Cefuroxime axetil is indicated for the treatment of mild to moderately severe infections caused by micro-organisms susceptible to cefuroxime, such as:

-  upper respiratory tract infections: acute otitis media, sinusitis, tonsillitis and pharyngitis

-  Lower respiratory tract infections like acute bronchitis, acute exacerbations of chronic bronchitis and pneumonia.

-  lower uncomplicated urinary tract infections: cystitis

-  skin and soft tissue infections: furunculosis, pyoderma and impetigo

-  treatment of early stage Lyme disease (stadium I) and subsequent prevention of late complications in adults and children above 12 years of age.

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

Cefuroxime axetil tablets are coated to mask their taste: they should not be chewed.

Most infections will respond to 250mg bd. In mild to moderate lower respiratory tract infections e.g. bronchitis 250mg bd should be given. For more severe lower respiratory tract infections, or if pneumonia is

suspected then 500mg bd should be given. For urinary tract infections a dose of 125mg bd is usually adequate; in pyelonephritis the recommended dose is 250mg bd. A single dose of one gram is recommended for the treatment of uncomplicated gonorrhoea.

Pneumonia: 1.5g cefuroxime (iv or im) for 48-72 hours, followed by 500mg bd (cefuroxime axetil) oral therapy for 7 days.

The usual duration of therapy is 7 days (ranging from 5 to 10 days). In case of pharyngotonsillitis caused by Streptococcus pyogenes a therapy duration of at least 10 days is indicated. The duration of treatment of early Lyme disease should be 20 days. In order to achieve optimum absorption cefuroxime axetil tablets should be taken shortly after meals.

The dosage depends on the severity of the infection. For severe infections parenteral forms of cefuroxime are recommended. Where appropriate cefuroxime axetil is effective when used following initial parenteral cefuroxime sodium in the treatment of pneumonia and acute exacerbations of chronic bronchitis. Acute exacerbation of chronic bronchitis: 50mg cefuroxime bd (iv or im) for 48-72 hours, followed by 500mg bd (cefuroxime axetil) oral therapy for 5-7 days.

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Dosage schedule for tablets:

Children under 5 years of age:

Cefuroxime axetil tablets are not suitable for use in children under the age

of 5. For patients in this age group it is advised to use an oral suspension. There is no experience in children under 3 months of age.

Dosage regimen in renal impairment, in dialysis patients and elderly :

No special precautions are necessary in patients with renal impairment or in elderly patients if the daily dosage does not exceed 1 gram. In patients with renal impairment and creatinine clearance below 20 ml/min cefuroxime axetil tablets should be dosed carefully. Patients undergoing haemodialysis will require a supplementary dose of cefuroxime at the end of each dialysis treatment.

If after administration of cefuroxime axetil sensitivity reactions occur, the use should be discontinued immediately and an appropriate treatment should be established.

Special care is indicated in patients who have experienced an allergic reaction to penicillins or other beta-lactams.

As with other broad spectrum antibiotics, prolonged use of cefuroxime axetil may result in the overgrowth of non-susceptible organisms (e.g., candida, enterococci and clostridium diffficile, which may require interruption of treatment.

In patients who develop severe diarrhoea during or after use of cefuroxime axetil, the risk of life threatening pseudomembranous colitis should be taken into account. The use of cefuroxime axetil should be discontinued and the appropriate treatment established. The use of preparations inhibiting the intestinal peristaltism is contra-indicated (see section 4.8).

A 20-day treatment of Lyme disease may cause the frequency of developing diarrhoea to increase.

Long term use of cefuroxime axetil may lead to an excess of pathogens resistant to cefuroxime axetil. It is of high importance that the patient is carefully checked. If a superinfection occurs during treatment, appropriate measures should be taken (see section 4.8 ).

The use of cefuroxime axetil is not recommended in patients with severe intestinal tract disorders accompanied by vomiting and diarrhoea, since in these situations a sufficient absorption can not be guaranteed.

Administration of a parenteral formulation of cefuroxime should be considered.

The Jarisch-Herxheimer reaction has been reported following cefuroxime axetil treatment of Lyme disease. The reaction results directly from the bactericidal activity of cefuroxime axetil on the spirochaete Borrelia burgdorferi. Patients should be informed of this common and usually self- limited reaction being a consequence of antibiotic treatment of Lyme disease.

Simultaneous use of medicines enhancing the pH of the stomach is not recommended (see section 4.5).

There is no clinical experience with the use of cefuroxime axetil in children under the age of 3 months. With respect to the treatment of early Lyme disease there is only clinical experience with children from the age of 12 and with adults.

Either the glucose oxidase or the hexokinase methods are recommended to determine the blood and plasma glucose levels in patients receiving cefuroxime axetil. Cefuroxime does not interfere in the alkaline picrate assay for creatinine (see section 4.5 ).

During the treatment with cefuroxime sodium, some children have experienced slight to moderate hearing loss.

    Simultaneous use of medicines enhancing the pH of the stomach decreases the bioavailability of cefuroxime axetil. It is recommended to

avoid this combination (see section 4.4).

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 axetil.

The concomitant administration of probenicid can produce higher and sustained concentrations of cefuroxime in the serum and in the bile.

Cefuroxime may interfere with the determination of glucose in urine with copper containing reagents (Benedict- or Fehling-solution, Clinitest). For the determination of blood- and plasma sugar levels in patients receiving cefuroxime axetil, the glucose-oxidase- or hexokinase method is recommended (see section 4.4).

The use of cefuroxime axetil 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).

Cephalosporin antibiotics at high dosage should be given with caution to patients receiving potent diuretics, aminoglycosides, or amphotericin as these combinations increases the risk of nephrotoxicity.

Use in pregnancy

There is no experimental evidence of embryopathic or teratogenic effects attributable to cefuroxime axetil but, as with all drugs, it should be administered with caution during early months of pregnancy. Cefuroxime is excreted in human milk, and consequently caution should be exercised when cefuroxime axetil is administered to a nursing mother.

There are no studies of the effect of cefuroxime axetil on the ability to drive and to handle machines. However, any effects are not to be expected.

Common (≥1/100 to <1/10) Uncommon (≥1/1,000 to <1/100)) Rare(≥1/10,000 to <1/1,000)) Very rare (<1/10,000))

Infections and infestations:

Rare

Pseudomembranous colitis

As with other antibiotics prolonged use may lead to secondary superinfections caused by insusceptible organisms, e.g. Candida, Enterococci and Clostridium difficile (see section 4.4).

Blood and the lymphatic system disorders

Rare

Decreased haemoglobin concentration, eosinophilia, leucopenia, neutropenia and thrombocytopenia

Very rare

Haemolytic anaemia

Immune system disorders:

Common

Jarisch-Herxheimer reaction following cefuroxime axetil treatment of Lyme disease (see section 4.4)

Rare

Serum sickness Very rare Anaphylaxis

Nervous system disorders

Uncommon Headache, dizziness Very rare

Restlessness, nervousness, confusion

Gastrointestinal disorders:

Common

Diarrhoea, nausea and vomiting. The frequency of diarrhoea is related to the administered dose and may rate up to 10% with tablets. The incidence is even higher (approx. 13%) at prolonged treatment of 20 days of early Lyme disease.

Hepato-biliary disorders:

Rare

Transient increases of hepatic enzyme levels (AST, ALT and LDH) and serum bilirubin

Very rare

Jaundice

Skin and subcutaneous tissue disorders:

Common

Skin rashes, urticaria, pruritus

Very rare

Erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis

Renal and urinary disorders

Common

Increased levels of creatinine and urea in serum, especially in patients with impaired renal function.

Uncommon

Acute interstitial nephritis

General disorders and administration site conditions:

Rare

Drug fever

Investigations

The use of cefuroxime axetil may be accompanied by a false positive Coombstest. This may interfere with the performance of cross matching tests with blood (see 4.5. Interactions).

Overdose of cephalosporins may cause cerebral irritancy leading to convulsions. In case of overdose cefuroxime serum levels can be reduced by haemodialysis and peritoneal dialysis.

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 (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:

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

Enterobacteriaceae: ≤ 4 μg/ml susceptible, ≥ 32 μg/ml resistant Staphylococcus spp.: ≤ 4 μg/ml susceptible, ≥ 32 μg/ml resistant Haemophilus spp.: ≤ 4 μg/ml susceptible; ≥ 16 μg/ml resistant Streptococcus pneumoniae: ≤ 1 μg/ml susceptible, ≥ 4 μg/ml resistant

Streptococcus spp. other than S. pneumoniae:

Streptococcal isolates susceptible to penicillin (MIC₉₀≤ 0.12 μg/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.

Absorption: After oral administration cefuroxime axetil is absorbed from the gastrointestinal tract and rapidly hydrolysed in the intestinal mucosa and blood causing the release of the active compound cefuroxime into the circulation. Optimum absorption occurs when Cefuroxime is taken shortly after a meal (50-60%). Under these circumstances maximum serum concentration is achieved after 2-3 hours.

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 ranges between 60 and 90 minutes and is prolonged in patients with renal impairment and in neonates.

Dialysis causes the decrease of cefuroxime serum levels.

Preclinical effects were observed in dosages far above the maximal human dosage which are therefore hardly relevant for the clinical use of cefuroxime axetil.

Microcrystalline cellulose, Croscarmellose, Sodium starch glycolate, Sodium lauryl sulfate , Colloidal silicon dioxide, Magnesium stearate , Opadry OY-L, FD&C Blue #1

Not applicable

Store below 30^oC.

Cefutil^® (250mg) F/C tablets: each pack contains 10 tablets in Al/Al blister packaging

No special requirements.