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Maxipime

2014-11-28 19:05:58 来源: 作者: 【大中小】浏览:413次评论:0条

MAXIPIME (Cefepime Hydrochloride, USP) for Injection

For Intravenous or Intramuscular Use

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, 7-(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 (CHNOS) 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 (CHNOS). 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.

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

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.

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 500 mg to 2 g intramuscularly and do not vary with respect to treatment duration.

Table 1: Average Plasma Concentrations in mcg/mL of Cefepime and Derived Pharmacokinetic Parameters (±SD), Intravenous Administration
	MAXIPIME
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	5.0	10.5	19.2
8 h	1.4	2.4	3.9
12 h	0.2	0.6	1.1
C_max, 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

Table 2: Average Plasma Concentrations in mcg/mL of Cefepime and Derived Pharmacokinetic Parameters (±SD), Intramuscular Administration
	MAXIPIME
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	12.0	26.3	51.3
4 h	6.9	16.0	31.5
8 h	1.9	4.5	8.7
12 h	0.7	1.4	2.3
C_max, mcg/mL	13.9 (3.4)	29.6 (4.4)	57.5 (9.5)
T_max, 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

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.

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	4.0	7.4 mcg/mL
Urine	500 mg IV	8	0–4	292 mcg/mL
	1 g IV	12	0–4	926 mcg/mL
	2 g IV	12	0–4	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	1.0	31.5 mcg/g

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 .)

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 C, AUC, and t 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 2 g intravenous dose. The absolute bioavailability of cefepime after an intramuscular dose of 50 mgper kg was 82.3 (±15)% in eight patients.

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:

Aerobic Gram-Positive Microorganisms:

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:

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

Aerobic Gram-Negative Microorganisms:

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.

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 method (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:

Table 4
	MIC (mcg/mL)
Microorganism	Susceptible (S)	Intermediate (I)	Resistant (R)
*NOTE: Isolates from these species should be tested for susceptibility using specialized dilution testing methods.¹ Also, isolates of Haemophilus spp. with MICs greater than 2 mcg/mL should be considered equivocal and shouldbe further eva luated.
Microorganisms otherthan Haemophilus spp.and Streptococcuspneumoniae	≤8	16	≥32
Haemophilus spp.*	≤2	—*	—*
S. pneumoniae*	≤0.5	1	≥2

Table 5
Microorganism	ATCC	MIC (mcg/mL)
Escherichia coli	25922	0.016–0.12
Staphylococcus aureus	29213	1–4
Pseudomonas aeruginosa	27853	1–4
Haemophilus influenzae	49247	0.5–2
Streptococcus pneumoniae	49619	0.06–0.25

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibilityof bacteria to antimicrobial compounds. One such standardized procedure 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):

Table 6
	Zone Diameter (mm)
Microorganism	Susceptible (S)	Intermediate (I)	Resistant (R)
*NOTE: Isolates from these species should be tested for susceptibility using specialized diffusion testing methods.² Isolates of Haemophilus spp. with zones smaller than 26 mm should be considered equivocal and should befurther eva luated. Isolates of S. pneumoniae should be tested against a 1-mcg oxacillin disk; isolates with oxacillin zone sizes largerthan or equal to 20 mm may be considered susceptible to cefepime.
Microorganisms otherthan Haemophilus spp.and S.pneumoniae	≥18	15–17	≤14
Haemophilus spp.*	≥26	—*	—*

Table 7
Microorganism	ATCC	Zone Size Range (mm)
Escherichia coli	25922	29–35
Staphylococcus aureus	25923	23–29
Pseudomonas aeruginosa	27853	24–30
Haemophilus influenzae	49247	25–31

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 ):

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.

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.

Table 8: Demographics of eva luable Patients (First Episodes Only)
	Cefepime	Ceftazidime
Total	164	153
ANC = absolute neutrophil count; SBP = systolic blood pressure
Median age (yr)	56.0 (range, 18–82)	55.0 (range, 16–84)
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, 0–500)	20 (range, 0–500)
Median duration of neutropenia (days)	6 (range, 0–39)	6 (range, 0–32)
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%)

Table 9: Pooled Response Rates for Empiric Therapy of Febrile Neutropenic Patients
	% Response
Outcome Measures	Cefepime (n=164)	Ceftazidime (n=153)
Primary episode resolvedwith no treatment modification, no new febrile episodes or infection, and oral antibiotics allowed for completion of treatment	51	55
Primary episode resolved with notreatment modification, no new febrile episodes or infection and no post-treatmentoral antibiotics	34	39
Survival, any treatment modification allowed	93	97
Primary episode resolved with notreatment modification and oral antibiotics allowed for completion of treatment	62	67
Primary episoderesolved with no treatment modification and no post-treatment oral antibiotics	46	51

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 cured patients. Subjects in the imipenem/cilastatin arm had higher APACHEII scores at baseline. The treatment groups were otherwise generally comparable with regard to their pretreatment characteristics. The overall clinical curerate among the protocol-valid patients was 81% (51 cured/63 eva luable patients) in the cefepime plus metronidazole group and 66% (62/94) in the imipenem/cilastatingroup. 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.

MAXIPIME is contraindicated in patients who have shown immediate hypersensitivity reactions to cefepime orthe cephalosporin class of antibiotics, penicillins or other beta-lactam antibiotics.

BEFORE THERAPY WITH MAXIPIME FORINJECTION IS INSTITUTED, CAREFUL INQUIRY SHOULD BE MADE TO DETERMINE WHETHERTHE PATIENT HAS HAD PREVIOUS IMMEDIATE HYPERSENSITIVITY REACTIONS TO CEFEPIME,CEPHALOSPORINS, PENICILLINS, OR OTHER DRUGS. IF THIS PRODUCT IS TO BE GIVENTO PENICILLIN-SENSITIVE PATIENTS, CAUTION SHOULD BE EXERCISED BECAUSE CROSS-HYPERSENSITIVITYAMONG BETA-LACTAM ANTIBIOTICS HAS BEEN CLEARLY DOCUMENTED AND MAY OCCUR INUP TO 10% OF PATIENTS WITH A HISTORY OF PENICILLIN ALLERGY. IF AN ALLERGICREACTION TO MAXIPIME OCCURS, DISCONTINUE THE DRUG. SERIOUS ACUTE HYPERSENSITIVITYREACTIONS MAY REQUIRE TREATMENT WITH EPINEPHRINE AND OTHER EMERGENCY MEASURESINCLUDING OXYGEN, CORTICOSTEROIDS, INTRAVENOUS FLUIDS, INTRAVENOUS ANTIHISTAMINES,PRESSOR AMINES, AND AIRWAY MANAGEMENT, AS CLINICALLY INDICATED.

Inpatients with creatinine clearance less than or equal to 60 mL/min, the doseof MAXIPIME (cefepime hydrochloride) should be adjusted to compensate forthe slower rate of renal elimination. Because high and prolonged serum antibioticconcentrations can occur from usual dosages in patients with renal impairmentor other conditions that may compromise renal function, the maintenance dosageshould be reduced when cefepime is administered to such patients. Continueddosage should be determined by degree of renal impairment, severity of infection,and susceptibility of the causative organisms. (See specific recommendationsfor dosing adjustment in DOSAGE AND ADMINISTRATION .)During postmarketing surveillance, serious adverse events have been reportedincluding life-threatening or fatal occurrences of the following: encephalopathy(disturbance of consciousness including confusion, hallucinations, stupor,and coma), myoclonus, seizures, and non-convulsive status epilepticus (see ADVERSEREACTIONS: Postmarketing Experience ). Most cases occurred inpatients with renal impairment who received doses of cefepime that exceededthe recommended dosage schedules. However, some cases of encephalopathy occurredin patients receiving a dosage adjustment for their renal function. In themajority of cases, symptoms of neurotoxicity were reversible and resolvedafter discontinuation of cefepime and/or after hemodialysis.

Clostridiumdifficile associated diarrhea (CDAD) has been reported with use ofnearly all antibacterial agents, including MAXIPIME, and may range in severityfrom mild diarrhea to fatal colitis. Treatment with antibacterial agents altersthe normal flora of the colon leading to overgrowth of C. difficile.

C.difficile produces toxins A and B, which contribute to the developmentof CDAD. Hypertoxin-producing strains of C. difficile causeincreased morbidity and mortality, as these infections can be refractory toantimicrobial therapy and may require colectomy. CDAD must be considered inall patients who present with diarrhea following antibiotic use. Careful medicalhistory is necessary since CDAD has been reported to occur over two monthsafter the administration of antibacterial agents.

IfCDAD is suspected or confirmed, ongoing antibiotic use not directed against C.difficile may need to be discontinued. Appropriate fluid and electrolytemanagement, protein supplementation, antibiotic treatment of C. difficile,and surgical eva luation should be instituted as clinically indicated.

Prescribing MAXIPIME in the absence of a proven or strongly suspected bacterial infectionor a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Aswith other antimicrobials, prolonged use of MAXIPIME may result in overgrowthof nonsusceptible microorganisms. Repeated eva luation of the patient’s conditionis essential. Should superinfection occur during therapy, appropriate measuresshould be taken.

Many cephalosporins, including cefepime,have been associated with a fall in prothrombin activity. Those at risk includepatients with renal or hepatic impairment, or poor nutritional state, as wellas patients receiving a protracted course of antimicrobial therapy. Prothrombintime should be monitored in patients at risk, and exogenous vitamin K administeredas indicated.

Positive direct Coombs’ tests have beenreported during treatment with MAXIPIME. In hematologic studies or in transfusioncross-matching procedures when antiglobulin tests are performed on the minorside or in Coombs’ testing of newborns whose mothers have received cephalosporinantibiotics before parturition, it should be recognized that a positive Coombs’test may be due to the drug.

MAXIPIME (cefepime hydrochloride)should be prescribed with caution in individuals with a history of gastrointestinaldisea