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

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)

Intramuscular - 250 mg four times a day.

Intravenous - 250 mg to 1 g four times a day.

The above systemic dosages may be doubled where 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.

Floxapen may be administered by other routes in conjunction with systemic therapy. (Proportionately lower doses should be given in children.)

Intrapleural - 250 mg once daily.

By nebuliser - 125 to 250 mg four times a day.

Intra-articular - 250 to 500 mg once daily.

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. 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.

Administration

Intramuscular: Add 2 ml Water for Injections BP to 500 mg vial contents.

Intravenous: Dissolve 250-500 mg in 5-10 ml Water for Injections BP. Administer by slow intravenous injection (three to four minutes). Floxapen may also be added to infusion fluids or injected, suitably diluted, into the drip tube over a period of three to four minutes.

Interpleural: Dissolve 250 mg in 5-10 ml Water for Injections BP.

Intra-articular: Dissolve 250-500 mg in up to 5 ml Water for Injections BP or 0.5% lidocaine hydrochloride solution.

Nebuliser solution: Dissolve 125-250 mg of the vial contents in 3 ml sterile water.

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.

Ocular administration.

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.

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. Serious anaphylactic reactions may require immediate emergency treatment with adrenaline (epinephrine). Ensure adequate airway and ventilation and give 100% oxygen. IV crystalloids, hydrocortisone, antihistamine and nebulised bronchodilators may also be required.

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).

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.

Floxapen injection contains approximately 51 mg sodium per g. This should be included in the daily allowance of patients on sodium restricted diets.

Care is necessary if very high doses of flucloxacillin are given, especially if renal function is poor, because of the risk of nephrotoxicity. Care is also necessary if large doses of sodium salts are given to 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.

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 breastfeeding 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. 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).

Nervous system disorders

Very rare:    In patients suffering from renal failure, neurological disorders with

convulsions are possible with the I.V. injection of high doses.

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).

These reactions are related neither to the dose nor to the route of administration. The onset of these effects may be delayed for up to two months post-treatment; 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.

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.

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 ^-lactamases.

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

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 14.5mg/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 mother’s milk: Flucloxacillin is excreted in small quantities in mother’s 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 Injection'. None

6.2 Incompatibilities

It is advisable not to combine flucloxacillin with other drugs in solution for parenteral administration.

Floxapen should not be mixed with blood products or other proteinaceous fluids (e.g. protein hydrolysates) or with intravenous lipid emulsions.

If Floxapen is prescribed concurrently with an aminoglycoside, the two antibiotics should not be mixed in the syringe, intravenous fluid container or giving set; precipitation may occur.

6.3 Shelf life

Floxapen Vials for Injection: Three years. After opening 24 hours.

6.4 Special precautions for storage

Floxapen Vials for Injection should be stored in a cool, dry place. Once reconstituted Floxapen solutions should be stored in a refrigerator (2-8^oC) and used within 24 hours

6.5 Nature and contents of container

Floxapen Vials 500 mg: Clear Type I glass vials with a chlorobutyl rubber bung and aluminium seal, boxes of 10.

Special precautions for disposal

Reconstituted solutions for IM or direct IV injection should normally be administered within 30 minutes of preparation. However, aqueous solutions of Floxapen Injection retain their activity for up to 24 hours when stored in a refrigerator (2°-8°C).

Floxapen may be added to most intravenous fluids (e.g. Water for Injections, sodium chloride 0.9%, glucose 5%, sodium chloride 0.18% with glucose 4%). Once reconstituted, Floxapen solutions should be stored in a refrigerator (2°-8°C) and used within 24 hours of preparation. Full particulars are given in the Package Enclosure Leaflet.

Reconstitution of Floxapen injections and preparation of Floxapen infusions must be carried out under appropriate aseptic conditions if the extended storage periods are required.

N.B. FLOXAPEN VIALS ARE NOT SUITABLE FOR MULTIDOSE USE.

Any residual Floxapen should be discarded.

7    MARKETING AUTHORISATION HOLDER

Actavis Group PTC ehf Reykjavikurvegi 76-78 220 Hafnarfjordur Iceland.

8    MARKETING AUTHORISATION NUMBER(S)

PL 30306/0020

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

15/05/1987 / 03/06/2005

10 DATE OF REVISION OF THE TEXT

01/04/2016