This information is intended for use by health professionals

1. Name of the medicinal product

Flucloxacillin 2g, powder for solution for injection or infusion

2. Qualitative and quantitative composition

Each vial contains 2g flucloxacillin as flucloxacillin sodium.

Each vial contains approximately 4.52 mmol (104 mg) sodium.

3. Pharmaceutical form

Powder for solution for injection or infusion

Glass vial containing white powder

4. Clinical particulars
4.1 Therapeutic indications

Flucloxacillin is indicated for the treatment of following infections, when due to sensitive Gram-positive organisms (see section 5.1):

Osteomyelitis

Endocarditis

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

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

4.2 Posology and method of administration

Posology

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

Usual adult dosage (including elderly patients)

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

The dosage 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.

Paediatric population

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.

Hepatic impairment

No dose reduction is necessary in patients with reduced hepatic function.

Method of administration

For intravenous injection or infusion.

For instructions on preparation of the solutions for administration, see section 6.6.

4.3 Contraindications

Hypersensitivity to the active substance or other β-lactam antibiotics (e.g. penicillins, cephalosporins).

Flucloxacillin is contra-indicated 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 enquiry should be made concerning previous hypersensitivity reactions to β-lactams. 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.

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.

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).

Care is necessary if very high doses of flucloxacillin are given, especially if renal function is poor, because of the risk of nephrotoxicity and/or neurotoxicity. Care is also necessary if large doses of sodium salts are given to patients with impaired renal function or heart failure.

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.

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

Caution is advised in patients with porphyria.

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.

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

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.

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).

This medicinal product contains approximately 4.52 mmol (104 mg) sodium per vial. This should be included in the daily allowance of patients on sodium restricted diets.

4.5 Interaction with other medicinal products and other forms of interaction

Other antibacterials:

Since bacteriostatic drugs such as chloramphenicol and tetracycline may interfere with the bactericidal effect of penicillins in the treatment of meningitis or in other situations in which a rapid bactericidal effect is necessary, it is best to avoid concurrent therapy.

Immunosuppressants:

There is reduced excretion of methotrexate (increased risk of toxicity).

Uricosuric agents:

Plasma concentrations of flucloxacillin are enhanced if probenecid is given concurrently.

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.

Paracetamol

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

Not relevant

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, <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.

MedDRA

System Organ Class

Frequency

Undesirable Effects

Blood and lymphatic system disorders

Very rare

Neutropenia (including agranulocytosis) and thrombocytopenia1.

Eosinophilia, haemolytic anaemia.

Immune system disorders

Very rare

Anaphylactic shock (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

Gastrointestinal disorders

Common2

Minor gastrointestinal disturbances

Very rare

Pseudomembranous colitis3

Metabolism and nutrition disorders

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).

Hepato-biliary disorders

Very rare

Hepatitis and cholestatic jaundice (see Section 4.4)4. Changes in liver function laboratory test results (reversible when treatment is discontinued).

There is evidence that the risk of flucloxacillin induced liver injury is increased in subjects carrying the HLA-B*5701 allele5.

Skin and subcutaneous tissue disorders

Uncommon2

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 nephritis1

General disorders and administration site conditions

Very rare

Fever sometimes develops more than 48 hours after the start of the treatment

1. These are reversible when treatment is discontinued.

2. The incidence of these AEs was derived from clinical studies involving a total of approximately 929 adult and paediatric patients taking flucloxacillin.

3. If pseudomembranous colitis develops, flucloxacillin treatment should be discontinued and appropriate therapy, e.g. oral vancomycin should be initiated.

4. Hepatitis and cholestatic jaundice may be delayed for up to two months post-treatment. In some cases the course has been protracted and lasted for several months. Hepatic events may be severe, and in very rare circumstances, deaths have been reported. Most reports of deaths have been in patients > 50 years of age and in patients with serious underlying disease.

5. 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.

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

Symptoms

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

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 narrow-spectrum antibiotic of the group of isoxazolyl penicillins; it is not inactivated by staphylococcal β-lactamases.

Mechanism of action

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.

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:

Micro-organisms

MIC (mg/l)

Staphylococcus aureus

0.1 to 0.25

Staphylococcus aureus (beta-lactamase +)

0.25 to 0.5

Streptococcus pneumoniae

0.25

Streptococcus pyogenes (Group A beta-haemolytic)†

0.1

Streptococcus viridans group

0.5

Clostridium tetani

0.25

Clostridium welchii

0.25

Neisseria meningitidis

0.1

† The Group A beta-haemolytic streptococci are less sensitive to the isoxazolyl penicillins than to penicillin G or penicillin V.

Pharmacokinetic/pharmacodynamic relationship

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

5.2 Pharmacokinetic properties

Absorption

After the intramuscular administration of a single 250 or 500mg dose of flucloxacillin to volunteers, mean peak concentrations of the drug in serum were approximately 10.5 and 16mg.l-1 respectively. High serum levels of the drug are achieved when administered by intravenous bolus injection or by slow intravenous infusion: 30 minutes and 2 hours after a single 500mg intravenous bolus injection of flucloxacillin the mean serum concentration of the drug was 38 and 7.5mg.l-1, respectively; 30 minutes and 3 hours after a single 1g intravenous bolus injection of flucloxacillin, the mean serum concentrations were 60 and 4mg.l-1respectively. The administration of 2g flucloxacillin by intravenous infusion over 20 minutes resulted in mean serum concentrations of 244 and 27.7mg.l-1 15 minutes and 120 minutes respectively after the end of the infusion.

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.

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.

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 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

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

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 syringe, intravenous fluid container or giving set; precipitation may occur.

6.3 Shelf life

3 years

Reconstituted solution: 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 to 8°C unless reconstitution/ dilution has taken place in controlled and validated aseptic conditions.

6.4 Special precautions for storage

Store below 25°C

6.5 Nature and contents of container

Clear Type I glass vials with bromobutyl rubber closure. Pack sizes: cartons of 1, 5, 10, 20 or 50 vials.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Intravenous use

Dissolve 2g in 40 ml Water for Injections. Administer by slow intravenous injection. Flucloxacillin may also be added to infusion fluids or injected, suitably diluted, into the drip tube over a period of 20-30 minutes.

Flucloxacillin 2g, Powder for Solution for Injection or Infusion has a displacement volume of approximately 1.5 ml when reconstituted as described above.

Flucloxacillin Injection may be added to the following infusion fluids:

Water for Injections

Sodium chloride 0.9%

Glucose 5%

Sodium chloride 0.18% with glucose 4%

Compound Sodium Lactate Intravenous Infusion (Ringer-Lactate solution; Hartmaan's Solution).

N.B. Flucloxacillin vials are not suitable for multidose use.

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

7. Marketing authorisation holder

Ibigen Srl,

Via Fossignano 2

04011 – Aprilia (LT)

Italy

8. Marketing authorisation number(s)

PL 31745/0032

9. Date of first authorisation/renewal of the authorisation

05/01/2017

10. Date of revision of the text

06/12/2017