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Cefepime (Cefepime Hydrochloride) - Description and Clinical Pharmacology

 
 



Rx only
For Intravenous or Intramuscular Use

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 bacteria.

DESCRIPTION

Cefepime for injection, USP is a semi-synthetic, broad spectrum, cephalosporin antibiotic for parenteral administration. The chemical name is 1-[[(6R,7R)-7-[2-(2-amino-4-thiazolyl)-glyoxylamido] -2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0] oct-2-en-3-yl]methyl]-1-methylpyrrolidinium chloride, 72-(Z)-(O-methyloxime), monohydrochloride, monohydrate, which corresponds to the following structural formula:



Cefepime hydrochloride is a white to pale yellow powder. Cefepime hydrochloride contains the equivalent of not less than 825 mcg and not more than 911 mcg of cefepime (C19H24N6O5S2) per mg, calculated on an anhydrous basis. It is highly soluble in water.

Cefepime for injection, USP is supplied for intramuscular or intravenous administration in strengths equivalent to 1 g, and 2 g of cefepime (see DOSAGE AND ADMINISTRATION). Cefepime for injection, USP is a sterile, dry mixture of cefepime hydrochloride and L-arginine. It contains the equivalent of not less than 90 percent and not more than 115 percent of the labeled amount of cefepime (C19H24N6O5S2). The L-arginine, at an approximate concentration of 707 mg/g of cefepime, is added to control the pH of the constituted solution at 4 to 6. Freshly constituted solutions of cefepime for injection, USP will range in color from pale yellow to amber.

CLINICAL PHARMACOLOGY

Cefepime is an antibacterial agent belonging to the cephalosporin class of antibacterials with in vitro antibacterial activity against facultative Gram-positive and Gram-negative bacteria.

Pharmacokinetics

The average plasma concentrations of cefepime observed in healthy adult male volunteers (n=9) at various times following single 30-minute infusions (IV) of cefepime 500 mg, 1 g, and 2 g are summarized in Table 1. Elimination of cefepime is principally via renal excretion with an average (±SD) half-life of 2 (±0.3) hours and total body clearance of 120 (±8) mL/min in healthy volunteers. Cefepime pharmacokinetics are linear over the range 250 mg to 2 g. There is no evidence of accumulation in healthy adult male volunteers (n=7) receiving clinically relevant doses for a period of 9 days.

Absorption

The average plasma concentrations of cefepime and its derived pharmacokinetic parameters after intravenous (IV) administration are portrayed in Table 1.


Table 1: Average Plasma Concentrations in mcg/mL of  Cefepime and Derived
Pharmacokinetic Parameters (±SD), Intravenous Administration
 
Cefepime for Injection
Parameter
500 mg IV
1 g IV
2 g IV
0.5 h
38.2
78.7
163.1
1 h
21.6
44.5
85.8
2 h
11.6
24.3
44.8
4 h
5
10.5
19.2
8 h
1.4
2.4
3.9
12 h
0.2
0.6
1.1
Cmax, mcg/mL
39.1 (3.5)
81.7 (5.1)
163.9 (25.3)
AUC, h•mcg/mL
70.8 (6.7)
148.5 (15.1)
284.8 (30.6)
Number of subjects (male)
9
9
9

 Following intramuscular (IM) administration, cefepime is completely absorbed. The average plasma concentrations of cefepime at various times following a single intramuscular injection are summarized in Table 2. The pharmacokinetics of cefepime are linear over the range of 500 mg to 2 g intramuscularly and do not vary with respect to treatment duration.   


Table 2: Average Plasma Concentrations in mcg/mL of Cefepime and Derived Pharmacokinetic Parameters (±SD), Intramuscular Administration
 
Cefepime for Injection
Parameter
500 mg IM
1 g IM
2 g IM
0.5 h
8.2
14.8
36.1
1 h
12.5
25.9
49.9
2 h
12
26.3
51.3
4 h
6.9
16
31.5
8 h
1.9
4.5
8.7
12 h
0.7
1.4
2.3
Cmax, mcg/mL
13.9 (3.4)
29.6 (4.4)
57.5 (9.5)
Tmax, h
1.4 (0.9)
1.6 (0.4)
1.5 (0.4)
AUC, h•mcg/mL
60 (8)
137 (11)
262 (23)
Number of subjects (male)
6
6
12

Distribution

The average steady-state volume of distribution of cefepime is 18 (±2) L. The serum protein binding of cefepime is approximately 20% and is independent of its concentration in serum.


Cefepime is excreted in human milk. A nursing infant consuming approximately 1000 mL of human milk per day would receive approximately 0.5 mg of cefepime per day (see PRECAUTIONS: Nursing Mothers).


Concentrations of cefepime achieved in specific tissues and body fluids are listed in Table 3.


Table 3: Average Concentrations of Cefepime in Specific Body Fluids (mcg/mL) or Tissues (mcg/g)

Tissue or Fluid

  Dose/ 
Route

# of Patients

Average Time of Sample Post-Dose (h)

Average Concentration
Blister Fluid
2 g IV
6
1.5
81.4 mcg/mL
Bronchial Mucosa
2 g IV
20
4.8
24.1 mcg/g
Sputum
2 g IV
5
4
7.4 mcg/mL
Urine
500 mg IV
8
0 to 4
292 mcg/mL
1 g IV
12
0 to 4
926 mcg/mL
2 g IV
12
0 to 4
3120 mcg/mL
Bile
2 g IV
26
9.4
17.8 mcg/mL
Peritoneal Fluid
2 g IV
19
4.4
18.3 mcg/mL
Appendix
2 g IV
31
5.7
5.2 mcg/g
Gallbladder
2 g IV
38
8.9
11.9 mcg/g
Prostate
2 g IV
5
1
31.5 mcg/g

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


Metabolism and Excretion

Cefepime is metabolized to N-methylpyrrolidine (NMP) which is rapidly converted to the N-oxide (NMP-N-oxide). Urinary recovery of unchanged cefepime accounts for approximately 85% of the administered dose. Less than 1% of the administered dose is recovered from urine as NMP, 6.8% as NMP-N-oxide, and 2.5% as an epimer of cefepime. Because renal excretion is a significant pathway of elimination, patients with renal dysfunction and patients undergoing hemodialysis require dosage adjustment (see DOSAGE AND ADMINISTRATION).

Specific Populations

Renal impairment: Cefepime pharmacokinetics have been investigated in patients with various degrees of renal impairment (n=30). The average half-life in patients requiring hemodialysis was 13.5 (±2.7) hours and in patients requiring continuous peritoneal dialysis was 19 (±2) hours. Cefepime total body clearance decreased proportionally with creatinine clearance in patients with abnormal renal function, which serves as the basis for dosage adjustment recommendations in this group of patients (see DOSAGE AND ADMINISTRATION).

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

Geriatric patients: Cefepime pharmacokinetics have been investigated in elderly (65 years of age and older) men (n=12) and women (n=12) whose mean (SD) creatinine clearance was 74 (±15) mL/min. There appeared to be a decrease in cefepime total body clearance as a function of creatinine clearance. Therefore, dosage administration of cefepime in the elderly should be adjusted as appropriate if the patient’s creatinine clearance is 60 mL/min or less (see DOSAGE AND ADMINISTRATION).

Pediatric patients:Cefepime pharmacokinetics have been evaluated in pediatric patients from 2 months to 11 years of age following single and multiple doses on every 8 hours (n=29) and every 12 hours (n=13) schedules. Following a single intravenous dose, total body clearance and the steady-state volume of distribution averaged 3.3 (±1) mL/min/kg and 0.3 (±0.1) L/kg, respectively. The urinary recovery of unchanged cefepime was 60.4 (±30.4)% of the administered dose, and the average renal clearance was 2 (±1.1) mL/min/kg. There were no significant effects of age or gender (25 male vs 17 female) on total body clearance or volume of distribution, corrected for body weight. No accumulation was seen when cefepime was given at 50 mg per kg every 12 hours (n=13), while Cmax, AUC, and t½ were increased about 15% at steady state after 50 mg per kg every 8 hours. The exposure to cefepime following a 50 mg per kg intravenous dose in a pediatric patient is comparable to that in an adult treated with a 2 g intravenous dose. The absolute bioavailability of cefepime after an intramuscular dose of 50 mg per kg was 82.3 (±15)% in eight patients.

Microbiology

Susceptibility Test Methods

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

Dilution Techniques

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method1,2 (broth and/or agar). The MIC should be interpreted according to the criteria provided in Table 4.

Diffusion Techniques

Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method.2,3    This procedure uses paper discs impregnated with 30 mcg cefepime to test the susceptibility of microorganisms to cefepime. The disc diffusion interpretive criteria are provided in Table 4.




Table 4: Susceptibility Test Interpretive Criteria for Cefepime¥
Pathogen
Minimum Inhibitory Concentrations (mcg/mL)
Disk Diffusion Zone Diameters
(mm)
(S)
Susceptible
(I)
Intermediate
(R)
Resistant
(S)
Susceptible
(I)
Intermediate
(R)
Resistant
 Enterobacteriaceae
≤2
4 to 8*
≥16
≥25
19 to 24*
≤18
Pseudomonas aeruginosa §
≤8
-
≥16
≥18
-
≤17
Streptococcus pneumoniae b
non-meningitis isolates
≤1
2
≥4
-
-
-
Streptococcus pyogenes
≤0.5
-
-
≥24
-
-
Viridans group streptococci
≤1
2
≥4
≥24
22 to 23
≤21

¥For patients with renal impairment see Table 11 in Dosage and Administration

*For isolates of Enterobacteriaceae with intermediate susceptibility, use a dose of 2 g every 8 hours in patients with normal renal function

§For P. aeruginosa, use 2 g IV every 8 hours in patients with normal renal function

bFor non-meningitis isolates, a penicillin MIC of ≤ 0.06 mcg/mL (or oxacillin zone ≥ 20 mm) can predict susceptibility to cefepime.

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


A report of “Susceptible” indicates that the antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations at the infection site necessary to inhibit growth of the pathogen. A report of “Intermediate” indicates that the results should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug product is physiologically concentrated or in situations where a high dosage of the drug can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that the antimicrobial  is not likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations usually achievable at the infection site; other therapy should be selected.


Quality Control


Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individual performing the test.1,2,3 Standard cefepime powder should provide the following range of MIC values noted in Table 5. For the diffusion technique using the 30 mcg disc, the criteria in Table 5 should be achieved.


Table 5: Acceptable Quality Control Ranges for Cefepime
QC Strain
Minimum Inhibitory Concentrations (mcg/mL)
Disk Diffusion
(zone diameters in mm)
Escherichia coli ATCC 25922
0.015 to 0.12
31 to 37
Staphylococcus aureus ATCC 29213
1 to 4
-
Staphylococcus aureus ATCC 25923
-
23 to 29
Pseudomonas aeruginosa ATCC 27853
0.5 to 4
24 to 30
Streptococcus pneumoniae ATCC 49619
0.03 to 0.25
28 to 35
Haemophilus influenzae ATCC 49247
0.5 to 2
25 to 31
Neisseria gonorrhoeae ATCC 49226
0.015 to 0.06
37 to 46

CLINICAL STUDIES

Febrile Neutropenic Patients


The safety and efficacy of empiric cefepime monotherapy of febrile neutropenic patients have been assessed in two multicenter, randomized trials comparing cefepime monotherapy (at a dose of 2 g intravenously every 8 hours) to ceftazidime monotherapy (at a dose of 2 g intravenously every 8 hours). These studies comprised 317 evaluable patients. Table 6 describes the characteristics of the evaluable patient population.

Table 6: Demographics of Evaluable Patients (First Episodes Only)

Total

Cefepime
Ceftazidime
164
153
Median age (yr)
56 (range, 18 to 82)
55 (range, 16 to 84)
Male
86 (52%)
85 (56%)
Female
78 (48%)
68 (44%)
Leukemia
65 (40%)
52 (34%)
Other hematologic malignancies
43 (26%)
36 (24%)
Solid tumor
54 (33%)
56 (37%)
Median ANC nadir (cells/microliter)
20 (range, 0 to 500)
20 (range, 0 to 500)
Median duration of neutropenia (days)
6 (range, 0 to 39)
6 (range, 0 to 32)
Indwelling venous catheter
97 (59%)
86 (56%)
Prophylactic antibiotics
62 (38%)
64 (42%)
Bone marrow graft
9 (5%)
7 (5%)
SBP less than 90 mm Hg at entry
7 (4%)
2 (1%)

 ANC = absolute neutrophil count; SBP = systolic blood pressure


Table 7 describes the clinical response rates observed. For all outcome measures, cefepime was therapeutically equivalent to ceftazidime.


Table 7: Pooled Response Rates for Empiric Therapy of Febrile Neutropenic Patients


Outcome Measures

% Response
 
Cefepime
 
(n=164)
 
Ceftazidime
 
(n=153)
Primary episode resolved with no treatment modification, no new febrile episodes or infection, and oral antibiotics allowed for completion of treatment
51
55
Primary episode resolved with no treatment modification, no new febrile episodes or infection and no post-treatment oral antibiotics
34
39
Survival, any treatment modification allowed
93
97
Primary episode resolved with no treatment modification and oral antibiotics allowed for completion of treatment
62
67
Primary episode resolved with no treatment modification and no post-treatment oral antibiotics
46
51

Insufficient data exist to support the efficacy of cefepime monotherapy in patients at high risk for severe infection (including patients with a history of recent bone marrow transplantation, with hypotension at presentation, with an underlying hematologic malignancy, or with severe or prolonged neutropenia). No data are available in patients with septic shock.


Complicated Intra-Abdominal Infections


Patients hospitalized with complicated intra-abdominal infections participated in a randomized, double-blind, multicenter trial comparing the combination of cefepime (2 g every 12 hours) plus intravenous metronidazole (500 mg every 6 hours) versus imipenem/cilastatin (500 mg every 6 hours) for a maximum duration of 14 days of therapy. The study was designed to demonstrate equivalence of the two therapies. The primary analyses were conducted on the protocol-valid population, which consisted of those with a surgically confirmed complicated infection, at least one pathogen isolated pretreatment, at least 5 days of treatment, and a 4 to 6 week follow-up assessment for cured patients. Subjects in the imipenem/cilastatin arm had higher APACHE II scores at baseline. The treatment groups were otherwise generally comparable with regard to their pretreatment characteristics. The overall clinical cure rate among the protocol-valid patients was 81% (51 cured/63 evaluable patients) in the cefepime plus metronidazole group and 66% (62/94) in the imipenem/cilastatin group. The observed differences in efficacy may have been due to a greater proportion of patients with high APACHE II scores in the imipenem/cilastatin group.


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