1. Name Of The Medicinal Product
Zinacef®
Cefuroxime (as sodium) INN for Injection or Infusion.
2. Qualitative And Quantitative Composition
Vials contain either 250mg, 750mg or 1.5g cefuroxime (as sodium).
3. Pharmaceutical Form
Cefuroxime is a white to cream powder to which appropriate amounts of water are added to prepare an off-white suspension for intramuscular use or a yellowish solution for intravenous administration.
4. Clinical Particulars
4.1 Therapeutic Indications
Zinacef is a bactericidal cephalosporin antibiotic which is resistant to most beta-lactamases and is active against a wide range of Gram-positive and Gram-negative organisms. It is indicated for the treatment of infections before the infecting organism has been identified or when caused by sensitive bacteria. In addition, it is an effective prophylactic against post-operative infection in a variety of operations. Usually Zinacef will be effective alone, but when appropriate it may be used in combination with an aminoglycoside antibiotic, or in conjunction with metronidazole, orally or by suppository or injection, (see Pharmaceutical precautions).
In situations where mixed aerobic and anaerobic infections are encountered or suspected (e.g. peritonitis, aspiration pneumonia, abscesses in the lung, pelvis and brain), or are likely to occur (e.g. in association with colorectal or gynaecological surgery) it is appropriate to administer Zinacef in combination with metronidazole.
Most of these infections will respond to an i.v. regimen of Zinacef (750mg) plus metronidazole injection (500mg/100ml) administered eight-hourly. In more severe or well established mixed infections, an i.v. regimen of Zinacef (1.5g) plus metronidazole injection (500mg/100ml) eight-hourly may be indicated. For the prophylaxis of infection in surgery (e.g. colorectal and gynaecological) a single dose of 1.5g Zinacef plus metronidazole injection (500mg/100ml) is appropriate.
Alternatively this may be followed by two 750mg doses of Zinacef plus metronidazole.
Indications include:
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 diseases.
Gonorrhoea particularly when 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.
Cefuroxime is also available as the axetil ester (Zinnat) for oral administration.
This permits the use of sequential therapy with the same antibiotic, when a change from parenteral to oral therapy is clinically indicated. Where appropriate Zinacef is effective when used prior to oral therapy with Zinnat (cefuroxime axetil) in the treatment of pneumonia and acute exacerbations of chronic bronchitis.
4.2 Posology And Method Of Administration
Intramuscular
Add 1ml water for injections to 250mg Zinacef or 3ml water for injections to 750mg Zinacef. Shake gently to produce an opaque suspension.
Intravenous
Dissolve Zinacef in water for injections using at least 2ml for 250mg, at least 6ml for 750mg or 15ml for 1.5g. For short intravenous infusion (e.g. up to 30 minutes), 1.5g may be dissolved in 50ml water for injections. 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.
General Recommendations
Adults: Many infections will respond to 750mg t.i.d. by im or iv injection. For more severe infections, this dose should be increased to 1.5g t.i.d. iv. The frequency of im or iv injection can be increased to six-hourly if necessary, giving total doses of 3g to 6g daily.
Where clinically indicated adults with pneumonia and acute exacerbations of chronic bronchitis have been shown to respond to 750mg or 1.5g bd, followed by oral therapy with Zinnat (see Sequential therapy).
Infants and Children: Doses of 30 to 100mg/kg/day given as three or four divided doses. A dose of 60mg/kg/day will be appropriate for most infections.
Neonates: Doses of 30 to 100mg/kg/day given as 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.
Elderly: See dosage in adults.
Other Recommendations
Gonorrhoea: 1.5g should be given as a single dose. This may be given as 2 x 750mg injections into different sites eg each buttock.
Meningitis: Zinacef 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 iv in three or four divided doses. This dosage may be reduced to 100mg/kg/day iv after three days or when clinical improvement occurs.
Neonates: The initial dosage should be 100mg/kg/day iv. A reduction to 50mg/kg/day iv may be made when clinically indicated.
Adults: 3g iv every eight hours. Data are not yet sufficient to recommend a dose for intrathecal administration.
Prophylaxis: The usual dose is 1.5g iv with induction of anaethesia for abdominal, pelvic and orthopaedic operations, but may be supplemented with two 750mg im doses eight and sixteen hours later. In cardiac pulmonary oesophageal and vascular operations, the usual dose is 1.5g iv with induction of anaesthesia continuing with 750mg im t.d.s. 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.
Sequential therapy:
Pneumonia:
1.5g bd (iv or im) for 48-72 hours, followed by 500mg bd Zinnat (cefuroxime axetil) oral therapy for 7 days.
Acute exacerbations of chronic bronchitis:
750mg bd (iv or im) for 48-72 hours, followed by 500mg bd Zinnat (cefuroxime axetil) oral therapy for 5-7 days.
Duration of both parenteral and oral therapy is determined by the severity of the infection and the clinical status of the patient.
Dosage in impaired renal function
Cefuroxime is excreted by the kidneys. Therefore, as with all such antibiotics, in patients with markedly impaired renal function it is recommended that the dosage of Zinacef should be reduced to compensate for its slower excretion. However, it is not necessary to reduce the dose until the creatinine clearance falls below 20ml/min. In adults with marked impairment (creatinine clearance 10-20ml/min) 750mg bd is recommended and with severe impairment (creatinine clearance <10ml/min) 750mg once daily is adequate. For patients on haemodialysis a further 750mg dose should be given at the end of each dialysis. When continuous peritoneal dialysis is being used, a suitable dosage is usually 750mg twice daily.
For patients in renal failure on continuous arteriovenous haemodialysis or high-flux haemofiltration in intensive therapy units a suitable dosage is 750mg twice daily. For low-flux haemofiltration follow the dosage recommended under impaired renal function.
Cefuroxime is also available as the axetil ester (Zinnat) for oral administration. This permits parenteral therapy with cefuroxime to be followed by oral therapy in situations where a change from parenteral to oral is clinically indicated.
4.3 Contraindications
Hypersensitivity to cephalosporin antibiotics
4.4 Special Warnings And Precautions For Use
Special care is indicated in patients who have experienced an allergic reaction to penicillins or beta-lactams.
Cephalosporin antibiotics at high dosage should be given with caution to patients receiving concurrent treatment with potent diuretics such as furosemide or aminoglycosides, as renal impairment has been reported with these combinations. Renal function should be monitored in these patients, the elderly, and those with pre-existing renal impairment (See section 4.2) Clinical experience with Zinacef has shown that this is not likely to be a problem at the recommended dose levels.
There may be some variation on 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 18-36 hours has been noted in some patients treated with cefuroxime sodium 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 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 treatment, then the patient's treatment should be reviewed. Please refer to the relevant prescribing information for cefuroxime axetil before initiating sequential therapy.
As with other antibiotics, prolonged use of cefuroxime may result in the overgrowth of non-susceptible organisms (e.g. Candida, enterococci, Clostridium difficile), which may require interruption of treatment.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
In common with other antibiotics, Zinacef may affect the gut flora, leading to lower oestrogen reabsorption and reduced efficacy of combined oral contraceptives.
As with other cephalosporin antibiotics in combination with potent diuretics such as furosemide or aminoglycosides, Zinacef may adversely affect renal function (See section 4.4).
Zinacef does not interfere in 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 Zinacef. This antibiotic does not interfere in the alkaline picrate assay for creatinine.
4.6 Pregnancy And Lactation
There is no experimental evidence of embryopathic or teratogenic effects attributable to Zinacef 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 Zinacef is administered to a nursing mother.
4.7 Effects On Ability To Drive And Use Machines
None reported.
4.8 Undesirable Effects
Adverse drug reactions are very rare (<1/10,000) and are generally mild and transient in nature.
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 undesirable effects. The frequencies assigned to all other undesirable effects (i.e., those occurring at <1/1000) were mainly determined using post-marketing data, and refer to a reporting rate rather than a true frequency.
The following convention has been used for the classification of frequency:
very common
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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.
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See also Skin and subcutaneous tissue disorders and Renal and urinary disorders.
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Transient rises in serum liver enzymes or bilirubin occur, particularly in patients with pre-existing liver disease, but there is no evidence of harm to the liver.
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See also Immune system disorders.
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See also Immune system disorders.
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Pain at the intramuscular injection site is more likely at higher doses. However it is unlikely to be a cause for discontinuation of treatment.
4.9 Overdose
Overdosage 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
Cefuroxime is a bactericidal cephalosporin antibiotic which is resistant to most beta-lactamases and is active against a wide range of Gram-positive and Gram-negative organisms.
It is highly active against Staphylococcus aureus, including strains which are resistant to penicillin (but not the rare methicillin-resistant strains), Staph. epidermidis, Haemophilus influenzae, Klebsiella spp., Enterobacter spp., Streptococcus pyogenes, Escherichia coli, Str. mitis (viridans group), Clostridium spp., Proteus mirabilis, Pr. rettgeri, Salmonella typhi, S. typhimurium and other Salmonella spp., Shigella spp., Neisseria spp. (including beta-lactamase producing strains of N. gonorrhoea) and Bordetella pertussis. It is also moderately active against strains of Pr. vulgaris, Morganella morganii (formerly Proteus morganii) and Bacteroides fragilis.
The following organisms are not susceptible to cefuroxime: Clostridium difficile, Pseudomonas spp., Campylobacter spp., Acinetobacter calcoaceticus, Legionella spp. and methicillin-resistant strains of Staph. aureus and Staph. epidermidis.
Some strains of the following genera have also been found not to be susceptible to Zinacef:
Strep. faecalis, Morganella morganii, Proteus vulgaris, Enterobacter spp., Citrobacter spp., Serratia spp. and Bacteroides fragilis.
In vitro the activities of Zinacef and aminoglycoside antibiotics in combination have been shown to be at least additive with occasional evidence of synergy.
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 probenecid 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
None stated
6. Pharmaceutical Particulars
6.1 List Of Excipients
None.
6.2 Incompatibilities
Cefuroxime is compatible with most commonly used intravenous fluids and electrolyte solutions.
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 Zinacef. However, if required, for patients receiving sodium bicarbonate injection by infusion the Zinacef may be introduced into the tube of the giving set.
Zinacef should not be mixed in the syringe with aminoglycoside antibiotics.
6.3 Shelf Life
Two years when stored below 25ºC and protected from light.
6.4 Special Precautions For Storage
Store below 25ºC and protect from light.
After constitution, Zinacef should be stored at 2 - 8ºC for no longer than 24 hours.
6.5 Nature And Contents Of Container
1) Moulded glass (type 1 or III) vials with bromobutyl or fluoro-resin laminated butyl rubber plug, overseal and flip-off cap containing either 250mg, 750mg or 1.5g Zinacef.
2) A bulk pack of 100 vials.
3) Monovial containing either 750mg or 1.5g Zinacef with transfer needle.
*Only the 1.5g injection pack is marketed (the infusion pack is not)
6.6 Special Precautions For Disposal And Other Handling
None.
Administrative Data
7. Marketing Authorisation Holder
Glaxo Operations UK Limited, Greenford, Middlesex UB6 0HE
Trading as
GlaxoSmithKline UK, Stockley Park West, Uxbridge, Middlesex UB11 1BT
8. Marketing Authorisation Number(S)
PL 00004/0263.
9. Date Of First Authorisation/Renewal Of The Authorisation
28 April 2002
10. Date Of Revision Of The Text
17th November 2008
11. Legal Status
POM
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