemiololgy and susceptibility patterns may contribute to the empiric selection of
therapy.

CONTRAINDICATIONS
Cefepime for injection is contraindicated in patients who have had previous hypersensitivity
reactions to cefepime or any component of the formulation or the cephalosporin class of
antibiotics, penicillins or other beta-lactam antibiotics. (See DOSAGE AND
ADMINISTRATION)

WARNINGS AND PRECAUTIONS

General
As with other antibiotics, prolonged use of cefepime for injection may result in
overgrowth of nonsusceptible organisms. Should superinfection occur during therapy,
appropriate measures should be taken.
Cefepime for injection should be used with caution in individuals with a history of
gastrointestinal disease, particularly colitis.
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.
Positive direct Coombs’ tests have been reported during treatment with cefepime for
injection. In hematologic studies or in transfusion cross-matching procedures when
antiglobulin tests are performed on the minor side or in Coombs’ testing of newborns
whose mothers have received cephalosporin antibiotics before parturition, it should be
recognized that a positive Coombs’ test may be due to the drug.

Severe Cutaneous Adverse Reactions

Severe cutaneous adverse reactions (SCAR) such as acute generalized exanthematous

pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS),
Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) have been reported
in association with beta-lactam treatment. When SCAR is suspected, Cefepime for
Injection should be discontinued and appropriate therapy and/or measures should be taken.

Hypersensitivity
Before therapy with cefepime for injection is instituted, careful inquiry should be made to
determine whether the patient has had previous immediate hypersensitivity reactions to
cefepime, cephalosporins, penicillins, or other beta-lactam antibiotics. Antibiotics should
be administered with caution to any patient who has demonstrated some form of allergy,
particularly to drugs. If an allergic reaction to cefepime for injection occurs, discontinue
the drug and institute supportive treatment as appropriate (e.g., maintenance of ventilation,
pressor amines, antihistamines, corticosteroids). Serious immediate hypersensitivity
reactions may require epinephrine and other supportive therapy.
Clostridium difficile-associated disease
Clostridium difficile-associated disease (CDAD) has been reported with use of many
antibacterial agents, including cefepime. CDAD may range in severity from mild diarrhea
to fatal colitis. It is important to consider this diagnosis in patients who present with
diarrhea, or symptoms of colitis, pseudomembranous colitis, toxic megacolon, or
perforation of colon subsequent to the administration of any antibacterial agent. CDAD
has been reported to occur over 2 months after the administration of antibacterial agents.
Treatment with antibacterial agents may alter the normal flora of the colon and may permit
overgrowth of Clostridium difficile. C. difficile produces toxins A and B, which contribute
to the development of CDAD. CDAD may cause significant morbidity and mortality.
CDAD can be refractory to antimicrobial therapy.

If the diagnosis of CDAD is suspected or confirmed, appropriate therapeutic measures

should be initiated. Mild cases of CDAD usually respond to discontinuation of
antibacterial agents not directed against Clostridium difficile. In moderate to severe
cases, consideration should be given to management with fluids and electrolytes, protein
supplementation, and treatment with an antibacterial agent clinically effective against
Clostridium difficile. Surgical evaluation should be instituted as clinically indicated, as
surgical intervention may be required in certain severe cases. (See ADVERSE
REACTIONS).
In Patients with Renal Impairment
In patients with impaired renal function (creatinine clearance ≤ 50 mL/min), the dose of
cefepime for injection should be adjusted to compensate for the slower rate of renal
elimination. Because high and prolonged serum antibiotic concentrations can occur from
usual dosages in patients with renal insufficiency or other conditions that may compromise
renal function, the maintenance dosage should be reduced when cefepime is administered
to such patients. Continued dosage should be determined by degree of renal impairment,
severity of infection, and susceptibility of the causative organisms (See specific
recommendations for dosing adjustments in DOSAGE AND ADMINISTRATION.)
During post-marketing surveillance, serious adverse events have been reported including
life-threatening or fatal occurrences of the following: encephalopathy (disturbance of
consciousness including confusion, hallucinations, stupor, and coma), myoclonus, seizures
(including non convulsive status epilepticus), and/or renal failure (see ADVERSE
REACTIONS: In Post-marketing Experience). Most cases occurred in patients with
renal impairment who received doses of cefepime that exceeded recommendations in
Table 2 of DOSAGE AND ADMINISTRATION. In the majority of cases, symptoms of
neurotoxicity were reversible and resolved after discontinuation of cefepime and/or after
hemodialysis.
In patients with hepatic impairment
The pharmacokinetics of cefepime were unaltered in patients with impaired hepatic
function who received a single 1g dose. Therefore, dosage adjustments are not required in
patients with hepatic impairment.
In patients with cystic fibrosis
The pharmacokinetics of cefepime do not change to a clinically significant degree in
patients with cystic fibrosis. It is not necessary to alter the dosage of cefepime in this
patient population.
Special Populations

Use in Pregnancy
There are no adequate and well-controlled studies in pregnant women.
Reproduction studies performed in mice and rats showed no evidence of fetal damage at
dose levels equivalent to (mouse) or slightly greater (rat) than the maximum human daily
dose when the daily doses are compared to those in man on a mg/m2 basis. Because animal
reproduction studies are not always predictive of human response, this drug should be
used during pregnancy only if the potential benefit justifies the potential risk.
Nursing Mothers
Cefepime is excreted in human breast milk in very low concentrations. Although less than
0.01% of a 1 g intravenous dose is excreted in milk, caution should be used when
cefepime 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 (nosocomial and community acquired), and as
empiric therapy in febrile neutropenic patients, have been established in the age groups 2
months up to 12 years. Use of cefepime for injection in these age groups is supported by
evidence from adequate and well-controlled studies of cefepime in adults with additional
pharmacokinetic and safety data from pediatric trials (See ACTION AND CLINICAL
PHARMACOLOGY and ADVERSE REACTIONS).
Safety and effectiveness in pediatric patients below the age of 2 months have not been
established. However, accumulation of other cephalosporin antibiotics in newborn infants
(resulting from prolonged drug half-life in this age group) has been reported.
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.
In elderly subjects
Healthy elderly male and female volunteers (≥ 65 years of age) who received a single 1 g
intravenous dose of cefepime had higher area under the curve (AUC) and lower renal
clearance values when compared to younger subjects. However, this appeared to be a
function of the decrease in creatinine clearance with increasing age. In patients with age-
normalized renal function, a dosage adjustment of cefepime is not necessary. Dosage
adjustments are recommended if renal function is compromised.
Of the more than 6400 adults treated with cefepime for injection in clinical studies, 35%
were 65 years or older while 16% were 75 years or older. When elderly patients received
the usual recommended adult dose, clinical efficacy and safety were comparable to clinical
efficacy and safety in nonelderly adult patients unless the patients had renal insufficiency.
Serious adverse events have occurred in elderly patients with renal insufficiency given
unadjusted doses of cefepime, including life-threatening or fatal occurrences of the
following: encephalopathy (disturbance of consciousness including confusion,
hallucinations, stupor and coma), myoclonus, seizures (including nonconvulsive status
epilepticus) and/or renal failure. (See WARNINGS AND PRECAUTIONS and
ADVERSE REACTIONS.)
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 ACTION AND CLINICAL
PHARMACOLOGY: Special populations; WARNINGS AND PRECAUTIONS; and
DOSAGE AND ADMINISTRATION.)

Susceptibility/Resistance

Development of Drug Resistant Bacteria

Prescribing Cefepime for Injection in the absence of a proven or strongly suspected
bacterial infection is unlikely to provide benefit to the patient and risks the development of
drug-resistant bacteria.

ADVERSE REACTIONS

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction
rates observed in the clinical trials may not reflect the rates observed in practice and
should not be compared to the rates in the clinical trials of another drug. Adverse drug
reaction information from clinical trials is useful for identifying drug-related adverse
events and for approximating rates.

Cefepime for injection is generally well tolerated. In clinical trials (N=5598) the most
common adverse events were gastrointestinal symptoms and hypersensitivity reactions.
Adverse events considered to be of probable relationship to cefepime for injection are
listed below.

Events that occurred at an incident of >0.1% - 1% (except where noted) were:

Hypersensitivity: rash (1.8%), pruritus, urticaria
Gastrointestinal: nausea, vomiting, oral monailiasis, diarrhea (1.2%), colitis
(including pseudomembranous colitis)
Central nervous system: headache
Other: fever, vaginitis, erythema

Events that occurred between 0.05% - 0.1% were: abdominal pain, constipation,
vasodilation, dyspnea, dizziness, paresthesia, genital pruritus, taste perversion, chills,
unspecified moniliasis, vaginal moniliasis, urogenital infection, and vaginitis.
Events of clinical significance that occurred at an incidence of < 0.05% included
anaphylaxis and seizures.

At the higher dose of 2 g q8h in febrile neutropenia, the incidence of probably-related

adverse events was higher among 1048 patients who received this dose of cefepime in
clinical trials. They consisted of rash (4%), diarrhea (3%), nausea (2%), vomiting (1%),
pruritis (1%), fever (1%), and headache (1%).

Local reactions at the site of intravenous infusion occurred in 5.2% of patients; these
included phlebitis (2.9%) and inflammation (0.1%). Intramuscular administration of
cefepime for injection was very well tolerated with 2.6% of patients experiencing pain or
inflammation at the injection site.

Laboratory test abnormalities that developed during clinical trials in patients with
normal baseline values were transient. Those that occurred at a frequency between 1% and
2% (unless noted) were: elevations in alanine aminotransferase (3.6%), asparate
aminotransferase (2.5%), alkaline phosphatase, total bilirubin, anemia, eosinophilia,
prolonged prothrombin time, and partial thromboplastin time (2.8%); positive Coombs’
test without hemolysis (18.7%) also occurred. Additionally, increased phosphorous,
decreased phosphorous (2.8%), increased calcium, decreased calcium (which was more
common in elderly patients) and increased potassium were observed.

As with some other cephalosporins, transient elevations of blood urea nitrogen and/or
serum creatinine and transient thrombocytopenia were observed in 0.5% to 1% of patients.
Transient leukopenia and neutropenia were also seen (< 0.5%). During post- marketing
experience, agranulocytosis has been reported rarely.

Renal insufficiency and hepatic failure have been reported in conjunction with cefepime
treatment. However, a causative relationship to cefepime therapy has not been determined
(see also Post Marketing Experience).

The following adverse events and altered laboratory tests have also been reported for
cephalosporin-class antibiotics: Stevens-Johnson syndrome, erythema multiforme, toxic
epidermal necrolysis, toxic nephropathy, aplastic anemia, hemolytic anemia, hemorrhage,
hepatic dysfunction including cholestasis, false positive test for urinary glucose, and
pancytopenia.

Pediatric Patients
A similar safety profile has been experienced in infants and children relative to the adult
population. No specific concerns have been identified.

Post Marketing Experience

In addition to the events reported during North American clinical trials with cefepime, the
following adverse experiences have been reported during worldwide post marketing
experience. Because of the uncontrolled nature of spontaneous reports, a causal
relationship to cefepime for injection treatment has not been determined.
As with some other drugs in this class, encephalopathy (disturbance of consciousness
including confusion, hallucinations, stupor and coma), seizures (including nonconvulsive
status epilepticus), myoclonus, and/or renal failure have been reported. Most cases
occurred in patients with renal impairment who received doses of cefepime for injection
that exceeded recommendations outlined in DOSAGE AND ADMINISTRATION. In
general, symptoms of neurotoxicity resolved after discontinuation of cefepime and/or
after hemodialysis however, some cases included a fatal outcome. Precautions should be
taken to adjust daily dosage in patients with renal insufficiency or other conditions that
may compromise renal function to reduce antibiotic concentrations that can lead or
contribute to these and other serious adverse events, including renal failure.

DRUG INTERACTIONS

The combination of cefepime with an aminoglycoside has been shown to be synergistic in

vitro. Although there is no evidence that cefepime adversely affects renal function at
normal therapeutic doses, the usual precautions, such as the monitoring of renal function,
should be applied if drugs with nephrotoxic potential (such as aminoglycosides and
potential diuretics) are administered with cefepime for injection.

The administration of cefepime may result in a false-positive reaction for glucose in the
urine when using a copper reduction test. It is recommended that glucose tests based on
enzymatic glucose oxidase reactions be used.

DOSAGE AND ADMINISTRATION

Cefepime for injection can be administered either intravenously or intramuscularly. The

dosage and route of administration should be determined according to the susceptibility of
the causative organisms, the severity of the injection, and the condition and renal function
of the patient. Guidelines for dosage of cefepime for injection in adults with normal renal
function are provided in Table 1.
TABLE 1
Recommended Dosage Schedule For Adults (12 years and older)
with normal renal function
Site and Type of Infection Dose (g) Route Frequency Duration
(days)
Mild to moderate urinary tract
infection (uncomplicated and 0.5-1 IV or IM q12h 7-10
complicated), including
pyelonephritis
Mild to moderate infections
including pneumonia, bronchitis 1 IV or IM q12h 10
and skin and skin-structure
infections
Severe infections including
pneumonia, septicemia and
complicated intra-abdominal 2 IV q12h 10
infections
Empiric therapy in febrile
neutropenic patients* 2 IV q8h 7**
*Cefepime has also been used in combination with an aminoglycoside or a glycopeptide in
patient populations which excluded high risk patients (See INDICATIONS AND CLINICAL
USE).

** Or until resolution of neutropenia.

Pediatric Patients (aged 2 months up to 12 years with normal renal function) Usual
recommended dosages
Empiric treatment of febrile neutropenia: Patients > 2 months of age with body
weight ≤ 40kg: 50 mg/kg IV q8h for 7-10 days.

Pneumonia, urinary tract infections, skin and skin structure infections: Patients > 2
months of age with body weight ≤ 40 kg: 50 mg/kg IV q12h for 10 days.

Experience with the use of cefepime for injection in pediatric patients < 2 months of age
is limited.

For pediatric patients with body weights > 40kg, adult dosing recommendations apply
(see Table 1). Dosage in pediatric patients should not exceed the maximum
recommended dosage in adults (2 g q8h). Experience with intramuscular administration
in pediatric patients is limited.

Infection
The usual duration of therapy is 7-10 days; however, more severe infections may require
longer treatment.

Impaired Hepatic Function:

No adjustment is necessary for patients with impaired hepatic function.

Impaired renal function

There is no need to adjust dosage in the elderly unless renal impairment is present.
Cefepime is excreted by the kidneys almost exclusively by glomerular filtration.
Therefore, in patients with impaired renal function (creatinine clearance ≤ 50 mL/min),
the dose of cefepime should be adjusted to compensate for the slower rate of renal
elimination. The recommended initial dose of cefepime in patients with mild to
moderate renal impairment should be the same as in patients with normal renal
function. An estimate of creatinine clearance should be made to determine the
appropriate maintenance dose. The recommended initial dose for patients on
hemodialysis and maintenance doses of cefepime for injection in patients with renal
insufficiency are presented in Table 2:
TABLE 2
Maintenance Dosing Schedule in Adult Patients With Renal
Impairment

Creatinine Clearance
(mL/min/1.73 m2) Recommended Maintenance Schedule
 Normal recommended dosing schedules, no adjustments needed
> 50 1 g q 12h 2 g q 12h 2 g q 8h
30-50 1 g q 24h 2 g q 24h 2 g q 12 h
11 – 29 500 mg q24h 1 g q24h 2 g q24h
< 11 250 mg q24h 500 mg q24h 1 g q24h
Hemodialysis* 500 mg q24h 500 mg q24h 500 mg q24h
* Pharmacokinetic modeling indicates that reduced dosing for these patients is necessary.
Patients receiving cefepime who are undergoing concomitant hemodialysis should be dosed
as follows: 1 gram loading dose on the first day of cefepime therapy and 500 mg per day
thereafter. On dialysis days, cefepime should be administered following dialysis. Whenever
possible cefepime should be administered at the same time each day.

When only serum creatinine measurement is available, the following formula

(proposed by Cockcroft and Gault) 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 value calculated using formula for males

Pediatric Patients with Impaired Renal Function

Since urinary excretion is the primary route of elimination of cefepime in pediatric
patients (see ACTION AND CLINICAL PHARMACOLOGY), an adjustment of
the dosage of cefepime for injection should also be considered in this population.

A dose of 50 mg/kg in patients aged 2 months up to 12 years is comparable to a dose of 2

g in an adult. As recommended in Table 2, the same increase in interval between doses
and/or reduction in dose should be used. When only serum creatinine is available,
creatinine clearance may be estimated using either of the following methods (proposed by
Schwartz, et al and Dechaux, et al, respectively):

Creatinine clearance (mL/min/1.73 m2) = 0.55 x height (centimeters)

serum creatinine (mg/dL)
or
Creatinine clearance (mL/min/1.73 m2) = 0.52 x height (centimeters) -3.6
serum creatinine (mg/dL)

Dialysis Patients: 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 recommended initial dose and maintenance schedule for
patients on hemodialysis are presented in Table 2.

In patients undergoing continuous ambulatory peritoneal dialysis, cefepime may be

administered at the same doses recommended for patients with normal renal function, i.e.,
500 mg, 1 g or 2 g (depending on the severity of the infection) at a dosage interval of
every 48 hours.
 ROUTE OF ADMINISTRATION

Intravenous administration: The intravenous route of administration is preferable for

patients with severe or life-threatening infections, particularly if the possibility of shock is
present.

For direct intravenous injection, the solution reconstituted as recommended (see

Reconstituted Solutions and Compatibility) should be slowly injected directly into the
vein over a period of three to five minutes. Alternatively, the injection can be made into
the tubing of an administration set while the patient is receiving a compatible intravenous
fluid.

For continuous intravenous infusion, reconstitute the 1 g or 2 g vial as recommended (see

Reconstituted Solutions and Compatibility) and add an appropriate quantity of the
resulting solution to one of the compatible intravenous fluids in an intravenous
administration set. The resulting solution should be administered over a period of
approximately 30 minutes.

For intermittent intravenous infusion, a Y-tube administration set can be used with
compatible solutions. However, during infusion of a solution containing cefepime, it is
desirable to discontinue the other solution.

Intramuscular administration: Cefepime for injection reconstituted as

recommended (see Reconstituted Solutions and Compatibility) to a final
concentration of 280 mg/mL is given by deep intramuscular injection into a large
muscle mass (such as the upper outer quadrant of the gluteus maximus).

Although cefepime for injection can be constituted with 0.5 % or 1.0 % lidocaine
hydrochloride, it is usually not required since cefepime causes little or no pain
upon intramuscular administration.

Reconstituted Solutions

For Intramuscular Injection:

The following diluents may be used for constituting cefepime for injection for
intramuscular injection:

Sterile water for

injection 0.9% sodium
chloride injection 5%
dextrose injection
Bacteriostatic water for injection with
paraben(s) Bacteriostatic water for injection
with benzyl alcohol
0.5 or 1 % lidocaine hydrochloride

Reconstitution Table – Intramuscular Injection

 Vial size Volume of diluent Approximate available Approximate cefepime
(g) to be added (mL) volume (mL) concentration (mg/mL)
1 2.4 3.6 280

For Direct Intravenous Injection:

Constitute cefepime for injection with 10 mL of sterile water for injection, 5 %
dextrose injection or 0.9% sodium chloride injection, as directed in the
reconstitution table below.

Reconstitution Table – Direct IV Injection

Vial size Volume of diluent Approximate available Approximate cefepime

(g) to be added (mL) volume (mL) concentration (mg/mL)
1 10 11.3 100
2 10 12.5 160

For Intravenous Infusion:

Reconstitute the 1 g, or 2 g vial as recommended in the reconstitution table above and

add an appropriate quantity of the resulting solution to one of the compatible
intravenous fluids in an intravenous administration set.

At concentrations between 1 and 40 mg/mL, cefepime for injection is compatible with

the following intravenous infusion fluids:
0.9% sodium chloride
injection 5 % or 10 %
dextrose injection M/6
sodium lactate injection
5 % dextrose and 0.9 % sodium chloride
injection Lactated Ringers and 5 % dextrose
injection
Normosol-R and Normosol-M in 5% dextrose injection.

Stability of Reconstituted or Diluted Solutions

Solutions for intramuscular or intravenous use reconstituted as well as diluted as
recommended with sterile water for injection, 0.9% sodium chloride injection or 5%
dextrose injection are stable for 72 hours when stored under refrigeration (2 – 8°C) and
protected from light. Solutions constituted as well as diluted with diluents other than
those listed above should be used immediately after reconstitution.

Compatibility
Cefepime for injection, prepared in 0.9% sodium chloride or 5% dextrose injection at a
concentration of 4 mg of cefepime/mL, is stable for 72 hours under refrigeration (2-8ºC)
when admixed with:
heparin (10 or 50 units/mL),
potassium chloride (10 or 40 mEq/mL),
 theophylline (0.8 mg/mL in 5 % dextrose
injection).

Cefepime for injection at a concentration of 40 mg/mL in 0.9 % sodium chloride

solution or 5 % dextrose injection was found to be compatible with AMIKIN*
(amikacin) (6 mg/mL).

Solutions of cefepime for injection, like solutions of most beta-lactam antibiotics, should
not be added to solutions of ampicillin, metronidazole, vancomycin, gentamicin,
tobramycin sulfate, or netilmicin sulfate because of physical or chemical incompatibility.
However, if concurrent therapy with cefepime for injection is indicated, each of these
antibiotics can be administered separately to the same patient.

As with all parenteral products, intravenous admixtures should be inspected visually for
clarity, particulate matter, precipitation, discolouration and leakage prior to
administration whenever solution and container permit.

OVERDOSAGE
Cefepime for injection is eliminated primarily by the kidneys. In case of severe
overdosage, especially in patients with compromised renal function, hemodialysis will
aid in the removal of cefepime from the body. Peritoneal dialysis is of no value.

Accidental overdosing has occurred when large doses were given to patients with
impaired renal function (see WARNINGS AND PRECAUTIONS). Symptoms of
overdose include encephalopathy (disturbance of consciousness including confusion,
hallucinations, stupor, and coma), myoclonus, seizures (including nonconvulsive status
epilepticus), and neuromuscular excitability.

For management of a suspected drug overdose, contact your regional Poison Control
Centre.

ACTION AND CLINICAL PHARMACOLOGY

Cefepime hydrochloride is a semi-synthetic broad-spectrum cephalosporin antibiotic

intended for intramuscular or intravenous administration. Cefepime is a bactericidal agent
that acts by inhibition of bacterial cell wall synthesis. It has a broad spectrum of activity
against a wide range of Gram-positive and Gram-negative bacteria.

Pharmacokinetics

The average plasma concentrations of cefepime in normal adult males at various times
following single 30-minute infusions and single intramuscular injections of 500 mg, 1 g
and 2 g are summarized below.

Mean Plasma Concentrations of Cefepime (µg/mL)

Cefepime
Dose 0.5 hr 1.0 hr 2.0 hr 4.0 hr 8.0 hr 12.0 hr
IV
500 mg 38.2 21.6 11.6 5.0 1.4 0.2
1g 78.7 44.5 24.3 10.5 2.4 0.6
2g 163.1 85.8 44.8 19.2 3.9 1.1
IM
500 mg 8.2 12.5 12.0 6.9 1.9 0.7
1g 14.8 25.9 26.3 16.0 4.5 1.4
2g 36.1 49.9 51.3 31.5 8.7 2.3
Mean Plasma Concentration-Time Profiles After Single Intravenous Infusions
Compared to MIC90 of Target Pathogens

Mean Plasma Concentration – Time Profiles

After Single Intramuscular Injections Compared to MIC90 of Target Pathogens
See MICROBIOLOGY for susceptibility break points.

Average elimination half-life of cefepime is approximately 2 hours, and does not vary
with respect to dose over the range of 250 mg to 2 g. There was no accumulation in
healthy subjects receiving doses up to 2 g intravenously every 8 hours for a period of
9 days. Total body clearance averages 120 mL/min. Average renal clearance of cefepime
is 110 mL/min, suggesting that cefepime is eliminated almost exclusively by renal
mechanisms, primarily glomerular filtration.

Urinary recovery of unchanged cefepime represents approximately 85% of dose,

resulting in high concentrations of cefepime in the urine. Serum protein binding of
cefepime averages 16.4% and is independent of its concentration in the serum. The
average steady state volume of distribution is 18 L.

Following intramuscular (IM) administration, cefepime is completely absorbed. The

pharmacokinetics of cefepime administered intramuscularly are linear over the range of
500 mg to 2 g and do not vary with respect to treatment duration.

Patients with Renal Impairment

Elimination half-life is prolonged in patients with various degrees of renal insufficiency,

with a linear relationship between total body clearance and creatinine clearance. This
serves as the basis for dosage adjustment recommendations in this group of patients (see
DOSAGE AND ADMINISTRATION). The average half-life is 13 hours in patients
with severe renal impairment requiring hemodialysis and 19 hours in those requiring
continuous ambulatory peritoneal dialysis.

Pediatric Patients

Cefepime pharmacokinetics have been evaluated in pediatric patients following single

and multiple 50 mg/kg doses on q8h (n = 29) and q12h (n =13) schedules. The mean
(± SD) age of the patients was 3.6 (± 3.3) years, and ranged from 2.1 months to 11.2
years. Following a single IV 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
overall mean elimination half-life was 1.7 (± 0.4) hours. The urinary recovery of
unchanged cefepime was 60.4 (± 30.4)% of the administered dose, and renal clearance
was the primary pathway of elimination, averaging 2.0 (± 1.1) mL/min/kg. There were no
significant differences in the pharmacokinetics of cefepime among pediatric patients of
various ages or between male (n = 25) and female patients (n = 17). There was no
evidence of accumulation of cefepime in patients treated for up to 14 days with either
regimen. The absolute bioavailability of cefepime after an IM dose of 50 mg/kg was 82.3
(± 15.6)% in eight patients. The exposure to cefepime, including minimum plasma
concentrations at steady state, following a 50 mg/kg IV dose in a pediatric patient is
comparable to that in adults treated with a 2 g IV dose. Please refer to the
PHARMACOLOGY section for a comparative summary of the mean pharmacokinetics
of cefepime in pediatric vs. adult patients.
STORAGE AND STABILITY

Store dry powder at room temperature (15°C to 30°C) and protect from light. The dry
powder may also be stored in the refrigerator (2°C to 8°C), protected from light.

Solutions for intramuscular or intravenous use reconstituted as well as diluted as

recommended with sterile water for injection, 0.9% sodium chloride injection or 5%
dextrose injection are stable for 72 hours when stored under refrigeration (2 – 8°C) and
protected from light. Solutions constituted as well as diluted with diluents other than
those listed above should be used immediately after reconstitution.

Note: parenteral drugs should be inspected visually for particulate matter before
administration, and not used if particulate matter is present.

As with other cephalosporins, the color of cefepime for injection powder (white to pale
yellow) and constituted solutions (pale yellow) may darken on storage. The product
potency is not adversely affected.

SPECIAL HANDLING INSTRUCTIONS

Not applicable

DOSAGE FORMS, COMPOSITION AND PACKAGING

Cefepime for injection is supplied as a sterile dry powder containing 725 mg of L-

arginine per gram of cefepime. The L-arginine is added to control the pH of the
reconstituted solution at 4.0 – 6.0.

It is available in single use 20 mL clear glass molded Type I vials, sealed with grey
bromobutyl rubber stopper and flip off seal containing 1 g or 2 g of cefepime activity and
supplied in cartons of 10.
 PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper Name: Cefepime hydrochloride

Chemical Name: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

Structural Formula:

Molecular Formula: C19H25 Cl N6O5S2.HCl.H2O

Molecular Weight: 571.50

Description

Cefepime hydrochloride is a white to pale yellow powder with a melting point of 190°C.
It is highly soluble in water (365 mg/mL at 23°C and pH of 0.5), freely soluble in
dimetylsulfoxide and methanol, soluble in propylene glycol and glycerin and slightly
soluble in ethanol. Cefepime has a partition coefficient (1-octanol buffer) of 0.027 at
23°C.

CLINICAL TRIALS

Not applicable
MICROBIOLOGY

Cefepime is a bactericidal agent that acts by inhibition of bacterial cell wall synthesis.
Cefepime has a broad spectrum of activity that encompasses a wide range of Gram-
positive and Gram-negative bacteria. Cefepime is highly resistant to hydrolysis by most
beta-lactamases, has a low affinity for chromosomally-encoded beta-lactamases and
exhibits rapid penetration into Gram-negative bacterial cells. The molecular targets of
cefepime are the penicillin binding proteins (PBP). In studies using Escherichia coli and
Enterobacter cloacae, cefepime bound with highest affinity to PBP 3 followed by PBP 2,
then PBPs 1a and 1b. Binding to PBP 2 occurs with significantly higher affinity than that
of other parenteral cephalosporins. This may enhance its antibacterial activity. The
moderate affinity of cefepime for PBPs 1a and 1b probably also contribute to its overall
bactericidal activity. Cefepime has been shown to be bactericidal by time-kill analysis
(killing-curves) and by determination of minimum bactericidal concentrations (MBC) for
a wide variety of bacteria. The cefepime MBC/MIC ratio was ≤ 2 for more than 80% of
isolates of all Gram-positive and Gram-negative species tested. Synergy with
aminoglycosides has been demonstrated in vitro, primarily with Pseudomonas
aeruginosa isolates.

The in vitro activity of cefepime against clinical isolates is shown below.

Organism Number of Low High MIC MIC50 MIC90

Isolates MIC mcg/mL mcg/mL
GRAM-NEGATIVE
Acinetobacter anitratus 54 1 > 128.000 3.311 26.355
Acinetobacter calcoaceticus 1 16 16
Acinetobacter lwoffi 14 ≤ 0.007 32 0.707 3.482
Achromobacter xylosoxidans 8 16 64 21.112
Aerococcus sp. 1 8 8
Aeromonas hydrophila 6 0.015 0.25 0.03
Alcaligenes faecalis 4 8 16
Bordetalla bronchiseptica 1 16 16
Citrobacter amalonaticus 2 0.015 0.03
Citrobacter freundii 30 0.015 2 0.04 1.32
Clostridium diversus 18 0.015 0.5 0.017 0.069
Edwardsiella tarda 1 ≤ 0.007 ≤ 0.007
Enterobacter aerogenes 36 0.015 2 0.029 0.345
Enterobacter cloacae 100 0.015 4 0.028 0.305
Enterobacter gergovia 1 0.015 0.015
Enterobacter taylorae 1 0.06 0.06
Escherichia coli 527 ≤ 0.007 16 0.019 0.053
Flavobacterium meningosepticum 2 8 16
Flavobacterium odoratum 1 128 128
Haemophilus influenzae 2 0.03 0.06
Haemophilus influenzae (P+) 13 0.03 0.5 0.038 0.097
Haemophilus influenzae (P-) 63 ≤ 0.007 2 0.035 0.057
Haemophilus parainfluenzae 2 0.03 0.06
Haemophilus parainfluenzae (P-) 3 0.03 0.06
 Organism Number of Low High MIC MIC50 MIC90
Isolates MIC mcg/mL mcg/mL
Klebsiella oxytoca 42 ≤ 0.007 1 0.02 0.052
Klebsiella ozaenae 1 0.015 0.015
Klebsiella pneumoniae 168 ≤ 0.007 16 0.022 0.094
Kluyvera sp. 1 0.125 0.125
Moraxella catarrhalis 5 0.125 0.5 0.21
Moraxella catarrhalis (P+) 19 0.125 2 0.215 0.856
Moraxella catarrhalis (P-) 3 0.06 0.125
Moraxella sp. 1 64 64
Morganella morganii 33 0.015 16 0.02 0.097
Neisseria flavescens 1 0.03 0.03
Neisseria gonorrhoeae 4 ≤ 0.007 ≤ 0.007 ≤ 0.007
Neisseria meningitidis 3 0.03 0.06
Neisseria mucosa 2 0.25 0.25
Neisseria subflava 1 0.06 0.06
Pantoea aglomerans 4 0.015 0.03
Pasteurella multocida 1 0.5 0.5
Proteus mirabilis 144 0.015 16 0.037 0.081
Proteus penneri 1 0.06 0.06
Proteus vulgaris 5 0.03 2
Providencia rettgeri 6 ≤ 0.007 0.125 0.021
Providencia stuartii 10 0.03 4 0.03 1
Pseudomonas aeruginosa 237 0.125 32 1.485 5.716
Pseudomonas cepacia 2 8 16
Pseudomonas fluorescens 7 0.25 8 1.682
Pseudomonas maltophilia 32 4 128 11.95 51.472
Pseudomonas putida 5 0.25 8 0.42
Pseudomonas stutzeri 1 0.5 0.5
Salmonella enteritidis 1 0.03 0.03
Salmonella sp. 1 0.03 0.03
Serratia marcescens 44 0.03 4 0.076 0.277
Streptococcus liquifaciens 1 0.5 0.5
Vibrio alginolyticus 1 0.5 0.5
GRAM-POSITIVE
Aerococcus viridans 1 0.03 0.03
Bacillus sp. 3 1 64
Corynebacterium sp. 16 0.06 16 0.177 0.66
Micrococcus sp. 2 0.25 > 128.000
Staphylococcus aureus 489 0.125 128.000 1.655 3.494
Staphylococcus aureus (MR) 21 8 > 128.000 > 128.000 > 128.000
Staphylococcus capitis 6 0.125 2 0.25
Staphylococcus cohnii 2 2 4
Staphylococcus epidermidis 134 0.03 32 0.442 4.245
Staphylococcus epidermidis (MR) 42 1 128 5.04 30.555
Staphylococcus haemolyticus 46 0.5 > 128.000 3.564 > 128.000
Staphylococcus hominis 21 0.25 > 128.000 1.072 > 4.925
Staphylococcus saprophyticus 1 > 128.000 > 128.000
Staphylococcus simulans 10 0.5 16 0.595 4
 Organism Number of Low High MIC MIC50 MIC90
Isolates MIC mcg/mL mcg/mL
Staphylococcus warneri 7 0.25 2 0.386
Staphylococcus coagulase (-) 1 4 4
Streptococcus agalactiae 6 0.03 4 0.038
Streptococcus bovis 3 0.06 0.125
Streptococcus durans 3 2 128
Streptococcus equinis 1 0.06 0.06
Streptococcus faecalis 248 0.5 > 128.000 23.315 95.977
Streptococcus faecium 30 4 > 128.000 > 128.000 > 128.000
Streptococcus milleri 7 0.015 0.5 0.027
Streptococcus mitis 23 0.015 4 0.054 1.481
Streptococcus mutans 2 0.03 0.06
Streptococcus pneumoniae 118 ≤ 0.007 0.25 0.016 0.071
Streptococcus salivarius 2 ≤ 0.007 0.03
Streptococcus sanguis 27 ≤ 0.007 0.5 0.068 0.268
Streptococcus (beta hemolytic) 4 0.06 0.125
Streptococcus (group A) 155 ≤ 0.007 32 0.011 0.022
Streptococcus (group B) 82 0.03 0.125 0.046 0.088
Streptococcus (group C) 7 0.015 0.5 0.085
Streptococcus (group D) 1 16 16
Streptococcus (group F) 7 0.015 0.5 0.025
Streptococcus (group G) 29 0.015 0.06 0.028

Cefepime is inactive against Clostridium difficile and against many strains of

Stenotrophomonas maltophilia (formerly Xanthomonas maltophilia and Pseudomonas
maltophilia).

Most strains of enterococci, e.g. Enterococcus faecalis, and methicillin-resistant

staphylococci are resistant to most beta-lactam antibiotics including cefepime.

CLINICAL ISOLATES IN VITRO SUSCEPTIBILITY

In a surveillance study, more than 12,000 clinical isolates were tested in 83 U.S. hospitals
using either the E-test method or the National Committee of Clinical Laboratory
Standards (NCCLS) approved microdilution (Microscan) method. Antimicrobial
susceptibility results obtained with the two different MIC methods are shown below:
 Cumulative Percent Susceptibility of Bacterial Isolates to Cefepime Using E-Test and
Microdilution Methods
Organism No. of Isolates Susceptibility (%)
Microdilution E-Test*
GRAM-NEGATIVE
Acinetobacter anitratus 24 58.3 50
Citrobacter freundii 19 100 100
Enterobacter aerogenes 25 100 100
Enterobacter cloacae 53 96.2 100
Escherichia coli 321 100 100
Klebsiella oxytoca 19 100 100
Klebsiella pneumoniae 112 99.1 100
Proteus mirabilis 71 100 100
Pseudomonas aeruginosa 187 82.4 87.7
Serratia marcescens 21 100 100
GRAM-POSITIVE
Enterococcus faecalis 111 0 0
Enterococcus spp. 7 0 0
Staphylococcus aureus (MS) 199 98.5 99
Staphylococcus aureus (MR) 69 21.7 23.2
Staphylococcus coagulase (-) (MS) 8 100 100
Staphylococcus coagulase (-) (MR) 11 45.5 66.7
Staphylococcus epidermidis (MS) 15 93.3 100
Staphylococcus epidermidis (MR) 21 45.7 60.9
* A plastic strip containing a concentration gradient of the antimicrobial agent to be used is
placed on an agar plate inoculated with the organisms to be tested in the same manner as for the
standard disk diffusion method.

In vitro results confirmed the susceptibility of most isolates tested to cefepime. The
activity of cefepime against Enterobacter species was > 90% and against Pseudomonas
aeruginosa was 78.2 to 82.5% depending on the method. Ninety-eight percent (98%) of
methicillin-susceptible Staphylococcus aureus strains were susceptible to cefepime with
similar results for methicillin-susceptible Staphylococcus epidermidis.

SUSCEPTIBILITY TESTS

Diffusion techniques

Quantitative methods that require measurement of zone diameters give the most precise
estimates of antibiotic susceptibility. The approved procedure of the NCCLS has been
recommended for use with disks to test susceptibility to cefepime. Interpretation involves
correlation of diameters obtained in the disk test with the minimum inhibitory
concentration (MIC) values for cefepime. Laboratory reports with standardized single-
disk susceptibility results using a 30 mcg cefepime disk should be interpreted according
to the following criteria.
 Microorganism Zone diameter (mm)
Susceptible (S) Intermediates (I) Resistant (R)
Microorganisms other
than Haemophilus spp.* ≥ 18 15-17 ≤ 14
and S. Pneumoniae*
Haemophilus spp.* ≥ 26 -* -*

*NOTE: Isolates from these species should be tested for susceptibility using specialized testing
methods. Isolates of Haemophilus spp. with zones < 26 mm should be considered equivocal and
should be further evaluated. Isolates of S. Pneumoniae should be tested against a 1 mcg
oxacillin disk; isolates with oxacillin zone sizes ≥ 20 mm may be considered susceptible to
cefepime.

A report of “Susceptible” indicates that the pathogen is likely to be inhibited by generally

achievable blood concentrations. A report of “Intermediate” indicates that the organism
would be susceptible if high dosage is used or if the infection is confined to tissues and
fluids (e.g., interstitial fluid and urine) in which high antibiotic levels are attained. A
report of “Resistant” indicates that the achievable concentration of the antibiotic is
unlikely to be inhibitory and other therapy should be selected.

Organisms should be tested with the cefepime disk because cefepime has been shown to
be active in vitro against certain strains found to be resistant with other beta-lactam disks.
The cefepime disk should not be used for testing susceptibility to other cephalosporins.
Standardized quality control procedures require the use of control organisms. The 30 mcg
cefepime disk should give the following zone diameters for the quality control strains.

Quality Control Limits for Tests with the 30 mcg Cefepime Disk
Organism ATCC Zone Size Range (mm)
Escherichia coli 25922 29 – 35
Pseudomonas aeruginosa 27853 24 – 30
Staphylococcus aureus 25923 23 – 29
Neisseria gonorrhoeae 49226 37 – 46
Haemophilus influenzae 49247 25 – 31

Dilution techniques

Using standardized dilution methods (broth, agar, microdilution) or equivalent, the MIC
values obtained should be interpreted according to the following criteria:
Microorganism MIC (mcg / mL)
Susceptible (S) Intermediate (I) Resistant (R)
Microorganism other than
Haemophilus spp.* and ≤8 16 ≥ 32
S. pneumoniae*
Haemophilus spp.* ≤2 0 -*
Streptococcus pneumoniae* ≤ 0.5 1* ≥2
 *NOTE: Isolates from these species should be tested for susceptibility using specialized
dilution testing methods. Strains of Haemophilus spp. with MIC’s greater than 2 mcg/mL
should be considered equivocal and should be further evaluated.

As with diffusion techniques, dilution techniques require the use of laboratory control
organisms. Standard cefepime powder should give the following MIC values for quality
control strains:
Quality Control Ranges of MIC (mcg/mL)
Organism ATCC MIC (mcg/mL)
Escherichia coli 25922 0.016 – 0.12
Staphylococcus aureus 29213 1–4
Pseudomonas aeruginosa 27853 1–8
Neisseria gonorrhoeae 49226 0.016 – 0.06
Haemophilus influenzae 49247 0.5 – 2

Separate susceptibility breakpoints and zone diameter interpretative standards for

Haemophilus influenzae, Neisseria gonorrhoeae and Streptococcus pneumoniae have
been established for cefepime by the NCCLS. The following tables summarize the
information published in Tables 2A, B, C (Aerobic Dilution) and (Disk Diffusion) of
NCCLS Document M100-S5 published in December 1994.

Organism Zone Diameter (mm) Interpretation

H. influenzae ≥ 26 S
N. gonorrhoeae ≥ 31 S
S. pneumoniae - -

Organism MIC (mcg/mL) Interpretation

H. influenzae ≤2 S
N. gonorrhoeae ≤ 0.5 S
≤ 0.5 S
S. pneumoniae 1 I
≥2 R

There are no breakpoints for resistance to cefepime for H. influenzae and N. gonorrhoeae
since no resistant isolates to cefepime have yet been detected. There are no zone diameter
criteria established for cefepime or any other cephalosporins to S. pneumoniae; disk
diffusion of cephalosporin is not predictive of MICs for S. pneumoniae.
 PHARMACOLOGY

Concentrations of cefepime achieved in specific tissues and body fluids following

intravenous administration are listed below.

Mean Concentrations of Cefepime in Various Body Fluids (mcg/mL) and Tissues (mcg/g)
Tissue or fluid I.V. Dose Number of Average time of Mean
(g) patients sample post-dose (hr) concentration
0.5 8 0–4 292 mcg/mL
Urine 1 12 0–4 926 mcg/mL
2 12 0–4 3120 mcg/mL
Bile 2 26 9.4 17.8 mcg/mL
Peritoneal fluid 2 19 4.4 18.3 mcg/mL
Blister fluid 2 6 1.5 81.4 mcg/mL
Bronchial mucosa 2 20 4.8 24.1 mcg/g
Sputum 2 6 4 7.4 mcg/mL
Prostate 2 5 1 31.5 mcg/g
Appendix 2 31 5.7 5.2 mcg/g
Gallbladder 2 38 8.9 11.9 mcg/g

Mean pharmacokinetic parameters of cefepime in pediatric and adult patients are

presented in the following tables.

Mean (SD) Pharmacokinetic Parameters of Cefepime in Pediatric Patients Following the IV

Administration of Single and
Multiple 50 mg/kg doses, q12hr
Group Dose N CMAX AUC* T-HALF CLT VSS
(mcg/mL) (mcg-hr/ mL) (hr) (mL/min/kg) (L/kg)
First 7 188.6 256 1.60 3.45 0.30
2 yr – < 6 yr (37.3) (71) (0.32) (0.86) (0.07)
Steady 7 174.1 240 1.55 4.02 0.38
State (70.0) (91) (0.27) (1.82) (0.19)
First 6 175.5 271 1.62 3.31 0.31
6 yr – < 12 yr (51.8) (86) (0.20) (1.22) (0.07)
Steady 6 182.0 271 1.55 3.25 0.28
State (43.5) (85) (0.22) (0.95) (0.03)
* AUC (INF) after the first dose and AUC (TAU) at steady state
Mean (SD) Pharmacokinetic Parameters of Cefepime in Pediatric Patients and Adult
Subjects Following the Administration of Single and Multiple Intravenous Doses
Group Dose N CMAX AUC* T- CLT† VSS†
HALF
Pediatric Patients – 50 mg/kg, q8h
2 mo - < 6 mo First 7 157.4 303.7 1.89 2.97 0.40
(23.0) (86.4) (0.63) (0.75) (0.08)
Steady 7 185.4 336.9 1.78 2.65 0.35
State (30.7) (98.5) (0.75) (0.57) (0.04)
First 10 173.1 279.2 1.57 3.41 0.34
6 mo - < 2 yr (21.7) (99.6) (0.51) (1.33) (0.06)
Steady 10 197.1 364.1 1.98 2.72 0.34
State (30.5) (165.7) (0.76) (1.10) (0.06)
First 6 191.7 245.1 1.68 3.46 0.35
2 yr - < 6 yr (19.5) (31.6) (0.23) (0.48) (0.09)
Steady 6 189.8 265.7 1.80 3.21 0.34
State (36.2) (46.1) (0.70) (0.46) (0.08)
First 6 188.9 289.1 1.65 3.00 0.33
6 yr - < 12 yr (34.8) (62.8) (0.26) (0.65) (0.07)
Steady 4 179.9 280.5 2.05 3.14 0.72
State (48.8) (66.6) (0.55) (0.95) (0.67)
First 4 114.1 258.1 1.84 3.13 0.40
12 yr - ≤ 18 yr (45.8) (178.5) (0.33) (1.35) (0.13)
Steady 3 177.4 351.7 2.26 1.79 0.45
State (13.8) (61.5) (0.66) (0.39) (0.27)
Adult Subjects 2 g, q8h
First 7 142 281 2.46 1.73 9.25
Adult (32.7) (43) (0.66) (0.25) (0.08)
Steady 7 145 281 2.39 1.74 0.23
State (17.9) (55) (0.49) (0.31) (0.03)
* AUC (INF) after the first dose and AUC(TAU) at steady state
† For adult subjects, mean values divided by an average body weight of 70 kg to
determine normalized values

Effect on fecal flora

Suppression of the natural gut microflora during antibiotic therapy may allow
colonisation of the gut by resistant microorganisms normally excluded from the body.
This can lead to serious complications such as overgrowth by Clostridium difficile and
subsequent pseudomembranous colitis.

Disturbance of the fecal flora is seen particularly with cephalosporins that concentrate in
the bile. Because cefepime is eliminated primarily via the kidney, this effect is less
marked.
The effect of multiple intravenous doses of cefepime on fecal flora has been investigated
in healthy volunteers. Little effect was observed after 6 days of treatment and
colonization by resistant organisms did not occur.

TOXICOLOGY

Acute Toxicity

Species/ Route Sex (N) Formulation** Doses Estimated

Strain (mg/kg) minimum lethal
dose (mg/kg)
Mouse / SW IV M (10) base 1000 - 2000 > 1500*
F (10)
Mouse / CD-1 IV M (10) NaCl 2500 – 3500 > 3500* (M)
F (10) > 3000* (F)
IV M (10) /L-arg 700 – 1500 1272* (M)
F (10) 1067* (F)
IV M (10 – 12) NaCl 400 – 1800 775 – 866*
Rat / SD IV M (10 – 12) 300 – 900 667 – 669*
F (10) base
IM M (10) NaCl 3000 > 3000
F (10)
IP M (10) NaCl 3000 > 3000
F (10)
SC M (10) NaCl 5000 > 5000
F (10)
Rabbit / NZ IV M (1 – 2) NaCl 2000 – 2500 > 2000
F (1 – 2)
Dog IV M (1) NaCl 2500 > 2500
F (1)
IV M (1) /L-arg 2000 > 2000
F (1)
Monkey IV M (1 – 2) base 2500 – 4000 > 4000
F (1 – 2)
IV M (1) NaCl 4000 > 4000
F (1)
* Median lethal dose
** Formulations: NaCl = Cefepime: NaCl, 1:1 mole; /L-arg = cefepime diHCI/L-arginine,
1:0.72 w/w ratio

With the exception of rabbits, where deaths due to enterotoxemia (related to the
antibacterial activity of cefepime) occurred 4 to 6 days after treatment, significant
toxicity in other species was limited to a brief period of time after intravenous injection
of the drug. In mice and rats, deaths generally occurred within the first few minutes
following intravenous administration and survivors appeared normal thereafter. Signs of
 toxicity in rodents included ataxia, decreased activity, respiratory difficulty, muscle
twitching, tremors, straub tail and convulsions.

In dogs and monkeys, signs of toxicity were transient and consisted of salivation, emesis
and or retching, tremors (dog) and dilated pupils (monkey). All animals appeared
clinically normal within a few hours after treatment.

Subacute Toxicity

Species / N (sex) / Dose Range Route Duration Formu- Principal Findings

Strain Group (mg/kg/day) lation1
Rat / SD 12 M 0 (water for IV 4 weeks Base All groups: No clinicopathologic or histopathologic
12 F injection), bolus changes related to cumulative drug toxicity.
100, 400, 8002 ≥ 400 mg/kg: 1 death (F) in 400 mg/kg group and 6 deaths
(4M, 2F) in 800 mg/kg group proceeded by ataxia,
decreased activity, respiratory difficulty, muscle twitching
and convulsions. Deaths within 2-10 minutes of dosing.
Rat / SD 10 M 0 (saline), IV 4 weeks /L-Arg All groups: Tissue alteration at injection site.
10 F 0 (L-arginine), ≥ 400 mg/kg: Increased kidney weight.
10, 400, 8002 800 mg/kg: Minimal cytoplasmic vacuolation of renal
tubules in 1 (F).
Rat / SD 10 M 0 (saline), 500, IP 4 weeks NaCl ≥ 500 mg/kg: Irritation at injection site. Transient hind
10 F 1000,1500 limb extension. Reddish discoloration and swelling of the
scrotum. Cecal enlargement/ semifluid fecal content.
≥ 1000 mg/kg: Decreased mean liver weight.
1500 mg/kg: Decreased body weight and body weight
gain.
Rat / SD 10 M 0 (saline), 100, SC 12 weeks NaCl All dose groups: Slight/mild irritation at injection site.
10 F 500, 10002 Slight to moderate increase in ALT and AST without
relation to dose or duration of treatment.
≥ 500 mg/kg: 1 (M) in 500 mg/kg group and 1 (M)
in 1000 mg/kg group sacrificed moribund; no relationship
to drug.
1000 mg/kg: Decreased body weight and food intake.
Moderate cytoplasmic vacuolation of proximal renal
tubules (F).
Dog / 2M 0 (L-arginine), IM 4 weeks /L-Arg All groups: Struggling and/or vocalization during injection
Beagle 2F 1002 and favouring of leg after injection. Salivation (F).
Increased serum AST in one control and 3 cefepime dogs
related to local muscle irritation. Minor irritation at
injection site.
Dog / 2M 0 (saline), 0 IV 4 weeks /L-Arg 100 mg/kg: Salivation (M) and emesis or retching (F)
Beagle 2F (L-arginine), during last weeks.
100, 300, 600 > 300 mg/kg: Salivation and emesis / retching during or
after dosing. Increased urine volume in intermediate dose
(M) and in high dose (M & F).
600 mg/kg: Decreased activity and slight muscle tremors
(F) noted briefly after dosing. Increased serum cholesterol
in 2 (F).
Dog / 3–5 0 (saline), 0 IV 4 weeks /L-Arg All groups: Dose-dependent salivation, retching / emesis,
Beagle M, F (L-arginine), (+ 4 flushing, pawing at head and increased heart rate prior to,
50, 300, 600 weeks during and briefly (< 30 minutes) after dosing. Dose
recovery) related increase in kidney weight.
≥ 300 mg/kg: Increased (PAS+) granules in proximal
renal tubules.
600 mg/kg: Hypoactivity. Slight decrease in platelets or
hemoglobin and hematocrit in 1/10 dogs. Slight increases
in sodium, protein, albumin and cholesterol. Significant
increase in kidney weight (F).
 Subacute Toxicity (cont’d)
Species / N (sex) / Dose Range Route Duration Formulation1 Principal Findings
Strain Group (mg/kg/day)
Monkey / 2M 0 (water for IV 4 weeks Base All dose groups: Red
Cynomolgus 2F injection), 100, discoloration and scabs at
300, 600 injection sties.
600 mg/kg: Salivation, emesis,
ataxia during or immediately
after dosing. Decrease food
intake and bodyweight loss in 1
(F).
Monkey / 1-2 0 (control), 0 (L- IV 4 weeks Sulfate / L-arg. All dose groups: Red
Cynomolgus M, F arginine / discoloration and scabs at
Sodium sulfate), injection sties.
600 600 mg/kg: Emesis after dosing.
Slightly decreased food intake in
1 (F). Cylindruria (hyaline and
waxy casts) and slight increase
in urine protein and specific
gravity.
Monkey / 2M 0 (saline), 100, IV 12 weeks NaCl All dose groups: Irritation at
Cynomolgus 2F 300, 600 injection site. Minimal increase
in (PAS+) granules in proximal
renal tubules (heterolysosomes).
≥ 300 mg/kg: Urinary casts
(hyaline) and increased
epithelial cells in urine.
600 mg/kg: One death (F) after
78th dose. Respiratory distress,
salivation, prostration with
flaccid hindlimbs and tremors
prior to death. Normal prior to
78th dose.
1
Formulation used: NaCl = cefepime: NaCl, 1:1 mole; /L-arg =cefepime diHCI / L- arginine, 1.0:0.72 w/w;
Sulfate / L-arginine = cefepime sulfate/L-arginine, 1:0.78 w/w
2
Daily dose equally divided below between a.m. and p.m. administration

Chronic Toxicity

Species / N (sex) / Dose Range Route Duration Formulation1 Principal Findings

Strain Group (mg/kg/day)
Rat / SD 25 M 0 (saline) SC 26 weeks / L-Arg All dose groups: Dose dependent injection site
25 F 0 (L- (12-week irritation with secondary alterations in RBC
arginine), recovery and/or WBC counts, increased organ weight
100, 500, period) and/or hematopoiesis in spleen, liver and bone
10002 marrow. Dose dependent increase in water
intake during first 2 months.
500 mg/kg: 1 (M) sacrificed moribund during
dosing; 1 (M) sacrificed during recovery period.
Deaths unrelated to acute or systemic drug
toxicity. Fibrosarcoma at injection site of 2 (M)
with onset during recovery period.
≥ 500 mg/kg: Increased food intake at
intermediate dose (F) and high dose (M & F).
Increased kidney weight with increased (PAS+)
granules in proximal renal tubules and
exacerbation of age-related nephropathy.
Enlarged ceca.
1000 mg/kg: 2 (M) sacrificed moribund during
treatment. Deaths unrelated to acute or systemic
drug toxicity. Decreased body weight and
weight gain (M).
Chronic Toxicity (cont’d)

Species / N (sex) / Dose Range Route Duration Formulation1 Principal Findings

Strain Group (mg/kg/day)
Dog / 5M 0 (saline), 0 IV 26 weeks / L-Arg.1 All dose groups: Salivation, retching/emesis
Beagle 5F (L-arginine), (12-week and flusing after dosing with cefepime and
50, 150, 450 recovery) L-arginine.
50 mg/kg: 1 (M) found dead on day 139 (not
drug related).
≥ 150 mg/kg: Anemia, thrombocytopenia
and/or leukopenia in 9/10 high dose and 8/10
intermediate dose dogs. Thrombocytopenia
and leukopenia after 34 days and anemia
after 54 days at 450 mg/kg. Effects occurred
later (day 63 for thrombocytopenia and after
3 months for anemia) at 150 mg/kg. Dosing
interrupted in 4 high and 1 intermediate dose
dogs with reversal of hematologic
alterations. Slight increase in chloride,
sodium and globulin. Slight decrease in
urobilinogen. Increased (PAS+) granules in
cytoplasm of renal proximal tubules
(heterolysosomes). Extramedullary
hematopoiesis and hemosiderosis in liver
and spleen related to hematologic (RBC)
changes. Changes in bone marrow density in
1 intermediate and 2 high dose dogs.
450 mg/kg: 1 (F) sacrificed due to
prothrombin deficiency related hemorrhage.
Occasional ataxia, decreased activity (1M,
2F) and tremors (2F) with return to normal
in 5 – 20 minutes.
Alopecia (1M, 1F).
1
Formulations used: NaCl = cefepime: NaCl, 1:1 mole; /L-arg = cefepime diHCl/ L-arginine, 1.0:0.72 w/w;
Sulfate / L-arginine = cefepime sulfate/L-arginine, 1:0.78 w/w
2
Daily dose equally divided between a.m. and p.m. administration
 Reproduction and Teratology
Species / N (sex) / Range Route Formul- Principal Findings
Strain Dose (mg/kg/day) ation1
SEGMENT I
Rat / SD 23 M 0 (saline), 250, 500 or 10002 as SC NaCl No adverse effects on reproductive performance or on
23 F follows: fertility. Reduced body weight gain and food intake in
M: 64 days prior to mating intermediate F0 (M) and high dose F0 (M and F). Higher
through day 7 post mating incidence of post-implantation losses at high dose but
F: 14 days before mating within historical range for controls; reduced body weight
through day 7 post mating gain and food intake may have contributed. No
malformations, a few delayed ossifications.
Rat / SD 24 M 0 (saline), 0 (L-arginine) 150, 500 SC / L-arg. Soft stool at high dose during 1st week of treatment.
24 F or 10002 as follows: Decreased body weight gain from day 28 – 63 for high
M: 63 days prior to mating dose F0 (M). Increased kidney weights at high dose with
and during mating decreased pituitary and adrenal weight for high dose (M).
F: 14 days prior to mating Cecal enlargement in F0 cefepime (F). No effect on
through lactation prenatal development or delivery; or on littering
implantation, survival or lactation. No effects on
development or behavior of F1. Decreased heart weights
in F1 high dose at weaning. Decreased testicular weight in
F1 high dose at 10 weeks and after mating.
SEGMENT II
Mice / 25 F 0 (saline), 300, 600, 1200 on days 6 IV NaCl No evidence of maternal toxicity, embryotoxicity or
CD 1 to 15 of gestation (sacrifice day 18 teratogenicity. Higher incidence of delayed ossification
of gestation) (phalanges) at high dose.
Rat / SD 34 F 0 (saline), 250, 500, 10002 on days SC NaCl One high dose F0 dam died on 8th day of treatment.
7 to 17 of gestation 22 F/group Decreased food intake for mid and high dose F0 dams.
sacrificed on day 21; remainder Fertility, gestation, parturition, lactation of F0 dams not
delivered 11 – 12 / sex / group of F1 affected. Slight inhibition of growth for (F) offspring. No
for perinatal and postnatal effect on F1 development (sensory, neuromuscular or
evaluation (F1 dams sacrificed on reproductive). No evidence of teratogenicity at any dose
gestation day 14). (F0 or F1).
Rat / SD 25 F 0 (saline), 250, 500, 10002 on days SC / L-arg. No evidence of embryolethality, fetotoxicity or
6 to 17 of gestation (sacrificed day teratogenicity at any dose. Decreased food intake and
20) maternal weight gain at high dose.
Rat / SD 12 F 0 (saline), 250, 500 or 10002 on SC / L-arg. Food intake decreased at all cefepime dose levels in early
days 7 to 17 of gestation. Eight gestation and increased in the mid and high dose groups
pups / litter evaluated through post- for F0 dams on PN days 4 – 7. Decreased thyroid weight
natal (PN) day 22. for mid and high dose F0 dams sacrificed PN day 22. No
Remainder sacrificed PN day 4. evidence of teratogenicity or effects on behavior or
F0 sacrificed PN day 22. development.
Rabbit / 30 F 0 (saline), 25,50,100 on days 6 to IV NaCl One high dose non-gravid death on gestation day 25. Red
NZW 18 of gestation (sacrificed day 20) urine in 2 mid and 2 high dose (F). Bodyweight decrease
at high dose. Low pregnancy rate for all groups including
controls. No evidence of embryotoxicity or teratogenicity
at any dose.
Rabbit / 20 F 0 (saline), 0 (L-arginine), 25, 50, IV / L-arg. Maternal toxicity at 100 mg/kg with gastrointestinal
NZW 100 on days 6 to 19 of gestation distress, reduced weight gain, food intake and four deaths.
(sacrificed day 29) Slightly reduced maternal weight gain in all other groups
including L-arginine control. Slightly reduced fetal
weight at 100 mg/kg. No evidence of teratogenicity.
SEGMENT III
Rat / SD 25 F 0 (saline), 250, 500, 10002 on SC / L-arg Decreased F0 weight gain and food intake during
gestation day 16 through lactation treatment for all cefepime groups. Decreased F1 body
day 20 Selected F1 (20/sex/dose) weight at high dose from birth through lactation. No
mated; adverse effects on F1 development including reproductive
F1 (F) sacrificed following performance with no effects on F2 generation through
lactation. F2 sacrificed 4 days after birth.
birth.
1
Formulations used: NaCl = cefepime: NaCI, 1:1 mole; /L-Arg = cefepime diHCl/L- arginine, 1.0:0.72 w/w
2
Daily dose equally divided between a.m. and p.m. doses
Special Studies
Following subcutaneous administration of 100 or 500 mg/kg/day to neonatal male rats on
postnatal days 6 to 19, cefepime showed no evidence of testicular toxicity.

No evidence of nephrotoxicity was apparent in rabbits following the intravenous

administration of cefepime in single doses ranging up to 1000 mg/kg. Following
intraperitoneal administration in mice and intradermal administration in guinea pigs, both
cefepime and cefepime conjugated to heterologous protein were weakly immunogenic.

The potential cardiovascular effects of cefepime administered intravenously were

investigated in anesthetized rats and dogs. No significant effects were noted in rats at
doses up to 400 mg/kg or in dogs at doses up to 450 mg/kg. In dogs, a 450 mg/kg bolus
injection of cefepime L-arginine, or an equivalent amount of L-arginine alone, was
followed by transient decreases in arterial blood pressure, heart rate, and peripheral
vascular resistance. Assessments of nervous system functions did not indicate significant
effects in either dogs or rats.

Mutagenicity and Genotoxicity

Cefepime was not mutagenic in the Ames/Salmonella and E. coli WP2uvrA reverse
mutation assays. The results of the Chinese hamster ovary (CHO)/HGPRT mammalian
cell gene mutation assay were also negative. These gene mutation assays were done both
with and without exogenous metabolic activation systems. In a DNA damage and repair
study with primary hepatocytes in culture, the results were also negative. The results of
clastogenesis were negative in a CHO fibroblast assay, but they were positive in a
primary human lymphocyte culture after a 20-hour exposure, but not after a 4-hour
exposure. The results were negative in both sister chromatid exchange and chromosome
aberration assays, both done in non-dividing lymphocytes indicating that cefepime did
not directly damage the DNA in these human lymphocytes.

In mice, cefepime administered by the intravenous route at doses greater than

1000 mg/kg produced no evidence of genotoxicity in bone marrow. Also in mice,
cefepime administered subcutaneously at doses up to 1000 mg/kg for two days or as a
single intravenous dose of 1200 mg/kg produced no toxicity in a micronucleus assay.
REFERENCES

1. Bosso JA, Saxon BA and Matsen JM

Comparative Activity of Cefepime, Alone and in Combination, Against Clinical
Isolates of Pseudomonas aeruginosa and Pseudomonas cepacia from Cystic Fibrosis
Patients Antimicrob. Agents and Chemother 35 (4): 783-784 (1991).

2. Barbhaiya RH, Knupp CA, et al.

Safety, Tolerance and Pharmacokinetic of Cefepime Administered Intramuscularly to
Healthy Subjects
J. Clin. Pharmacol. 30: 900-910 (1990).

3. Barbhaiya RH, Forgue ST, et al.

Pharmacokinetics of Cefepime After Single and Multiple Intravenous Administration
in Healthy Subjects
Antimicrob. Agents Chemother. 36: 552-557 (1992).

4. Barbhaiya RH, Knupp CA and Pittman KA

Effect of Age and Gender on the Pharmacokinetics of Cefepime
Antimicrob. Agents Chemother. 36(6): 1181-1185 (1992).

5. Barbhaiya RH, Knupp CA, et al.

Pharmacokinetics of Cefepime in Subjects with Renal Insufficiency
Clin. Pharmacolol. Ther. 48: 268-276 (1990).

6. Barbhaiya RH, Knupp CA, et al.

Pharmacokinetics of Cefepime in Patients Undergoing Continuous Peritoneal Dialysis
Antimicrob. Agents Chemother. 36(7): 1387-1391 (1992).

7. Barbhaiya RH, Knupp CA, et al.

Lack of Pharmacokinetics Interaction Between Cefepime and Amikacin in Humans
Antimicrob. Agents Chemother. 36(7): 1382-1386 (1992).

8. Chadha D, Wise R, et al.

Cefepime Concentrations in Bronchial Mucosa and Serum Following a Single 2
Gram Intravenous Dose
J. Antimircrob. Chemother. 25: 959-963 (1990).

9. Edelstein H, Chirurgi V, et al
A Randomized Trial of Cefepime (BMY-28142) and Ceftazidime for the Treatment
of Pneumonia
J. Antimicrob. Chemother. 28: 569-575 (1991).

10. Gentry LO and Rodriguez-Gomez G

Randomized Comparison of Cefepime and Ceftazidime for Treatment of Skin,
Surgical Wound, and Complicated Urinary Tract Infections in Hospitalized Subjects
Antimircrob. Agents and Chemother. 35(11): 2371-2374 (1991).
11. Giamarellou H
Clinical Experience with the Fourth Generation Cephalosporins
J. Chemotherapy 8: Suppl. 2: 91-104 (1996).

12. Kalman D, Barriere SL and Lamar Johnson B

Pharmacokinetic Disposition and Bactericidal Activities of Cefepime, Ceftazidime,
and Cefoperazone in Serum and Blister Fluid
Antimicrob. Agents and Chemother. 36(2): 453-457 (1992).

13. Kessler RE, Bies M, et al.

Comparison of a New Cephalosporin, BMY-28142, with other Broad Spectrum β-
lactam Antibiotics
Antimicrob. Agents Chemother. 27: 207-216 (1985)

14. Kovarik JM, ter Maarten JC, et al.

Pharmacokinetics of Cefepime in Patients with Respiratory Tract Infections
Antimicrob. Agents Chemother. 34: 1885-1888 (1990).

15. Neu HC
Safety of Cefepime: A New Extended-Spectrum Parenteral Cephalosporin
The Amer.J.Med. 100: 6A-68S-6A-75S (1996).

16. Nye KJ, Shi YG, Andrews JM and Wise R

Pharmacokinetics and Tissue Penetration of Cefepime
J. Antimicrob. Chemother. 24: 23-28 (1989).

17. Ramphal R et al.

Clinical Experience with Single Agent and Combination Regimens in the
Management of Infection in the Febrile Neutropenic Patient
The Amer. J. Med. 100: 6A-83S-6A-89S (1996).

18. Okamoto MP, Chin A, et al.

Analysis of Cefepime Tissue Penetration into Human Appendix
Pharmacotherpy 11: 353-358 (1991).

19. Oster S, Edelstein H, et al.

Open Trial of Cefepime (BMY-28142) for Infections in Hospitalized Patients
Antimicrob. Agents and Chemother. 34(6): 954-957 (1990).

20. Shah PM
The Position of Recently Developed Broad-Spectrum Antibiotics in Bacterial
Septicemia
Chemotherapy 8: Suppl. 2: 105-111 (1996).

21. NCCLS Document M 100-S5, Vol. 14, No. 16, Fifth International Supplement,
December 1994.

22. NCCLS Document M2-A5, Vol. 13, No. 24, December 1993.
23. NCCLS Document M7-A3, Vol. 13, No. 25, December 1993.

24. Cefepime Hydrochloride Injection: Six-Month Periodic Safety Update Report, 17

May 2000, ISN 1560.1.

25. Cockcroft DW and Gault MH

Prediction of creatinine clearance from serum creatinine
Nephron. 16: 31-41 (1976).

26. Schwartz GJ, et al

A Simple Estimate of Glomerular Filtration Rate in Children Derived From Body
Length and Plasma Creatinine.
Pediatrics 58 (2) 259-263 (1976).

27. Dechaux M, et al
Créatinine Plasmatique, Clearance et Excrétion Urinaire de la Créatinine Chez
I’enfant
Arch. France Péd. 35: 53-62 (1978)

28. Product Monograph – Maxipime (cefepime hydrochloride). Bristol-Myers Squibb

Canada. Date of Revision: September 23, 2008.
 IMPORTANT: PLEASE READ

PART III: CONSUMER INFORMATION What the important nonmedicinal ingredients

are: L-arginine
PrCEFEPIME FOR INJECTION
What dosage forms it comes in:
(cefepime hydrochloride) It is available in single use vials containing 1 g and 2
g of cefepime activity.
This leaflet is part III of a three-part "Product
Monograph" published when Cefepime for
WARNINGS AND PRECAUTIONS
injection was approved for sale in Canada and is
designed specifically for Consumers. This leaflet is a Before receiving cefepime for injection and to get the
summary and will not tell you everything about best possible treatment, be sure to tell your doctor if
Cefepime for injection. Contact your doctor or you:
pharmacist if you have any questions about the  Have had an allergic reaction to cefepime
drug. for injection or other medicines such as
cephalosporins, penicillins or other beta-
Antibacterial drugs like Cefepime for injection lactam antibiotics.
treat only bacterial infections. They do not treat  Have a history of gastrointestinal disease,
viral infections such as the common cold. Although particularly colitis
you may feel better early in treatment, Cefepime for  Have kidney disease or liver disease
injection should be used exactly as directed. Misuse  Are pregnant or could become pregnant
or overuse of Cefepime for injection could lead to during treatment
the growth of bacteria that will not be killed by  Are breast feeding
Cefepime for injection (resistance). This means that It is important for your doctor to have this
Cefepime for injection may not work for you in the information before prescribing your treatment and
future. Do not share your medicine. dosage.

ABOUT THIS MEDICATION INTERACTIONS WITH THIS MEDICATION

Ask your doctor or pharmacist before using any other
What the medication is used for: medicine, including over-the-counter medicines,
Cefepime for injection is indicated in the treatment of vitamins, and herbal products.
the following infections when caused by susceptible Increased kidney toxicity has been reported when
bacteria: other specific types of antibiotics have been given
 Lower respiratory tract infections with cefepime for injection.
 Urinary tract infections
 Skin infections If you have diabetes, this medicine could affect a
 Peritonitis urine test for sugar.
 Bacterial septicemia
Ask your doctor how you should do a urine sugar
What it does: test.
Cefepime for injection is an antibiotic, which belongs PROPER USE OF THIS MEDICATION
to a class of drugs called cephalosporins. Cefepime for Usual dose: cefepime for injection can be given
injection works by killing bacteria which cause either as an injection into a vein or into your muscle.
infections in the body. The dosage and route of administration is determined
according to the susceptibility of the causative
When it should not be used: organisms, the severity of the infection, and your
Cefepime for injection will not be administered if you general condition including your kidney function. In
the event of overdosage, contact your doctor, hospital
have had an allergic reaction to cefepime or other emergency department or regional Poison Control
Centre.
antibiotics such as cephalosporins, penicillins or other

beta-lactam antibiotics. SIDE EFFECTS AND WHAT TO DO ABOUT THEM

What the medicinal ingredient is: Like other medicines, cefepime for injection can cause
Cefepime Hydrochloride some side effects. If you experience any of the
following uncommon but serious side effects, seek
emergency medical attention or contact your doctor
 IMPORTANT: PLEASE READ

immediately: or genitals, itching,

 Allergic reaction: Itching or hives, swelling in severe rash, bumps
your face or hands, swelling or tingling in your under the skin, skin
mouth or throat, chest tightness, trouble pain, skin color
changes (redness,
breathing
yellowing, purplish)
 Blistering, peeling, red skin rash
 Change in how much or how often you urinate • Swelling and
 Confusion, hallucinations, loss of consciousness redness of eyes or
or seizures face
 Dark-colored urine or pale stools
• Flu-like feeling,
 Severe diarrhea that may contain blood
fever, chills, body
 Fever, chills, cough, sore throat, or body aches aches, swollen
 Severe nausea, vomiting, loss of appetite, or pain glands, cough
in your upper stomach
 Unusual bleeding, bruising, or weakness • Shortness of
 Yellowing of your skin or the whites of your breath, chest pain
eyes or discomfort
 White spots or sores on lips or in mouth
HOW TO STORE IT
Other, less serious side effects may be more likely to
occur. Talk to your doctor if you experience: All medicines should be kept out of reach of children.
 Diarrhea (mild)
 Headache Store dry powder at room temperature (15-30C) and
 Mild skin rash or itching protect from light. The dry powder may also be stored
 Vaginal itching or discharge in the refrigerator (2-8°C), protected from light.
 Pain, itching, burning, swelling, or a lump under
your skin at injection site Reporting Side Effects
You can report any suspected side effects associated with
Other side effects may occur that usually do not need the use of health products to Health Canada by:
medical attention. These side effects may go away
during treatment as your body adjusts to the medicine.  Visiting the Web page on Adverse Reaction
However, check with your doctor for any side effect Reporting (https://www.canada.ca/en/health-
that seems unusual or that is especially bothersome. canada/services/drugs-health-products/medeffect-
canada/adverse-reaction-reporting.html) for
This is not a complete list of side effects. For any information on how to report online, by mail or
unexpected effects while taking cefepime for injection, fax; or
contact your doctor or pharmacist.
 Calling toll-free at 1-866-234-2345.
Serious side effects and what to do about them
NOTE: Contact your health professional if you need
Talk to your Stop
healthcare taking
information about how to manage your side effects. The
professional drug and Canada Vigilance Program does not provide medical
Symptom / effect Only get advice.
if In all immediat
sever cases e medical MORE INFORMATION
e help
Severe Cutaneous
For more information, please contact your doctor,
Adverse Reactions
(SCAR) (severe skin
pharmacist or other healthcare professional.
reactions that may also
affect other organs): This leaflet plus the full product monograph, prepared
for health professionals, can be obtained by contacting
• Skin peeling,
 DISpedia, Apotex's Drug Information Service at: 1-
scaling, or blistering 800-667-4708
(with or without
pus) which may This leaflet can also be found at:
also affect your http://www.apotex.ca/products
eyes, mouth, nose
 IMPORTANT: PLEASE READ

This leaflet was prepared by Apotex Inc., Toronto,

Ontario, M9L 1T9.

Date of Revision: April 20, 2020

Mfg.by: Orchid Healthcare

(A Division of Orchid
Chemicals &
Pharmaceuticals Ltd.)
Plot No: B3-B6 & B11-B14, SIPCOT Industrial
Park, Irungattukottai- 602 105, Sriperumbudur
P.O., Kancheepuram District, INDIA.