FLUCLOXACILLIN SODIUM FOR INJECTION 500 MG - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Flucloxacillin Sodium for Injection 500 mg

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Flucloxacillin sodium 500 mg per vial

Excipient(s) with known effect:

Sodium 25.37mg (1.408 mmol) (see section 4.4).

For the full list of excipients, see section 6.1.

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 ß-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

Posology

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.

Paediatric population

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. The maximum recommended dose in adults is 1 g every 8 to 12 hours.

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.

Hepatic impairment

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

Method of administration

Intramuscular:

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

Intravenous :

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 :

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

Intra-articular :

Dissolve 250–500 mg in up to 5ml Water for Injections 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 is contraindicated in patients with a history of hypersensitivity to the active substanceB-lactam antibiotics (e.g. penicillins, cephalosporins) or the excipients listed in section 6.1. It is also contraindicated in patients with a previous history of flucloxacillin-associated jaundice/hepatic dysfunction. It is also contraindicated for 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 B-lactams. Cross-sensitivity between penicillins and cephalosporins is well documented.

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.

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 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).

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. 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.

This medicinal product contains 25.37mg sodium per 500mg, equivalent to 1.27% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

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.

The occurrence at the treatment initiation of a feverish generalized erythema associated with pustula may be a symptom of acute generalized 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.)

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.

Breast-feeding

Trace quantities of flucloxacillin 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

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 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.

Very rare: Neutropenia (including agranulocytosis) and thrombocytopenia. These are reversible when treatment is discontinued. Eosinophilia, haemolytic anaemia.

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

V ery 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.

* 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.

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.

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

* 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)

Very rare: Arthralgia and and myalgia sometimes develop more than 48 hours after the start of the treatment.

Very rare: Interstitial nephritis.

This is reversible when treatment is discontinued..

Very rare: Fever sometimes develops >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 or search for MHRA Yellow Card in the Google Play or Apple App Store

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

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 P-lactamase-producing strains.

Mechanism of action

Flucloxacillin inhibits one or more enzymes (often referred to as penicillinbinding 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 P-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.

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:

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

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.

Biotransfomation:

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. Sixty five per cent 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.

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

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

6.1 List of excipients

None

6.2 Incompatibilities

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

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.

500 mg (im/iv) – Packs of 5, 10, 50, 100

Not all pack sizes may be marketed

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.

Kent Pharma UK Limited,

The Bower, 4 Roundwood Avenue,

Stockley Park, Heathrow,

United Kingdom,

UB11 1AF

8 MARKETING AUTHORISATION NUMBER(S)

PL 51463/0052