Document: spc-doc_PL 25174-0009 change

• spc-doc_PL 25174-0009
• spc-doc_PL 39655-0016

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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Cefuroxime 1.5g Powder for Solution for Injection or Infusion.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Vials contain 1.5g cefuroxime (as sodium salt). For full list of excipients, see section 6.1

3    PHARMACEUTICAL FORM

Powder for solution for injection or infusion. White or off-white powder.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

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 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 Cefuroxime 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 Cefuroxime in combination with metronidazole.

Most of these infections will respond to an i.v. regimen of Cefuroxime (750mg) plus metronidazole injection (500mg/100ml) administered eight-hourly. In more severe or well established mixed infections, an i.v. regimen of Cefuroxime (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 Cefuroxime plus metronidazole injection (500mg/100ml) is appropriate.

Alternatively this may be followed by two 750mg doses of Cefuroxime 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 such as meningitis.

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

This permits the use of sequential therapy with the same antibiotic, when a change from parenteral to oral therapy is clinically indicated.

Where appropriate, Cefuroxime is effective when used prior to oral therapy with cefuroxime axetil in the treatment of pneumonia and acute exacerbations of chronic bronchitis.

4.2 Posology and method of administration Route and method of administration

Cefuroxime 1.5g may be administered by intravenous injection or infusion. For instructions on dilution of the product before administration, see section 6.6.

Normal dosage

Adults:

Many infections will respond to 750mg t.i.d. by i.m. or i.v. injection. For more severe infections, this dose should be increased to 1.5g t.i.d. i.v. The frequency of i.m. or i.v. 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 b.d., followed by oral therapy with cefuroxime axetil (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

1.5g should be given as a single dose. This may be given as 2 x 750mg injections into different sites e.g. each buttock.

Meningitis:

Cefuroxime 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 i.v. in three or four divided doses. This dosage may be reduced to 100mg/kg/day i.v. after three days or when clinical improvement occurs.

Neonates: The initial dosage should be 100mg/kg/day i.v. A reduction to 50mg/kg/day i.v. may be made when clinically indicated.

Adults: 3g i.v. every eight hours. Data are not yet sufficient to recommend a dose for intrathecal administration.

Prophylaxis:

The usual dose is 1.5g i.v. with induction of anaethesia for abdominal, pelvic and orthopaedic operations, but may be supplemented with two 750mg i.m. doses eight and sixteen hours later. In cardiac pulmonary oesophageal and vascular operations, the usual dose is 1.5g i.v. with induction of anaesthesia continuing with 750mg i.m. 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 b.d. (i.v. or i.m.) for 48-72 hours, followed by 500mg b.d. cefuroxime axetil oral therapy for 7 days.

Acute exacerbations of chronic bronchitis:

750mg b.d. (i.v. or i.m.) for 48-72 hours, followed by 500mg b.d. 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 Cefuroxime 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 b.d. 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 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 cefuroxime or to any of the cephalosporins. Previous immediate and/or severe hypersensitivity reaction to a penicillin or to any other type of beta-lactam drug.

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.

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.

This medicinal product contains 73.5 mg sodium per dose. To be taken into consideration by patients on a controlled sodium diet.

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 and aminoglycosides, as these combinations are suspected of adversely affecting renal function. Clinical experience with Cefuroxime has shown that this is not likely to be a problem at the recommended dose levels.

Cefuroxime 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 Cefuroxime. This antibiotic does not interfere in the alkaline picrate assay for creatinine.

4.6 Fertility, Pregnancy and lactation

There is no experimental evidence of embryopathic or teratogenic effects attributable to Cefuroxime but, as with all drugs, it should be administered with caution during the early months of pregnancy.

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 pre-existing 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: www.mhra.gov.uk/yellowcard.

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

Pharmacodynamic properties

Pharmacotherapeutic group: cephalosporins and related substances, ATC-Code: J01D A06

Mode of action

Cefuroxime axetil owes its in vivo bactericidal activity to the parent compound cefuroxime. 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.

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 P-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 P-lactamase) may be clinically resistant to therapy with cephalosporins despite apparent in vitro susceptibility and should be considered as resistant.

Breakpoints:

According to the NCCLS (National Committee on Clinical Laboratory Standards) in 2001 the following breakpoints have been defined for cefuroxime:

Enterobacteriaceae: < 4 pg/ml susceptible, > 32 pg/ml resistant Staphylococcus spp.: < 4 pg/ml susceptible, > 32 pg/ml resistant Haemophilus spp.: < 4 pg/ml susceptible; > 16 pg/ml resistant Streptococcus pneumoniae : < 1 pg/ml susceptible, > 4 pg/ml resistant Streptococcus spp. other than S. pneumoniae:

Streptococcal isolates susceptible to penicillin (MIC90 < 0.12 pg/ml) may be considered susceptible to cefuroxime.

Susceptibility:

The prevalence of 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 such that the utility of the agent in at least some types of infections is questionable.

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

No additional data of relevance.

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 Cefuroxime. However, if required, for patients receiving sodium bicarbonate injection by infusion the Cefuroxime may be introduced into the tube of the giving set.

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

6.3 Shelf life

Un-opened dry powder: 3 years

Reconstituted solution: 24 hours stored in the conditions recommended in section 6.4.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless reconstitution/dilution (etc) has taken place in controlled and validated aseptic conditions.

6.4 Special precautions for storage

Up-opened dry powder:    Store below 30°C. Store in the original package.

Reconstituted solution:    The reconstituted solution should be stored at 2-

8°C for no longer than 24 hours.

Refer to section 6.3 for the storage of sterile products that have been opened, diluted or reconstituted.

6.5 Nature and contents of container

A type II transparent, colourless glass vial, with a bromobutyl stopper and a green aluminum and polypropylene flip off cap with adhesive labels.

Cefuroxime 1.5g Powder for Injection or Infusion is available in 20 and 100ml vial packs of 1, 10 or 20 vials. Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Cefuroxime 1.5g when dissolved in Water for Injections forms a yellowish, clear solution for intravenous administration.

Intravenous injection

1.5g of Cefuroxime should be dissolved in 15ml of Water for Injections. Shake gently to produce a clear solution.

Intravenous infusion

1.5g of Cefuroxime should be dissolved in 50ml of Water for Injections. Shake gently to produce a clear solution. The reconstituted solution for infusion should be administered as a short time infusion over 30 minutes.

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.

On reconstitution, product must be mixed vigorously for at least 90 seconds prior to withdrawing into the syringe; and if not given immediately, again just prior to administration.

Any unused product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Laboratorio Reig Jofre S.A.

C/Gran Capitan, 10