Cefepime

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Cefepime Prescribing Information

Cefepime for Injection is a cephalosporin antibacterial indicated for the treatment of the following infections caused by susceptible strains of the designated microorganisms:

•Pneumonia. (
1.1 Pneumonia
Cefepime for Injection is indicated in the treatment of pneumonia (moderate to severe) caused by susceptible strains of
Streptococcus pneumoniae
, including cases associated with concurrent bacteremia,
Pseudomonas aeruginosa
,
Klebsiella pneumoniae
, or
Enterobacter
species.
)
•Empiric therapy for febrile neutropenic patients. (
1.2 Empiric Therapy for Febrile Neutropenic Patients
Cefepime for Injection as monotherapy is indicated for empiric treatment of febrile neutropenic patients. In patients at high risk for severe infection (including patients with a history of recent bone marrow transplantation, with hypotension at presentation, with an underlying hematologic malignancy, or with severe or prolonged neutropenia), antimicrobial monotherapy may not be appropriate. Insufficient data exist to support the efficacy of cefepime monotherapy in such patients [
see Clinical Studies (14.1)
].
)
•Uncomplicated and complicated urinary tract infections (including pyelonephritis). (
1.3 Uncomplicated and Complicated Urinary Tract Infections (including pyelonephritis)
Cefepime for Injection is indicated in the treatment of uncomplicated and complicated urinary tract infections (including pyelonephritis) caused by susceptible isolates of
Escherichia coli
or
Klebsiella pneumoniae
, when the infection is severe, or caused by
Escherichia coli
,
Klebsiella pneumoniae
, or
Proteus mirabilis
, when the infection is mild to moderate, including cases associated with concurrent bacteremia with these bacteria.
)
•Uncomplicated skin and skin structure infections. (
1.4 Uncomplicated Skin and Skin Structure Infections
Cefepime for Injection is indicated in the treatment of uncomplicated skin and skin structure infections caused by
Staphylococcus aureus
(methicillin-susceptible isolates only) or
Streptococcus pyogenes
.
)
•Complicated intra-abdominal infections (used in combination with metronidazole) in adults. (
1.5 Complicated Intra-abdominal Infections (used in combination with metronidazole)
Cefepime for Injection is indicated in the treatment of complicated intra-abdominal infections (used in combination with metronidazole) in adults caused by susceptible isolates of
Escherichia coli
, viridans group streptococci,
Pseudomonas aeruginosa
,
Klebsiella pneumoniae
,
Enterobacter
species, or
Bacteroides fragilis
[
see Clinical Studies (14.2)
].
)

1.6 Usage

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Cefepime for Injection and other antibacterial drugs, Cefepime for Injection should be used only to treat 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.

)

^§For

Pseudomonas aeruginosa

, use 2 g IV every 8 hours. (

2.1 Dosage for Adults

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

Table 1: Recommended Dosage Schedule for Cefepime for Injection in Adult Patients with Creatinine Clearance (CrCL) Greater Than 60 mL/min
or until resolution of neutropenia. In patients whose fever resolves but who remain neutropenic for more than 7 days, the need for continued antimicrobial therapy should be re-evaluated frequently. *Intramuscular route of administration is indicated only for mild to moderate, uncomplicated or complicated UTIs due to E. coli . ^§For P. aeruginosa , use 2 g IV every 8 hours.
Site and Type of Infection	Dose	Frequency	Duration
Site and Type of Infection	Dose	Frequency	(days)
Adults	Intravenous (IV)/Intramuscular (IM)
Moderate to Severe Pneumonia^§	1 to 2 g IV	Every 8 to 12 hours	10
Empiric therapy for febrile neutropenic patients	2 g IV	Every 8 hours	7*
Mild to Moderate Uncomplicated or Complicated Urinary Tract Infections, including pyelonephritis	0.5 to 1 g IV/IM**	Every 12 hours	7 to 10
Severe Uncomplicated or Complicated Urinary Tract Infections, including pyelonephritis	2 g IV	Every 12 hours	10
Moderate to Severe Uncomplicated Skin and Skin Structure Infections	2 g IV	Every 12 hours	10
Complicated Intra-abdominal Infections^§(used in combination with metronidazole)	2 g IV	Every 8 to 12 hours	7 to 10

)

*Or until resolution of neutropenia. (

2.1 Dosage for Adults

Table 1: Recommended Dosage Schedule for Cefepime for Injection in Adult Patients with Creatinine Clearance (CrCL) Greater Than 60 mL/min
or until resolution of neutropenia. In patients whose fever resolves but who remain neutropenic for more than 7 days, the need for continued antimicrobial therapy should be re-evaluated frequently. *Intramuscular route of administration is indicated only for mild to moderate, uncomplicated or complicated UTIs due to E. coli . ^§For P. aeruginosa , use 2 g IV every 8 hours.
Site and Type of Infection	Dose	Frequency	Duration
Site and Type of Infection	Dose	Frequency	(days)
Adults	Intravenous (IV)/Intramuscular (IM)
Moderate to Severe Pneumonia^§	1 to 2 g IV	Every 8 to 12 hours	10
Empiric therapy for febrile neutropenic patients	2 g IV	Every 8 hours	7*
Mild to Moderate Uncomplicated or Complicated Urinary Tract Infections, including pyelonephritis	0.5 to 1 g IV/IM**	Every 12 hours	7 to 10
Severe Uncomplicated or Complicated Urinary Tract Infections, including pyelonephritis	2 g IV	Every 12 hours	10
Moderate to Severe Uncomplicated Skin and Skin Structure Infections	2 g IV	Every 12 hours	10
Complicated Intra-abdominal Infections^§(used in combination with metronidazole)	2 g IV	Every 8 to 12 hours	7 to 10

)

**Intramuscular route of administration is indicated only for mild to moderate, uncomplicated or complicated UTIs due to

E. coli

. (

2.1 Dosage for Adults

Table 1: Recommended Dosage Schedule for Cefepime for Injection in Adult Patients with Creatinine Clearance (CrCL) Greater Than 60 mL/min
or until resolution of neutropenia. In patients whose fever resolves but who remain neutropenic for more than 7 days, the need for continued antimicrobial therapy should be re-evaluated frequently. *Intramuscular route of administration is indicated only for mild to moderate, uncomplicated or complicated UTIs due to E. coli . ^§For P. aeruginosa , use 2 g IV every 8 hours.
Site and Type of Infection	Dose	Frequency	Duration
Site and Type of Infection	Dose	Frequency	(days)
Adults	Intravenous (IV)/Intramuscular (IM)
Moderate to Severe Pneumonia^§	1 to 2 g IV	Every 8 to 12 hours	10
Empiric therapy for febrile neutropenic patients	2 g IV	Every 8 hours	7*
Mild to Moderate Uncomplicated or Complicated Urinary Tract Infections, including pyelonephritis	0.5 to 1 g IV/IM**	Every 12 hours	7 to 10
Severe Uncomplicated or Complicated Urinary Tract Infections, including pyelonephritis	2 g IV	Every 12 hours	10
Moderate to Severe Uncomplicated Skin and Skin Structure Infections	2 g IV	Every 12 hours	10
Complicated Intra-abdominal Infections^§(used in combination with metronidazole)	2 g IV	Every 8 to 12 hours	7 to 10

)

Recommended Dosage in Adults with Creatinine Clearance (CrCL)

Greater Than 60 mL/min (

2.1 Dosage for Adults

Table 1: Recommended Dosage Schedule for Cefepime for Injection in Adult Patients with Creatinine Clearance (CrCL) Greater Than 60 mL/min
or until resolution of neutropenia. In patients whose fever resolves but who remain neutropenic for more than 7 days, the need for continued antimicrobial therapy should be re-evaluated frequently. *Intramuscular route of administration is indicated only for mild to moderate, uncomplicated or complicated UTIs due to E. coli . ^§For P. aeruginosa , use 2 g IV every 8 hours.
Site and Type of Infection	Dose	Frequency	Duration
Site and Type of Infection	Dose	Frequency	(days)
Adults	Intravenous (IV)/Intramuscular (IM)
Moderate to Severe Pneumonia^§	1 to 2 g IV	Every 8 to 12 hours	10
Empiric therapy for febrile neutropenic patients	2 g IV	Every 8 hours	7*
Mild to Moderate Uncomplicated or Complicated Urinary Tract Infections, including pyelonephritis	0.5 to 1 g IV/IM**	Every 12 hours	7 to 10
Severe Uncomplicated or Complicated Urinary Tract Infections, including pyelonephritis	2 g IV	Every 12 hours	10
Moderate to Severe Uncomplicated Skin and Skin Structure Infections	2 g IV	Every 12 hours	10
Complicated Intra-abdominal Infections^§(used in combination with metronidazole)	2 g IV	Every 8 to 12 hours	7 to 10

)

Site and Type of Infection

Dose

Frequency

Duration (days)

Moderate to Severe Pneumonia^§

1-2 g IV

Every 8-12 hours

Empiric Therapy for Febrile Neutropenic Patients

2 g IV

Every 8 hours

Mild to Moderate Uncomplicated or Complicated Urinary Tract Infections

0.5-1 g IV/IM**

Every 12 hours

7-10

Severe Uncomplicated or Complicated Urinary Tract Infections

2 g IV

Every 12 hours

Moderate to Severe Uncomplicated Skin and Skin Structure Infections

2 g IV

Every 12 hours

Complicated Intra-abdominal Infections^§ (used in combination with metronidazole)

2 g IV

Every 12 hours

7-10

Pediatric Patients (2 months to 16 years)

Recommended dosage in pediatric with CrCL greater than 60 mL/min. (

2.2 Pediatric Patients (2 months up to 16 years)

The maximum dose for pediatric patients should not exceed the recommended adult dose.

The usual recommended dosage in pediatric patients up to 40 kg in weight for durations as given above for adults is:

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

)

•The usual recommended dosage in pediatric patients is 50 mg per kg per dose administered every 12 hours (every 8 hours for febrile neutropenia). (
2.2 Pediatric Patients (2 months up to 16 years)
The maximum dose for pediatric patients should not exceed the recommended adult dose.
The usual recommended dosage in pediatric patients up to 40 kg in weight for durations as given above for adults is:
- •50 mg per kg per dose, administered every 12 hours for uncomplicated and complicated urinary tract infections (including pyelonephritis), uncomplicated skin and skin structure infections, and pneumonia (see below).
- •For moderate to severe pneumonia due to
  P. aeruginosa
  give 50 mg per kg per dose, every 8 hours.
- •50 mg per kg per dose, every 8 hours for febrile neutropenic patients.
)

•

Patients with Renal Impairment:

Adjust dose in patients with CrCL less than or equal to 60 mL/min. (

2.3 Dosage Adjustments in Patients with Renal Impairment

Adult Patients

Adjust the dose of Cefepime for Injection in patients with creatinine clearance less than or equal to 60 mL/min to compensate for the slower rate of renal elimination. In these patients, the recommended initial dose of Cefepime for Injection should be the same as in patients with CrCL greater than 60 mL/min except in patients undergoing hemodialysis. The recommended doses of Cefepime for Injection in patients with renal impairment are presented in Table 2.

When only serum creatinine is available, the following formula (Cockcroft and Gault equation)¹may 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 × serum creatinine (mg/dL)

Females: 0.85 × above value

Table 2: Recommended Dosing Schedule for Cefepime for Injection in Adult Patients With Creatinine Clearance Less Than or Equal to 60 mL/min
Creatinine Clearance (mL/min)	Recommended Maintenance Schedule
Greater than 60	500 mg every 12 hours	1 g every 12 hours	2 g every 12 hours	2 g every 8 hours
30 to 60	500 mg every 24 hours	1 g every 24 hours	2 g every 24 hours	2 g every 12 hours
11 to 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
HemodialysisOn hemodialysis days, cefepime should be administered following hemodialysis. Whenever possible, cefepime should be administered at the same time each day.	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 for Injection may be administered at the recommended doses at a dosage interval of every 48 hours (see Table 2).

In patients undergoing hemodialysis, approximately 68% of the total amount of cefepime present in the body at the start of dialysis will be removed during a 3-hour dialysis period. The dosage of Cefepime for Injection for hemodialysis patients is 1 g on Day 1 followed by 500 mg every 24 hours for the treatment of all infections except febrile neutropenia, which is 1 g every 24 hours.

Cefepime for Injection should be administered at the same time each day and following the completion of hemodialysis on hemodialysis days (see Table 2).

Pediatric 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 Tables 1and 2) are recommended for pediatric patients.

)

•Geriatric Use: Serious neurologic adverse reactions have occurred in geriatric patients with renal insufficiency given unadjusted doses of cefepime. (
8.5 Geriatric Use
Of the more than 6400 adults treated with Cefepime for Injection in clinical studies, 35% were 65 years or older while 16% were 75 years or older. When geriatric patients received the usual recommended adult dose, clinical efficacy and safety were comparable to clinical efficacy and safety in non-geriatric adult patients.
Serious adverse events have occurred in geriatric patients with renal insufficiency given unadjusted doses of cefepime, including life-threatening or fatal occurrences of the following: encephalopathy, myoclonus, and seizures [
see Warnings and Precautions (5.2), Adverse Reactions (6.2)
].
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and renal function should be monitored [
see Clinical Pharmacology (12.3), Warnings and Precautions (5.2), Dosage and Administration (2.3)
].
)

•

Hypersensitivity Reactions:

Cross-hypersensitivity among beta-lactam antibacterial drugs may occur in up to 10% of patients with a history of penicillin allergy. If an allergic reaction to Cefepime for Injection occurs, discontinue the drug. (

5.1 Hypersensitivity Reactions

Before therapy with Cefepime for Injection is instituted, careful inquiry should be made to determine whether the patient has had previous immediate hypersensitivity reactions to cefepime, cephalosporins, penicillins, or other beta-lactams. Exercise caution if this product is to be given to penicillin-sensitive patients because cross-hypersensitivity among beta-lactam antibacterial drugs has been clearly documented and may occur in up to 10% of patients with a history of penicillin allergy. If an allergic reaction to Cefepime for Injection occurs, discontinue the drug and institute appropriate supportive measures.

)

•

Neurotoxicity:

May occur especially in patients with renal impairment administered unadjusted doses. If neurotoxicity associated with Cefepime for Injection therapy occurs, discontinue the drug. (

5.2 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.

)

•

Clostridioides difficile

-Associated Diarrhea

(CDAD):

Evaluate if diarrhea occurs. (

5.3
Clostridioides difficile
-Associated Diarrhea

Clostridioides difficile

-Associated Diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Cefepime for Injection, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of

C. difficile.

C. difficile

produces toxins A and B, which contribute to the development of CDAD. Hypertoxin-producing strains of

C. difficile

cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial drug use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against

C. difficile

may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial drug treatment of

C. difficile

, and surgical evaluation should be instituted as clinically indicated.

)

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