Flucloxacillin 250 mg powder for solution for injection/infusion – Summary of Product Characteristics (SmPC) for healthcare professionals

1 NAME OF THE MEDICINAL PRODUCT

Flucloxacillin 250 mg powder for solution for injection/infusion

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains 250 mg flucloxacillin (as flucloxacillin sodium monohydrate)

Each 250 mg vial contains 0.55 mmol (13 mg) sodium

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Powder for solution for injection/infusion

White or almost white colour powder.

4.1 Therapeutic indications

Flucloxacillin is indicated for the treatment of the following infections due to sensitive Gram-positive organisms, including β-lactamase-producing staphylococci and streptoccoci. 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.
• Impetigo, Furunculosis, Infected wounds

Respiratory tract infections:

• Pneumonia, Lung abscess, Empyema
• Sinusitis, Pharyngitis, Otitis media and externa
• Tonsillitis, Quinsy

Other infections caused by flucloxacillin-sensitive organisms:

Flucloxacillin 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.

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

4.2 Posology and method of administration

Posology

The dosage depends on age, weight and renal function of the patient, as well as the severity and nature of the infection.

For instructions on the preparation of solution see section 6.6. For incompatibilities see section 6.2.

Intramuscular or intravenous

Adults and adolescents over 12 years of age

Total daily dosage of 1g – 6 g administered in -3 – 6 divided doses, by intravenous or intramuscular injection.

In case of severe infections: Up to 8 g per day administered in three to four infusions(over 20 to 30 min).

The maximum dose of 12 g per day should not be exceeded.

Methicillin-susceptible Staphylococcus aureus. Endocarditis: 2 g of flucloxacillin every 6 h, increasing to 2 g every 4 h in patients weighing >85 kg

Surgical prophylaxis: 2 g intravenous (bolus or infusion) upon induction of anaesthesia followed by 500 mg six hourly IV, IM or orally upto 72 hours, to be repeated every 6 h for 24 h in cases of vascular and orthopaedic surgery, and for 48 h in cases of cardiac or coronary surgery.

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

No intramuscular single bolus injection or infusion should exceed 2 g.

Flucloxacillin may be administered by other routes in conjunction with systemic therapy (Proportionately lower doses should be given in children) Intrapleural-250mg once daily

By nebuliser-125 to 250 mg four times a day

Intra-articular- 250 to 500mg once daily

Paediatric population

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

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

Children under 12 years of age

The dose is 25 to 50 mg/kg/24 hours administered in three to four equally divided doses by intramuscular or intravenous injection.

In cases of severe infections: up to 100 mg/kg/24 hours in three to four divided doses.

No single bolus injection or infusion should exceed 33 mg/kg.

Children aged 10 to 14 years usually receive a daily dose of 1.5 g to 2 g and children aged 6 to 10 years 0.75 g to 1.5 g, divided into three to four equal doses.

Premature infants, neonates, suckling and infants

Flucloxacillin should be administered to premature infants and neonates only after strict risk-benefit assessment because of the possible triggering of kernicterus (see also section 4.4).

Neonates and premature babies and infants generally receive 40 to 50 mg / kg body weight daily, divided into three to four equal doses. An increase in the daily dose to a maximum of 100 mg/kg body weight may be possible.

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. The maximum recommended dose in adults is 1 g every 8 to 12 hours. In anuric patients, the maximum dosage is 1 g every 12 h.

Flucloxacillin is not significantly removed by dialysis and hence no supplementary dosages need 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.

Method of administration:

Intramuscular, intravenous, Intrapleural, Intra-articular and Nebuliser solution.

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

4.3 Contraindications

Flucloxacillin must not be given to patients with a history of hypersensitivity to beta-lactam antibiotics (e.g. penicillins, cephalosporins) or to any of the excipients listed in section 6.1.

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

Ocular or subconjunctival administration is contraindicated.

4.4 Special warnings and precautions for use

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

Serious and occasionally fatal hypersensitivity reactions (anaphylaxis) have been reported in patients receiving beta-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 beta-lactam hypersensitivity.

If an allergic reaction or anaphylaxis occurs, flucloxacillin should be discontinued and the appropriate therapy instituted. Serious anaphylactoid 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.

The occurrence at the treatment initiation of a feverish generalised erythema associated with pustula may be a symptom of acute generalised exanthematous pustulosis (AGEP) (see section 4.8). In case of AGEP diagnosis, flucloxacillin should be discontinued and any subsequent administration of flucloxacillin contra-indicated.

Hypokalaemia (potentially life threatening) can occur with the use of flucloxacillin, especially in high doses. Hypokalaemia caused by flucloxacillin can be resistant to potassium supplementation. Regular measurements of potassium levels are recommended during the therapy with higher doses of flucloxacillin. Attention for this risk is warranted also when combining flucloxacillin with hypokalaemia-inducing diuretics or when other risk factors for the development of hypokalaemia are present (e.g. malnutrition, renal tubule dysfunction)

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 extremely rare circumstances, deaths have been reported (see section 4.8).

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 sodium salts are given to patients with impaired renal function.

Special caution is advised regarding drug induces liver injury in subjects harbouring the HLA-B*5701 haplotype, as this is currently evaluated in a growing number of subjects with HIV-infection whom may also be at increased risk for exposure to flucloxacillin

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

Special caution is essential in the newborn because of the risk of hyperbilirubinemia. 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.

Care is required when treating some patients with spirochaete infections such as syphilis or leptospirosis because the Jarisch- Herxheimer reaction may occur shortly after treatment with a penicillin is started.

In case of severe and persistent diarrhoea, the possibility of pseudomembranous colitis should be considered; flucloxacillin therapy should be discontinued.

Contact with flucloxacillin should be avoided since skin sensitisation may occur.

Caution is advised in patients with porphyria.

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.

Caution is advised when flucloxacillin is administered concomitantly with paracetamol due to the increased risk of high anion gap metabolic acidosis (HAGMA). Patients at high risk for HAGMA are in particular those with severe renal impairment, sepsis or malnutrition especially if the maximum daily doses of paracetamol are used.

After co-administration of flucloxacillin and paracetamol, a close monitoring is recommended in order to detect the appearance of acid–base disorders, namely HAGMA, including the search of urinary 5-oxoproline.

If flucloxacillin is continued after cessation of paracetamol, it is advisable to ensure that there are no signals of HAGMA, as there is a possibility of flucloxacillin maintaining the clinical picture of HAGMA (see section 4.5).

Sodium content: This medicinal product contains 13 mg sodium per vial, equivalent to 0.65 % of the WHO recommended maximum daily intake of 2 g sodium for an adult.

The maximum daily dose of this product is equivalent to 30.36% of the WHO recommended maximum daily intake for sodium.

Flucloxacillin 250 mg powder for solution for injection/infusion is considered high in sodium. This should be particularly taken into account for those on a low salt diet.

4.5 Interaction with other medicinal products and other forms of interaction

Flucloxacillin (CYP450 inducer) has been reported to significantly decrease plasma voriconazole concentrations. If concomitant administration of flucloxacillin with voriconazole cannot be avoided, monitor for potential loss of voriconazole effectiveness (e.g. by therapeutic drug monitoring); increasing the dose of voriconazole may be needed.

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

In common with other antibiotics, flucloxacillin may affect the gut flora, leading to lower oestrogen re-absorption and reduced efficacy of combined oral contraceptives.

Bacteriostatic medicinal products (chloramphenicol, erythromycins, sulphonamides, and tetracyclines) may interfere with the bactericidal action of flucloxacillin.

Immunosuppressants:

Methotrexate, reduced excretion may occur with flucloxacillin (increased risk of toxicity).

Interference with diagnostic tests:

Penicillins may produce false-positive results with the direct antiglobulin (Coombs') test, falsely high urinary glucose results with the copper sulphate test and falsely high urinary protein results, but glucose enzymatic tests (e.g. Clinistix) and bromophenol blue tests (e.g. Multistix or Albustix) are not affected.

Caution should be taken when flucloxacillin is used concomitantly with paracetamol as concurrent intake has been associated with high anion gap metabolic acidosis, especially in patients with risk factors (see section 4.4.).

4.6 Fertility, Pregnancy and lactation

Pregnancy

Data on a limited number of exposed pregnancies indicate no adverse effects of flucloxacillin on pregnancy or on the health of the foetus/new-born child. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development.

Caution should be exercised when prescribing to pregnant women.

Breastfeeding

Flucloxacillin diffuses into breast milk in a limited amount and in rare cases this can lead to diarrhoea and/or fungal colonisation of the mucosa in the infant. The possibility of sensitisation of the infant to beta-lactam drugs should be considered.

Fertility

There are no data available on fertility.

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

Adverse reactions listed below are classified according to frequency and System Organ Class (SOC).

very common (≥1/10);

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);

Not known (cannot be estimated from the available data). Unless otherwise stated, the frequency of the adverse reactions has been derived from more than 30 years of post-marketing reports.

*The incidence of these adverse events (AEs) was derived from clinical studies involving 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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Gastrointestinal effects such as nausea, vomiting and diarrhoea may be evident

With high parenteral doses of penicillins, neurotoxicity (e.g.

convulsions, encephalopathy), blood disorders (e.g. neutropenia, haemolytic anaemia, prolongation of bleeding time, defective platelet function) or

electrolyte disturbances may occur. Treatment is symptomatic.

Flucloxacillin is not removed from the circulation by haemodialysis.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antibacterials for systemic use; Beta-lactamase resistant penicillins, ATC code: J01CF05.

Flucloxacillin is a semisynthetic penicillin (beta-lactam antibiotic; isoxazolylpenicillin) with a narrow spectrum of activity primarily against Gram-positive organisms, including β

-lactamase-producing strains.

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.

Mechanism of action

Flucloxacillin inhibits one or more enzymes (often referred to as penicillin-binding proteins, PBPs) in the biosynthetic pathway of bacterial peptidoglycan, which is an integral structural component of the bacterial cell wall. Inhibition of peptidoglycan synthesis leads to weakening of the cell wall, which is usually followed by cell lysis and death.

Mechanism of resistance

Resistance to isoxazolylpenicillins (so-called methicillin-resistance) is caused by the bacteria producing an altered penicillin binding protein. Cross resistance may occur in the beta-lactam group with other penicillins and cephalosporins. Methicillin-resistant staphylococci generally have low susceptibility for all beta-lactam antibiotics.

Antimicrobial activity

Flucloxacillin is active against both β

-lactamase-positive and –negative strains of Staphylococcus aureus and other aerobic Gram-positive cocci, with the exception of Enterococcus faecalis. Gram- positive anaerobes are generally susceptible (MIC 0.25-2 mg/l) but Gram-negative bacilli or anaerobes are moderately to fully resistant. Enterobacteria is fully resistant to flucloxacillin as well as methicillin-resistant staphylococci.

Strains of the following organisms are generally sensitive to the bactericidal action of flucloxacillin in vitro.

The minimal inhibitory concentrations (MIC) of flucloxacillin are quoted below:

5.2 Pharmacokinetic properties

Absorption

The peak serum levels of flucloxacillin reached after 1h are as follows:

After 500mg by the i.m. route: approximately 16.5 mg/l

Distribution

Protein binding: the serum protein binding rate is 95%. Flucloxacillin diffuses well into most tissues. 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 milk.

Biotransformation

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

Elimination

Excretion occurs mainly through the kidney. Sixty five per cent of the dose administered orally and 76.1% of the does administered parenterally is recovered in unaltered active form in the urine within 8h. A small portion of the dose administered is excreted in the bile. The excretion of flucloxacillin is slowed in cases of renal failure.

Neonates and infants

The clearance of flucloxacillin is considerably slower in neonates compared with adults and a mean elimination half life of approximately four and a half hours has been reported in neonates. Special care should be taken during administration of flucloxacillin to the newborn (see section 4.4).

Younger infants (<6 months) achieve higher plasma concentrations of flucloxacillin than older children when given the same dose.

Patients with renal impairment

In patients with severe renal impairment the elimination half life of flucloxacillin increases to values of between 135-173 min. Modified dosage is required if renal impairment is severe, with creatinine clearance <10 ml/min (see section 4.2).

Patients with hepatic impairment

Hepatic disease is thought unlikely to influence the pharmacokinetics of flucloxacillin as the antibiotic is cleared primarily via the renal route.

Pharmacokinetic/pharmacodynamic relationship

The time above the minimum inhibitory concentration (T>MIC) is considered to be the major determinant of efficacy for flucloxacillin.

5.3 Preclinical safety data

There is no preclinical data of relevance to the prescriber, which are additional to those already included in other sections of the SmPC.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

None

6.2 Incompatibilities

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

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

Ringer's solution is not compatible with flucloxacillin for injection/infusion

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf life

3 years.

Reconstituted/diluted solution: Chemical and physical in-use stability has been demonstrated for 1 hour at controlled room temperature 20-25°C or for 24 hours at 2-8°C.

From a microbiological point of view, unless the method of opening/ reconstitution/dilution precludes the risk of microbial contamination, 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 not be longer than the times stated above for the chemical and physical in-use stability.

6.4 Special precautions for storage

For single use only. Discard any unused solution

This medicinal product does not require any special storage conditions.

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

6.5 Nature and contents of container

Flucloxacillin 250mg Powder for Solution for Injection or Infusion is packed in Type-I moulded clear glass vials stoppered with grey chlorobutyl rubber stoppers and sealed with aluminium seals having polypropylene disc.

Packs sizes: Packs of 10 vials

6.6 Special precautions for disposal

Flucloxacillin may be added to the following intravenous fluids

water for Injections,

sodium chloride 0.9%,

glucose 5%,

sodium chloride 0.18% with glucose 4%

Flucloxacillin may be added to the following infusion fluids:

water for injections,

sodium chloride 0.9%,

glucose 5%,

sodium chloride 0.18% with glucose 4%

Intramuscular:

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

Intravenous:

Dissolve 250 mg in 5 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: Dissolve 250 mg in 5-10 ml Water for Injection.

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

Nebuliser solution: Dissolve 250 mg of the vial contents in 3 ml Water for Injection.

Appearance of the solution

Clear colourless or pale yellow solution, free from visible particles.

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

7 MARKETING AUTHORISATION HOLDER

Eugia (UK) Limited

1 Roundwood Avenue,

Stockley Park,

Uxbridge,

UB11 1AF,

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 56284/0017

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

18/04/2023

10 DATE OF REVISION OF THE TEXT

20/07/2026