4.1. Therapeutic indications

Treatment of infections due to sensitive gram-positive organisms, including β-lactamase-producing staphylococci and streptococci. Typical indications include:

Respiratory tract infections such as pneumonia, pharyngitis, tonsillitis,

lung abscess, empyema, sinusitis, quinsy, otitis media and external.

Skin and soft tissue infections such as boils, abscesses, carbuncles, infected skin infections (e.g. ulcers, eczema and acne), furunculosis, cellulitis, infected wounds and burns, skin-graft protection, impetigo.

Other infections due to Flucloxacillin-sensitive organisms such as enteritis, endocarditis, meningitis, osteomyelitis, septicaemia and urinary tract infections.

Prophylaxis during major surgery, where appropriate for example, cardiothoracic and orthopaedic surgery.

Parenteral usage is indicated where oral dosage is inappropriate. Consideration should be given to official local guidance (e.g. national recommendations) on the appropriate use of antibacterial agents.

Susceptibility of the causative organism to the treatment should be tested (if possible), although therapy may be initiated before the results are available.

4.2. Posology and method of administration

Posology

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

Adults (including the elderly)

Oral - 250 mg four times a day.

In serious infections, the dosage may be doubled.

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

Under 2 years: 62.5mg four times daily

2-10 years: 125mg four times daily

Premature infants, neonates, sucklings and infants

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

Renal impairment:

The use of Flucloxacillin (like other penicillins) in patients with renal impairment does not usually require dosage reduction. However, in the presence of severe renal failure (creatinine clearance less than 10ml/min), a reduction in dose or an extension of dose interval should be considered. Flucloxacillin is not significantly removed by dialysis and so no supplementary dosages need to be administered either during or at the end of the dialysis period. The maximum recommended dose in adults is 1 g every 8 to 12 hours.

Hepatic impairment:

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

Method of administration

For oral use only.

Flucloxacillin capsules should be taken at least 1 hour before or 2 hours after meals.

The capsules should be taken with a full glass of water (250 ml), to reduce the risk of oesophageal pain (see section 4.8).

Patients should not lay down immediately after Flucloxacillin capsules intake.

4.3. Contraindications

Hypersensitivity to the active substance, to any of the ingredients listed in section 6.1, or to β-lactam antibiotics (e.g. penicillins, cephalosporins).

Flucloxacillin is contra-indicated in patients with a previous history of Flucloxacillin-associated jaundice/ hepatic dysfunction.

4.4. Special warnings and precautions for use

The use of flucloxacillin (like other penicillins) in patients with renal impairment does not usually require dosage reduction. In the presence of severe renal failure (creatinine clearance less than 10ml/min), however, a reduction in dose or an extension of dose interval should be considered because of the risk of neurotoxicity.

Flucloxacillin is not significantly removed by dialysis and so no supplementary dosages need to be administered either during or at the end of the dialysis period.

Hepatitis and cholestatic jaundice have been reported. These reactions are related neither to the dose nor to the route of administration. Flucloxacillin should be used with caution in patients with evidence of hepatic dysfunction, patients >50 years and those with serious underlying disease all of whom are at increased risk of hepatic reactions. The onset of these hepatic 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. In very rare cases, a fatal outcome has been reported (see section 4.8).

As for other penicillins contact with the skin should be avoided as sensitisation may occur.

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.

Patients with a known history of allergy are more likely to develop a hypersensitivity reaction.

Prolonged use of an anti-infective agent may occasionally result in overgrowth of non- susceptible organisms.

Before initiating therapy with flucloxacillin careful enquiry should be made concerning any previous hypersensitivity to β-lactams. Patients receiving βlactam antibiotics have been reported to experience serious and occasionally fatal hypersensitivity reactions (anaphylaxis). Although anaphylaxis is more frequent following parenteral therapy, it has occurred in patients on oral therapy. Patients with a history of βlactam hypersensitivity are more likely to experience these reactions.

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.

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.

Regular monitoring of hepatic and renal functions is recommended during prolonged treatments (e.g. osteomyelitis, endocarditis).

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).

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).

Excipients

This medicine contains 1.1 mmol sodium (25mg) per capsule. To be taken into consideration by patients on a controlled sodium diet.

4.5. Interaction with other medicinal products and other forms of interaction

Probenecid and sulfinpyrazone delays the renal tubular secretion of Flucloxacillin upon concurrent administration.

Other drugs, such as piperacillin, which are excreted via renal tubular secretion, may interfere with flucloxacillin elimination.

Oral typhoid vaccine may be inactivated by flucloxacillin.

Flucloxacillin reduces the excretion of methotrexate which can cause methotrexate toxicity.

Flucloxacillin may reduce the response to sugammadex.

There are rare cases of altered international normalised ratio (INR) in patients taking warfarin and prescribed a course of flucloxacillin. If co-administration is necessary, the prothrombin time or international normalised ratio should be carefully monitored during addition or withdrawal of flucloxacillin.

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: The product has been in clinical use since 1970. Animal studies have shown no evidence of teratogenic effects. and the limited number of reports 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 breastfeeding 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

Flucloxacillin has no or negligible influence on the ability to drive and use machines.

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, <1/1,000), 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.

System Organ Class

Frequency

Adverse Events

Blood and lymphatic system disorders

Very rare:

Neutropenia (including agranulocytosis) and thrombocytopenia. These are reversible when treatment is discontinued. Haemolytic anaemia, Eosinophilia.

Immune system disorders

Very rare:

Anaphylactic shock (exceptional with oral administration) (see section 4.4), angioneuroticoedema. If any hypersensitivity reaction occurs, the treatment should be discontinued. (See also Skin and subcutaneous tissue disorders).

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.

Not Known:

Oesophageal pain and related events#

Hepatobiliary disorders

Very rare:

Hepatitis and cholestatic jaundice. (see section 4.4). 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.

Skin and subcutaneous tissue disorders

*Uncommon:

Rash, urticaria and purpura.

Very rare:

Erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necroylsis. (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.

Metabolism and nutrition disorders

Very rare:

Post marketing experience: 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

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

#oesophagitis, burn oesophageal, throat irritation, oropharyngeal pain or oral pain.

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

With high doses ( mainly parenteral), neurotoxicity may develop.

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.