Cefepime hydrochloride.
Cefepime hydrochloride is a semi-synthetic broad spectrum cephalosporin antibiotic for parenteral administration. The chemical name is Pyrrolidinium, 1-[[7-[[(2-amino-4- thiazolyl)(methoxyimino)acetyl]amino]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3- yl] methyl]-1-methyl-,chloride, monohydrochloride, monohydrate, [6R-[6,7(Z)]], which corresponds to the following structural formula: Cefepime hydrochloride is a white to pale yellow powder with a molecular formula of C19H25N6O5S2.Cl.HCl.H2O and a molecular weight of 571.5. It is highly soluble in water.
Average plasma concentrations of cefepime observed in normal adult males at various times following single 30-minute infusions of 500mg, 1g and 2g are summarised in Table 1. Following intramuscular administration, cefepime is completely absorbed. The average plasma concentrations of cefepime at various times following a single IM injection are summarised in Table 1.
| Cefepime dose | 0.5 hr | 1 hr | 2 hr | 4 hr | 8 hr | 12 hr |
| 500mg IV | 33.6 | 18.9 | 11.3 | 4.6 | 1.0 | 0.6 |
| 1g IV | 66.9 | 41.8 | 25.3 | 11.0 | 2.8 | 0.8 |
| 2g IV | 127.6 | 81.7 | 45.4 | 20.1 | 4.6 | 1.2 |
| 500mg IM | 8.2 | 12.5 | 12.0 | 6.9 | 1.9 | 0.7 |
| 1g IM | 14.8 | 25.9 | 26.3 | 16.0 | 4.5 | 1.4 |
| 2g IM | 36.1 | 49.9 | 51.3 | 31.5 | 8.7 | 2.3 |
Concentrations of cefepime achieved in specific tissues and body fluids are listed in Table 2.
| Tissue or fluid | Dose (IV) | Average time of sample post-dose (hr) | Mean concentration |
| Urine | 500mg | 0-4 | 292 |
| 1g | 0-4 | 926 | |
| 2g | 0-4 | 3120 | |
| Bile | 2g | 9.4 | 7.7 |
| Peritoneal fluid | 2g | 4.4 | 16.4 |
| Blister fluid | 2g | 1.5 | 24.5 |
| Bronchial mucosa | 2g | 4.8 | 24.1 |
| Sputum | 2g | 4.0 | 7.4 |
| Prostate | 2g | 1.0 | 31.5 |
| Appendix | 2g | 5.7 | 5.2 |
| Gallbladder | 2g | 8.9 | 11.9 |
The average elimination half-life of cefepime is approximately 2 hours, and the disposition of cefepime does not vary with respect to dose over the range of 250mg to 2g. There is no evidence of 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, demonstrating that cefepime is eliminated almost exclusively by renal mechanisms, primarily glomerular filtration. Cefepime is metabolised to N-methylpyrrolidine which is rapidly converted to the N-oxide. Urinary recovery of unchanged cefepime represents approximately 85% of dose, resulting in high concentrations of cefepime in the urine. The serum protein binding of cefepime averages 16.4% and is independent of its concentration in the serum. 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 healthy adults; Dosage adjustments in the elderly are recommended if renal function is compromised (see PRECAUTIONS and DOSAGE AND ADMINISTRATION). The pharmacokinetics of cefepime do not change to a clinically significant degree in cystic fibrosis patients. The pharmacokinetics of cefepime are unaltered in patients with impaired hepatic function who received a single 1g dose. It is not necessary to alter the dosage of cefepime in these patient populations. Studies in patients with various degrees of renal insufficiency have demonstrated a prolongation in elimination half-life. There is a linear relationship between total body clearance and 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). The average half-life in severely impaired patients requiring dialysis therapy is 13 hours for haemodialysis or 19 hours for continuous ambulatory peritoneal dialysis.
Single- and multiple-dose pharmacokinetics of cefepime were evaluated in patients ranging in age from 2 months to 16 years who received 50 mg/kg doses administered by IV infusion; multiple doses were administered every 8 or 12 hours for at least 48 hours. Mean plasma concentrations of cefepime after the first dose were similar to those at steady state, with only slight accumulation seen upon repeated dosing. Other pharmacokinetic parameters in infants and children were not different between first-dose and steady-state determinations, regardless of dosing schedule (q12h or q8h). There were also no differences in pharmacokinetics among the various patient ages or between male and female patients. Following a single IV dose, total body clearance averaged 3.3 mL/min/kg and average volume of distribution was 0.3 L/kg. The overall mean elimination half-life was 1.7 hours. The urinary recovery of unchanged cefepime was 60.4% of the administered dose, and renal clearance was the primary pathway of elimination, averaging 2.0 mL/min/kg. No acccumulation was seen when cefepime was given at 50mg/kg q12 h (n= 13), while Cmax, AUC, and t2, were increased approximately 15% at steady state after 50mg/kg q 8h. Clinically relevant changes in the pharmacokinetics of cefepime have not been observed in cystic fibrosis 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 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 strains of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS section.
Enterobacter Escherichia coli Klebsiella pneumoniae Proteus mirabilis
Pseudomonas aeruginosa
Staphylococcus aureus
(methicillin-susceptible strains only)
Streptococcus pneumoniae
Streptococcus pyrogenes
(Lancefield's Group A streptococci)
Enterobacter aerogenes * 0%
Enterobacter cloacae * 0%
Escherichia coli * 0%
Haemophilus influenzae 0%
Klebsiella pneumoniae * 0%
Proteus mirabilis * 0%
Pseudomonas aeruginosa * 3%
Staphylococcus aureus (methicillin susceptible) 0.2%
Streptococcus pneumoniae * 3%
Streptococcus pyogenes * 0%
Intermediate
Insusceptible
Staphylococcus aureus (methicillin resistant)
* Clinical efficacy has been demonstrated for susceptible isolates in approved clinical indications. Note: 1-20% of Enterobacteriacae have an acquired resistance mechanism (depressed synthesis of ampC beta lactamase or production of an ESBL) which decreases susceptibility to cefepime resulting in MICs in the 1-16 mcg/ml range. The following in vitro data are available, but the clinical significance is unknown. Cefepime has been shown to have in vitro activity against most strains 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.
Staphylococcus epidermidis
(methicillin-susceptible strains only)
Staphylococcus saprophyticus
Streptococcus agalactiae
(Lancefield's Group B streptococci) Viridans group streptococci
NOTE: Most strains of entrococci, eg Entercoccus faecalis, and methicillin-resistant staphylococci are resistant to cefepime.
Aerobic Gram-Negative Microorganisms: Acinetobacter calcoaceticus subsp. lwoffi Citrobacter diversus
Citrobacter freundii Enterobacter agglomerans
Haemophilius influenzae
(including beta-lactamase producing strains)
Hafnia alvei Klebsiella oxytoca
Moraxella catarrhalis
(including beta-lactamase producting strains)
Morganella morganii Proteus vulgaris Providencia rettgeri Providencia stuartii Serratia marcescens
NOTE: Cefepime is inactive against many strains of Stenotrophomonas (formally
Xanthomonas maltophilia and Pseudomonas maltophilia).
NOTE: Cefepime is inactive against most strains of Clostridium difficile. The prevalence of acquired resistance may vary geographically and with time for selected species. Information about the local resistance pattern should be obtained from a local bacteriological laboratory and taken into account in the choice of empiric therapy.
Dilution or diffusion techniques - either quantitative (MIC) or breakpoint, should be used following a regularly updated, recognised and standardised method (eg NCCLS). Standardised susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. A report of 'Susceptible' indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentration usually achievable. A report of 'Intermediate' indicates 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.
Cefepime has been studied in a clinical trial of surgical prophylaxis. A multi-centre, randomised, open-label study enrolled a total of 615 adult subjects who were to be treated by elective colo-rectal surgery. A single dose of 2g of either cefepime or ceftriaxone was administered intravenously to subjects followed by a single dose of metronidazole 500mg IV, starting approximately 1 hour prior to surgery. The primary study endpoint was the absence of infection at the operative site and of intrabdominal infection. Clinical outcomes are shown in Table 3 below.
| Number (%) of subjects | |||
| Cefepime (N= 307) | Ceftriaxone (N= 308) | Total (N= 615) | |
| 1) Sucess | 231 (75) | 232 (75) | 463 (75) |
| 2) Failure | 50 (16) | 46 (15) | 96 (16) |
| - primary site infection | 22 | 22 | 44 |
| - unexplained use of antibiotics | 23 | 20 | 43 |
| - septicaemia and bacteraemia | 5 | 4 | 9 |
| 3) Unable to determine | 26 (8) | 30 (10) | 56 (9) |
| - distant site infection | 20 | 23 | 43 |
| - other | 6 | 7 | 13 |
Adults:
Maxipime is indicated in 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. . Intra-abdominal infections, including peritonitis and biliary tract infections. . Gynaecological infections. . Septicaemia . Empiric treatment in febrile neutropenic patients (See Precautions) Maxipime is also indicated for surgical prophylaxis in patients undergoing intra-abdominal surgery. In this indication it is essential that metrodinazole also be administered.
Paediatrics
:
Maxipime is indicated in paediatric patients over 2 months of age for the treatment of the infections listed below when caused by susceptible bacteria: . Pneumonia . Urinary tract infections, both complicated, including pyelonephritis, and uncomplicated infections . Skin and skin structure infections . Septicaemia . Empiric treatment in febrile neutropenic patients (See Precautions) 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 appropriately as monotherapy prior to identification of the causative organisms(s). In the treatment of febrile neutropenia, consideration should be given to the need for other antibiotics in combination with Maxipime. In patients who are at risk of mixed aerobic-anaerobic infection, including infections in which Bacterioides fragilis may be present, concurrent initial therapy with an anti-anaerobic agent is recommended before the causative organism(s) is known.
Cefepime is contraindicated in patients who have shown immediate hypersensitivity reactions to any component of the formulation (including L-arginine), the cephalosporin class of antibiotics, penicillins or other beta-lactam antibiotics.
In patients with impaired renal function, such as reduction of urinary output because of renal insufficiency (creatinine clearance <= 50 mL/min) or other conditions that may compromise renal function, the dosage of cefepime should be adjusted to compensate for the slower rate of renal elimination. Because high and prolonged serum antibiotic concentrations can occur from usual doses in patients with renal insufficiency or other conditions that may compromise renal function, the maintenance dosage should be reduced when cefepime is administered to such patients. Continued dosage should be determined by degree of renal impairment, severity of infection, and susceptibility of the causative organisms (see DOSAGE AND ADMINISTRATION and PHARMACOLOGY). During postmarketing surveillance, the following serious adverse events have been reported: reversible encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor and coma), myclonus, seizures (including nonconclusive status epilepticus), and/or renal failure (see ADVERSE REACTIONS). Most cases occurred in patients with renal impairment who received doses of Maxipime that exceeded recommendations. In general, symptoms of neurotoxicity resolved after discontinuation of cefepime and/or after haemodialysis however, some cases included a fatal outcome. Renal function should be monitored carefully if drugs with nephrotoxic potential, such as aminoglycosides and potent diuretics, are administered with Maxipime. Before therapy with cefepime 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 immediate hypersensitivity reactions may require adrenalin 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. Treatment with broad- spectrum antibiotics alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is a primary cause of antibiotic-associated colitis. 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. In patients (adult and paediatric) at high risk for severe infection (including patients with a history of recent bone marrow transplantation, with hypotension at presentation, with an underlying haematologic 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. As with other antibiotics, prolonged use of cefepime may result in overgrowth of nonsusceptible organisms. Should superinfection occur during therapy, appropriate measures should be taken. Cefepime should be prescribed with caution in individuals with a history of gastrointestinal disease, particularly colitis. If neutropenia occurs as a result of prolonged therapy, cefepime should be discontinued and alternative antibiotic therapy used.
Renal function should be monitored carefully if drugs with nephrotoxic potential, such as aminoglycosides and potent diuretics, are administered with cefepime. Nephrotoxicity has been reported following concomitant administration of other cephalosporins with aminoglycoside antibiotics or potent diuretics such as frusemide.
Although no long-term studies in animals have been performed to evaluate carcinogenic potential, a battery of in vitro and in vivo tests for genotoxicity have been conducted. The overall conclusion of this testing is that cefepime is not genotoxic. Standard tests to assess fertility in rats show no impairment of fertility at exposure levels nearly two-fold higher than the calculated maximal daily human exposure.
Reproduction studies performed in mice and rats showed no evidence of impaired fertility or harm to the foetus at dose levels equivalent to (mouse) or slightly greater (rat) than the maximum human daily dose when the daily doses are compared to those in man on a mg/m2 basis. There are, however, 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.
Cefepime is excreted in human breast milk in very low concentrations. Although less than 0.01% of a 1g IV dose is excreted in milk, caution should be used when cefepime is administered to a nursing woman.
Cefepime has not been studied for use during labour and delivery. Treatment should only be given if clearly indicated.
Experience with the use of cefepime in paediatric patients aged less than 2 months is limited. Safety and effectiveness in paediatric patients below the age of 2 months have not been established. Therefore the administration of cefepime to patients less than 2 months of age is not recommended.
Of the more than 6400 adults treated with Maxipime in clinical studies, 35% were 65 years or older while 16% were 75 years or older. 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 unless the patients had renal insufficiency. 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). Cefepime 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 PRECAUTIONS, ADVERSE REACTIONS and PHARMACOLOGY). Serious adverse events, including encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor and coma), myclonus, seizures (including nonconclusive status epileticus), and/or renal failure have occurred in geriatric patients with renal insufficiency given the usual dose of cefepime (see PRECAUTIONS and ADVERSE REACTIONS).
The effect of Maxipime on driving and operating machinery has not been studied.
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%), pruritis, urticaria Gastrointestinal: nausea, vomiting, oral moniliasis, diarrhea (1.2%), colitis (including pseudomembranous colitis) Central nervous system: headache Other: fever, vaginitis, erythema Events that occurred at an incidence of 0.05% - 0.1% were abdominal pain, constipation, vasodilation, dyspnea, dizziness, paresthesia, genital pruritis, taste perversion, chills and unspecified moniliasis. Events that occurred at an incidence of < 0. 05% included anaphylaxis and seizures. Local reactions at the site of IV infusions 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, anaemia, eosinophilia, prolonged prothrombin time, partial prothrombin time (2.8%), and positive Coombs' test without haemolysis (18.7%). Transient elevations of serum urea, and/or serum creatinine and transient thrombocytopenia were observed in 0.5% to 1% of patients. Transient leukopenia and neutropenia were also seen (< 0.5%).
Postmarketing Experience
During postmarketing experience, encephalopathy (disturbance of conciousness including confucion, hallucinations, stupor and coma), seizures, myoclonus and/or renal failure have been reported. Most cases occured in patients with renal impairment who received doses of cefepime that exceeded recommendations (see also PRECAUTIONS). Anaphylaxis including anaphylactic shock, transient leucopoenia, neutropenia, agranulocytosis and thrombocytopenia have been reported rarely. Because of the uncontrolled nature of these spontaneous reports, a causal relationship to Maxipime has not been determined. The following adverse reactions and altered laboratory tests have been reported for cephalosporin-class antibiotics: Urticaria, Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, renal dysfunction, toxic nephropathy, aplastic anaemia, hemolytic anaemia, haemorrhage, hepatic dysfunction including cholestasis, and false positive tests for urinary glucose.
Paediatrics
The safety profile of Maxipime in infants and children is similar to that seen in adults. The most frequently reported adverse event considered related to Maxipime in clinical trials was rash.
The usual adult dosage and route of administration of Maxipime is 1g administered intravenously or intramuscularly every 12 hours. However, the dosage and route vary according to the susceptibility of the causative organisms, the severity of the infection, and the condition and renal function of the patient. Guidelines for dosage of Maxipime are provided in Table 4. The usual duration of therapy is 7-10 days; however, more severe infections may require longer treatment.
| Severity of Infection | Dose & route of administration | Dosing Interval |
| Mild to moderate urinary tract infections: | 500mg - 1g IV or IM | q12h |
| Mild to moderate infections other than UTI: | 1g IV or IM | q12h |
| Severe infections: | 2g IV | q12h |
| Very severe or life-threatening infections: | 2g IV | q8h |
The dose recommendation for prophylaxis to prevent infection in adults undergoing intra- abdominal surgery is as follows: A single 2 g IV dose of Maxipime (as a 30-minute infusion, see DOSAGE AND ADMINISTRATION) starting 60 minutes before initial surgical incision. A single 500 mg IV dose of metronidazole should be administered immediately following completion of the Maxipime infusion. The metronidazole dose should be prepared and administered in accordance with official product labeling. Due to incompatibility, Maxipime and metronidazole should not be mixed together in the same container (see COMPATIBILITY AND STABILITY); flushing of the intravenous line with a compatible fluid before infusion of the metronidazole is recommended. If the surgical procedure lasts longer than 12 hours from the initial prophylactic dose, a second dose of Maxipime followed by metronidazole should be administered 12 hours following the initial prophylactic dose.
Usual recommended dosages:
Pneumonia, urinary tract infections, and skin and skin structure infections:
Patients
> 2 months of age with body weight 40 kg: 50 mg/kg q12h. For more severe infections, a dosage schedule of q8h can be used. Empiric treatment of febrile neutropenia: Patients > 2 months of age with body weight 40 kg: 50 mg/kg q8h. The usual duration of therapy is 7-10 days; however, more severe infections may require longer treatment. For paediatric patients with body weights > 40kg, adult dosing recommendations apply (see Table 4). For patients older than 12 years who are 40 kg, the dosage recommendations for younger patients 40 kg should be used. Dosage in paediatric patients should not exceed the maximum recommended dosage in adults (2 g q8h). Experience with intramuscular administration in paediatric patients is limited and this route is not recommended.
No adjustment is necessary for patients with impaired hepatic function.
In patients with impaired renal function, the dose of cefepime should be adjusted to compensate for the slower renal elimination. The recommended initial dose of cefepime in patients with mild to moderate renal impairment should be the same as in patients with normal renal function. The recommended maintenance doses of cefepime in patients with renal insufficiency are presented in Table 5. When only a serum creatinine measurement 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: Males: Creatinine clearance (mL/min) = weight (kg) x (140 - age) 814 x serum creatinine (mmol/L) Females: 0.85 x value calculated using formula for males
| Creatine clearance (mL/min) | Recommended Maintenance Dosage | |||
| > 50 | (Usual dose, no adjustment necessary) 2 g q8h 2 g q12h 1 g q12h 500 mg q12h | |||
| 30 - 50 | 2 g q12h | 2 g q24h | 1 g q24h | 500 mg q24h |
| 11 - 29 | 2 g q24h | 1 g q24h | 500 mg q24h | 500 mg q24h |
| 10 | 1 g q24h | 500 mg q24h | 250 mg q24h | 250 mg q24h |
| Haemodialysis * | 500 mg q24h | 500 mg q24h | 500 mg q24h | 500 mg q24h |
| * Pharmacokinetic modeling indicates that reduced dosing for these patients is necessary. Patients receiving cefepime who are undergoing concomitant haemodialysis should be dosed as follows: 1 gram loading dose on the first day of cefepime therapy and 500mg per day thereafter. On dialysis days, cefepime should be administered following dialysis. Whenever possible cefepime should be administered at the same time each day. | ||||
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. In patients undergoing continuous ambulatory peritoneal dialysis, cefepime may be administered at normally recommended doses, ie: 500mg, 1g or 2g, depending on infection severity, at a dosage interval of every 48 hours.
Since urinary excretion is the primary route of elimination of cefepime in paediatric patients (see PHARMACOLOGY), an adjustment of the dosage of cefepime should also be considered in patients < 12 years of age with renal impairment. A dose of 50 mg/kg in patients aged 2 months up to 12 years, and a dose of 30 mg/kg in patients aged 1 month up to 2 months, are comparable to a dose of 2 g in an adult. As recommended in Table 5 above, the same increase in interval between doses and/or reduction in dose should be used.
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). The dosage and route vary according to the susceptibility of the causative organisms, the severity of the infection, renal function, and overall condition of the patient. When using Maxipime for Surgical Prophylaxis it is essential that metronidazole also be administered.
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 5% Glucose Injection or 0.9% Sodium Chloride, as directed in Table 6. Slowly inject directly into the vein over a period of three to five minutes or inject 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). Alternatively, constitute the 1g or 2g piggyback (100mL) bottle with 50 or 100mL of a compatible IV fluid listed in the Compatibility and Stability section. The resulting solution should be administered over a period of approximately 30 minutes.
Maxipime should be reconstituted with one of the following diluents: Sterile water for Injections, 0.9% Sodium Chloride or 5% Glucose Injection (refer to Table 6). Although Maxipime can be constituted with 0.5% or 1.0% lignocaine hydrochloride, it is usually not required because Maxipime causes little or no pain upon IM administration. Experience with intramuscular administration in paediatric patients is limited and this route is not recommended.
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% Glucose Injection, M/6 Sodium Lactate Injection, 5% Glucose and 0.9% Sodium Chloride Injection, Lactated Ringers and 5% Glucose Injection. Cefepime in 0.9% Sodium Chloride or 5% Glucose Injection is compatible when admixed with heparin (10 or 50 units/mL), potassium chloride (10 or 40m Eq/L) and theophylline (0.8mg/mL in 5% Glucose Injection). Cefepime at a concentration of 40mg/mL in 0.9% Sodium Chloride or 5% Glucose Injection was found to be compatible with Amikin (amikacin 6mg/mL).
Maxipime (Cefepime Hydrochloride for Injection) should be reconstituted with the following diluents: Sterile Water for Injections, 0.9% Sodium Chloride, 5% Glucose Injection, or 0.5% or 1% lignocaine hydrochloride.
Maxipime should be reconstituted immediately before use and used as soon as practicable after reconstitution, any residue being discarded. If there is any delay in use of the reconstituted Maxipime it should be stored at 20C-80C for a maximum of 24 hours. Solutions of cefepime, like those of most beta-lactam antibiotics, should not be added to solutions of gentamicin, metronidazole, vancomycin, tobramycin sulphate or netilmicin sulphate because of physical or chemical incompatibility. However, if concurrent therapy with cefepime and gentamicin is indicated, each of these antibiotics can be administered separately to the same patient . Note: Parenteral drugs should be inspected visually for particulate matter before administration and not used if particulate matter is present. As with other cephalosporins, the colour of reconstituted Maxipime may darken on storage, however, product potency is not adversely affected. Reconstituted solutions should be protected from light.
| Amount of diluent to be added (mL) | Approximate available volume (mL) | * Approximate cefepime concentration (mg/mL) | |
| Intravenous | 5 | 5.6 | 88 |
| 500mg vial | |||
| 1g vial | 10 | 11.3 | 88 |
| 2g vial (or 77 mL | 10 | 12.6 | 158 |
| bottle) | |||
| Infusion (100mL) 1 g bottle 2g bottle | 50 or 100 50 or 100 | 50 or 100 50 or 100 | 20 or 10 38 or 20 |
| Intramuscular | 1.5 | 2.2 | 230 |
| 500mg vial | |||
| 1g vial | 3.0 | 4.4 | 230 |
In case of severe overdosage, especially in patients with compromised renal function, dialysis will aid in the removal of cefepime from the body; peritoneal dialysis is of no value. Accidental overdosing has occurred when large doses were given to patients with impaired renal function (see DOSAGE AND ADMINISTRATION, PRECAUTIONS and ADVERSE REACTIONS). Symptoms of overdosage include encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, and coma), myoclonus, seizures and neuromuscular excitability.
Maxipime is a sterile dry mixture of cefepime hydrochloride and L-arginine. Maxipime is available in: 1g (15mL vial) 2g (77mL (bottle) vial)
Maxipime in the dry state in original cartons should be stored at less than 25oC. Protect from light. To avoid the risk of microbial contamination, reconstituted Maxipime should be administered as soon as possible after reconstitution.
| 500mg Vial | AUST R | 52796 (not marketed) |
| 1g Vial | AUST R | 52805 |
| 2g Vial | AUST R | 52806 (not marketed) |
| 2g 77mL (Bottle) Vial | AUST R | 52809 |
Bristol-Myers Squibb Australia Pty Ltd 4 Nexus Court, Mulgrave, Victoria 3170, Australia.
6 September 2002
1 November 2012