Floxapen vial for injection 250 mg – Summary of Product Characteristics (SmPC) for healthcare professionals

1 NAME OF THE MEDICINAL PRODUCT

FLOXAPEN® Vials for Injection

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Floxapen Vials for Injection (Flucloxacillin Injection BP). Each vial contains 250 mg flucloxacillin as Flucloxacillin Sodium BP.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Floxapen Injection: Vials containing sterile powder for reconstitution.

4 CLINICAL PARTICULARS

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

4.1 Therapeutic indications

Floxapen is indicated for the treatment of infections due to sensitive Gram-positive organisms, including β-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 Impetigo Furunculosis Infected wounds

Respiratory tract infections:

Pneumonia Lung abscess Empyema Sinusitis Pharyngitis Otitis media and externa 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

Posology

Usual adult dosage (including elderly patients)

Adults and adolescents over 12 years of age

Total daily dosage of 1 g – 6 g administered in 3-6 divided doses, by i.v. or i.m. injection.

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

No intramuscular single bolus injection should exceed 2 g.

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

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.

Paediatric population

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.

Children under 12 years of age

25 to 50 mg/kg/24 hours administered in three to four equally divided doses by i.m. or i.v. 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.

Renal impairment 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.

Method of administration

Intramuscular: Add 1.5 ml Water for Injections BP to 250 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 the active substance, β-lactam antibiotics (e.g. penicillins, cephalosporins) or to any of the excipients listed in section 6.1.

• Flucloxacillin is contra-indicated in patients with a previous history of flucloxacillin-associated jaundice/hepatic dysfunction.
• Ocular or subconjunctival administration.

4.4 Special warnings and precautions for use

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

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

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 hypokalemia-inducing diuretics or when other risk factors for the development of hypokalemia are present (e.g. malnutrition, renal tubule disfunction).

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.

This medicinal product contains 48.8 mg sodium per 1g of injection, equivalent to 2.4% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

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.

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.

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).

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.

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

Bacteriostatic drugs may interfere with the bactericidal action of flucloxacillin.

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.)

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.

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 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.

Breast-feeding: 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), not known (cannot be estimated from the available data).

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.

Metabolism and nutrition disorders

Post marketing experience: very rare cases of high anion gap metabolic acidosis, when flucloxacillin is used concomitantly with paracetamol, generally in the presence of risk factors (see section 4.4.)

Not known: Hypokalaemia

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).

Hepatitis and cholestatic jaundice 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.

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).

Not Known: AGEP – acute generalized exanthematous pustulosis (see section 4.4)

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 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 and should be treated symptomatically.

Flucloxacillin is not removed from the circulation by haemodialysis.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: 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.

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.

PK/PD relationship

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

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 cefalosporins. 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. Grampositive 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:

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.²

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

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

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

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 is recovered in unaltered active form in the urine within 8h. ¹ 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 creatinin 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.

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 250 mg: Clear Type I glass vials with Chlorobutyl rubber bung and aluminium seal, boxes of 10.

6.6 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

Accord Healthcare Limited

Sage House

319 Pinner Road

North Harrow

Middlesex

HA1 4HF

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 20075/0587

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

15/05/1987 / 03/06/2005

10 DATE OF REVISION OF THE TEXT

11/09/2023