1. Name Of The Medicinal Product
Cefuroxime 1500 mg powder for solution for injection/infusion
2. Qualitative And Quantitative Composition
1 vial contains 1500 mg of cefuroxime as 1578 mg of cefuroxime sodium.
1 infusion bottle contains 1500 mg of cefuroxime as 1578 mg of cefuroxime sodium.
For a full list of excipients, see section 6.1
3. Pharmaceutical Form
Powder for solution for injection/infusion.
White to yellowish powder.
4. Clinical Particulars
4.1 Therapeutic Indications
Cefuroxime is indicated in the parenteral treatment of the following infections caused by sensitive pathogens:
• respiratory tract infections: e.g. acute and chronic bronchitis, bacterial pneumonia
• infections of the ear, nose and throat,
• urinary tract infections
• infections of skin and soft tissue
• bone and joint infections
• obstetric and gynaecological infections
Consideration should be given to official guidance on the appropriate use of antibacterial agents.
4.2 Posology And Method Of Administration
Route of Administration:
By intravenous injection or infusion.
Usual dosage for Adults and the Elderly:
Most infections will respond to cefuroxime 750 mg three times a day. For more severe infections, the dose may be increased to 1.5 g three times a day by intravenous injection.
The intramuscular method of administration is reserved to exceptional clinical situations and should undergo a risk-benefit assessment.
Special advice for intramuscular injection has to be regarded (please refer to section 6.6).
If necessary, the frequency of administration of cefuroxime can be increased to four times a day up to total daily doses of 3 g to 6 g.
Infants, toddlers and Children:
The daily dosage range is 30 to 100 mg/kg/day given as three or four divided doses. Most infections will respond to a dose of 60 mg/kg/day.
Neonates ( see section 5.2):
The daily dosage range is 30 to 100 mg/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.
For impaired renal function:
It is not necessary to reduce the dose if creatinine clearance is more than 20 ml/min. The recommended maintenance doses in impaired renal function are as follows:
Creatinine clearance (ml/min)
|
Recommended dosage of cefuroxime (mg)
|
Frequency of dosage (hours)
|
> 20
|
normal dosage
|
|
10-20
|
750
|
12
|
< 10
|
750
|
24
|
CAPD patients
|
750
|
12
|
Patients on CAVH/CAVHD
|
750
|
12
|
Special precautions are required if creatinine clearance is <10 ml/minute under appropriate expert supervision.
Patients undergoing haemodialysis will require a further 750 mg dose of cefuroxime at the end of each dialysis treatment. A suitable dosage for patients on continuous peritoneal dialysis is usually 750 mg twice daily.
A dosage of 750 mg twice daily is recommended for patients in renal failure on continuous arteriovenous haemodialysis or high flux haemofiltration in intensive therapy units. For low flux haemofiltration follow the dosage recommended under impaired renal function.
Cefuroxime is usually effective as a single therapy in the treatment of the above infections.
4.3 Contraindications
Hypersensitivity to Cefuroxime or to any other cephalosporin antibiotics.
Previous immediate and/or severe hypersensitivity reaction to penicillin or any beta-lactam drug.
4.4 Special Warnings And Precautions For Use
Special care is indicated in patients who have experienced an allergic reaction to a penicillin or to any other type of beta-lactam drug.
If after administration of cefuroxime sodium sensitivity reactions occur, the use should be discontinued immediately and an appropriate treatment should be established.
Special care should be taken in patients with hepatic dysfunction.
Renal function should be monitored in the elderly, and those with pre-existing renal impairment (see section 4.2). Clinical experience with cefuroxime sodium 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.
As with other broad spectrum antibiotics, prolonged use of cefuroxime sodium may result in the overgrowth of non-susceptible organisms (e.g. candida, enterococci and clostridium dificile) which may require interruption of treatment.
In patients who develop severe diarrhoea during or after use of cefuroxime sodium, the risk of life threatening pseudo-membranous colitis should be taken into account. The use of cefuroxime sodium should be discontinued and the appropriate treatment established. The use of preparations inhibiting intestinal peristalsis is contra-indicated (see section 4.8).
Long term use of cefuroxime sodium may lead to an excess of pathogens resistant to cefuroxime sodium. It is of high importance that the patient is carefully checked. If a super-infection occurs during treatment, appropriate measures should be taken (see section 4.8).
Either the glucose oxidase or the hexokinase methods are recommended to determine the blood and plasma glucose levels in patients receiving cefuroxime sodium. Cefuroxime does not interfere in the alkaline picrate assay for creatinine (see section 4.5).
Cefuroxime is excreted via the kidneys. Therefore a dosage adjustment is required in patients with impaired renal function (see section 4.2).
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Cephalosporin antibiotics at high dosage should be given with caution to patients receiving concurrent treatment with potent diuretics such as furosemide, aminoglycosides and amphotericin as concomitant use increases the risk of nephrotoxicity.Renal function should be monitored in these patients.
Concomitant therapy with probenecid can reduce the renal excretion of cephalosporins. Plasma concentrations are enhanced if probenecid is given concomitantly.
Since bacteriostatic drugs may interfere with the bactericidal action of cephalosporins, it is advisable to avoid giving tetracyclines, macrolides, or chloramphenicol in conjunction with cefuroxime.
Urine sugar tests using reduction methods may show false positive reactions, therefore enzymatic methods should be used (see section 4.4).Cefuroxime sodium 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 (see section 4.4).
During intravenous administration admixture with other medications in solution should be avoided.
Sodium bicarbonate is not recommended for the dilution of Cefuroxime.
The use of cefuroxime sodium may be accompanied by a false positive Coombs test. This may interfere with the performance of cross matching tests with blood (see section 4.8 ).
4.6 Pregnancy And Lactation
Use in pregnancy
There are not sufficient data on the use of cefuroxime sodium during pregnancy to assess its possible harmfulness. So far, animal tests have not yielded evidence of harmfulness. Cefuroxime crosses the placenta. Cefuroxime sodium should not be used during pregnancy unless considered essential by the physician
Use during lactation
Cefuroxime is excreted to a small degree in human milk; breast feeding should be avoided in women using cefuroxime sodium.
4.7 Effects On Ability To Drive And Use Machines
Cefuroxime may sometimes be associated with side effects, such as dizziness, that may impair the ability to drive a vehicle, to operate machinery or to work safely (see section 4.8).
4.8 Undesirable Effects
Common (
Uncommon (
Rare (
Very rare (<1/10,000), not known (cannot be extimated from the available data)
Infections and infestations:
Rare
As with other antibiotics prolonged use may lead to secondary superinfections caused by insusceptible organisms, e.g. Candida, Enterococci and Clostridium difficile
Blood and the lymphatic system disorders
Common
Neutropenia, eosinophilia
Uncommon
Leukopenia, decreased haemoglobin concentration, positive Coomb´s test
Rare
Thrombocytopenia
Very rare
Haemolytic anemia
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, serum sickness
Very rare
Anaphylaxis, cutaneous vasculitis
See also “Skin and subcutaneous tissue disorders” and “Renal and urinary disorders”.
Nervous system disorders:
Uncommon
Headache, dizziness
Very rare
Vertigo, restlessness, nervousness, confusion
Ear and labyrinth disorders:
Mild to moderate hearing loss has been reported in some children treated for meningitis with cefuroxime.
Gastrointestinal disorders:
Uncommon
Gastrointestinal disturbance s such as diarrhoea, nausea and vomiting have been reported.
Very rare
Pseudomembranous colitis
Hepato-biliary disorders:
Common
Transient rise in liver enzymes.Uncommon
Transient rise in bilirubin.
Very rare
Jaundice
Transient rises in serum liver enzymes or bilirubin occur, particulary 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, Stevens-Johnson syndrome and toxic epidermal necrolysis.
See also “Immune system disorders”.
Renal and urinary disorders
Uncommon
Acute interstitial nephritis.
Nephrotoxicity has been reported. Acute renal tubular necrosis has followed excessive dosage and has also been associated with its use in older patients or those with pre-existing renal impairment.
Very rare
Elevations in serum creatinine, elevations in blood urea nitrogen and decreased creatinine clearance (see section 4.4).
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, this is unlikely to be a cause for discontinuation of treatment. After rapid intravenous administration of cefuroxime heat sensations or nausea may occur.
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
General properties:
ATC classification
Pharmacotherapeutic group: cephalosporins and related substances.
ATC-Code: J01D A06
Mode of action
All cephalosporins (β-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 β-lactam antibiotic has bound to these receptors, the transpeptidation reaction is inhibited and peptidoglycan synthesis is blocked. Bacterial lysis is the end result.
Mechanism 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 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 organisms
• drug efflux pumps
Methicillin-resistant staphylococci (MRS) are resistant to all currently available β-lactam antibiotics including cefuroxime.
Penicillin-resistant Streptococcus pneumoniae are cross-resistant to cephalosporins such as cefuroxime through alteration of penicillin binding proteins.
Beta-lactamase negative, ampicillin resistant (BLNAR) strains of H. influenzae should be considered resistant to cefuroxime despite apparent in vitro susceptibility.
Strains of Enterobacteriaceae, in particular Klebsiella spp. and Escherichia coli that produce ESBLs (extended spectrum β-lactamase) may be clinically resistant to therapy with cephalosporins despite apparent in vitro susceptibility and should be considered as resistant.
Breakpoints :
The following MIC breakpoints separating susceptible from intermediately susceptible organism and intermediately susceptible from resistant organisms are used.
Table 1: EUCAST (European Committee on Antimicrobial Susceptibility Testing)
Susceptibility breakpoints.
Organism
|
susceptible
|
resistant > (mg/l)
|
EnterobacteriaceaeA
|
8
|
8
|
Staphylococcus spp B .
|
-*
|
-*
|
Streptococcus (group A, B, C, G)C
|
-
|
-
|
Streptococcus pneumoniae
|
0.5
|
1
|
Haemophilus influenzae
|
1
|
2
|
Moraxella catarrhalis
|
1
|
2
|
Non species-related breakpointsD
|
4
|
8
|
A The breakpoints relate to a dosage of 1.5 g three times per day and to Escherichia coli, Proteus mirabilis and Klebsiella spp. only.
B The susceptibility of staphylococci to cephalosporins is inferred from the methicillin susceptibility.
C The susceptibility of streptococcus groups A, B, C and G can be inferred from their susceptibility to benzylpenicillin.
D Generally based on serum pharmacokinetics.
Susceptibility :
The prevalence of resistance may vary geographically and with time for selected species and local information is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.
Commonly susceptible species
|
|
Aerobes, Gram positive :
Staphylococcus aureus (methicillin-susceptible)
Coagulase-negative staphylococci (methicillin-susceptible)
Streptococcus agalactiae
Streptococcus pneumoniae
Streptococcus pyogenes
|
Aerobes, Gram negative :
Haemophilus influenzae
Moraxella catarrhalis
Proteus mirabilis
Proteus rettgeri
|
Anaerobes
Peptococcus species
Peptostreptococcus species
|
Other organisms:
Borrelia burgdorferi
|
Species for which resistance may be a problem
|
Citrobacter species
Escherichia coli
Enterobacter species
Klebsiella species
|
Resistant
Acinetobacter species
Bacteroides fragilis
Clostridium difficile
Enterococci
Listeria monocytogenes
Morganella morganii
Proteus vulgaris
Pseudomonas species
Serratia species
|
5.2 Pharmacokinetic Properties
Absorption
Cefuroxime is poorly absorbed from the gastro-intestinal tract and is given by intramuscular or intravenous injection or infusion as the sodium salt. Peak plasma concentration of 27 μg per ml have been achieved about 45 minutes after an intramuscular dose of 750 mg with measurable amounts present 8 hours after a dose.
Distribution
Cefuroxime is widely distributed in the body including pleural fluid, sputum, bone, synovial fluid, and aqueous humour, but only achieves therapeutic concentrations in the CSF when the meninges are inflamed. About 50% of cefuroxime in the circulation is bound to plasma proteins. It diffuses across the placenta and has been detected in breast milk.
Metabolism
Cefuroxime is not metabolized.
Elimination
Most of the dose of cefuroxime is excreted unchanged. About 50% is excreted by glomerular filtration and about 50% through renal tubular secretion within 24 hours, with the majority being eliminated within 6 hours; high concentrations are achieved in the urine. Small amounts of cefuroxime are excreted in bile.
Probenecid competes with cefuroxime for renal tubular secretion resulting in higher and more prolonged plasma concentrations of cefuroxime. The plasma half-life is about 70 minutes after either intramuscular, or intravenous injection and is prolonged in patients with renal impairment and in neonates.
5.3 Preclinical Safety Data
Cefuroxime sodium has a very low order of toxicity as demonstrated by acute toxicity studies. Investigations of chronic toxicity in several animal species (rat, dog and monkey) yielded no indications of drug related toxicological effects. The most prominent treatment-related effect was tissue damage at the injection sites.
A cefuroxime ester did not show clinically relevant effects when tested in vitro and in vivo for genotoxic potential.
Preclinical nephrotoxicity studies showed the product can cause renal damage in some species when administered in very high doses. Its nephrotoxicity increases when administered in combination with glycerol and furosemide.
No long-term investigations for determination of tumorigenic potential were performed.
Investigations in rabbits and mice did not demonstrate reproductive toxicity or teratogenic-effects. Cefuroxime has been shown to pass the placenta.
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.
6. Pharmaceutical Particulars
6.1 List Of Excipients
None.
6.2 Incompatibilities
Cefuroxime should not be mixed in the syringe with aminoglycoside antibiotics.
Mixing of cefuroxime with sodium bicarbonate solutions significantly affects the colour of the solution. Therefore, this solution is not recommended for the dilution of cefuroxime. If required, the cefuroxime solution in water for injections can be introduced into the tubing of the giving set in patients receiving sodium bicarbonate solution by infusion.
6.3 Shelf Life
24 months.
Do not store above 25°C.
Reconstituted solution: Chemical and physical stability has been demonstrated for 2 hours at 25°C and for 24 hours at 2°C – 8°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°C – 8 °C, unless reconstitution has taken place in controlled and validated aseptic conditions.
6.4 Special Precautions For Storage
Keep the vial/infusion bottle in the outer carton in order to protect from light.
Reconstituted solution: The product should be used immediately. Keep the vial/infusion bottle in outer carton in order to protect from light.
6.5 Nature And Contents Of Container
30 ml vials of clear glass type III (Ph. Eur.) closed with rubber stopper and flip-off bordered caps.
100 ml infusion bottles of clear glass type II (Ph. Eur.) closed with rubber stopper and flipp-off bordered caps.
Pack sizes: 1, 5, 10, 25, 50, 100 vials/infusion bottles.
Not all pack sizes may be marketed.
6.6 Special Precautions For Disposal And Other Handling
Compatibility with intravenous solutions
Cefuroxime remains stable for 2 hours at room temperature and 24 h at 2 °C – 8 °C, if dissolved in:
− water for injections
− 0.9 % sodium chloride solution
− 5 % glucose solution
Instructions for reconstitution
Cefuroxime 1500 mg powder for solution for injection/infusion should NOT be administered intramuscularly.
Cefuroxime 1500 mg powder for solution for injection/infusion as intravenous injection:
Dissolve Cefuroxime 1500 mg powder for solution for injection/infusion in at least 15 ml of water for injections, 0.9 % sodium chloride solution or 5 % glucose solution. Shake gently to produce a clear solution.
Cefuroxime 1500 mg powder for solution for injection/infusion as short intravenous infusion:
For short intravenous infusion (e.g. up to 30 minutes) Cefuroxime 1500 mg powder for solution for injection/infusion may be dissolved in 50 ml of water for injection, 0.9 % sodium chloride solution or 5 % glucose solution. These solutions may be given directly into the vein or introduced into the tubing of the giving set. Shake gently to produce a clear solution.
The contents and concentrations of cefuroxime as solution/suspension are shown in the table below:
mg cefuroxime per vial
|
addition of ml solvent
|
volume ml of final solution / suspension
|
Concentration mg/ml
|
250
750
1500
1500
|
2
6
15
50
|
2.2
6.8
16.5
51.5
|
114
110
91
29
|
Note: Antibiotics should not be added to routine infusion fluids. Most infusion fluids are given over 6 to 8 hours and this is impractical for antibiotic therapy. Cefuroxime should be given over short periods (30 minutes).
When reconstituted for intravenous injection, the white to yellowish powder gives a colourless to brownish-yellow solution respectively.
As for all parenteral medicinal products, inspect the reconstituted solution / suspension visually for particulate matter and discoloration prior to administration. The reconstituted solution is clear. For single use only. Any remaining solution should be discarded.
7. Marketing Authorisation Holder
Sandoz Ltd
Frimley Business Park,
Frimley,
Camberley,
Surrey,
GU16 7SR.
United Kingdom
8. Marketing Authorisation Number(S)
PL 04416/0620
9. Date Of First Authorisation/Renewal Of The Authorisation
20th July 2005
10. Date Of Revision Of The Text
November 2010
