4.1. Therapeutic indications

Flucloxacillin is indicated for the treatment of the following infections in adults and children caused by flucloxacillin-sensitive gram positive organisms (see section 5.1):

-Osteomyelitis

-Endocarditis

Treatment of patients with bacteraemia that occurs in association with, or is suspected to be associated with, any of the infections listed above.

Flucloxacillin may also be used in the peri-operative prophylaxis for 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

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

Usual adult dosage (including elderly patients)

Intramuscular - 250 mg four times a day.

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

The above systemic dosages 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 or intramuscular injection or infusion.

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

4.3. Contraindications

Flucloxacillin should not be given to patients with a history of hypersensitivity to 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.

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.

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. 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.

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).

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 50.74 mg sodium per 1 g, equivalent to 2.54% of the WHO recommended daily intake of 2 g sodium for an adult.

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).

Oral contraceptives:

Flucloxacillin may decrease the efficacy of oestrogen-containing oral contraceptives.

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.

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.

ParacetamolCaution 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 risks 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

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

Metabolism and nutrition disorders

Very rare

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 (cannot be estimated from the available data)

Hypokalaemia

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 to The Medicines Authority at the following contact details: 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