SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Flucloxacillin Sodium for Injection 250 mg

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Flucloxacillin sodium 250 mg per vial

3    PHARMACEUTICAL FORM

Powder for solution for injection

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

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

Skin and soft tissue infections: boils, abscesses, carbuncles, furunculosis, cellulitis; infected skin conditions, e.g. ulcer, eczema and acne; infected wounds, infected burns, protection for skin grafts and impetigo.

Respiratory tract infections: pneumonia, lung abscess, empyema, sinusitis, pharyngitis, tonsillitis, quinsy, otitis media and externa.

Other infections caused by flucloxacillin-sensitive organisms: osteomyelitis, enteritis, endocarditis, urinary tract infection, meningitis, septicaemia.

Flucloxacillin is also indicated for use as a prophylactic agent during major surgical procedures where appropriate: for example, cardiothoracic and orthopaedic surgery.

Parental 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.

Adults:

Usual adult dosage (including elderly patients)

Intramuscular - 250 mg four times a day.

Intravenous - 250 mg to 1g four times a day

The above systemic dosages may be doubled where necessary;

Treatment of osteomyelitis, endocarditis - Up to 8g daily in divided doses six to eight hourly.

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

Flucloxacillin may be administered by other routes in conjunction with systemic therapy. Intrapleural - 250 mg once daily By nebuliser - 125 to 250 mg four times a day.

Intra-articular - 250 to 500 mg once daily.

Children:

Proportionately lower doses should be given in children.

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

Abnormal renal function:

In common with other penicillins, Flucloxacillin 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. Flucloxacillin 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.

Intramuscular Administration:

Add 1.5 ml Water for Injections to 250 mg vial contents or 2 ml Water for Injections to 500 mg vial contents.

Intravenous Administration:

Dissolve 250-500 mg in 5-10 ml Water for Injections or 1-2g in 15-20 ml Water for Injections. Administer by slow intravenous injection (three to four minutes). Flucloxacillin may also be added to infusion fluids or injected, suitably diluted, into the drip tube over a period of three to four minutes.

Intrapleural Administration:

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

Intraarticular Administration:

Dissolve 250-500 mg in up to 5ml Water for Injections or 0.5% lignocaine hydrochloride solution.

Nebuliser Solution Administration:

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

4.3 Contraindications

Flucloxacillin Sodium for Injection is contraindicated in patients with a penicillin or other P-lactam (e.g. cephalosporins) hypersensitivity. It is also contraindicated in patients with a previous history of flucloxacillin-associated jaundice/hepatic dysfunction. It is also contraindicated for 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 B-lactams. Serious and occasionally fatal hypersensitivity reactions (anaphylaxis) have been reported in patients receiving B-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 people with a history of B-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 of age 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. Also, special caution is essential in the newborn because of the potential risk for high serum levels of flucloxacillin due to a reduced rate of renal excretion.

During prolonged treatments (eg osteomyelitis, endocarditis), regular monitoring of hepatic and renal function is recommended.

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

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

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    Interactions with other medicinal products and other forms of interaction

The plasma concentration is enhanced if probenecid is given concurrently; probenecid decreases the renal tubular secretion of flucloxacillin. There is decreased excretion of methotrexate (increased risk of toxicity).

Please see section 6.2.

4.6    Fertility, 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 effect. 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

During lactation, trace quantities of penicillins can be detected in breast milk. Consequently, 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

None

4.8 Undesirable effects

The following convention has been utilised for the classification of the 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

Immune system disorders:

Very rare: Anaphylactic shock (exceptional with oral administration) (see section 4.4), 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.

Gastro-intestinal disorders *Common: minor gastro-intestinal disturbances (eg nausea, diarrhoea)

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). 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 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 and myalgia sometimes develop more than 48 hours after the start of the treatment.

Renal and urinary disorders

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 at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Problems of overdosage with flucloxacillin are unlikely to occur; nausea, vomiting and diarrhoea may be seen; if encountered they may be treated symptomatically. Flucloxacillin is not removed from the circulation by haemodialysis.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Flucloxacillin is a bactericidal antibiotic that is particularly useful against penicillinase-producing staphylococci. Flucloxacillin is a semisynthetic member of the penicillin family. The penicillin nucleus consists of a thiazolidine ring fused with a P-lactam ring to which is attached a side chain. The side chain determines most of the antibacterial properties of the penicillin in question. Flucloxacillin kills bacteria by interfering in the synthesis of the bacterial cell wall.

Flucloxacillin resists the action of bacterial penicillinase probably because of the steric hindrance induced by the acyl side chain which prevents the opening of the P-lactam ring.

Flucloxacillin is active against Gram-positive organisms with the exception of Streptococcus faecalis. In general, it is not active against Gram-negative bacilli or anerobes. It is also regarded as not being effective against methicillin resistant staphylococcus aureus.

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.

Biotransformation: 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.

Elimination: 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

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

6 PHARMACEUTICAL PARTICULARS

List of excipients

None

Flucloxacillin should not be mixed with blood products or other proteinaceous fluids (eg protein hydrolysates) or with intravenous lipid emulsions.

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

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

6.3 Shelf life

36 months

6.4 Special precautions for storage

Do not store above 25°C. Keep container in outer carton.

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 2-8°C, unless re-constitution / dilution has taken place in controlled and validated aseptic conditions.

6.5 Nature and contents of container

Type III uncoloured glass vials with rubber stoppers. Packs of 5, 10, 50, 100

6.6 Special precautions for disposal

Flucloxacillin may be added to most intravenous fluids (eg Water for Injections, sodium chloride 0.9%, glucose 5%, sodium chloride 0.18% with glucose 4%).

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

Flucloxacillin vials are not suitable for multidose use. Any residual flucloxacillin should be discarded.

7 MARKETING AUTHORISATION HOLDER

Villerton Invest SA 40 Avenue Monterey L-2163 Luxembourg

8    MARKETING AUTHORISATION NUMBER(S)

PL 24780/0013

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

26 September 2003

10 DATE OF REVISION OF THE TEXT

22/09/2016