SUMMARY OF PRODUCT CHARACTERISTICS

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1 SUMMARY OF PRODUCT CHARACTERISTICS 1. NAME OF THE MEDICINAL PRODUCT Cefuroxime 250mg Powder for Injection 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each vial contains 250mg cefuroxime (as sodium salt) 3. PHARMACEUTICAL FORM Powder for solution for injection Powder for suspension for injection Vial containing white sterile powder 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Cefuroxime 250mg Powder 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 such as 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 where penicillin is not suitable 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. 1

2 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 750mg three times daily by intramuscular or intravenous injection. For more severe infections, this dose should be increased to 1.5g three times daily intravenously. The frequency of dosage may be increased to six-hourly injections (intramuscular or intravenous) giving total daily doses of 3g to 6g. Infants and Children: Doses of 30 to 100mg/kg/day given as three or four divided doses. A dose of 60 mg/kg/day will be appropriate for most infections. Neonates: Doses of 30 to 100mg/kg/day given as two of three divided doses. In the first weeks of life the serum half-life of cefuroxime can be three to five times that in adults. Elderly: See dosage in adults Gonorrhoea: 1.5g should be given as a single dose or as two 750mg injections into different sites e.g. each buttock. Meningitis: Cefuroxime Powder for Injection is suitable for sole therapy of bacterial meningitis due to sensitive strains. The following dosages are recommended. Infants and children: 200 to 240mg/kg/day intravenously in three or four divided doses. This dosage may be reduced to 100mg/kg/day after three days or when clinical improvement occurs. Neonates: The initial dose should be 100mg/kg/day intravenously. This may be reduced to 50mg/kg/day when clinically indicated. Adults: 3g intravenously every eight hours. No data are currently available to recommend a dose for intrathecal administration. Prophylaxis: The usual dose is 1.5g intravenously with induction of anaesthesia. For abdominal, pelvic and orthopaedic operations this may be followed with two 750mg doses 8 and 16 hours later. For cardiac pulmonary, oesophageal and vascular operations, this may be supplemented with 750mg intramuscularly three times a day for a further 24 to 48 hours. In total joint replacement, 1.5g cefuroxime powder may be mixed dry with each pack of methyl methacrylate cement polymer before adding the liquid monomer. 2

3 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 20ml/min, as follows: Marked impairment (creatinine clearance 10 20ml/min): 750mg twice daily Severe impairment (creatinine clearance <10ml/min): 750mg once daily For patients on haemodialysis, a further 750mg dose should be given at the end of each dialysis. Continuous peritoneal dialysis: 750mg twice daily. Renal failure on continuous arteriovenous haemodialysis or high-flux haemofiltration in intensive therapy units: 750mg twice daily. Low-flux haemofiltration: as for impaired renal function. 4.3 Contraindications Hypersensitivity to cefuroxime or other cephalosporin antibiotics. Cephalosporins are contraindicated in patients who have had a previous immediate and/or severe hypersensitivity reaction to any penicillin or to any other beta-lactam drug. 4.4 Special warnings and precautions for use Before therapy with cefuroxime is initiated, careful enquiry should be made to determine whether the patient has had any previous hypersensitivity reactions to cefuroxime, cephalosporins, penicillins or other beta-lactam drugs. Cefuroxime is contraindicated in patients who have had a previous immediate and/or severe hypersensitivity reaction to a penicillin or other beta-lactam drug. It should therefore be given with caution to patients who have had any other type of hypersensitivity reaction to a penicillin or any other beta-lactam drug. As with other antibiotics, prolonged use of cefuroxime may result in the overgrowth of nonsusceptible organisms (e.g. Candida, Enterococci, Clostridium difficile), which may require interruption of treatment. Pseudomembranous colitis has been reported with the use of broadspectrum antibiotics, therefore, it is important to consider its diagnosis in patients who develop serious diarrhoea during or after antibiotic use. There may be some variation in the results of biochemical tests of renal function, but these do not appear to be of clinical importance. As a precaution, renal function should be monitored if this is already impaired. Delayed sterilisation of the CSF in patients with Haemophilus influenzae meningitis may result in an adverse outcome such as deafness and/or neurological sequelae. Persistence of positive CSF cultures of H. influenzae at hours has been noted in some patients treated with cefuroxime injection and as with other therapeutic regimens used in the treatment of meningitis, hearing loss has been reported in some children. With a sequential therapy regime the timing of change to oral therapy is determined by the severity of the infection, clinical status of the patient and susceptibility of the pathogens involved. The change to oral therapy should only be made once there is a clear clinical improvement. If there has been no clinical improvement after 72 hours of parenteral 3

4 treatment, then the patient s treatment should be reviewed. Please refer to the relevant prescribing information for oral cefuroxime axetil before initiating sequential therapy. This medicinal product contains approximately 2.2 mmol (51mg) sodium per gram. This should be taken into consideration for patients on a controlled sodium diet. 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. Plasma levels of cefuroxime are reduced by dialysis. Cephalosporin antibiotics at high doses should be given with caution to patients receiving concurrent treatment with potent diuretics such as furosemide and aminoglycosides, as these combinations are suspected of adversely affecting renal function. Clinical experience with cefuroxime given by injection has shown that this is not likely to be a problem at the recommended dose levels. A positive Coomb s test has been reported during treatment with cephalosporins. This phenomenon can interfere with cross matching of blood. Cefuroxime does not interfere with enzyme-based tests for glycosuria. 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. It is recommended that either the glucose oxidase or hexokinase methods are used to determine blood/plasma glucose levels in patients receiving Cefuroxime Powder for injection. This antibiotic does not interfere with the alkaline picrate assay for creatinine. 4.6 Pregnancy and lactation There is no experimental evidence of embryopathic or teratogenic effects attributable to Cefuroxime Powder for injection but, as with all drugs, it should be administered with caution during the early months of pregnancy. Cefuroxime is excreted in human milk and consequently caution should be exercised when Cefuroxime Powder for injection is administered to a nursing mother. 4.7 Effects on ability to drive and use machines Cefuroxime Powder for injection has no reported influence on the ability to drive and use machines. No studies on the effects on the ability to drive and use machines have been performed. 4.8 Undesirable effects Adverse reactions to cefuroxime sodium when given by injection have occurred relatively infrequently and have been generally mild and transient in nature. 4

5 The following convention has been used for the classification of frequency: Very common 1/10, Common 1/100 and <1/10, Uncommon 1/1000 and <1/100, Rare 1/10,000 and <1/1000, Very rare <1/10,000. Infections and infestations Rare: Candida overgrowth from prolonged use. Blood and lymphatic system disorders Common: Neutropenia, eosinophilia. Uncommon: Leukopenia, decreased haemoglobin concentration, positive Coomb s test. Rare: Thrombocytopenia. Very rare: Haemolytic anaemia. 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. Immune system disorders Hypersensitivity reactions including: Uncommon: Skin rash, urticaria and pruritus. Rare: Drug fever. Very rare: Interstitial nephritis, anaphylaxis. See also Skin and subcutaneous tissue disorders and Renal and urinary disorders. Gastrointestinal disorders Uncommon: Gastrointestinal disturbance. Very rare: Pseudomembranous colitis. Hepatobiliary disorders Common: Transient rise in liver enzymes. Uncommon: Transient rise in bilirubin. Transient rises in serum liver enzymes or bilirubin occur, particularly in patients with preexisting liver disease, but there is no evidence of harm to the liver. Skin and subcutaneous tissue disorders Very rare: Erythema multiforme, toxic epidermal necrolysis and Stevens Johnson Syndrome. See also Immune system disorders. Renal and urinary disorders Very rare: Elevations in serum creatinine, elevations in blood urea nitrogen and decreased creatinine clearance (See Section 4.4 Special Warnings and Precautions for use). See also Immune system disorders. General disorders and administration site conditions Common: Injection site reactions which may include pain and thrombophlebitis. Pain at the intramuscular injection site is more likely at higher doses. However it is unlikely to be a cause for discontinuation of treatment.. 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: 5

6 4.9 Overdose Overdose of cephalosporins can cause cerebral irritation leading to convulsions. Serum levels of cefuroxime can be reduced by haemodialysis or peritoneal dialysis. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Second generation cephalosporins ATC code: J01D C02 Mechanism of action: Like other beta-lactam drugs, cefuroxime exerts antibacterial activity by binding to and inhibiting the action of certain bacterial cell wall synthetic enzymes namely the penicillin binding proteins. This results in the interruption of cell wall (peptidoglycan) biosynthesis which leads to bacterial cell lysis and death. Mechanisms of Resistance: Bacterial resistance to cefuroxime may be due to one or more of the following mechanisms: hydrolysis by beta-lactamases. Cefuroxime may be efficiently hydrolysed by certain of the extended-spectrum beta-lactamases (ESBLs) and by the chromosomally encoded (AmpC) enzyme that may be induced or stably depressed 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 organisms drug efflux pumps Breakpoints: The following clinical MIC breakpoints for bacteria have been defined for cefuroxime according to EUCAST: Enterobacteriaceae: 8mg/L for susceptible, >8mg/L for resistant S pneumoniae: 0.5 mg/l for susceptible, >1 mg/l for resistant Streptococcus spp: 0.5 mg/l for susceptible, >0.5 mg/l for resistant H. influenzae and M. catarrhalis: 1 mg/l for susceptible, >2 mg/l for resistant Non-species related breakpoints: 4 mg/l for susceptible, >8 mg/l for resistant 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 is such that the utility of the agent in at least some types if infections is questionable. Commonly susceptible species Aerobes, Gram positive: Staphylococcus aureus (methicillin susceptible) Coagulase-negative staphylococci (methicillin susceptible) Staphylococcus agalactiae Staphylococcus pneumoniae Staphylococcus pyrogenes Aerobes, Gram negative: 6

7 Escherichia coli Haemophilus influenzae Klebsiella species Moraxella catarrhalis Neisseria gonorrhoeae Proteus mirablis Proteus rettgeri Anaerobes: Peptococcus species Peptostreptococcus species Other organisms: Borrelia burgdorferi Species for which resistance may be a problem Acinetobacter species Citrobacter species Enterobacter species Morganella morganii Resistant: Bacteroides fragilis Clostridium difficile Enterococci Listeria monocytogenes Proteus vulgaris Pseudomonas species Serratia species 5.2 Pharmacokinetic properties Peak levels of cefuroxime are achieved within 30 to 45 minutes after intramuscular administration. The serum half-life after either intramuscular or intravenous injection is approximately 70 minutes. Concurrent administration of probenicid prolongs the excretion of the antibiotic and produces an elevated peak serum level. There is almost complete recovery of unchanged cefuroxime in the urine within 24 hours of administration, the major part being eliminated in the first six hours. Approximately 50% is excreted through the renal tubules and approximately 50% by glomerular filtration. Concentrations of cefuroxime in excess of the minimum inhibitory levels for common pathogens can be achieved in bone, synovial fluid and aqueous humor. Cefuroxime passes the blood-brain barrier when the meninges are inflamed. 5.3 Preclinical safety data No additional data of relevance 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients None 7

8 6.2 Incompatibilities Solutions containing cefuroxime should no be mixed with or added to solutions containing other agents other than those listed below (see section 6.6) The ph of 2.74% w/v sodium bicarbonate injection BP considerably affects the colour of solutions and therefore this solution is not recommended for the dilution of cefuroxime powder. However, if required, for patients receiving sodium bicarbonate injection by infusion, the cefuroxime powder for injection may be introduced into the tube of the giving set. Cefuroxime powder for injection should not be mixed in the syringe with aminoglycoside antibiotics. 6.3 Shelf life Two years. Reconstituted solution: Chemical and physical stability has been demonstrated for 24 hours at 2 C 8 C and for 8 hours at 25 C. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user and would normally be no longer than 24 hours at 2-8 C unless reconstitution has taken place in controlled and validated aseptic conditions. 6.4 Special precautions for storage Keep vials in the outer carton to protect from light. 6.5 Nature and contents of container 10 ml Type I glass vial with chlorobutyl rubber stopper and aluminium cap containing 250 mg cefuroxime (as sodium salt). Cartons contain 1, 5, 10, 20 or 50 vials. Not all pack sizes may be marketed. 6.6 Instructions for use and handling This medicinal product is for single use only. Discard any unused contents. Intramuscular use Add 1ml water for injections to 250mg Cefuroxime Powder for injection. Shake gently to produce an opaque suspension (final volume: 1.1ml). Intravenous use Dissolve Cefuroxime Powder for injection in water for injections using at least 2ml for 250mg (final volume: 2.1ml), at least 6ml for 750mg (final volume: 6.4ml) or 15ml for 1.5g (final volume: 15.8ml), to produce a clear solution. For short intravenous infusion (e.g. up to 30 minutes), 1.5g may be dissolved in 50ml water for injections (final volume: 50.9ml). 8

9 Reconstituted solutions may be diluted with: 10% dextrose 0.9% sodium chloride injection M/6 sodium lactate injection Ringer's injection Lactated Ringer's injection These solutions may be given directly into the vein or introduced into the tubing of the giving set if the patient is receiving parenteral fluids. 7. MARKETING AUTHORISATION HOLDER Villerton Invest SA 40 Avenue Monterey L-2163 Luxembourg 8. MARKETING AUTHORISATION NUMBER PL 24780/ DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 01/10/ DATE OF REVISION OF THE TEXT 16/04/2015 9