SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Cefuroxime Sodium for Injection 1.5g

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

Each vial contains as the active ingredient Cefuroxime Sodium for Injection equivalent to 1.5 g of cefuroxime.

3    PHARMACEUTICAL FORM

Vials containing an off-white to slightly yellow sterile powder for solution for injection or infusion.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Cefuroxime Sodium for Injection is indicated for the treatment of infections caused by susceptible strains of the designated micro-organisms, or before the infecting organism has been identified, in the diseases listed below.

Respiratory tract infections, for example, acute and chronic bronchitis, infected bronchiectasis, bacterial pneumonia, lung abscess and post operative chest infections.

Ear, nose and throat infections, for example, sinusitis, tonsillitis and pharyngitis.

Urinary tract infections, for example, acute and chronic pyelonephritis, cystitis and asymptomatic bacteriuria.

Soft tissue infections, for example, cellulitis, erysipelas, peritonitis and wound infections.

Bone and joint infections for example, osteomyelitis and septic arthritis.

Obstetric and gynaecological infections, pelvic inflammatory disease.

Gonorrhoea, particularly if penicillin is unsuitable.

Other infections, including septicaemia and meningitis.

Prophylaxis against infection in abdominal, pelvic, orthopaedic, cardiac, pulmonary, oesophageal and vascular surgery where there is increased risk from infection.

Consideration should be given to official local guidance (e.g. national recommendations) on the appropriate use of antibacterial agents.

Susceptibility of the causative organism to the treatment should be tested (if possible), although therapy may be initiated before the results are available.

4.2 Posology and Method of Administration

Usually cefuroxime is effective when administered alone, but when appropriate it may be used in combination with metronidazole or an aminoglycoside.

General Dosage

Adults: Many infections will respond to 750 mg three times daily by intramuscular or intravenous injection. For more severe infections this dose should be increased to 1.5 g three times daily intravenously. The frequency of dosage may be increased to six-hourly injections intramuscular or intravenous, giving total daily doses of 3 g to 6 g.

Infants and children: Doses of 30 to 100 mg/kg/day given in three or four divided doses. A dose of 60 mg/kg/day will be appropriate for most infections.

Neonates: Doses of 30 to 100 mg/kg/day given in two or three divided doses. In the first weeks of life the serum half-life of cefuroxime can be three to five times that in adults.

Gonorrhoea

1.5 g should be given as a single dose or as two 750 mg injections into different sites, eg each buttock.

Meningitis

Cefuroxime therapy is suitable for sole therapy of bacterial meningitis due to sensitive strains.

Infants and children: 200 to 240 mg/kg/day intravenously in three or four divided doses. This dosage may be reduced to 100 mg/kg/day after three days or when clinical improvement occurs.

Neonates: The initial dosage should be 100 mg/kg/day intravenously. This dosage may be reduced to 50 mg/kg/day after three days or when clinical improvement occurs.

Adults: 3 g intravenously every eight hours. No data is currently available to recommend a dose for intrathecal administration.

Prophylaxis

The usual dose is 1.5 g intravenously with induction of anaesthesia. For orthopaedic, pelvic and abdominal operations this may be followed with two 750 mg doses 8 and 16 hours later. For vascular, cardiac, oesophageal and pulmonary operations this may be supplemented with 750 mg intramuscularly three times a day for a further 24 to 48 hours.

In total joint replacement, 1.5 g cefuroxime powder may be mixed dry with each pack of methyl methacrylate cement polymer before adding the liquid monomer.

Dosage in Impaired Renal Function

As cefuroxime is excreted by the kidneys, the dosage should be reduced to allow for slower excretion in patients with impaired renal function, once creatinine clearance falls below 20 ml/min, as follows.

Marked impairment (creatinine clearance 10 to 20 ml/min)	750 mg twice daily
Severe impairment (creatinine clearance of less than 10 ml/min) *	750 mg once daily
Continuous peritoneal dialysis	750 mg twice daily
Renal failure on continuous arteriovenous haemodialysis or high-flux haemofiltration in intensive therapy units	750 mg twice daily

Low-flux haemofiltration	as for impaired renal
	function

* For patients on haemodialysis, a further 750 mg should be given at the end of each dialysis session.

4.3 Contraindications

Contraindicated in patients hypersensitive to the cephalosporin group of antibiotics.

4.4 Special warnings and precautions for use

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.

Cephalosporin antibiotics at high dosage should be given with caution to patients receiving potent diuretics or aminoglycosides as these combinations are suspected of adversely affecting renal function. Clinical experience has shown that this is not likely to be a problem at the recommended dose levels.

4.5 Interaction with other medicinal products and other forms of interaction

Concurrent administration of probenecid prolongs the excretion of cefuroxime and produces an elevated peak serum level.

Concurrent administration of potent diuretics, aminoglycosides may adversely affect renal function. (see section 4. 4)

Interference with Laboratory Tests

Slight interference may occur with the copper reduction methods (Fehling's, Benedict's) but this should not lead to false-positive results. Cefuroxime does not interfere with the enzyme based tests for glycosuria, or with the alkaline picrate method for creatinine. It is recommended that either the hexokinase or glucose oxidase methods are used for determination of blood/plasma glucose levels.

4.6 Pregnancy and lactation

Studies in animals revealed no evidence of embryopathic or teratogenic effects due to cefuroxime, but as with all drugs it should be used with caution during pregnancy.

Since cefuroxime is excreted in human milk, caution should be exercised when administering this antibiotic to a nursing mother.

4.7 Effects on ability to drive and use machines

Cefuroxime is not known to affect the ability to drive or use machines. No Data Held

4.8 Undesirable effects

Hypersensitivity reactions: Including skin rashes (maculopapular and urticarial), interstitial nephritis, drug fever and, very rarely, anaphylaxis. As with any antibiotic, prolonged use may lead to overgrowth of non-susceptible organisms, eg, Candida.

As with other cephalosporins, there have been rare reports of erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis.

Gastro-intestinal disturbance: Including, very rarely, pseudomembranous colitis, which has been reported with most broad spectrum antibiotics.

Haematological: A decrease in haemoglobin concentration, eosinophilia, leucopenia and neutropenia have been observed. Positive Coombs' tests have been reported. As with other cephalosporins, thrombocytopenia has been reported rarely.

Hepatic: Transient rises in liver enzymes or serum bilirubin have been observed, particularly in patients with pre-existing liver disease, but there is no evidence of hepatic involvement.

Renal: There may be some variation in the results of biochemical tests of renal function, but these results do not appear to be of clinical significance.

Other: Transient pain may be experienced at the site of intramuscular injection. Occasionally thrombophlebitis may occur at the site of intravenous injection. A burning sensation may be observed after intravenous injection. Mild to moderate hearing loss has been reported in some children treated for meningitis. Dizziness and headache has been reported in patients receiving cefuroxime.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard

4.9 Overdose

Overdosage of cephalosporins can lead to cerebral irritation and seizures. With seizures the drug should be discontinued and appropriate anticonvulsive and supportive therapy administered. Serum levels of cefuroxime can be reduced by haemodialysis or peritoneal dialysis.

5.    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic Properties

Cefuroxime is a cephalosporin antibiotic, ATC code J01DA06 Cephalosporins and related substances. All cephalosporins (P- lactam antibiotics) inhibit cell wall production and are selective inhibitors of peptidoglycan synthesis. The initial step in drug action consists of binding of the drug to cell receptors, called Penicillin-Binding Proteins. After a P- lactam antibiotic has bound to these receptors, the transpeptidation reaction is inhibited and peptidoglycan synthesis is blocked. Bacterial lysis is the end result.

Susceptibility

The following MIC breakpoints separating susceptible from intermediately susceptible organism and intermediately susceptible from resistant organism are used.

Table 1: Susceptibility breakpoints

Bacterial Breakpoints		Organism
NCCLS Breakpoints S:... 8 mg/L I:16 S:... 4 mg/L I:8 S:... 4 mg/L I:8 S:... 1 mg/L I:2 S:... 0.5 mg/L I:1	R:—32 mg/L R:—16 mg/L R:—16 mg/L R: —4 mg/L R: —2 mg/L	Enterobacteriaceae Enterococcus Haemophilus influenzae Neisseria gonorrhoeae Streptococcus pneumoniae
DIN Breakpoints S:... 4 mg/L I:8	R:—16 mg/L	All bacterial isolates
BSAC Breakpoints S:... 1 mg/L I:2-16 S:. 1 mg/L	R:—32 mg/L R: —2 mg/L	Acinetobacter spp. and Enterobacteriaceae Streptococcus pneumoniae, Moraxella catarrhalis, Neisseria gonorrhoeae, Haemophilus influenzae

NCCLS: National Committee for Clinical Laboratory Standards

DIN: Deutches Institut fur Normung

BSAC: British Society for Antimicrobial Chemotherapy

S: Susceptible, I: Intermediately susceptible, R: Resistant

The prevalence of resistance may vary geographically and with time for selected species and local information is desirable, particularly when treating several infections. This information gives only an approximate guidance on probabilities whether organisms will be susceptible to cefuroxime or not.

Table 2: Range of bacterial resistance to cefuroxime in Europe.

CATEGORY	RANGE OF RESISTANCE IN EUROPE
SUSCEPTIBLE
GRAM + VE AEROBES Staph.aureus (methicillin-susceptible strains) Staph.epidermidis (methicillin-	0-46%
susceptible strains) Streptococcus pneumoniae Streptococcus pyogenes Streptococcus viridans	2-17%
GRAM - VE AEROBES	0-29%
Escherichia coli	6-21%
Haemophilus influenzae Klebsiella spp.

Moraxella catarrhalis	0-17%
Neisseria spp. Proteus mirabilis	0-75%
Providencia spp. including Providencia rettgeri Providencia rettgeri only ANAEROBES Clostridium perfringens
INTERMEDIATE
GRAM - VE AEROBES
Bordetella pertussis Citrobacter	21-52%
Enterobacter spp. ANAEROBES Bacteroides fragilis	36-83%
INSUSCEPTIBLE
GRAM + VE AEROBES Enterococcus faecalis Staph. Aureus (methicillin-resistant strains) Staph. epidermidis (methicillin-resistant strains) GRAM - VE AEROBES
Acinetobacter spp. Campylobacter spp. Legionella spp. Pseudomonas spp.	70-94%
Serratia spp. Morganella morganii Proteus vulgaris ANAEROBES Clostridium difficile	75-100%

Cross-reactivity between cefuroxime and other antibiotics

Cross-resistance between cefuroxime and several other P-lactam antibiotics including amoxicillin, methicillin, penicillin and ampicillin and some cephalosporins has been recorded.

Amoxicillin-sensitive Haemophilus influenzae are more likely to be susceptible to cefuroxime than amoxicillin-resistant Haemophilus influenzae. Similarly, methicillin-sensitive Staphylococcus aureus and Staphylococcus epidermidis are usually cefuroxime-susceptible, while methicillin-resistant Staphylococcus aureus and Staphylococcus epidermidis are resistant to cefuroxime.

Resistance of Staphylococcus aureus and Streptococcus pneumoniae to penicillin can result in an increase in the cefuroxime MIC50 and MIC90 values for these organisms. In addition, resistance of Escherichia coli and Haemophilus influenzae to ampicillin may result in an increase of the cefuroxime MIC₅₀ values for these organisms.

Mechanisms of resistance to cefuroxime

Known mechanisms of resistance in targeted pathogens are the following:

1)    Production of ^-lactamases which are able to hydrolyse cefuroxime efficiently (e.g. several of the extended-spectrum and chromosomally-mediated P-lactamases).

2)    Reduced affinity of Penicillin- Binding Proteins for cefuroxime (e.g. Penicillin-resistant Streptococcus pneumoniae).

3)    Cell wall impermeability.

4)    Efflux pumps.

5.2 Pharmacokinetic properties

The serum half-life after either intramuscular or intravenous administration is approximately 70 minutes. After intramuscular injection the peak serum level occurs after about 45 minutes.

The antibiotic can be found in bone, synovial fluid and aqueous humour above the minimum inhibitory levels for common pathogens. The blood-brain barrier can be passed by cefuroxime when the meninges are inflamed.

Cefuroxime is excreted approximately 50% by glomerular filtration and 50% through the renal tubules. Cefuroxime is almost completely recovered unchanged in the urine within 24 hours, most being excreted within six hours.

5.3 Preclinical safety data

There is no experimental evidence of embryopathic or teratogenic effects attributable to cefuroxime.

6.1 List of excipients

Each vial contains only the active ingredient cefuroxime sodium.

6.2 Incompatibilities

Cefuroxime should not be mixed in the syringe with aminoglycoside antibiotics.

6.3 Shelf life

Before reconstitution: Three years.

In keeping with good pharmaceutical practice, freshly constituted suspensions or solutions should be used immediately. If this is not practicable then solution may be stored at 2°C-8°C (in a refrigerator) for up to 24 hours.

6.4 Special precautions for storage

Protect from light. Before reconstitution do not store above 25°C. After reconstitution the product may be stored at 2°C-8°C (in a refrigerator) for up to 24 hours.

6.5 Nature and contents of container

Type III flint glass vial stoppered with halobutyl closures and sealed with aluminium seals that may be combined with a polypropylene cap.

Pack sizes of 1 and 10 vials. Not all pack sizes may be marketed.

Special precautions for disposal

No Data Held

Instructions for Use and Handling:

Intravenous administration: Dissolve cefuroxime in Water for Injections using at least 15 ml for 1.5 g. For short intravenous infusion 1.5 g may be dissolved in 50 ml of Water for Injections. Reconstituted solutions may be diluted with

5% or 10% Dextrose

5% Dextrose containing 0.2%, 0.225%, 0.45% or 0.9% Sodium Chloride Injection

5% Dextrose containing 20 mEq Potassium Chloride

0.9% Sodium Chloride Injection

M/6 Sodium Lactate Injection

Ringer's Injection

Lactated Ringer's Injection

Heparin (10 and 50 units/ml) in 0.9% Sodium Chloride Injection 10 mEq Potassium Chloride in 0.9% Sodium Chloride Injection

These solutions may be given directly into a vein or introduced into the tubing of the giving set if the patient is receiving parenteral fluids.

7 MARKETING AUTHORISATION HOLDER

Flynn Pharma Ltd Alton House,

4 Herbert Street,

Dublin 2,

Ireland

8 MARKETING AUTHORISATION NUMBER(S)

PL 13621/0019

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

07/04/1998 / 01/06/2005

DATE OF REVISION OF THE TEXT

17/01/2009

10