Notes
Distributed by Southern XP Pty Ltd
1 Name of Medicine
Cefuroxime sodium.
2 Qualitative and Quantitative Composition
Each vial contains 750 mg or 1.5 g cefuroxime as cefuroxime sodium. See Table 1.
For the full list of excipients, see Section 6.1 List of Excipients.
3 Pharmaceutical Form
Powder for injection.
White or almost white to yellowish powder.
4.1 Therapeutic Indications
Cefuroxime SXP is indicated in adults and children of 40 kg or greater in weight for the prevention of infections associated with certain surgical procedures of the gastrointestinal (including oesophageal), orthopaedic, cardiovascular and gynaecological systems (including caesarean section) (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties).
In the prevention of infections in which it is very likely that anaerobic organisms will be encountered, cefuroxime should be administered with additional appropriate antibacterial agents such as metronidazole.
Consideration should be given to official guidance on the appropriate use of antibacterial agents, as antibiotic prophylaxis is not required in all gastrointestinal, orthopaedic, cardiovascular and gynaecological procedures or surgeries.
For patients with specific cardiac conditions which predispose them to endocarditis who are undergoing abdominal surgery for which surgical antibiotic prophylaxis is indicated, the prophylaxis regimen should additionally include an antibiotic active against enterococci.
For patients undergoing orthopaedic or cardiovascular surgery known to be, or at risk of being, colonised or infected with methicillin-resistant S. aureus (MRSA), add an antibiotic with activity against MRSA, such as vancomycin.
Cefuroxime SXP is not indicated in children < 40 kg in weight.
4.2 Dose and Method of Administration
Dose.
See Table 2.
Renal impairment. Cefuroxime is primarily excreted by the kidneys. As with all such antibiotics, in patients with markedly impaired renal function (i.e. Clcr < 20 mL/minute) it is recommended that the dosage of cefuroxime should be reduced to compensate for its slower excretion.
Dialysis.
Serum levels of cefuroxime are typically reduced when patients are concurrently undergoing haemodialysis or peritoneal dialysis.
Pharmacokinetic data in patients with renal impairment is included in Section 5.2 Pharmacokinetic Properties. This should be taken into consideration with regard to the dosing interval for affected patients.
In patients with creatinine clearance < 20 mL/min, 1.5 g IV every 24 hours is the maximum dose that should be given due to delayed excretion of the drug in renal impairment.
Hepatic impairment. Cefuroxime is primarily eliminated by the kidney. In patients with hepatic dysfunction this is not expected to affect the pharmacokinetics of cefuroxime.
Method of administration.
Contains no antimicrobial agent. Product is for single use in one patient only. Discard any residue.
Cefuroxime should be administered by intravenous injection over a period of 3 to 5 minutes directly into a vein or via a drip tube or infusion over 30 to 60 minutes.
Instructions for constitution.
See Table 3.
Compatibility.
Cefuroxime sodium is compatible with the following infusion fluids. It will retain potency for up to 6 hours at 25°C and 24 hours at 2°C-8°C (in refrigerator) in: 0.18% w/v sodium chloride plus 4% dextrose injection BP; 5% dextrose and 0.9% sodium chloride injection; 5% dextrose and 0.45% sodium chloride injection; 5% dextrose and 0.225% sodium chloride injection; M/6 sodium lactate injection; potassium chloride (10 and 40 mEq/L) in 0.9% sodium chloride injection; dextrose (glucose); sodium chloride; Ringer solution; Ringer's lactate.
Freshly prepared solution for IV administration is yellowish.
Solution can turn darker when standing but change of intensity of colour of diluted solution does not affect safety of administration and effectiveness of medicinal product.4.3 Contraindications
Hypersensitivity to cefuroxime or to any of the excipients listed in Section 6.1 List of Excipients.
Patients with known hypersensitivity to cephalosporin antibiotics.
History of severe hypersensitivity (e.g. anaphylactic reaction) to any other type of beta-lactam antibacterial agent (penicillins, monobactams and carbapenems).
4.4 Special Warnings and Precautions for Use
Identified precautions.
Neurotoxicity. There have been reports of neurotoxicity associated with cephalosporin treatment. Symptoms of neurotoxicity include encephalopathy, seizures and/or myoclonus. Risk factors for developing neurotoxicity with cephalosporin treatment include being elderly, renal impairment, central nervous system disorders and intravenous administration. Withdrawal of the medicine should be considered if there are signs of neurotoxicity.
Hypersensitivity reactions. As with all beta-lactam antibacterial agents, serious and occasionally fatal hypersensitivity reactions have been reported. There have been reports of hypersensitivity reaction which progressed to Kounis syndrome (acute allergic coronary arteriospasm that can result in myocardial infarction, see Section 4.8 Adverse Effects (Undesirable Effects)). In case of severe hypersensitivity reactions, treatment with cefuroxime must be discontinued immediately and adequate emergency measures must be initiated.
Before beginning treatment, it should be established whether the patient has a history of severe hypersensitivity reactions to cefuroxime, to other cephalosporins or to any other type of beta-lactam agent. Caution should be used if cefuroxime is given to patients with a history of non-severe hypersensitivity to other beta-lactam agents.
Cephalosporin antibiotics may, in general, be given safely to patients who are hypersensitive to penicillins, although cross-reactions have been reported. Special care is indicated in patients who have experienced an anaphylactic reaction to penicillin.
Severe cutaneous adverse reactions (SCARS).
Severe cutaneous adverse reactions including: Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS), which can be life-threatening or fatal, have been reported in association with cefuroxime treatment (see Section 4.8 Adverse Effects (Undesirable Effects)).
At the time of prescription patients should be advised of the signs and symptoms and monitored closely for skin reactions. If signs and symptoms suggestive of these reactions appear, cefuroxime should be withdrawn immediately and an alternative treatment considered. If the patient has developed a serious reaction such as SJS, TEN or DRESS with the use of cefuroxime, treatment with cefuroxime must not be restarted in this patient at any time.
Concurrent treatment with potent diuretics or aminoglycosides. Cephalosporin antibiotics at high dosage should be given with caution to patients receiving concurrent treatment with potent diuretics such as furosemide or aminoglycosides. Renal impairment has been reported during use of these combinations. Renal function should be monitored in the elderly and those with known pre-existing renal impairment (see Section 4.2 Dose and Method of Administration).
Overgrowth of non-susceptible microorganisms. Use of cefuroxime may result in the overgrowth of Candida. Prolonged use may also result in the overgrowth of other non-susceptible microorganisms (e.g. enterococci and Clostridium difficile), which may require interruption of treatment (see Section 4.8 Adverse Effects (Undesirable Effects)).
Antibacterial agent-associated pseudomembranous colitis has been reported with use of cefuroxime and may range in severity from mild to life threatening. This diagnosis should be considered in patients with diarrhoea during or subsequent to the administration of cefuroxime (see Section 4.8 Adverse Effects (Undesirable Effects)). Discontinuation of therapy with cefuroxime and the administration of specific treatment for Clostridium difficile should be considered. Medicinal products that inhibit peristalsis should not be given.
Intra-abdominal infections. Due to its spectrum of activity, cefuroxime is not suitable for the treatment of infections caused by Gram-negative non-fermenting bacteria (see Section 5.1 Pharmacodynamic Properties).
Interference with diagnostic tests. The development of a positive Coomb's test associated with the use of cefuroxime may interfere with cross matching of blood (see Section 4.8 Adverse Effects (Undesirable Effects)).
Slight interference with copper reduction methods (Benedict's, Fehling's, Clinitest) may be observed. However, this should not lead to false-positive results, as may be experienced with some other cephalosporins.
As a false negative result may occur in the ferricyanide test, it is recommended that either the glucose oxidase or hexokinase methods are used to determine blood/plasma glucose levels in patients receiving cefuroxime sodium.
Intracameral use and eye disorders. Cefuroxime SXP is not formulated for intracameral use. Individual cases and clusters of serious ocular adverse reactions have been reported following unapproved intracameral use of cefuroxime sodium compounded from vials approved for intravenous/intramuscular administration. These reactions included macular oedema, retinal oedema, retinal detachment, retinal toxicity, visual impairment, visual acuity reduced, vision blurred, corneal opacity and corneal oedema.
Important information about excipients. Cefuroxime SXP powder for solution for injection or infusion contains sodium. This should be considered for patients who are on a controlled sodium diet.
Use in obesity. Antibiotic pharmacokinetics are altered in obese patients, therefore dosage adjustment may be necessary.
Use in renal impairment.
Cefuroxime is primarily excreted by the kidneys. As with all such antibiotics, in patients with markedly impaired renal function (i.e. Clcr < 20 mL/minute) it is recommended that the dosage of cefuroxime should be reduced to compensate for its slower excretion (see Section 5.2 Pharmacokinetic Properties).
Dialysis.
Serum levels of cefuroxime are typically reduced when patients are concurrently undergoing haemodialysis or peritoneal dialysis.
Pharmacokinetic data in patients with renal impairment is included in Section 5.2 Pharmacokinetic Properties. This should be taken into consideration with regard to the dosing interval for affected patients (see Section 4.2 Dose and Method of Administration).
Use in the elderly.
Following IM or IV administration, the absorption, distribution and excretion of cefuroxime in elderly patients are similar to younger patients with equivalent renal function. However, as elderly patients are more likely to have decreased renal function, care should be taken in cefuroxime dose selection, and it may be useful to monitor renal function (see Section 4.2 Dose and Method of Administration).
Paediatric use.
Cefuroxime SXP is not indicated in children < 40 kg, infants and neonates.
Precautions for adults are also applicable to paediatric use.
In children, the serum half-life of 60 to 90 minutes is similar to that observed in adults.
Effects on laboratory tests.
As a false negative result may occur in the ferricyanide test, it is recommended that either the glucose oxidase or hexokinase methods are used to determine blood/plasma glucose levels in patients receiving cefuroxime axetil. This antibiotic does not interfere in the alkaline picrate assay for creatinine.4.5 Interactions with Other Medicines and Other Forms of Interactions
Cefuroxime may affect the gut flora, leading to lower oestrogen reabsorption and reduced efficacy of combined oral contraceptives.
Cefuroxime is excreted by glomerular filtration and tubular secretion. Concomitant use of probenecid is not recommended. Concurrent administration of probenecid prolongs the excretion of the antibiotic and produces an elevated peak serum level.
Potential nephrotoxic drugs and loop diuretics.
High-dosage treatments with cephalosporins should be carried out with caution in patients who are taking strong-acting diuretics (such as furosemide) or potential nephrotoxic preparations (such as aminoglycoside antibiotics), since impairment of renal function through such combinations cannot be ruled out.
Other interactions.
Determination of blood/plasma glucose levels (see Section 4.4 Special Warnings and Precautions for Use).
Concomitant use with oral anticoagulants may give rise to increased international normalised ratio (INR).
(Also see Section 4.2 Dose and Method of Administration; Section 6.2 Incompatibilities.)4.6 Fertility, Pregnancy and Lactation
Effects on fertility.
There are no data on the effects of cefuroxime sodium on fertility in humans. Reproductive studies in animals have shown no effects on fertility.
(Category B1)
There are limited amounts of data from the use of cefuroxime in pregnant women. Studies in animals have shown no reproductive toxicity (see Section 5.3 Preclinical Safety Data). Cefuroxime SXP should be prescribed to pregnant women only if the benefit outweighs the risk.
Cefuroxime has been shown to cross the placenta and attain therapeutic levels in amniotic fluid and cord blood after intramuscular or intravenous dose to the mother.
Frequent urination, as is the case in many pregnancies, can lead to an increase in the elimination rate of cefuroxime. Combined with a larger volume of distribution, and the likelihood of a consequential decrease in serum concentration, dose adjustment may be required to ensure sufficient antimicrobial coverage is maintained.
Cefuroxime is excreted in human milk in small quantities. Adverse reactions at therapeutic doses are not expected, although a risk of diarrhoea and fungal infection of the mucous membranes cannot be excluded. The decision whether to use cefuroxime therapy in a breastfeeding woman should take into account the benefits of breastfeeding for the child as well as the benefit of therapy for the woman.4.7 Effects on Ability to Drive and Use Machines
The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration. However, based on known adverse reactions, cefuroxime is unlikely to have an effect on the ability to drive and use machines.
4.8 Adverse Effects (Undesirable Effects)
The most common adverse reactions are phlebitis, transient pain at injection site, rash, eosinophilia, neutropenia, transient rise in liver enzymes or bilirubin, particularly in patients with pre-existing liver disease, but there is no evidence of harm to the liver.
The frequency categories assigned to the adverse reactions below are estimates, as for most reactions suitable data for calculating incidence are not available. In addition, the incidence of adverse reactions associated with cefuroxime sodium may vary according to the indication.
Data from clinical trials were used to determine the frequency of very common to rare adverse reactions. The frequencies assigned to all other adverse reactions (i.e. those occurring at < 1/10,000) were mainly determined using post-marketing data and refer to a reporting rate rather than a true frequency.
Treatment related adverse reactions, all grades, are listed (Table 4) by MedDRA body system organ class, frequency and grade of severity. The following convention has been utilised for the classification of frequency: very common ≥ 1/10; common ≥ 1/100 to < 1/10, uncommon ≥ 1/1,000 to < 1/100; rare ≥ 1/10,000 to < 1/1,000; very rare < 1/10,000 and not known (cannot be estimated from the available data).
Description of selected adverse reactions.
Cephalosporins as a class tend to be absorbed onto the surface of red cell membranes and react with antibodies directed against the drug to produce a positive Coomb's test (which can interfere with cross matching of blood) and very rarely haemolytic anaemia.
Transient rises in serum liver enzymes or bilirubin have been observed which are usually reversible.
Pain at the intramuscular injection site is more likely at higher doses. However it is unlikely to be a cause for discontinuation of treatment.
Paediatric population.
The safety profile for cefuroxime sodium in children is consistent with the profile in adults.
Cephalosporin-class adverse reactions.
Several cephalosporins have been implicated in triggering seizures, particularly in patients with renal impairment when the dosage was not reduced (see Section 4.2 Dose and Method of Administration). If seizures associated with drug therapy occur, the drug should be discontinued. Anticonvulsant therapy can be given if clinically indicated.
Post-marketing experience.
Nervous system disorders.
Seizures, encephalopathy, myoclonus - frequency not known.
Skin and subcutaneous tissue disorders.
Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) (baboon syndrome).
Reporting suspected adverse effects.
Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at http://www.tga.gov.au/reporting-problems.4.9 Overdose
Overdose can lead to neurological sequelae including encephalopathy, convulsions and coma. Symptoms of overdose can occur if the dose is not reduced appropriately in patients with renal impairment (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use).
Serum levels of cefuroxime can be reduced by haemodialysis or peritoneal dialysis.
For information on the management of overdose, contact the Poison Information Centre on 13 11 26 (Australia).
5 Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: antibacterials for systemic use, Second-generation cephalosporins, ATC code: J01DC02.
Mechanism of action.
Cefuroxime inhibits bacterial cell wall synthesis following attachment to penicillin binding proteins (PBPs). This results in the interruption of cell wall (peptidoglycan) biosynthesis, which leads to bacterial cell lysis and death.
Clinical trials.
A large number of randomised, comparative clinical trials involving the use of cefuroxime sodium have been undertaken worldwide and reported in the literature.
Cefuroxime has shown to be as safe and efficacious as other commonly used antimicrobial agents in each of the approved indications.
Cefuroxime has also demonstrated superiority to placebo when used prophylactically prior to surgery.
Mechanism of resistance.
Bacterial resistance to cefuroxime may be due to one or more of the following mechanisms:
hydrolysis by beta-lactamases including (but not limited to) extended-spectrum beta-lactamases (ESBLs), and Amp-C enzymes, that may be induced or stably derepressed in certain aerobic Gram-negative bacterial species;
reduced affinity of penicillin-binding proteins for cefuroxime;
outer membrane impermeability, which restricts access of cefuroxime to penicillin binding proteins in Gram-negative bacteria;
bacterial efflux pumps.
Organisms that have acquired resistance to other injectable cephalosporins are expected to be resistant to cefuroxime. Depending on the mechanism of resistance, organisms with acquired resistance to penicillins may demonstrate reduced susceptibility or resistance to cefuroxime.
Cefuroxime sodium breakpoints.
Minimum inhibitory concentration (MIC) breakpoints established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) are as follows (breakpoints apply to daily IV cefuroxime doses of 0.75 g x 3, unless otherwise specified) (see Table 5).
Microbiological susceptibility.
The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is known and the utility of the agent in at least some types of infections is questionable.
Cefuroxime is usually active against the following microorganisms in vitro (see Table 6).
5.2 Pharmacokinetic Properties
Absorption.
Following intravenous (IV) doses of 750 and 1,000 mg, serum concentrations were approximately 44 and 75 microgram/mL, respectively, at 10 minutes.
AUC and Cmax appear to increase linearly with increase in dose over the single dose range of 250 to 1000 mg following IV administration.
Based on a two-compartment model, the AUC for the lower doses nearly doubled as the dose doubled, but this relationship did not hold true for 1 g dose.
There was no evidence of accumulation of cefuroxime in the serum from normal volunteers following repeat intravenous administration of 1,500 mg doses every 8 hours.
Distribution.
Protein binding has been stated as approximately 33%. The average volume of distribution ranges from 9.3 to 15.8 L/1.73 m2 following IV administration over the dosage range of 250 to 1000 mg.
Concentrations of cefuroxime in excess of the minimum inhibitory levels for common pathogens can be achieved in the tonsilla, sinus tissues, bronchial mucosa, bone, pleural fluid, joint fluid, synovial fluid, interstitial space fluid, subcutaneous adipose tissue, bile and sputum. Cefuroxime passes the blood-brain barrier in small amounts when the meninges are inflamed but the drug is not recommended for the treatment of meningitis.
Metabolism.
HPLC analysis of patient urine samples confirmed that at least 95% of the administered dose is excreted as unchanged cefuroxime; cefuroxime is not metabolised.
Excretion.
Cefuroxime is excreted by glomerular filtration and tubular secretion. The serum half-life after either intramuscular or intravenous injection is approximately 65 to 70 minutes. There is an almost complete recovery (greater than 90%) of unchanged cefuroxime in urine within 24 hours of administration. The majority of the cefuroxime is excreted within the first 6 hours. The average renal clearance ranges from 114 to 170 mL/min/1.73 m2 following IV administration over the dosage range of 250 to 1000 mg.
Special patient population.
The pharmacokinetics of cefuroxime sodium are altered in the following patient populations.
Elderly. Following IV administration, the absorption, distribution and excretion of cefuroxime in elderly patients are similar to younger patients with equivalent renal function. However, as elderly patients are more likely to have decreased renal function, care should be taken in cefuroxime dose selection, and it may be useful to monitor renal function (see Section 4.2 Dose and Method of Administration).
Paediatric population. Cefuroxime SXP is not indicated in children < 40 kg, infants and neonates.
In children, the serum half-life of 60 to 90 minutes is similar to that observed in adults.
Renal impairment. Cefuroxime is primarily excreted by the kidneys. As with all such antibiotics, in patients with markedly impaired renal function (i.e. Clcr < 20 mL/minute) it is recommended that the dosage of cefuroxime should be reduced to compensate for its slower excretion (see Section 4.2 Dose and Method of Administration).
Dialysis.
Serum levels of cefuroxime are typically reduced when patients are concurrently undergoing haemodialysis or peritoneal dialysis.
The half-life for patients with GFRs of 20-50 mL/min were calculated to be 1.8 to 3.4 hours and for GFRs < 20 mL/min, 6.1 to 22.5 hours. With dialysis, these values decreased to 3.1 hours in haemodialysis and 5.4 hours in peritoneal dialysis. This should be taken into consideration with regard to the dosing interval for affected patients (see Section 4.2 Dose and Method of Administration).
Hepatic impairment. Since cefuroxime is primarily eliminated by the kidney, hepatic dysfunction is not expected to have an effect on the pharmacokinetics of cefuroxime.
Obesity. Obese patients present a higher volume of distribution, which may result in a consequential decrease in serum and/or tissue concentrations. To ensure clinical effectiveness, tissue concentrations should remain above the minimum inhibitory concentration (MIC), therefore dose adjustment may be required to ensure sufficient antimicrobial coverage is maintained. (See Section 4.4 Special Warnings and Precautions for Use.)
PK/PD relationship.
For cephalosporins, the most important pharmacokinetic-pharmacodynamic index correlating with in vivo efficacy has been shown to be the percentage of the dosing interval (%T) that the unbound concentration remains above the minimum inhibitory concentration (MIC) of cefuroxime for individual target species (i.e. %T > MIC).
5.3 Preclinical Safety Data
Non-clinical data reveal no specific hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, and toxicity to reproduction and development.
Gamma glutamyl transpeptidase activity in rat urine is inhibited by various cephalosporins, however the level of inhibition is less with cefuroxime. This may have significance in the interference in clinical laboratory tests in humans.
Genotoxicity.
Non-clinical data reveal no specific hazard for humans based on conventional studies of genotoxicity.
Carcinogenicity.
No carcinogenicity studies have been performed; however, there is no evidence to suggest carcinogenic potential.6 Pharmaceutical Particulars
6.1 List of Excipients
None.
6.2 Incompatibilities
Do not mix in the syringe with aminoglycoside antibiotics.
6.3 Shelf Life
In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.
Reconstituted solution.
Immediate use of the reconstituted solution is recommended.
Chemical and physical stability.
Chemical and physical stability has been demonstrated:
for 5 hours at 25°C and 48 hours at 2-8°C (in refrigerator) for the reconstituted solutions for intramuscular or intravenous injection;
or 6 hours at 25°C and 24 hours at 2-8°C (in refrigerator) for the reconstituted solutions for intravenous infusion.
From a microbiological point of view, the product should be used immediately. If storage is necessary, hold at 2°-8°C for not more than 24 hours.
6.4 Special Precautions for Storage
Store below 25°C, in the original package.
For storage conditions for the reconstituted and diluted medicinal product, see Section 6.3 Shelf Life.
6.5 Nature and Contents of Container
Cefuroxime SXP 750 mg powder for solution for injection or infusion:
Type I clear glass vials with a nominal capacity of 15 mL, sealed with a 20 mm bromobutyl rubber stopper and an aluminium cap.
Packs of 5 and 10 vials.
Cefuroxime SXP 1.5 g powder for solution for injection or infusion:
Type I clear glass vials with a nominal capacity of 15 mL, sealed with a 20 mm bromobutyl rubber stopper and an aluminium cap.
Pack of 1 vial.
6.6 Special Precautions for Disposal
In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.
6.7 Physicochemical Properties
Chemical structure.
Chemical name: sodium;(6R,7R)-3-(carbamoyloxymethyl)-7-[[(2Z)-2-(furan-2-yl)-2-methoxyiminoacetyl] amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate.
Chemical formula: C16H15N4NaO8S.
Molecular weight: 446.366.
CAS number.
56238-63-2.7 Medicine Schedule (Poisons Standard)
S4 (Prescription only medicine).
Summary Table of Changes
