SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

FLOXAPEN® Oral Suspension 250mg/5ml FLUCLOXACILLIN Oral Suspension 250mg/5ml

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Floxapen Oral Suspension (Flucloxacillin Oral Suspension) when reconstituted each 5 ml contains 250 mg flucloxacillin as Flucloxacillin Magnesium.

For a full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Floxapen Oral Suspension: Bottles containing powder for the preparation of suspension.

4    CLINICAL PARTICULARS

Flucloxacillin is an isoxazolyl penicillin of the P-lactam group of antibiotics which exerts a bactericidal effect upon many Gram-positive organisms including P-lactamase-producing staphylococci and streptococci.

4.1    Therapeutic indications

Floxapen is indicated for the treatment of infections due to sensitive Gram-positive organisms, including P-lactamase producing staphylococci and streptococci. Typical indications include:

Skin and soft tissue infections:
Boils	Cellulitis	Infected burns
Abscesses	Infected skin conditions,	Protection for skin grafts
Carbuncles	e.g. ulcer, eczema, and acne
Furunculosis	Infected wounds	Impetigo

Respiratory tract infections:

Pneumonia Lung abscess Sinusitis    Pharyngitis

Tonsillitis    Quinsy

Other infections caused by Floxapen-sensitive organisms: Osteomyelitis Urinary tract infection Enteritis    Meningitis

Endocarditis Septicaemia

Floxapen is also indicated for use as a prophylactic agent during major surgical procedures when appropriate; for example cardiothoracic and orthopaedic surgery.

Parenteral usage is indicated where oral dosage is inappropriate.

4.2 Posology and method of administration

Premature infants, neonates, sucklings and infants

Other pharmaceutical forms/strengths may be more appropriate for administration to this population.

Depends on the age, weight and renal function of the patient, as well as the severity of the infection.

Usual adult dosage (including elderly patients)

Oral - 250 mg four times a day.

Usual children's dosage 2-10 years: half adult dose Under 2 years: quarter adult dose.

Abnormal renal function: In common with other penicillins, Floxapen usage in patients with renal impairment does not usually require dosage reduction. However, in the presence of severe renal failure (creatinine clearance < 10 ml/min) a reduction in dose or an extension of dose interval should be considered. The maximum recommended dose in adults is 1 g every 8 to 12 hours.

Floxapen is not significantly removed by dialysis and hence no supplementary dosages need to be administered either during, or at the end of the dialysis period.

Hepatic impairment

Dose reduction in patients with reduced hepatic function is not necessary.

Osteomyelitis, endocarditis - Up to 8 g daily, in divided doses six to eight hourly.

Surgical prophylaxis - 1 to 2 g IV at induction of anaesthesia followed by 500 mg six hourly IV, IM or orally for up to 72 hours.

Administration

Oral: Oral doses should be administered half to one hour before meals.

4.3 Contraindications

Flucloxacillin should not be given to patients with a history of hypersensitivity to P-lactam antibiotics (e.g. penicillins, cephalosporins) or excipients.

Flucloxacillin is contra-indicated in patients with a previous history of flucloxacillin-associated jaundice/hepatic dysfunction.

4.4 Special warnings and precautions for use

Before initiating therapy with flucloxacillin, careful enquiry should be made concerning previous hypersensitivity reactions to P-lactams. Cross-sensitivity between penicillins and cephalosporins is well documented.

Serious and occasionally fatal hypersensitivity reactions (anaphylaxis) have been reported in patients receiving P-lactam antibiotics. Although anaphylaxis is more frequent following parenteral therapy, it has occurred in patients on oral therapy. These reactions are more likely to occur in individuals with a history of P-lactam hypersensitivity. If anaphylaxis occurs, flucloxacillin should be discontinued and the appropriate therapy instituted. In cases of serious anaphylactic reactions immediate emergency treatment may be required, as appropriate.

Flucloxacillin should be used with caution in patients with evidence of hepatic dysfunction, (patients > 50 years and those with serious underlying disease. In these patients, hepatic events may be severe, and in very rare circumstances, deaths have been reported (see section 4.8).

Dosage should be adjusted in renal impairment (see section 4.2).

Special caution is essential in the newborn because of the risk of hyperbilirubinaemia. Studies have shown that, at high dose following parenteral administration, flucloxacillin can displace bilirubin from plasma protein binding sites, and may therefore predispose to kernicterus in a jaundiced baby. In addition, special caution is essential in the newborn because of the potential for high serum levels of flucloxacillin due to a reduced rate of renal excretion.

During prolonged treatments (e.g. osteomyelitis, endocarditis), regular monitoring of hepatic and renal functions is recommended.

Prolonged use may occasionally result in overgrowth of non-susceptible organisms.

Only applicable for formulations containing sodium

Contains sodium. To be taken into consideration by patients on a controlled

sodium diet.

The use of flucloxacillin (like other penicillins) in patients with renal impairment does not usually require dosage reduction. In the presence of severe renal failure (creatinine clearance less than 10ml/min), however, a reduction in dose or an extension of dose interval should be considered because of the risk of neurotoxicity (see section 4.2).

Sodium content: The sodium salt of flucloxacillin contains 10.3mg of sodium per 5ml. This should be included in the daily allowance of patients on sodium restricted diets.

Magnesium content: The magnesium salt of flucloxacillin contains 5.7mg of magnesium per 5ml. This should be considered in patients with impaired renal function.

4.5 Interaction with other medicinal products and other forms of interaction

Probenecid decreases the renal tubular secretion of flucloxacillin. Concurrent administration of probenecid delays the renal excretion of flucloxacillin.

Bacteriostatic drugs may interfere with the bactericidal action of flucloxacillin.

4.6 Pregnancy and lactation

Pregnancy: Animal studies with flucloxacillin have shown no teratogenic effects. The product has been in clinical use since 1970 and the limited number of reported cases of use in human pregnancy have shown no evidence of untoward effects. The decision to administer any drug during pregnancy should be taken with the utmost care. Therefore flucloxacillin should only be used in pregnancy when the potential benefits outweigh the potential risks associated with treatment.

Lactation: Trace quantities of flucloxacillin can be detected in breast milk. The possibility of hypersensitivity reactions must be considered in breast-feeding infants. Therefore flucloxacillin should only be administered to a breast-feeding mother when the potential benefits outweigh the potential risks associated with the treatment.

4.7 Effects on ability to drive and use machines

Adverse effects on the ability to drive or operate machinery have not been observed.

4.8 Undesirable effects

The following convention has been utilised for the classification of undesirable effects:- Very common ( >1/10), common ( >1/100, <1/10), uncommon ( >1/1000, <1/100), rare ( >1/10,000, <1/1000), very rare ( <1/10,000).

Unless otherwise stated, the frequency of the adverse events has been derived from more than 30 years of post-marketing reports.

Blood and lymphatic system disorders

Very rare:    Neutropenia (including agranulocytosis) and

thrombocytopenia. These are reversible when treatment is discontinued. Eosinophilia, haemolytic anaemia.

Immune system disorders

Very rare:    Anaphylactic shock (exceptional with oral administration) (see

Item 4.4 Warnings), angioneurotic oedema.

If any hypersensitivity reaction occurs, the treatment should be discontinued. (See also Skin and subcutaneous tissue disorders).

Gastrointestinal disorders

*Common:    Minor gastrointestinal disturbances.

Very rare:    Pseudomembranous colitis.

If pseudomembranous colitis develops, flucloxacillin treatment should be discontinued and appropriate therapy, e.g. oral vancomycin should be initiated.

Hepato-biliary disorders

Very rare:    Hepatitis and cholestatic jaundice. (See Section 4.4 Special

Warnings and Special Precautions for Use). Changes in liver function laboratory test results (reversible when treatment is discontinued).

Hepatitis and cholestatic jaundice may be delayed for up to two months posttreatment; in several cases the course of the reactions has been protracted and lasted for some months. Hepatic events may be severe and in very rare circumstances a fatal outcome has been reported. Most reports of deaths have been in patients > 50 years and in patients with serious underlying disease.

There is evidence that the risk of flucloxacillin induced liver injury is increased in subjects carrying the HLA-B*5701 allele. Despite this strong association, only 1 in 500-1000 carriers will develop liver injury. Consequently, the positive predictive value of testing the HLA-B*5701 allele for liver injury is very low (0.12%) and routine screening for this allele is not recommended.

Skin and subcutaneous tissue disorders

*Uncommon: Rash, urticaria and purpura.

Very rare:    Erythema multiforme, Stevens-Johnson syndrome and toxic

epidermal necrolysis.

(See also Immune system disorders).

Musculoskeletal and connective tissue disorders

Very rare:    Arthralgia and myalgia sometimes develop more than 48

hours after the start of the treatment.

Renal and urinary disorders Very rare:    Interstitial nephritis.

This is reversible when treatment is discontinued.

General disorders and administration site conditions

Very rare: Fever sometimes develops more than 48 hours after the start of

the treatment.

*The incidence of these AEs was derived from clinical studies involving a total of approximately 929 adult and paediatric patients taking flucloxacillin.

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; website: www.mhra.gov.uk/yellowcard

4.9 Overdose

Gastrointestinal effects such as nausea, vomiting and diarrhoea may be evident and should be treated symptomatically.

Flucloxacillin is not removed from the circulation by haemodialysis.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Properties: Flucloxacillin is a narrow-spectrum antibiotic of the group of isoxazolyl penicillins; it is not inactivated by staphylococcal P-lactamases.

Activity: Flucloxacillin, by its action on the synthesis of the bacterial wall, exerts a bactericidal effect on streptococci except those of group D (Enterococcusfaecalis) staphylococci. It is not active against methicillin-resistant staphylococci.

There is evidence that the risk of flucloxacillin induced liver injury is increased in subjects carrying the HLA-B*5701 allele. Despite this strong association, only 1 in 500-1000 carriers will develop liver injury. Consequently, the positive predictive value of testing the HLA-B*5701 allele for liver injury is very low (0.12%) and routine screening for this allele is not recommended.

5.2 Pharmacokinetic properties

Absorption:

Flucloxacillin is stable in acid media and can therefore be administered either by the oral or parenteral route. The peak serum levels of flucloxacillin reached after one hour are as follows:

•    After 250 mg by the oral route    (in fasting subjects): Approximately 8.8 mg/l.

•    After 500 mg by the oral route    (in fasting subjects): Approximately 14.5 mg/l.

•    After 500 mg by the IM route:    Approximately 16.5 mg/l.

The total quantity absorbed by the oral route represents approximately 79% of the quantity administered.

Distribution:

Flucloxacillin diffuses well into most tissue. Specifically, active concentrations of flucloxacillin have been recovered in bones: 11.6 mg/l (compact bone) and 15.6 mg/l (spongy bone), with a mean serum level of

8.9 mg/l.

Crossing the meningeal barrier: Flucloxacillin diffuses in only small proportion into the cerebrospinal fluid of subjects whose meninges are not inflamed.

Crossing into mothers' milk: Flucloxacillin is excreted in small quantities in mothers' milk.

Metabolism:

In normal subjects approximately 10% of the flucloxacillin administered is metabolised to penicilloic acid. The elimination half-life of flucloxacillin is in the order of 53 minutes.

Excretion: Excretion occurs mainly through the kidney. Between 65.5% (oral route) and 76.1% (parenteral route) of the dose administered is recovered in unaltered active form in the urine within 8 hours. A small portion of the dose administered is excreted in the bile. The excretion of flucloxacillin is slowed in cases of renal failure.

Protein binding: The serum protein-binding rate is 95%.

5.3 Preclinical safety data

No further information of relevance to add.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Floxapen Oral Suspension: Saccharin sodium, xanthan gum, citric acid, sodium citrate, sodium benzoate, blood orange, tutti fruitti, menthol dry flavours and sucrose.

6.2    Incompatibilities

None known.

6.3    Shelf life

Floxapen Oral Suspension: Two years (following reconstitution: 14 days).

6.4    Special precautions for storage

Floxapen Oral Suspension: Do not store above 25°C.

Once dispensed, Floxapen Oral Suspension (bottles) remain stable for 14 days stored in a refrigerator (5°C).

6.5    Nature and contents of container

Floxapen Oral Suspension 250 mg/5 ml: Clear glass bottles, reconstituted volume of 61 ml or 100 ml.

6.6    Special precautions for disposal

If a dilution of the reconstituted Oral Suspension is required, Syrup BP should be used.

7    MARKETING AUTHORISATION HOLDER

Actavis Group PTC ehf