Cefuroxime 1.5 g Powder for Solution for Injection or Infusion

Cefuroxime 1.5 g Powder for Solution for Injection or Infusion

Each vial contains 1.5 g cefuroxime (as sodium).

The total quantity of sodium per vial is 81 mg

Powder for solution for injection or infusion.

White or off-white powder.

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 exacerbations 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 gynaecologicalsurgery (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.

Posology

Table 1. Adults and children ≥ 40 kg

Table 2. Children < 40 kg

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 in renal impairment

Hepatic impairment

Cefuroxime is primarily eliminated by the kidney. In patients with hepatic dysfunction this is not expected to affect 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.

Intramuscular injections should be injected well within the bulk of a relatively large muscle and not more than 750 mg should be injected at one site. For doses greater than 1.5 g intravenous administration should be used.

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

Hypersensitivity to cefuroxime or to any of the cephalosporins.

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

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.

Intracameral use and eye disorders

Cefuroxime 1.5 g Powder for Solution for Injection or Infusion is not formulated for intracameral use. Individual cases and clusters of serious ocular adverse reactions have been reported following unapproved intracameral use of cefuroxime sodium compounded from vials approved for intravenous/intramuscular administration. These reactions included macular oedema, retinal oedema, retinal detachment, retinal toxicity, visual impairment, visual acuity reduced, vision blurred, corneal opacity and corneal oedema.

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 Coombs 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

Cefuroxime 1.5 g Powder for Solution for Injection or Infusion contains 81 mg sodium per vial, equivalent to 4% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

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 probenecid 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: refer to section 4.4. . Concomitant use with oral anticoagulants may give rise to increased international normalised ratio (INR).

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.

Breast-feeding

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.

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.

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 <1/10,000) 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.

Tabulated list of adverse reactions

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

Not known (cannot be estimated from the available data).

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 Coombs 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 likely at higher doses. However it is unlikely to be a cause for discontinuation of treatment.

Paediatric population

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

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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

Overdosage can ead 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.

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.

Mechanism of resistance

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

• hydrolysis by beta-lactamasesincluding (but not limited to) extended-spectrum beta-lactamases (ESBLs), and by AmpC 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.

Cefuroxime sodium breakpoints:

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

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 such that 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.

Absorption

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

AUC and Cmax 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 half-life after either intramuscular or intravenous injection is approximately 70 minutes.

There is almost complete recovery (85 to 90%) of unchanged cefuroxime in the urine within 24 hours of administration, the major part being eliminated in the first six 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).

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.

None.

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.

Un-opened dry powder: 3 years

Reconstituted solution: Store at 2-8°C and use within 24 hours

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.

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

For storage conditions after reconstitution of the medicinal product, see section 6.3.

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

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

Cefuroxime 1.5 g when dissolved in Water for Injections forms an off-white, opaque suspension for intramuscular use or a yellowish, clear solution for intravenous administration.

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

Intramuscular injection

1.5 g of cefuroxime should be dissolved in 6 mL of Water for Injections. Shake gently to produce an opaque suspension. Not more than 750 mg cefuroxime should be injected at one site, see section 4.2.

Intravenous injection

1.5 g of cefuroxime should be dissolved in 15 mL of Water for Injections. Shake gently to produce a clear solution. This solution may be given directly into the vein or introduced into the tubing of the giving set if the patient is receiving parenteral fluids.

Intravenous infusion

20 ml vial: 1.5 g of cefuroxime should be dissolved in 15 mL of Water for Injections. Shake gently to produce a clear solution. The reconstituted solution should then be added to 50 or 100 mL of compatible infusion fluid (see information on compatibility, below).

100 ml vial: 1.5 g of cefuroxime should be dissolved in 50 mL of Water for Injections. Shake gently to produce a clear solution.

Addition volumes and concentrations which may be useful when fractional doses are required.

When Water for Injections is added to 1.5 g cefuroxime the resulting volume is affected by the displacement factor of the drug substance, giving the approximate concentrations in mg/mL detailed in the table below.

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

Compatibility

1.5 g cefuroxime sodium constituted with 15 mL Water for Injection may be added to metronidazole injection (500 mg/100 mL) and both retain their activity for up to 24 hours below 25°C.

1.5 g cefuroxime sodium is compatible with azlocillin 1 g (in 15 mL) or 5 g (in 50 mL) for up to 24 hours at 4°C or 6 hours below 25°C.

Cefuroxime sodium (5 mg/mL) in 5% w/v or 10% w/v xylitol injection may be stored for up to 24 hours at 25°C.

Cefuroxime sodium is compatible with aqueous solutions containing up to 1% lidocaine hydrochloride.

Cefuroxime sodium is compatible with the following infusion fluids. It will retain potency for up to 24 hours at room temperature in:

0.9% w/v Sodium Chloride Injection BP

5% Dextrose Injection BP

0.18% w/v Sodium Chloride plus 4% Dextrose Injection BP

5% Dextrose and 0.9% w/v Sodium Chloride Injection BP

5% Dextrose and 0.45% Sodium Chloride Injection

5% Dextrose and 0.225% Sodium Chloride Injection

10% Dextrose Injection

10% Invert Sugar in Water for Injection

Ringer's Injection USP

Lactated Ringer's Injection USP

M/6 Sodium Lactate Injection

Compound Sodium Lactate Injection BP (Hartmann's Solution).

The stability of cefuroxime sodium in 0.9% w/v Sodium Chloride Injection BP and in 5% Dextrose Injection is not affected by the presence of hydrocortisone sodium phosphate.

Cefuroxime sodium has also been found compatible for 24 hours at room temperature when admixed in IV infusion with:

Heparin (10 and 50 units/mL) in 0.9% w/v Sodium Chloride Injection BP;

Potassium Chloride (10 and 40 mEqL) in 0.9% w/v Sodium Chloride Injection BP.

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

Laboratorio Reig Jofré, S.A.

C/ Gran Capitán, 10

08970 Sant Joan Despí (Barcelona)

Spain

PL 25174/0009

12/11/2009

[date of variation approval]