For Intravenous or Intramuscular Use

To reduce the development of drug-resistant bacteria and maintain the effectiveness of MAXIPIME® andother antibacterial drugs, MAXIPIME should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

DESCRIPTION

MAXIPIME (cefepime hydrochloride, USP) is a semi-synthetic, broad spectrum, cephalosporinantibiotic 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 structuralformula:

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

MAXIPIME for Injection is supplied for intramuscular or intravenous administration in strengths equivalent to 500 mg, 1 g, and2 g of cefepime. (See DOSAGE AND ADMINISTRATION.)MAXIPIME 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 115percent of the labeled amount of cefepime (C19H24N6O5S2). The L-arginine, at an approximate concentration of 725 mg/gof cefepime, is added to control the pH of the constituted solution at 4.0–6.0. Freshly constituted solutions of MAXIPIME will range in color from colorlessto amber.

CLINICAL PHARMACOLOGY

Cefepime is an antibacterial agent belonging to the cephalosporin class of antibacterials with in vitro antibacterialactivity 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 timesfollowing 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 renalexcretion with an average (±SD) half-life of 2.0 (±0.3) hours and total body clearance of 120.0 (±8.0) mL/min in healthy volunteers. Cefepime pharmacokineticsare 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.

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

Distribution

The average steady-state volume of distribution of cefepime is 18.0 (±2.0) L. The serum protein binding of cefepime is approximately20% 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.

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 recoveryof 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 andpatients undergoing hemodialysis require dosage adjustment. (See DOSAGE AND ADMINISTRATION.)

Specific Populations

Renal impairment: Cefepime pharmacokinetics have been investigated in patients with various degrees ofrenal impairment (n=30). The average half-life in patients requiring hemodialysis was 13.5 (±2.7) hours and in patients requiring continuous peritoneal dialysiswas 19.0 (±2.0) hours. Cefepime total body clearance decreased proportionally with creatinine clearance in patients with abnormal renal function, whichserves 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 patientswith hepatic impairment who received a single 1 g dose (n=11).

Geriatric patients: Cefepime pharmacokinetics have been investigated in elderly(65 years of age and older) men (n=12) and women (n=12) whose mean (SD) creatinine clearance was 74.0 (±15.0) mL/min. There appeared to be a decrease in cefepimetotal body clearance as a function of creatinine clearance. Therefore, dosage administration of cefepime in the elderly should be adjusted as appropriateif the patient's creatinine clearance is 60 mL/min or less. (See DOSAGE AND ADMINISTRATION.)

Pediatric patients: Cefepime pharmacokinetics have been eva luated in pediatricpatients 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 singleintravenous 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 urinaryrecovery of unchanged cefepime was 60.4 (±30.4)% of the administered dose, and the average renal clearance was 2.0 (±1.1) mL/min/kg. There were no significanteffects of age or gender (25 male vs 17 female) on total body clearance or volume of distribution, corrected for body weight. No accumulation was seenwhen cefepime was given at 50 mg per kg every 12 hours (n=13), while Cmax, AUC, and t½ were increased about 15% at steady stateafter 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 inan adult treated with a 2g intravenous dose. The absolute bioavailability of cefepime after an intramuscular dose of 50mgper kg was 82.3 (±15)% in eight patients.

Microbiology

Cefepime is a bactericidal agent that acts by inhibition of bacterial cell wall synthesis.Cefepime has a broad spectrum of in vitro activity that encompasses a wide range of Gram-positive and Gram-negative bacteria. Cefepime has a lowaffinity for chromosomally-encoded beta-lactamases. Cefepime is highly resistant to hydrolysis by most beta-lactamases and exhibits rapid penetration intoGram-negative bacterial cells. Within bacterial cells, the molecular targets of cefepime are the penicillin binding proteins (PBP).

Cefepime has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.

Aerobic Gram-Negative Microorganisms:

 

Enterobacter

 

Escherichia coli

 

Klebsiella pneumoniae

 

Proteus mirabilis

 

Pseudomonas aeruginosa

Aerobic Gram-Positive Microorganisms:

 

Staphylococcus aureus (methicillin-susceptible isolates only)

 

Streptococcus pneumoniae

 

Streptococcus pyogenes (Lancefield’s Group A streptococci)

 

Viridans group streptococci

The following in vitro data are available, but their clinical significance is unknown. Cefepime has been shown to have in vitro activity against most isolates ofthe following microorganisms; however, the safety and effectiveness of cefepime in treating clinical infections due to these microorganisms have not beenestablished in adequate and well-controlled trials.

Aerobic Gram-Positive Microorganisms:

 

Staphylococcus epidermidis (methicillin-susceptible isolates only)

 

Staphylococcus saprophyticus

 

Streptococcus agalactiae (Lancefield’s Group B streptococci)

NOTE: Most isolates of enterococci, eg, Enterococcus faecalis, and methicillin-resistant staphylococci are resistant to cefepime.

Aerobic Gram-Negative Microorganisms:

 

Acinetobacter calcoaceticus subsp. lwoffii

 

Citrobacter diversus

 

Citrobacter freundii

 

Enterobacter agglomerans

 

Haemophilus influenzae (including beta-lactamase producing isolates)

 

Hafnia alvei

 

Klebsiella oxytoca

 

Moraxella catarrhalis (including beta-lactamase producing isolates)

 

Morganella morganii

 

Proteus vulgaris

 

Providencia rettgeri

 

Providencia stuartii

 

Serratia marcescens

NOTE: Cefepime is inactive against many isolates of Stenotrophomonas (formerly Xanthomonas maltophilia and Pseudomonas maltophilia).

Anaerobic Microorganisms:

NOTE: Cefepime is inactive against most isolates of Clostridium difficile.

Susceptibility Tests

Dilution Techniques

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provideestimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized proceduresare based on a dilution method1 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrationsof cefepime powder. The MIC values should be interpreted according to the following criteria:

A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reachesthe concentrations usually achievable. A report of “Intermediate” indicates that the result should be considered equivocal, and, if the microorganismis not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicabilityin body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a bufferzone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that thepathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy shouldbe selected.

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technicalaspects of the laboratory procedures. Laboratory control microorganisms are specific strains of microbiological assay organisms with intrinsic biologicalproperties relating to resistance mechanisms and their genetic expression within bacteria; the specific strains are not clinically significant in theircurrent microbiological status. Standard cefepime powder should provide the following MIC values (Table 5) when tested against the designated qualitycontrol strains:

Diffusion Techniques

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibilityof bacteria to antimicrobial compounds. One such standardized procedure2 requires the use of standardized inoculum concentrations. This procedure uses paperdisks impregnated with 30 mcg of cefepime to test the susceptibility of microorganisms to cefepime. Interpretation is identical to that stated above for resultsusing dilution techniques.

Reports from the laboratory providing results of the standard single-disk susceptibility test with a 30-mcgcefepime disk should be interpreted according to the following criteria:

As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms to control the technicalaspects of the laboratory procedures. Laboratory control microorganisms are specific strains of microbiological assay organisms with intrinsic biologicalproperties relating to resistance mechanisms and their genetic expression within bacteria; the specific strains are not clinically significant in theircurrent microbiological status. For the diffusion technique, the 30-mcg cefepime disk should provide the following zone diameters in these laboratory testquality control strains (Table 7):

INDICATIONS AND USAGE

MAXIPIME is indicated in the treatment of the following infections caused by susceptible strains of the designatedmicroorganisms (see also PRECAUTIONS: Pediatric Use and DOSAGE AND ADMINISTRATION):

 

Pneumonia (moderate to severe) caused by Streptococcus pneumoniae, includingcases associated with concurrent bacteremia, Pseudomonas aeruginosa, Klebsiellapneumoniae, or Enterobacter species.

 

Empiric Therapy for Febrile Neutropenic Patients. Cefepime as monotherapy is indicatedfor empiric treatment of febrile neutropenic patients. In patients at high risk for severe infection (including patients with a history of recent bonemarrow transplantation, with hypotension at presentation, with an underlying hematologic malignancy, or with severe or prolonged neutropenia), antimicrobialmonotherapy may not be appropriate. Insufficient data exist to support the efficacy of cefepime monotherapy in such patients. (See CLINICAL STUDIES.)

 

Uncomplicated and Complicated Urinary Tract Infections (including pyelonephritis) caused by Escherichiacoli or Klebsiella pneumoniae, when the infection is severe, or caused by Escherichia coli, Klebsiella pneumoniae, or Proteus mirabilis, when the infection is mild to moderate, including cases associated with concurrent bacteremia with these microorganisms.

 

Uncomplicated Skin and Skin Structure Infections caused by Staphylococcus aureus (methicillin-susceptible strains only) or Streptococcus pyogenes.

 

Complicated Intra-abdominal Infections (used in combination with metronidazole) caused by Escherichiacoli, viridans group streptococci, Pseudomonas aeruginosa, Klebsiellapneumoniae, Enterobacter species, or Bacteroidesfragilis. (See CLINICAL STUDIES.)

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

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 intravenouslyevery 8 hours). These studies comprised 317 eva luable patients. Table 8 describes the characteristics of the eva luable patient population.

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

Insufficient data exist to support the efficacy of cefepime monotherapy in patients at high risk for severe infection (including patientswith a history of recent bone marrow transplantation, with hypotension at presentation, with an underlying hematologic malignancy, or with severe orprolonged 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, multicentertrial comparing the combination of cefepime (2 g every 12 hours) plus intravenous metronidazole (500 mg every 6 hours) versus imipenem/cilastatin (500 mg every6 hours) for a maximum duration of 14 days of therapy. The study was designed to demonstrate equivalence of the two therapies. The primary analyses wereconducted on the protocol-valid population, which consisted of those with a surgically confirmed complicated infection, at least one pathogen isolatedpretreatment, at least 5 days of treatment, and a 4 to 6 week follow-up assessment for cur