Data Sheet

Maxipime^®

Cefepime hydrochloride powder for injection 500mg, 1g and 2g .

Presentation

Maxipime is a sterile dry mixture of cefepime hydrochloride and L-arginine. The L-arginine, at an approximate concentration of 725 mg/g of cefepime, is added to control the pH of the constituted solution at 4.0-6.0.

Cefepime hydrochloride is a white to pale yellow powder with a molecular formula of C₁₉H₂₅N₆O₅S₂.Cl.HCl.H₂0 and a molecular weight of 571.5. It is highly soluble in water. Constituted solutions of Maxipime will vary in colour from colourless to amber.

Maxipime is available in:

500mg (15mL vial)
1g (15mL vial)
2g (77mL vial)

Uses

Cefepime hydrochloride is a semi-synthetic broad spectrum cephalosporin antibiotic for parenteral administration.

Actions

Cefepime is a bactericidal agent that acts by inhibition of bacterial wall synthesis. It has a broad spectrum of activity against a wide range of gram-positive and gram-negative bacteria including most strains resistant to aminoglycosides or third-generation cephalosporins such as ceftazidime. Cefepime is highly resistant to hydrolysis by most beta-lactamases, has a low affinity for chromosomally-encoded beta-lactamases, and exhibits rapid penetration into gram-negative bacterial cells.

In studies using Escherichia coli and Enterobacter cloacae, cefepime bound with highest affinity to penicillin binding protein (PBP) 3 followed by PBP 2, then PBPs 1a and 1b. Binding to PBP 2 occurs with significantly higher affinity than that of other parenteral cephalosporins. This may enhance its antibacterial activity. The moderate affinity of cefepime for PBPs 1a and 1b probably also contributes to its overall bactericidal activity.

Cefepime has been shown to be bactericidal by time-kill analysis (killing-curves) and by determination of minimum bactericidal concentrations (MBC) for a wide variety of bacteria. The cefepime MBC/MIC ratio was 2 for more than 80% of isolates of all gram-positive and gram-negative species tested. Synergy with aminoglycosides has been demonstrated in vitro, primarily with P seudomonas aeruginosa isolates. Cefepime has been shown to be active against most strains of the following organisms:

Gram-positive Aerobes:

Staphylococcus aureus (including beta-lactamase-producing strains)

Staphylococcus epidermidis (including beta-lactamase-producing strains)

Other staphylococci including S. hominis, S. saprophyticus

Streptococcus pyogenes (Group A streptococci)

Streptococcus agalactiae (Group B streptococci)

Streptococcus pneumoniae (including intermediate penicillin resistant strains with penicillin MIC of 0.1 to 1 mcg/mL)

Other -haemolytic streptococci (Groups C, G, F), S. bovis (Group D), Viridans streptococci.

NB: Most strains of enterococci, eg: Enterococcus faecalis, and methicillin-resistant staphylococci are resistant to most cephalosporins including cefepime.

Gram-negative Aerobes:

Pseudomonas sp. including P. aeruginosa, P. putida, P. stutzeri

Escherichia coli

Klebsiella sp. including K. pneumoniae, K. oxytoca, K. ozaenae

Enterobacter sp. including E. cloacae, E. aerogenes, E. agglomerans, E. sakazakii

Proteus sp. including P. mirabilis, P. vulgaris

Acinetobacter calcoaceticus (subsp. anitratus, lwoffi)

Aeromonas hydrophila

Capnocytophaga sp.

Citrobacter sp. including C. diversus, C. freundii

Campylobacter jejuni

Gardnerella vaginalis

Haemophilus ducreyi

Haemophilus influenzae (including beta-lactamase-producing strains)

Haemophilus parainfluenzae

Hafnia alvei

Legionella sp.

Morganella morganii

Moraxella catarrhalis (Branhamella catarrhalis) (including beta-lactamase-producing strains)

Neisseria gonorrhoeae (including beta-lactamase-producing strains)

Neisseria meningitidis

Providencia sp. including P. rettgeri, P. stuartii

Salmonella sp.

Serratia including S. marcescens, S. liquefaciens

Shigella sp.

Yersinia enterocolitica

Note: Cefepime is inactive against many strains of Stenotrophomonas maltophilia (formerly known as Xanthomonas maltophilia and Pseudomonas maltophilia.

Anaerobes:

Bacteroides sp.

Clostridium perfringens

Fusobacterium sp.

Mobiluncus sp.

Peptostreptococcus sp.

Prevotella melaninogenica (formerly known as Bacteroides melaninogenicus).

Veillonella sp.

Note: Cefepime is inactive against Bacteroides fragilis and Clostridium difficile.

Susceptibility Tests

Diffusion Techniques:

Laboratory reports with standardized single-disk susceptibility results using a 30mcg cefepime disk should be interpreted according to the following criteria:

A report of "Susceptible" indicates that the pathogen is likely to be inhibited by generally achievable blood concentrations. A report of "Intermediate" indicates that the organism would be susceptible when high dosage is used or when the infection is confined to tissues and fluids (eg: interstitial fluid and urine) in which high antibiotic levels are attained. A report of "Resistant" indicates that the achievable concentration of the antibiotic is unlikely to be inhibitory and other therapy should be selected.

Organisms should be tested with the cefepime disk because cefepime has been shown to be active in vitro against certain strains found to be resistant with other beta-lactam disks. The cefepime disk should not be used for testing susceptibility to other cephalosporins. Standardized quality control procedures require the use of control organisms.

Dilution Techniques:

Using standardized dilution methods, the MIC values obtained should be interpreted according to the following criteria:

As with diffusion techniques, dilution techniques require the use of laboratory control organisms.

Pharmacokinetics

Adults:

Average plasma concentrations of cefepime observed in normal adult males at various times following single 30-minute infusions or intramuscular injections of 500mg, 1g and 2g are summarized in Table 1. Following intramuscular administration, cefepime is completely absorbed.

Concentrations of cefepime achieved in specific tissues and body fluids are listed in Table 2.

Cefepime is metabolised to N-methylpyrrolidine which is rapidly converted to the N-oxide. Urinary recovery of unchanged cefepime accounts for approximately 85% of the administered dose; high concentrations of unchanged cefepime are found in the urine. Less than 1% of the administered dose is recovered from urine as N-methylpyrrolidine, 6.8% as the N-oxide, and 2.5% as an epimer of cefepime. Serum protein binding of cefepime averages 16.4% and is independent of concentration in the serum.

The average elimination half-life of cefepime is approximately 2 hours, and does not vary with respect to dose over the range of 250mg to 2g. There was no accumulation in healthy subjects receiving doses up to 2g intravenously every 8 hours for a period of 9 days. Total body clearance averages 120mL/min. The average renal clearance of cefepime is 110mL/min, suggesting that cefepime is eliminated almost exclusively by renal mechanisms, primarily glomerular filtration.

Healthy volunteers 65 years old or older, who received a single 1g IV dose of cefepime had higher AUC and lower renal clearance values compared to younger subjects. Dosage adjustments in the elderly are recommended if renal function is compromised (see Precautions and Dosage And Administration ).

The pharmacokinetics of cefepime are unaltered in patients with impaired hepatic function who received a single 1g dose. The pharmacokinetics of cefepime do not change to a clinically significant degree in cystic fibrosis patients. It is not necessary to alter the dosage of cefepime in these patient populations.

Elimination half-life is prolonged in patients with various degrees of renal insufficiency, with a linear relationship between total body clearance and creatinine clearance. This serves as the basis for dosage adjustment recommendations in this group of patients (see Dosage And Administration ). The average half-life in severely impaired patients requiring dialysis therapy is 13 hours for haemodialysis or 19 hours for continuous ambulatory peritoneal dialysis.

Indications

Adults:

Maxipime is indicated in adults for the treatment of the infections listed below when caused by susceptible bacteria.

• Lower respiratory tract infections, including pneumonia and bronchitis.
• Urinary tract infections, both complicated, including pyelonephritis, and uncomplicated infections.
• Skin and skin structure infections.
• Septicaemia.
• Intra-abdominal infections, including peritonitis and biliary tract infections
• Empiric treatment of febrile neutropenia

Culture and susceptibility studies should be performed when appropriate to determine susceptibility of the causative organism(s) to cefepime. Empiric therapy with Maxipime may be instituted before results of susceptibility studies are known; however, once these results become available, the antibiotic treatment should be adjusted accordingly.

Because of its broad spectrum of bactericidal activity against gram-positive and gram-negative bacteria, Maxipime can be used as monotherapy prior to identification of the causative organisms(s). In patients who are at risk of mixed aerobic-anaerobic infection, particularly if bacteria not susceptible to cefepime may be present (see Actions ), concurrent initial therapy with an anti-anaerobic agent is recommended before the causative organism(s) is known. Once these results become available, combination therapy with Maxipime and other anti-infective agents may or may not be necessary, depending on the susceptibility profile.

Dosage And Administration

Maxipime can be administered either intravenously or intramuscularly. The dosage and route vary according to the susceptibility of the causative organisms, the severity of the infection, renal function and the overall condition of the patient.

Adults:

Guidelines for dosage of Maxipime for adults with normal renal function are provided in Table 3.

* The usual duration of therapy is 7-10 days; however, more severe infections may require longer treatment. For empirical treatment of febrile neutropenia, usual duration of therapy is 7 days or until resolution of neutropenia.

Patients with Impaired Renal Function:

The initial dose of cefepime is the same as in patients with normal renal function. The recommended maintenance doses of cefepime in patients with renal insufficiency are presented in Table 4.

* The initial dose is the same as in patients with normal renal function

When only serum creatinine is available, the following formula (Cockcroft and Gault equation) may be used to estimate creatinine clearance. The serum creatinine should represent a steady state of renal function:

Dialysis Patients:

In patients undergoing haemodialysis, 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. A repeat dose, equivalent to the initial dose, should be given at the completion of each dialysis session. In patients undergoing continuous ambulatory peritoneal dialysis, cefepime may be administered at the same doses recommended for patients with normal renal function, ie: 500mg, 1g or 2g, depending on infection severity, at a dosage interval of every 48 hours.

Impaired Hepatic Function:

No adjustment is necessary for patients with impaired hepatic function.

Preparation of Solutions and Administration:

Maxipime may be given intravenously or by deep intramuscular injection into a large muscle mass (such as the upper outer quadrant of the gluteus maximus).

Maxipime powder is to be reconstituted using the volumes of diluent shown in Table 6; the diluents to be used are identified following the table.

Intravenous Administration:

The IV route of administration is preferable for patients with severe or life-threatening infections, particularly if the possibility of shock is present.

For direct IV administration, reconstitute Maxipime with 5 or 10mL of Sterile Water for Injection, 5% Dextrose Injection or 0.9% Sodium Chloride, as directed in Table 5. The resulting solution should be injected directly into the vein over a period of three to five minutes or injected into the tubing of an administration set while the patient is receiving a compatible IV fluid (see Compatibility and Stability).

For intravenous infusion, reconstitute the 500mg, 1g, or 2g vial, as noted above for direct IV administration, and add an appropriate quantity of the resulting solution to an IV container with one of the compatible IV fluids (see Compatibility and Stability).

Intramuscular Administration:

Maxipime should be reconstituted with one of the following diluents at the volumes shown in Table 5: Sterile water for Injection, 0.9% Sodium Chloride, 5% Dextrose Injection, or Bacteriostatic Water for Injection with Parabens or Benzyl Alcohol then administered by deep intramuscular injection into a large muscle mass (such as the upper outer quadrant of the gluteus maximus). In a pharmacokinetic study, doses up to 1g (volumes <3.1 mL) were administered at single injection sites; the maximum dose (2g/6.2 mL) was administered at two injection sites. Although MAXIPIME can be constituted with 0.5% or 1.0% Lidocaine hydrochloride, it is usually not required because Maxipime causes little or no pain upon IM administration.

Compatibility and Stability:

Intravenous:

Maxipime ( Cefepime Hydrochloride for Injection) is compatible at concentrations between 1 and 40mg/mL with the following IV infusion fluids: 0.9% Sodium Chloride, 5% or 10% Dextrose Injection, M/6 Sodium Lactate Injection, 5% Dextrose and 0.9% Sodium Chloride Injection, Lactated Ringers and 5% Dextrose Injection. These solutions are stable up to 24 hours at room temperature or 7 days under refrigeration.

Maxipime admixture compatibility and stability information is summarised in Table 6.

^a Aminosyn(r) II 4.25% in dextrose 25% with electrolytes and calcium
^b Inpersol(r) with 4.25% dextrose
NS 0.9% Sodium Chloride Injection
D5W 5% Dextrose Injection
NA not applicable
RT/L room temperature and light

Solutions of Maxipime, like those of most beta-lactam antibiotics, should not be added to solutions of metronidazole, vancomycin, gentamicin, tobromycin sulphate, or netilmicin sulphate because of physical or chemical incompatibility. However, if concurrent therapy with Maxipime is indicated, each of these antibiotics can be administered separately.

Intramuscular:

Maxipime ( Cefepime Hydrochloride for Injection) constituted as directed (in Table 5) is stable for 24 hours at room temperature or for 7 days under refrigeration with the following diluents: Sterile Water for Injection, 0.9% Sodium Chloride, 5% Dextrose Injection, Bacteriostatic Water for Injection with Parabens or Benzyl Alcohol, or 0.5% or 1% Lidocaine hydrochloride.

Note:

Parenteral drugs should be inspected visually for particulate matter before administration.

As with other cephalosporins, the colour of Maxipime may darken on storage, however, product potency is unaffected.

Contraindications

Maxipime is contraindicated in patients who have had previous hypersensitivity reactions to any component of the formulation, the cephalosporin class of antibiotics, penicillins or other beta-lactam antibiotics.

Warnings And Precautions

Before therapy with Maxipime is instituted, careful inquiry should be made to determine whether the patient has had previous immediate hypersensitivity reactions to cefepime, cephalosporins, penicillins, or other beta-lactam antibiotics. Antibiotics should be administered with caution to any patient who has demonstrated some form of allergy, particularly to drugs. If an allergic reaction to Maxipime occurs, discontinue the drug and treat the patient appropriately. Serious hypersensitivity reactions may require epinephrine and other supportive therapy.

Pseudomembranous colitis has been reported with virtually all broad-spectrum antibiotics including cefepime; therefore, it is important to consider this diagnosis in patients who develop diarrhoea in association with the use of antibiotics. Mild cases of pseudomembranous colitis may respond to drug discontinuation alone. In moderate to severe cases, management should include fluid, electrolyte and protein supplementation. When colitis does not improve after drug discontinuation or when it is severe, it should be treated with an antibiotic clinically effective against Clostridium difficile. Other causes of colitis should also be considered. Maxipime should be prescribed with caution in individuals with a history of gastrointestinal disease, particularly colitis.

As with other antibiotics, prolonged use of Maxipime may result in overgrowth of nonsusceptible organisms. Should superinfection occur during therapy, appropriate measures should be taken.

In patients with impaired renal function, such as reduction of urinary output because of renal insufficiency (creatinine clearance 50mL/min) or other conditions that may compromise renal function, the dosage of Maxipime should be adjusted to compensate for a slower rate of renal elimination (see Dosage And Administration and Actions ). Serious adverse events, including encephalopathy, seizures, myoclonus, and/or renal failure, have been reported in postmarketing experience in patients with renal impairment who receive unadjusted doses of Maxipime (see Adverse Events ). Renal function should be monitored carefully if drugs with nephrotoxic potential, such as aminoglycosides and potent diuretics, are administered with Maxipime.

Carcinogenesis, Mutagenesis, and Impairment of Fertility:

No long-term studies in animals have been performed to evaluate carcinogenic potential. In vitro and in vivo tests for genotoxicity have shown that cefepime is not genotoxic. No impairment of fertility has been seen in rats.

Usage in Pregnancy-Category B1:

Reproductive studies in mice, rats and rabbits showed no evidence of fetal damage; however, there are no adequate and well-controlled studies 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.

Nursing Mothers:

Cefepime is excreted in human breast milk in very low concentrations. Caution should be used when cefepime is administered to a nursing woman.

Labour and Delivery:

Cefepime has not been studied for use during labour and delivery. Treatment should only be given if clearly indicated.

Paediatric Use:

Although studies in paediatric patients are ongoing, the safety and effectiveness of Maxipime in children has not been established.

Geriatric Use:

In clinical studies, when geriatric patients received the usual recommended adult dose, clinical efficacy and safety were comparable to clinical efficacy and safety in non-geriatric adult patients. There was a modest prolongation in elimination half-life and lower renal clearance values compared to those seen in younger persons. Dosage adjustments are recommended if renal function is compromised (see Dosage And Administration ).

Driving/Operating Machinery:

The effect of Maxipime on driving and operating machinery has not been studied.

Adverse Effects

Maxipime is generally well tolerated. In clinical trials (N=5598) the most common adverse events were gastrointestinal symptoms and hypersensitivity reactions. Adverse events considered to be of definite, probable, or possible relationship to Maxipime are listed below.

Events that occurred at an incidence of > 0.1% - 1% (except where noted) were:

• Hypersensitivity - rash (1.8%), pruritus, urticaria.
• Gastrointestinal - nausea, vomiting, oral moniliasis, diarrhea (1.2%), colitis (including pseudomembranous colitis)
• Central nervous system - headache
• Other - fever, vaginitis, erythema

Events that occurred between 0.05% - 0.1% were: abdominal pain, constipation, vasodilation, dyspnea, dizziness, paraesthesia, genital pruritis, taste perversion, chills and unspecified moniliasis.

Adverse events that occurred at an incidence of <0.05% included anaphylaxis and seizures.

Local reactions at the site of IV infusion occurred in 5.2% of patients; these included phlebitis (2.9%) and inflammation (0.1%). Intramuscular administration of Maxipime was very well tolerated with 2.6% of patients experiencing pain or inflammation at the injection site.

Laboratory test abnormalities that developed during clinical trials in patients with normal baseline values were transient. Those that occurred at a frequency between 1% and 2% (unless noted) were elevations in alanine aminotransferase (3.6%), aspartate aminotransferase (2.5%), alkaline phosphatase, total bilirubin, eosinophilia, prolonged prothrombin time, partial thromboplastin time (2.8%), decreases in calcium and positive Coombs' test without haemolysis (18.7%). Transient elevations of blood urea nitrogen and/or serum creatinine and transient thrombocytopenia were observed in 0.5% to 1% of patients. Transient leucopenia and neutropenia were also observed (< 0.5%). During postmarketing experience, agranulocytosis has been reported rarely.

During postmarketing experience, encephalopathy, seizures, myoclonus, and/or renal failure have been reported in patients with renal impairment who received unadjusted doses of cefepime (see Precautions ). Because of the uncontrolled nature of these spontaneous reports, a causal relationship to Maxipime has not been determined.

The following adverse events and altered laboratory tests have been reported for cephalosporin-class antibiotics: Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, toxic nephropathy, aplastic anaemia, haemolytic anaemia, haemorrhage, and false positive tests for urinary glucose.

Interactions

Renal function should be carefully monitored if high doses of aminoglycosides are to be administered with cefepime or if aminoglycoside therapy is prolonged, because of the potential nephrotoxicity and ototoxicity of aminoglycoside antibiotics. Nephrotoxicity has been reported following concomitant administration of other cephalosporins with aminoglycoside antibiotics or potent diuretics such as frusemide.

Overdosage

In case of severe overdosage, especially in patients with compromised renal function, haemodialysis will aid in the removal of cefepime from the body; peritoneal dialysis is of no value. Accidental overdosing can occur if large doses are given to patients with reduced renal function (see Precautions ).

Pharmaceutical Precautions

Maxipime in the dry state original cartons should be stored at less than 30° C.

Medicine Classification

Prescription Only Medicine.

Package Quantities

500mg (15mL vial)

1g (15mL vial)

2g (77mL vial)

All available as 1's.

Name And Address

Bristol-Myers Squibb (NZ) Ltd
Stanway Business Park
Tower 2, Level 1
646 Great South Road
Ellerslie,
Auckland
NEW ZEALAND

Date Of Preparation

February 1999.