SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Cefuroxime 1500 mg powder for solution for injection or infusion

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Cefuroxime 1500 mg powder for solution for injection / infusion: Each vial contains cefuroxime sodium corresponding to 1500 mg cefuroxime.

Each vial contains approximately 83 mg (3.54 mmol) sodium.

For the full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

1500 mg powder for solution for injection / infusion. White or almost white powder.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Cefuroxime is indicated for the treatment of the infections listed below in adults and children, including neonates (from birth) (see sections 4.4 and 5.1).

•    Community acquired pneumonia

•    Acute exacerbation of chronic bronchitis

•    Complicated urinary tract infections, including pyelonephritis

•    Soft-tissue infections: cellulitis, erysipelas and wound infections

•    Intra-abdominal infections (see section 4.4)

•    Prophylaxis against infection in gastrointestinal (including oesophageal), orthopaedic, cardiovascular, and gynaecological surgery (including caesarean section).

In the treatment and prevention of infections in which it is very likely that anaerobic organisms will be encountered, cefuroxime should be administered with additional appropriate antibacterial agents.

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

4.2 Posology and method of administration

Posology

Table 1: Adults and children > 40 kg

Indication	Dosage
Community acquired pneumonia and acute exacerbations of chronic bronchitis	750 mg every 8 hours (intravenously or intramuscularly)
Soft-tissue infections: cellulitis, erysipelas and wound infections
Intra-abdominal infections
Complicated urinary tract infections, including pyelonephritis	1.5 g every 8 hours (intravenously or intramuscularly)
Severe infections	750 mg every 6 hours (intravenously) 1.5 g every 8 hours (intravenously)
Surgical prophylaxis for gastrointestinal, gynaecological surgery (including caesarean section) and orthopaedic operations	1.5 g with the induction of anaesthesia. This may be supplemented with two 750 mg doses (intramuscularly) after 8 hours and 16 hours.
Surgical prophylaxis for cardiovascular and oesophageal operations	1.5 g with induction of anaesthesia followed by 750 mg (intramuscularly) every 8 hours for a further 24 hours.

Table 2: Children < 40 kg

	Infants and toddlers > 3 weeks and children < 40 kg	Infants (birth to 3 weeks)
Community acquired pneumonia	30 to 100 mg/kg/day (intravenously) given as 3 or 4 divided doses; a dose of 60 mg/kg/day is appropriate for most infections	30 to 100 mg/kg/day (intravenously) given as 2 or 3 divided doses (see section 5.2)
Complicated urinary tract infections, including pyelonephritis
Soft-tissue infections: cellulitis, erysipelas and wound infections
[ntra-abdominal infections

Renal impairment

Cefuroxime is primarily 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.

Table 3: Recommended doses for cefuroxime in renal impairment

Creatinine clearance	T1/2 (hours)	Dose [mg]
> 20 ml/min/1.73 m2	1.7-2.6	It is not necessary to reduce the standard dose (750 mg to 1.5 g three times daily)
10-20 ml/min/1.73 m2	4.3-6.5	750 mg twice daily
< 10 ml/min/1.73 m2	14.8-22.3	750 mg once daily
Patients on haemodialysis	3.75	A further 750 mg dose should be given intravenously or intramuscularly at the end of each dialysis; in addition to parenteral use, cefuroxime sodium can be incorporated into the peritoneal dialysis fluid (usually 250 mg for every 2 litres of dialysis fluid).
Patients in renal failure on continuous arteriovenous haemodialysis (CAVH) or high-flux haemofiltration (HF) in intensive therapy units	7.9-12.6 (CAVH) 1.6 (HF)	750 mg twice daily; for low-flux haemofiltration follow the dosage recommended under impaired renal function.

Hepatic impairment

Cefuroxime is primarily eliminated by the kidney. In patients with hepatic dysfunction this is not expected to effect the pharmacokinetics of cefuroxime.

Method of administration

Cefuroxime should be administered by intravenous injection over a period of 3 to 5 minutes directly into a vein or via a drip tube or infusion over 30 to 60 minutes, or by deep intramuscular injection. For instructions on reconstitution of the medicinal product before administration, see section 6.6.

4.3 Contraindications

Hypersensitivity to cefuroxime.

Patients with known hypersensitivity to cephalosporin antibiotics.

History of severe hypersensitivity (e.g. anaphylactic reaction) to any other type of beta-lactam antibacterial agent (penicillins, monobactams and carbapenems).

4.4 Special warnings and precautions for use

Hypersensitivity reactions

As with all beta-lactam antibacterial agents, serious and occasionally fatal hypersensitivity reactions have been reported. In case of severe hypersensitivity reactions, treatment with cefuroxime must be discontinued immediately and adequate emergency measures must be initiated.

Before beginning treatment, it should be established whether the patient has a history of severe hypersensitivity reactions to cefuroxime, to other cephalosporins or to any other type of beta-lactam agent. Caution should be used if cefuroxime is given to patients with a history of non-severe hypersensitivity to other beta-lactam agents.

Concurrent treatment with potent diuretics or aminoglycosides

Cephalosporin antibiotics at high dosage should be given with caution to patients receiving concurrent treatment with potent diuretics such as furosemide or aminoglycosides. Renal impairment has been reported during use of these combinations. Renal function should be monitored in the elderly and those with known pre-existing renal impairment (see section 4.2).

Overgrowth of non-susceptible microorganisms

Use of cefuroxime may result in the overgrowth of Candida. Prolonged use may also result in the overgrowth of other non-susceptible microorganisms (e.g. enterococci and Clostridium difficile), which may require interruption of treatment (see section 4.8).

Antibacterial agent-associated pseudomembranous colitis has been reported with use of cefuroxime and may range in severity from mild to life threatening. This diagnosis should be considered in patients with diarrhoea during or subsequent to the administration of cefuroxime (see section 4.8). Discontinuation of therapy with cefuroxime and the administration of specific treatment for Clostridium difficile should be considered. Medicinal products that inhibit peristalsis should not be given.

Intra-abdominal infections

Due to its spectrum of activity, cefuroxime is not suitable for the treatment of infections caused by Gram-negative non-fermenting bacteria (see section 5.1).

Interference with diagnostic tests

The development of a positive Coomb’s Test associated with the use of cefuroxime may interfere with cross matching of blood (see section 4.8).

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.

As a false negative result may occur in the ferricyanide test, it is recommended that either the glucose oxidase or hexokinase methods are used to determine blood/plasma glucose levels in patients receiving cefuroxime sodium.

Important information about excipients

This medicinal product contains sodium. This should be considered for patients who are on a controlled sodium diet.

4.5 Interaction with other medicinal products and other forms of interaction

Cefuroxime may affect the gut flora, leading to lower oestrogen reabsorption and reduced efficacy of combined oral contraceptives.

Cefuroxime is excreted by glomerular filtration and tubular secretion. Concomitant use of probenicid is not recommended. Concurrent administration of probenecid prolongs the excretion of the antibiotic and produces an elevated peak serum level.

Potential nephrotoxic drugs and loop diuretics

High-dosage treatments with cephalosporins should be carried out with caution on patients who are taking strong-acting diuretics (such as furosemide) or potential nephrotoxic preparations (such as aminoglycoside antibiotics), since impairment of renal function through such combinations cannot be ruled out.

Other Interactions

Determination of blood/plasma glucose levels: Please refer to section 4.4.

Concomitant use with oral anticoagulants may give rise to increased international normalised ratio (INR).

4.6 Fertility, pregnancy and lactation

Pregnancy

There are limited amounts of data from the use of cefuroxime in pregnant women. Studies in animals have shown no reproductive toxicity (see section 5.3). Cefuroxime should be prescribed to pregnant women only if the benefit outweighs the risk.

Cefuroxime has been shown to cross the placenta and attain therapeutic levels in amniotic fluid and cord blood after intramuscular or intravenous dose to the mother.

Breastfeeding

Cefuroxime is excreted in human milk in small quantities. Adverse reactions at therapeutic doses are not expected, although a risk of diarrhoea and fungus infection of the mucous membranes cannot be excluded. A decision must be made whether to

discontinue breast-feeding or to discontinue/abstain from cefuroxime therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Fertility

There are no data on the effects of cefuroxime sodium on fertility in humans. Reproductive studies in animals have shown no effects on fertility.

4.7 Effects on ability to drive and use machines

No studies on the effects of cefuroxime on the ability to drive and use machines have been performed. However, based on known adverse reactions, cefuroxime is unlikely to have an effect on the ability to drive and use machines.

4.8 Undesirable effects

The most common adverse reactions are neutropenia, eosinophilia, transient rise in liver enzymes or bilirubin, particularly in patients with pre-existing liver disease, but there is no evidence of harm to the liver and injection site reactions.

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 adverse reactions. The frequencies assigned to all other adverse reactions (i.e. those occurring at <1/10000) were mainly determined using post-marketing data, and refer to a reporting rate rather than a true frequency.

Treatment related adverse reactions, all grades, are listed below by MedDRA body system organ class, frequency and grade of severity. The following convention has been utilised for the classification of frequency: very common > 1/10; common > 1/100 to < 1/10, uncommon > 1/1000 to < 1/100; rare > 1/10000 to < 1/1000; very rare < 1/10000 and not known (cannot be estimated from the available data).

System organ class	Common	Uncommon	Not known
Infections and infestations			Candida overgrowth, overgrowth of Clostridium difficile
Blood and lymphatic system disorders	neutropenia, eosinophilia, decreased haemoglobin	leukopenia, positive Coomb’s test	thrombocytopenia, haemolytic anaemia

	concentration
Immune system disorders			drug fever, interstitial nephritis, anaphylaxis, cutaneous vasculitis
Gastrointestinal disorders		gastrointestinal disturbance	pseudomembranous colitis
Hepatobiliary disorders	transient rise in liver enzymes	transient rise in bilirubin
Skin and subcutaneous tissue disorders		skin rash, urticaria and pruritus	erythema multiforme, toxic epidermal necrolysis and Stevens-Johnson syndrome, angioneurotic oedema
Renal and urinary disorders			elevations in serum creatinine, elevations in blood urea nitrogen and decreased creatinine clearance (see section 4.4)
General disorders and administration site conditions	injection site reactions which may include pain and thrombophlebitis
Description of selected adverse reactions 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.
Transient rises in serum liver enzymes or bilirubin have been observed which are usually reversible.
Pain at the intramuscular injection site is more to be a cause for discontinuation of treatment.		likely at higher doses. However it is unlikely

Paediatric population

The safety profile for cefuroxime sodium in children is consistent with the profile in adults.

4.9 Overdose

Overdose can lead to neurological sequelae including encephalopathy, convulsions and coma. Symptoms of overdose can occur if the dose is not reduced appropriately in patients with renal impairment (see sections 4.2 and 4.4).

Serum levels of cefuroxime can be reduced by haemodialysis or peritoneal dialysis.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Antibacterials for systemic use, second-generation cephalosporins, ATC code: J01DC02

Mechanism of action

Cefuroxime inhibits bacterial cell wall synthesis following attachment to penicillin binding proteins (PBPs). This results in the interruption of cell wall (peptidoglycan) biosynthesis, which leads to bacterial cell lysis and death.

PD/PK relationship

The efficacy is mainly determined by the length of time, during which the drug level is above the minimal inhibitory concentration of the pathogen.

Mechanism of resistance

Bacterial resistance to cefuroxime may be due to one or more of the following mechanisms:

•    Hydrolysis by beta-lactamases including (but not limited to) extended-spectrum beta-lactamases (ESBLs), and Amp-C enzymes, 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 bacteria.

•    Bacterial efflux pumps.

Organisms that have acquired resistance to other injectable cephalosporins are expected to be resistant to cefuroxime. Depending on the mechanism of resistance, organisms with acquired resistance to penicillins may demonstrate reduced susceptibility or resistance to cefuroxime.

Breakpoints

Minimum inhibitory concentration (MIC) breakpoints established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) are as follows

Microorganism	Sensitive	Resistant
Enterobacteriaceae1	^ 8 mg/l2	> 8 mg/l

1    The cephalosporin breakpoints for Enterobacteriaceae will detect all clinically important resistance mechanisms (including ESBL and plasmid mediated AmpC). Some strains that produce beta-lactamases are susceptible or intermediate to 3^rd or 4^th generation cephalosporins with these breakpoints and should be reported as found, i.e. the presence or absence of an ESBL does not in itself influence the categorisation of susceptibility. In many areas, ESBL detection and characterisation is recommended or mandatory for infection control purposes.

2    Breakpoint relates to a dosage of 1.5 g x 3 and to E. coli, P. mirabilis and Klebsiella spp. only.

3    Susceptibility of staphylococci to cephalosporins is inferred from the methicillin susceptibility except for ceftazidme and cefixime and ceftibuten, which do not have breakpoints and should not be used for staphylococcal infections.

4    The beta-lactam susceptibility of beta-haemolytic streptococci groups A, B, C and G is inferred from the penicillin susceptibility.

5    Breakpoints apply to daily intravenous dose of 750 mg x 3 and a high dose of at least 1.5 g x 3.

Microbiological 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 of resistance is known and the utility of the agent in at least some types of infections is questionable.

Cefuroxime is usually active against the following microorganisms in vitro.

All methicillin-resistant S. aureus are resistant to cefuroxime.

In vitro the activities of cefuroxime sodium and aminoglycoside antibiotics in combination have been shown to be at least additive with occasional evidence of synergy.

5.2 Pharmacokinetic properties

Absorption

After intramuscular (IM) injection of cefuroxime to normal volunteers, the mean peak serum concentrations ranged from 27 to 35 pg/ml for a 750 mg dose and from 33 to 40 pg/ml for a 1000 mg dose, and were achieved within 30 to 60 minutes after administration. Following intravenous (IV) doses of 750 and 1500 mg, serum concentrations were approximately 50 and 100 pg/ml, respectively, at 15 minutes.

AUC and C_max appear to increase linearly with increase in dose over the single dose range of 250 to 1000 mg following IM and IV administration. There was no evidence of accumulation of cefuroxime in the serum from normal volunteers following repeat intravenous administration of 1500 mg doses every 8 hours.

Distribution

Protein binding has been stated as 33 to 50%, depending on the methodology used. The average volume of distribution ranges from 9.3 to 15.8 l/1.73 m² following IM or IV administration over the dosage range of 250 to 1000 mg. Concentrations of cefuroxime in excess of the minimum inhibitory levels for common pathogens can be achieved in the tonsilla, sinus tissues, bronchial mucosa, bone, pleural fluid, joint fluid, synovial fluid, interstitial fluid, bile, sputum and aqueous humour. Cefuroxime passes the blood-brain barrier when the meninges are inflamed.

Biotransformation Cefuroxime is not metabolised.

Elimination

Cefuroxime is excreted by glomerular filtration and tubular secretion. The serum halflife after either intramuscular or intravenous injection is approximately 70 minutes. There is an almost complete recovery (85 to 90%) of unchanged cefuroxime in urine within 24 hours of administration. The majority of the cefuroxime is excreted within the first 6 hours. The average renal clearance ranges from 114 to 170 ml/min/1.73 m² following IM or IV administration over the dosage range of 250 to 1000 mg.

Special patient populations

Gender

No differences in the pharmacokinetics of cefuroxime were observed between males and females following a single IV bolus injection of 1000 mg of cefuroxime as the sodium salt.

Elderly

Following IM or IV administration, the absorption, distribution and excretion of cefuroxime in elderly patients are similar to younger patients with equivalent renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in cefuroxime dose selection, and it may be useful to monitor renal function (see section 4.2).

Paediatrics

The serum half-life of cefuroxime has been shown to be substantially prolonged in neonates according to gestational age. However, in older infants (aged >3 weeks) and in children, the serum half-life of 60 to 90 minutes is similar to that observed in adults.

Renal impairment

Cefuroxime is primarily excreted by the kidneys. As with all such antibiotics, in patients with markedly impaired renal function (i.e. C1_cr < 20 ml/minute) it is recommended that the dosage of cefuroxime should be reduced to compensate for its slower excretion (see section 4.2). Cefuroxime is effectively removed by haemodialysis and peritoneal dialysis.

Hepatic impairment

Since cefuroxime is primarily eliminated by the kidney, hepatic dysfunction is not expected to have an effect on the pharmacokinetics of cefuroxime.

PK/PD relationship

For cephalosporins, the most important pharmacokinetic-pharmacodynamic index correlating with in vivo efficacy has been shown to be the percentage of the dosing interval (%T) that the unbound concentration remains above the minimum inhibitory concentration (MIC) of cefuroxime for individual target species (i.e. %T > MIC).

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and toxicity to reproduction and development. No carcinogenicity studies have been performed; however, there is no evidence to suggest carcinogenic potential.

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

This medicinal product must not be mixed with other medicinal products and other solutions for injection or infusion except those mentioned in section 6.6. Cefuroxime should not be mixed with aminoglycoside antibiotics.

Mixing of cefuroxime with sodium hydrogen carbonate 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.

For information about compatible solutions, please see section 6.6.

6.3 Shelf life

2 years

Shelf-life of the prepared solution

The chemical and physical stability of the prepared solution has been demonstrated for 3 hours at 25°C and for 12 hours at 5°C. From a microbiological point of view, the prepared solution should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.

6.4 Special precautions for storage

Do not store above 25°C. Keep the vial in the outer carton in order to protect from light.

For storage conditions after reconstitution, see section 6.3.

6.5 Nature and contents of container

Cefuroxime 1500 mg is supplied in 50 ml and 100 ml colourless type II glass vials closed with chlorobutyl rubber stoppers and flip-off seal.

Pack sizes: Packages with 1, 5 or 10 vials.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Table 4: Addition volumes and solution concentrations, which may be useful when fractional doses are required.

Instructions for reconstitution

Addition volumes and solution concentrations, which may be useful when fractional doses are required
Vial size		Amount of water to be added (ml)	Approximate cefuroxime concentration (mg/ml)**
1500 mg	intramuscular	6 ml	216
	intravenous bolus	at least 15ml	94
	intravenous infusion	15 ml *	94

Reconstituted solution to be added to 50 or 100 ml of compatible infusion fluid (see information on compatibility, below)

** The resulting volume of the solution of cefuroxime in reconstitution medium is increased due the displacement factor of the drug substance resulting in the listed concentrations in mg/ml.

Preparation of the solution for injection

For the preparation of the solution, Cefuroxime 1500 mg is dissolved in at least 15 ml of water for injections.

The intravenous injection should be carried out slowly over a time of 3-5 minutes.

Preparation of the solution for infusion

For short-term infusion, Cefuroxime 1500 mg is dissolved in 50 ml water for injections, isotonic sodium chloride solution or 5% glucose solution and infused over a time of about 20 minutes.

Cefuroxime 1500 mg can also be dissolved in 100 ml isotonic sodium chloride solution or 5% glucose solution for slow infusion over a time of about 60 minutes.

Compatibility with intravenous liquids

The following solvents are suitable for preparation of the solution:

-    water for injections

-    5% glucose solution

-    physiological sodium chloride solution.

The reconstituted solution is yellowish to brownish. Differences in colour and intensity do not have any influence on the safety and efficacy.

As for all parenteral medicinal products, inspect the reconstituted solution visually for particulate matter and discoloration prior to administration. The solution should only be used if the solution is clear and practically free from particles.

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

7    MARKETING AUTHORISATION HOLDER

IPP International Pharma Partners GmbH Marienplatz 10-12 94081 Furstenzell Germany

Phone 0049 (0) 8502 9184 410 Fax 0049 (0) 8502 9184 492

8    MARKETING AUTHORISATION NUMBER(S)

PL 39689/0004

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

08/01/2013

10    DATE OF REVISION OF THE TEXT

08/01/2013