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cefepime hydrochloride injection
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
To reduce the development of drug-resistant bacteria and maintain the effectiveness of Cefepime Injection and other antibacterial drugs, Cefepime Injection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
Cefepime Injection is indicated for pneumonia (moderate to severe) caused by Streptococcus pneumoniae, including cases associated with concurrent bacteremia, Pseudomonas aeruginosa, Klebsiella pneumoniae, or Enterobacter species.
1.2 Empiric Therapy for Febrile Neutropenic Patients
Cefepime Injection as monotherapy is indicated for empiric treatment of febrile neutropenic patients. In patients at high risk for severe infection (including patients with a history of recent bone marrow transplantation, with hypotension at presentation, with an underlying hematologic malignancy, or with severe or prolonged neutropenia), antimicrobial monotherapy may not be appropriate. Insufficient data exist to support the efficacy of cefepime monotherapy in such patients [see Clinical Studies (14)].
1.3 Uncomplicated and Complicated Urinary Tract Infections (including pyelonephritis)
Cefepime Injection is indicated for uncomplicated and complicated urinary tract infections (including pyelonephritis) caused by Escherichia coli or Klebsiella pneumoniae, when the infection is severe, or caused by Escherichia coli, Klebsiella pneumoniae, or Proteus mirabilis, when the infection is mild to moderate, including cases associated with concurrent bacteremia with these microorganisms.
1.4 Uncomplicated Skin and Skin Structure Infections
Cefepime Injection is indicated for uncomplicated skin and skin structure infections caused by Staphylococcus aureus (methicillin-susceptible isolates only) or Streptococcus pyogenes.
1.5 Complicated Intra-abdominal Infections
Cefepime Injection is indicated for complicated intra-abdominal infections (used in combination with metronidazole) caused by Escherichia coli, viridans group streptococci, Pseudomonas aeruginosa, Klebsiella pneumoniae, Enterobacter species, or Bacteroides fragilis [see Clinical Studies (14)].
2 DOSAGE AND ADMINISTRATION
2.1 Adults and Pediatric Population
The recommended adult and pediatric dosages and routes of administration are outlined in Table 1. Cefepime Injection should be administered intravenously over approximately 30 minutes.
2.2 Patients with Hepatic Impairment
No adjustment is necessary for patients with hepatic impairment.
2.3 Patients with Renal Impairment
In patients with creatinine clearance less than or equal to 60 mL/min, the dose of Cefepime Injection should be adjusted to compensate for the slower rate of renal elimination. The recommended initial dose of Cefepime Injection should be the same as in patients with normal renal function except in patients undergoing hemodialysis. The recommended doses of Cefepime Injection in patients with renal impairment are presented in Table 2.
When only serum creatinine is available, the following formula (Cockcroft and Gault equation)1 may be used to estimate creatinine clearance. The serum creatinine should represent a steady state of renal function:
In patients undergoing continuous ambulatory peritoneal dialysis, Cefepime Injection may be administered at normally recommended doses at a dosage interval of every 48 hours (see Table 2).
In patients undergoing hemodialysis, approximately 68% of the total amount of cefepime present in the body at the start of dialysis will be removed during a 3-hour dialysis period. The dosage of Cefepime Injection for hemodialysis patients is 1 g on Day 1 followed by 500 mg every 24 hours for the treatment of all infections except febrile neutropenia, which is 1 g every 24 hours. Cefepime Injection should be administered at the same time each day following the completion of hemodialysis on hemodialysis days (see Table 2).
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)], changes in the dosing regimen proportional to those in adults (see Table 1 and Table 2) are recommended for pediatric patients.
2.4 Directions for Use of Cefepime Injection in GALAXY Container
Cefepime Injection in GALAXY Container (PL 2040 Plastic) is for intravenous administration using sterile equipment after thawing to room temperature.
Thawing of Plastic Container
Thaw frozen container at room temperature 25°C (77°F) or under refrigeration 5°C (41°F). Do not force thaw by immersion in water baths or by microwave irradiation. [See How Supplied/Storage and Handling (16).]
Check for minute leaks by squeezing container firmly. If leaks are detected, discard solution as sterility may be impaired.
Do not add supplementary medication.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Components of the solution may precipitate in the frozen state and will dissolve upon reaching room temperature with little or no agitation. Potency is not affected. Agitate after solution has reached room temperature. If after visual inspection the solution remains cloudy or if an insoluble precipitate is noted or if any seals or the outlet port are not intact, the container should be discarded.
Caution: Do not use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is complete.
Preparation for intravenous administration.
Cefepime Injection should be administered intravenously over approximately 30 minutes.
Intermittent intravenous infusion with a Y-type administration set can be accomplished with compatible solutions. However, during infusion of Cefepime Injection, it is desirable to discontinue the other solution.
Solutions of cefepime, like those of most beta-lactam antibiotics, should not be added to solutions of ampicillin at a concentration greater than 40 mg per mL, and should not be added to metronidazole, vancomycin, gentamicin, tobramycin, netilmicin sulfate or aminophylline because of potential interaction. However, if concurrent therapy with cefepime is indicated, each of these antibiotics can be administered separately.
3 DOSAGE FORMS AND STRENGTHS
Cefepime Injection is contraindicated in patients who have shown immediate hypersensitivity reactions to cefepime or the cephalosporin class of antibiotics, penicillins or other beta-lactam antibiotics.
Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products.
5 WARNINGS AND PRECAUTIONS
Before therapy with Cefepime Injection is instituted, careful inquiry should be made to determine whether the patient has had previous immediate hypersensitivity reactions to cefepime, cephalosporins, penicillins, or other drugs. If this product is to be given to penicillin-sensitive patients, caution should be exercised because cross-hypersensitivity among beta-lactam antibiotics has been clearly documented and may occur in up to 10% of patients with a history of penicillin allergy. If an allergic reaction to Cefepime Injection occurs, discontinue the drug. Serious acute hypersensitivity reactions may require treatment with epinephrine and other emergency measures including oxygen, corticosteroids, intravenous fluids, intravenous antihistamines, pressor amines, and airway management, as clinically indicated.
5.2 Renal Impairment
In patients with creatinine clearance less than or equal to 60 mL/min, the dose of Cefepime 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 impairment or other conditions that may compromise renal function, the maintenance dosage should be reduced when Cefepime Injection is administered to such patients. Continued dosage should be determined by degree of renal impairment, severity of infection, and susceptibility of the causative organisms. Refer to specific recommendations for dosing adjustment [See Dosage and Administration (2)]. During postmarketing 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, and seizures [see Adverse Reactions (6.2)]. Most cases occurred in patients with renal impairment who received doses of cefepime that exceeded the recommended dosage schedules. However, some cases of encephalopathy occurred in patients receiving a dosage adjustment for their renal function. In the majority of cases, symptoms of neurotoxicity were reversible and resolved after discontinuation of cefepime and/or after hemodialysis.
5.3 Clostridium difficile Associated Diarrhea
Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Cefepime Injection, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.
C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic 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 antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
5.4 Risk of Development of Drug-Resistant Bacteria
Prescribing cefepime in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
As with other antimicrobials, prolonged use of cefepime may result in overgrowth of nonsusceptible microorganisms. Repeated evaluation of the patient’s condition is essential. Should superinfection occur during therapy, appropriate measures should be taken.
5.5 Patients with Meningeal Seeding/Meningitis
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.
5.6 Drug/Laboratory Test Interactions
The administration of cefepime may result in a false-positive reaction for glucose in the urine when using CLINITEST tablets. It is recommended that glucose tests based on enzymatic glucose oxidase reactions (such as CLINISTIX) be used.
Positive direct Coombs’ tests have been reported during treatment with cefepime. 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.
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.
5.7 Patients with a History of Gastrointestinal Disease
Cefepime Injection should be prescribed with caution in individuals with a history of gastrointestinal disease, particularly colitis.
5.8 Possible Effects of Arginine on Glucose Metabolism
Cefepime Injection contains arginine to adjust pH [see Description (11)]. Arginine has been shown to alter glucose metabolism and elevate serum potassium transiently when administered at 33 times the amount provided by the maximum recommended human dose of cefepime. The effect of lower doses is not presently known.
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
In clinical trials using multiple doses of cefepime, 4137 patients were treated with the recommended dosages of cefepime (500 mg to 2 g intravenously every 12 hours). Sixty-four (1.5%) patients discontinued medication due to adverse events thought by the investigators to be possibly, probably, or almost certainly related to drug toxicity. Thirty-three (51%) of these 64 patients who discontinued therapy did so because of rash. The percentage of cefepime-treated patients who discontinued study drug because of drug-related adverse events was very similar at daily doses of 500 mg, 1 g, and 2 g every 12 hours (0.8%, 1.1%, and 2.0%, respectively). However, the incidence of discontinuation due to rash increased with the higher recommended doses.
The following adverse events were thought to be probably related to cefepime during evaluation of the drug in clinical trials conducted in North America (n=3125 cefepime-treated patients).
At the higher dose of 2 g every 8 hours, the incidence of probably-related adverse events was higher among the 795 patients who received this dose of cefepime. They consisted of rash (4%), diarrhea (3%), nausea (2%), vomiting (1%), pruritus (1%), fever (1%), and headache (1%).
The following adverse laboratory changes, irrespective of relationship to therapy with cefepime, were seen during clinical trials conducted in North America.
A similar safety profile was seen in clinical trials of pediatric patients [see Use in Specific Populations (8.4)].
6.2 Postmarketing Experience
In addition to the events reported during North American clinical trials with cefepime, the following adverse experiences have been reported during worldwide postmarketing experience. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
As with some other drugs in this class, encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, and coma), myoclonus, and seizures have been reported. Although most cases occurred in patients with renal impairment who received doses of cefepime that exceeded the recommended dosage schedules, some cases of encephalopathy occurred in patients receiving a dosage adjustment for their renal function [see Warnings and Precautions (5)]. If seizures associated with drug therapy occur, the drug should be discontinued. Anticonvulsant therapy can be given if clinically indicated. Precautions should be taken to adjust daily dosage in patients with renal impairment 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.
As with other cephalosporins, anaphylaxis including anaphylactic shock, transient leukopenia, neutropenia, agranulocytosis, and thrombocytopenia have been reported.
6.3 Cephalosporin-class Adverse Reactions
In addition to the adverse reactions listed above that have been observed in patients treated with cefepime, the following adverse reactions have been reported for cephalosporin-class antibiotics:
Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, renal impairment, toxic nephropathy, aplastic anemia, hemolytic anemia, hemorrhage, hepatic impairment including cholestasis, and pancytopenia.
7 DRUG INTERACTIONS
Renal function should be monitored carefully if high doses of aminoglycosides are to be administered with Cefepime Injection because of the increased potential of nephrotoxicity and ototoxicity of aminoglycoside antibiotics.
8 USE IN SPECIFIC POPULATIONS
Pregnancy Category B. Cefepime was not teratogenic or embryocidal when administered during the period of organogenesis to rats at doses up to 1000 mg/kg/day (1.6 times the recommended maximum human dose calculated on a mg/m2 basis) or to mice at doses up to 1200 mg/kg (approximately equal to the recommended maximum human dose calculated on a mg/m2 basis) or to rabbits at a dose level of 100 mg/kg (0.3 times the recommended maximum human dose calculated on a mg/m2 basis).
There are, however, no adequate and well-controlled studies of cefepime use in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
8.2 Labor and Delivery
Cefepime has not been studied for use during labor and delivery. Treatment should only be given if clearly indicated.
8.3 Nursing Mothers
Cefepime is excreted in human breast milk in very low concentrations (0.5 mcg/mL). Caution should be exercised when Cefepime Injection is administered to a nursing woman.
8.4 Pediatric Use
The safety and effectiveness of cefepime in the treatment of uncomplicated and complicated urinary tract infections (including pyelonephritis), uncomplicated skin and skin structure infections, pneumonia, and as empiric therapy for febrile neutropenic patients have been established in the age groups 2 months up to 16 years. Use of Cefepime Injection in these age groups is supported by evidence from adequate and well-controlled studies of cefepime in adults with additional pharmacokinetic and safety data from pediatric trials [see Clinical Pharmacology (12)].
Safety and effectiveness in pediatric patients below the age of 2 months have not been established. There are insufficient clinical data to support the use of Cefepime Injection in pediatric patients under 2 months of age or for the treatment of serious infections in the pediatric population where the suspected or proven pathogen is Haemophilus influenzae type b.
Cefepime Injection in GALAXY Container should be used only in pediatric patients who require the entire 1 or 2 g dose and not any fraction thereof.
8.5 Geriatric Use
Of the more than 6400 adults treated with cefepime in clinical studies, 35% were 65 years or older while 16% were 75 years or older. When geriatric patients received the usual recommended adult dose, clinical efficacy and safety were comparable to clinical efficacy and safety in nongeriatric adult patients.
Serious adverse events have occurred in geriatric patients with renal impairment given unadjusted doses of cefepime, including life-threatening or fatal occurrences of the following: encephalopathy, myoclonus, and seizures [see Warnings and Precautions (5) and Adverse Reactions (6)].
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and renal function should be monitored [see Clinical Pharmacology (12), Warnings and Precautions (5), and Dosage and Administration (2)].
Patients who receive an overdose should be carefully observed and given supportive treatment. In the presence of renal impairment, hemodialysis, not peritoneal dialysis, is recommended to aid in the removal of cefepime from the body. Accidental overdosing has occurred when large doses were given to patients with impaired renal function. Symptoms of overdose include encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, and coma), myoclonus, seizures, and neuromuscular excitability [see Warnings and Precautions (5), Adverse Reactions (6), and Dosage and Administration (2)].
Cefepime Injection in GALAXY Containers (PL 2040 Plastic) is a sterile, injectable product consisting of Cefepime Hydrochloride, USP, a semi-synthetic, broad spectrum, cephalosporin antibiotic for parenteral administration. The chemical name is 1-[[(6R,7R)-7-[2-(2-Amino-4-thiazolyl) glyoxylamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0] oct-2-en-3-yl]methyl]-1-methylpyrrolidinium chloride, 72-(Z)-(O-methyloxime), monohydrochloride, monohydrate, which corresponds to the following structural formula:
Cefepime hydrochloride (monohydrate) has a molecular mass of 571.50 and a molecular formula of C19H25ClN6O5S2•HCl•H2O.
Cefepime Injection in GALAXY Container (PL 2040 Plastic) is a frozen, iso-osmotic, sterile, non-pyrogenic premixed solution supplied for intravenous administration in strengths equivalent to 1 g and 2 g of cefepime [see Dosage and Administration (2)]. It contains the equivalent of not less than 90 percent and not more than 115 percent of the labeled amount of cefepime (C19H24N6O5S2).
The solution is intended for intravenous use after thawing to room temperature. The components and dosage formulations are given in the table below:
Cefepime Injection will range in color from colorless to amber.
The plastic container is fabricated from a specially designed multilayer plastic (PL 2040). Solutions are in contact with the polyethylene layer of this container and can leach out certain chemical components of the plastic in very small amounts within the expiration period. The suitability of the plastic has been confirmed in tests in animals according to the USP biological tests for plastic containers, as well as by tissue culture toxicity studies.
12 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.
12.1 Mechanism of Action
Cefepime is an antibacterial drug. [See Clinical Pharmacology (12.4)]
Similar to other beta-lactam antimicrobial agents, the time that the unbound plasma concentration of cefepime exceeds the MIC of the infecting organism has been shown to best correlate with efficacy in animal models of infection. However, the pharmacokinetic/pharmacodynamic relationship for cefepime has not been evaluated in patients.
The average plasma concentrations of cefepime observed in healthy adult male volunteers (n=9) at various times following single 30-minute intravenous infusions of cefepime 500 mg, 1 g, and 2 g are summarized in Table 6. Elimination of cefepime is principally via renal excretion with an average (±SD) half-life of 2 (±0.3) hours and total body clearance of 120 (±8) mL/min in healthy volunteers. Cefepime pharmacokinetics are linear over the range 250 mg to 2 g. There is no evidence of accumulation in healthy adult male volunteers (n=7) receiving clinically relevant doses for a period of 9 days.
The average steady-state volume of distribution of cefepime is 18.0 (±2.0) L. The serum protein binding of cefepime is approximately 20% and is independent of its concentration in serum.
Cefepime is excreted in human milk. A nursing infant consuming approximately 1000 mL of human milk per day would receive approximately 0.5 mg of cefepime per day [see Use in Specific Populations (8.3)].
Concentrations of cefepime achieved in specific tissues and body fluids are listed in Table 7.
Data suggest that cefepime does cross the inflamed blood-brain barrier. The clinical relevance of these data is uncertain at this time.
Metabolism and Excretion
Cefepime is metabolized to N-methylpyrrolidine (NMP), which is rapidly converted to the N-oxide (NMP-N-oxide). Urinary recovery of unchanged cefepime accounts for approximately 85% of the administered dose. Less than 1% of the administered dose is recovered from urine as NMP, 6.8% as NMP-N-oxide, and 2.5% as an epimer of cefepime. Because renal excretion is a significant pathway of elimination, patients with renal dysfunction and patients undergoing hemodialysis require dosage adjustment [see Dosage and Administration (2)].
Patients with Renal Impairment
Cefepime pharmacokinetics have been investigated in patients with various degrees of renal impairment (n=30). The average half-life in patients requiring hemodialysis was 13.5 (±2.7) hours and in patients requiring continuous peritoneal dialysis was 19 (±2.0) hours. Cefepime total body clearance decreased proportionally with creatinine clearance in patients with abnormal renal function, which serves as the basis for dosage adjustment recommendations in this group of patients [see Dosage and Administration (2)].
Patients with Hepatic Impairment
The pharmacokinetics of cefepime were unaltered in patients with hepatic impairment who received a single 1 g dose (n=11).
Cefepime pharmacokinetics have been investigated in elderly (65 years of age and older) men (n=12) and women (n=12) whose mean (SD) creatinine clearance was 74.0 (±15.0) mL/min. There appeared to be a decrease in cefepime total body clearance as a function of creatinine clearance. Therefore, dosage administration of cefepime in the elderly should be adjusted as appropriate if the patient’s creatinine clearance is 60 mL/min or less [see Dosage and Administration (2)].
Cefepime pharmacokinetics have been evaluated in pediatric patients from 2 months to 11 years of age following single and multiple doses on every 8 hours (n=29) and every 12 hours (n=13) schedules. Following a single intravenous dose, total body clearance and the steady-state volume of distribution averaged 3.3 (±1.0) mL/min/kg and 0.3 (±0.1) L/kg, respectively. The urinary recovery of unchanged cefepime was 60.4 (±30.4)% of the administered dose, and the average renal clearance was 2.0 (±1.1) mL/min/kg. There were no significant effects of age or gender (25 male vs. 17 female) on total body clearance or volume of distribution, corrected for body weight. No accumulation was seen when cefepime was given at 50 mg per kg every 12 hours (n=13), while Cmax, AUC, and t1/2 were increased about 15% at steady state after 50 mg per kg every 8 hours. The exposure to cefepime following a 50 mg per kg intravenous dose in a pediatric patient is comparable to that in an adult treated with a 2 g intravenous dose.
Cefepime is a bactericidal agent that acts by inhibition of bacterial cell wall synthesis. Cefepime has a broad spectrum of in vitro activity that encompasses a wide range of Gram-positive and Gram-negative bacteria. Cefepime has a low affinity for chromosomally-encoded beta-lactamases. Cefepime is highly resistant to hydrolysis by most beta-lactamases and exhibits rapid penetration into Gram-negative bacterial cells. Within bacterial cells, the molecular targets of cefepime are the penicillin binding proteins (PBP).
Cefepime has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections [see Indications and Usage (1)].
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 of the following microorganisms; however, the safety and effectiveness of cefepime in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled trials.
NOTE: Most isolates of enterococci, e.g., Enterococcus faecalis, and methicillin-resistant staphylococci are resistant to cefepime.
NOTE: Cefepime is inactive against many isolates of Stenotrophomonas (formerly Xanthomonas maltophilia and Pseudomonas maltophilia).
NOTE: Cefepime is inactive against most isolates of Clostridium difficile.
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 procedure. Standardized procedures are based on a dilution method2 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of 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 reaches the concentrations usually achievable. A report of "Intermediate" indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.
Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Laboratory control microorganisms are specific strains of microbiological assay organisms with intrinsic biological properties relating to resistance mechanisms and their genetic expression within bacteria; the specific strains are not clinically significant in their current microbiological status. Standard cefepime powder should provide the following MIC values (Table 9) when tested against the designated quality control strains:
Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure3 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 30 mcg of cefepime to test the susceptibility of microorganisms to cefepime. Interpretation is identical to that stated above for results using dilution techniques.
Reports from the laboratory providing results of the standard single-disk susceptibility test with a 30-mcg cefepime 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 technical aspects of the laboratory procedures. Laboratory control microorganisms are specific strains of microbiological assay organisms with intrinsic biological properties relating to resistance mechanisms and their genetic expression within bacteria; the specific strains are not clinically significant in their current microbiological status. For the diffusion technique, the 30-mcg cefepime disk should provide the following zone diameters in these laboratory test quality control strains (Table 11):
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
No animal carcinogenicity studies have been conducted with cefepime. In chromosomal aberration studies, cefepime was positive for clastogenicity in primary human lymphocytes, but negative in Chinese hamster ovary cells. In other in vitro assays (bacterial and mammalian cell mutation, DNA repair in primary rat hepatocytes, and sister chromatid exchange in human lymphocytes), cefepime was negative for genotoxic effects. Moreover, in vivo assessments of cefepime in mice (2 chromosomal aberration and 2 micronucleus studies) were negative for clastogenicity. No untoward effects on fertility were observed in rats when cefepime was administered subcutaneously at doses up to 1000 mg/kg/day (1.6 times the recommended maximum human dose calculated on a mg/m2 basis).
14 CLINICAL STUDIES
14.1 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 12 describes the characteristics of the evaluable patient population.
Table 13 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 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.
14.2 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.
16 HOW SUPPLIED/STORAGE AND HANDLING
Cefepime Injection is supplied as a frozen, iso-osmotic, sterile, nonpyrogenic solution in 50 mL and 100 mL single-dose GALAXY containers (PL 2040 Plastic) as follows:
Store at or below –20°C (-4°F).
Handle frozen product containers with care. Product containers may be fragile in the frozen state.
Thaw frozen container at room temperature 25°C (77°F) or under refrigeration 5°C (41°F). Do not force thaw by immersion in water baths or by microwave irradiation.
The thawed solution remains stable for 7 days under refrigeration 5°C (41°F) or 24 hours at room temperature 25°C (77°F). Do not refreeze.
17 PATIENT COUNSELING INFORMATION
Baxter and Galaxy are registered trademarks of Baxter International Inc.
Clinitest is a registered trademark of Siemens Healthcare Diagnostics Inc.
Clinistix is a registered trademark of Bayer Healthcare LLC.
PACKAGE LABEL - PRINCIPLE DISPLAY PANEL
Baxter 1 g
GALAXY 50 mL NDC 0338-1301-41
Single-Dose Container Iso-osmotic Sterile Nonpyrogenic
Each 50 mL contains: Cefepime Hydrochloride, USP equivalent to 1 g of
cefepime with approx. 1.03 g of Dextrose Hydrous, USP added to adjust
osmolality. Approx. 725 mg of L-Arginine, USP added per g of cefepime to
adjust the pH. The pH may have been adjusted with hydrochloric acid and/or
additional L-Arginine, USP. The pH is 4.0 - 6.0.
Dosage: Intravenously as directed by a physician. See insert.
Cautions: Do not add supplementary medication. Must not se used in series
connections. Check for minute leaks and solution clarity.
Store at or below -20°C/-4°F. Thaw at room temperature (25°C/77°F) or under
refrigeration (5°C/41°F). DO NOT FORCE THAW BY IMMERSION IN WATER BATHS OR BY MICROWAVE IRRADIATION. Thawed solution remains stable for
7 days under refrigeration (5°C/41°F) or 24 hours at room temperature (25°C/77°F). Do not
U.S. Pat. Nos. 4,686,125; 4,779,997
Baxter and GALAXY are trademarks of Baxter International Inc.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA PL 2040 Plastic
Made in USA
Thaw at room temperature (25°C/77°F) or under refrigeration (5°C/41°F). DO NOT FORCE THAW BY IMMERSION IN WATER BATHS OR BY MICROWAVE IRRADIATION. Thawed solution remains stable for 7 days under refrigeration (5°C/41°F) or 24 hours at room
Handle frozen product containers with care. Product containers may be fragile in the frozen state.
Baxter and Galaxy are registered trademarks of Baxter International Inc.
Baxter Healthcare Corporation, Deerfield, IL 60015 USA
Made in USA
PL 2040 Plastic
12 - 50 mL Single-Dose Containers. Iso-osmotic. NDC 0338-1301-41
Store at or below -20°C/-4°F. Do not refreeze. Code 2G3578
*BAR CODE POSITION ONLY
Each 50 mL contains: Cefepime Hydrochloride, USP equivalent to 1 g of cefepime with approx. 1.03 g of Dextrose Hydrous, USP added to adjust osmolality. Approx. 725 mg of L-Arginine, USP added per g of cefepime to adjust the pH. The pH may have been adjusted with hydrochloric acid and/or additional L-Arginine, USP. The pH is 4.0 - 6.0.
Dosage: Intravenously as directed by a physician. See insert.
Cautions: Do not add supplementary medication. Must not be used in series connections. Check for minute leaks and solution clarity. Check for minute leaks by squeezing thawed bag firmly. If leaks are found, discard bag as sterility may be impaired. Do not use unless solution is clear.
Revised: 09/2010 BAXTER HEALTHCARE CORPORATION
Reproduced with permission of U.S. National Library of Medicine
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