Flucloxacillin 125 mg/5ml Granules for Oral Solution Sugar Free – Summary of Product Characteristics (SmPC) for healthcare professionals

1 NAME OF THE MEDICINAL PRODUCT

Flucloxacillin 125 mg/5ml Granules for Oral Solution Sugar Free

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Flucloxacillin sodium 136.00 mg equivalent to 125 mg flucloxacillin per 5 ml of reconstituted product.

Excipients with known effect: Each 5 ml contains 668 mg of sorbitol, 9 mg of sodium, 9.5 mg of aspartame, 2 mg of sodium propyl parahydroxybenzoate and 6 mg of sodium methyl parahydroxybenzoate.

For full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Granules for oral solution.

White to off white granules.

4.1 Therapeutic indications

Flucloxacillin 125 mg/5ml Granules for Oral Solution is indicated for the treatment of infections due to gram-positive organisms including infections caused by β

-lactamase-producing staphylococci and Streptococci.

Typical indications include:

SKIN AND SOFT TISSUE INFECTIONS: boils, abscesses, carbuncles, infected skin conditions e.g. ulcer, eczema, and acne, furunculosis, cellulitis, infected wounds and burns, protection for skin grafts and impetigo.

RESPIRATORY TRACT INFECTIONS: pneumonia, lung abscess, empyema, sinusitis, pharyngitis, Otitis media and externa, tonsillitis and quinsy.

OTHER INFECTIONS CAUSED BY FLUCLOXACILLIN-SENSITIVE ORGANISMS: osteomyelitis, enteritis, endocarditis, urinary tract infection, meningitis, septicaemia.

AS A PROPHYLACTIC: agent during major surgical procedures where appropriate e.g. 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 ELDERLY): 250 mg four times daily. In serious infections the dose may be doubled.

Osteomyelitis, endocarditis: Up to 8g daily, in divided doses six to eight hourly.

Surgical prophylaxis: 1 –2 g IV at induction of anaesthesia followed by 500 mg six hourly IV, IM or orally for up to 72 hours.

Paediatric population:

Over 10 years – 250mg four times daily

2 – 10 years - 125mg four times daily

Under 2 years - 62.5mg four times daily.

Premature infants, neonates, sucklings and infants

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

ABNORMAL RENAL FUNCTION:

In common with other penicillins, dose reduction is usually not required in patients with renal impairment. However, in the presence of severe renal impairment (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:

For oral use.

Flucloxacillin 125 mg/5ml Granules for Oral Solution Sugar Free, should be taken at least 1 hour before or 2 hours after meals. Flucloxacillin 125 mg/5ml Granules for Oral Solution Sugar Free, should be taken with a full glass of water (250 ml) afterwards, to reduce the risk of oesophageal pain (see section 4.8). Patients should not lay down immediately after Flucloxacillin 125 mg/5ml Granules for Oral Solution Sugar Free, intake.

For instructions on dilution of the product before administration, see section 6.6.

4.3 Contraindications

Patients with a history of hypersensitivity to the active substance or to any of the excipients listed in section 6.1, or to β

-lactam antibiotics, (eg, 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 10 ml/min), however, a reduction in dose or an extension of dose interval should be considered because of the risk of neurotoxicity (see section 4.2).

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 these patients, hepatic events may be severe, and in very rare circumstances, deaths have been reported (see section 4.8).

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

Before initiating therapy with flucloxacillin careful enquiry should be made concerning any previous hypersensitivity to β-lactams. Cross-sensitivity between penicillins and cephalosporins is well documented. Patients receiving β-lactam 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 β-lactam hypersensitivity are more likely to experience these reactions.

If anaphylaxis occurs, flucloxacillin should be discontinued and the appropriate therapy instituted. In cases of serious anaphylactic reactions immediate emergency treatment with adrenalin (epinephrine) may be required, as appropriate. Ensure adequate airway and ventilation and give 100% oxygen. IV crystalloids, hydrocortisone, antihistamine and nebulised bronchodilators may also be required.

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

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

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 contraindicated.

Dosage should be adjusted in renal impairment (see section 4.2). Special caution is essential in the newborn because of the risk of hyperbilirubinemia. 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. Overgrowth of non-susceptible organisms may occasionally result after prolonged use of an anti-infective agent.

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 dysfunction).

Sorbitol: Each 5 ml contains 668 mg of sorbitol. Patients with hereditary fructose intolerance (HFI) should not take/be given this medicinal product. This medicinal product contains 9 mg sodium per dose. If this medicine is taken at dosage of up to 8g per day for the treatment of osteomyelitis or endocarditis, the maximum daily dose of this product is equivalent to 29% of the WHO recommended maximum daily intake for sodium. This should be particularly taken into account for those on a low salt diet.

Aspartame: Contains a source of phenylalanine. May be harmful for people with phenylketonuria.

Sodium propyl parahydroxybenzoate and sodium methyl parahydroxybenzoate: May cause allergic reactions (possibly delayed).

4.5 Interactions with other medicinal products and other forms of interaction

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.

Probenecid and sulfinpyrazone decreases excretion of flucloxacillin by decreasing tubular secretion.

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

Methotrexate excretion is reduced by flucloxacillin which can cause methotrexate toxicity.

In common with other antibiotics, penicillins/flucloxacillin may affect the gut flora, leading to lower oestrogen reabsorption and may decrease the efficacy of combined oral contraceptives. Patients should be warned of this.

Bacteriostatic medicinal products (chloramphenicol, erythromycins, sulphonamides, and tetracyclines) may interfere with the bactericidal action of flucloxacillin.

Oral typhoid vaccine may be inactivated by flucloxacillin.

Flucloxacillin may reduce the response to Sugammadex.

There are rare cases of decreased 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.

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).

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.

4.6 Fertility, pregnancy and lactation

Pregnancy:

Studies conducted with animals 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 medicinal product during pregnancy should be taken with the utmost care. Therefore flucloxacillin should only be used in pregnancy when the potential benefits outweigh the risks associated with treatment.

Use in pregnancy should be reserved for cases considered essential by the clinician.

Breastfeeding:

Trace quantities of the medicinal product are excreted in the 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 to <1/10); Uncommon (≥

1/1000 to <1/100); Rare (≥

1/10,000 to <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.

Blood and lymphatic system disorders

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

Immune system disorders

Very rare: Anaphylactic shock (exceptional with oral administration) (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 IV injection of high doses.

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

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*

*Oesophagitis, burn oesophageal, throat irritation, oropharyngeal pain or oral pain.

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 necrolysis.

Not known: AGEP acute generalised exanthematous pustulosis (see section 4.4) (See also Immune system disorders).

Musculoskeletal and connective tissue disorders

Very rare: Arthralgia and myalgia sometimes develop more than 48 hours after the start of 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 is reported to be 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

With high doses (mainly parenteral) neurotoxicity may develop. Gastrointestinal effects such as nausea, vomiting and diarrhoea may be evident, if encountered they should be treated symptomatically. More specific measures may be necessary in patients with impaired renal function. Flucloxacillin is not removed from the circulation by haemodialysis.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Beta-lactamase resistant penicillins, ATC code: J01CF05

Properties: Flucloxacillin is a narrow-spectrum antibiotic of the group of isoxazolyl penicillins; it is not inactivated by staphylococcal β

-lactamases.

Activity: Flucloxacillin, by its action on the synthesis of the bacterial wall, exerts a bactericidal effect on streptococci except those of group D (Enterococcus faecalis) and staphylococci. It is not active against methicillin-resistant staphylococci.

Risk of hepatic injury

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.

Mode 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 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 are 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:

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 14.5 mg/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.

Absorption is delayed by food, with peak serum levels being approximately halved compared with the fasting state. Therefore, it is recommended that flucloxacillin be taken 0.5 to 1 hour before meals.

Distribution:

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.

Protein binding:

The serum protein-binding rate is 95%.

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 creatinine clearance <10ml/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 relevant information additional to that already contained elsewhere in the SmPC.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium Propyl Parahydroxybenzoate (E217)

Sodium Methyl Parahydroxybenzoate (E219)

Sodium Citrate

Citric Acid Anhydrous

Aspartame (E951)

Cherry Flavour (containing flavourings, maltodextrin, gum acacia (E414), triacetin (E1518), propylene glycol (E1520) and ascorbic acid (E300))

Sorbitol (E420)

6.2 Incompatibilities

Incompatible with colistin sulphomethate sodium, gentamicin, kanemycin and Polymicin B Sulphate. Loss of potency after mixing with streptomycin has also been reported.

6.3 Shelf life

Before reconstitution: 3 years.

After reconstitution: 1 week.

6.4 Special precautions for storage

In the form of dry granules: Do not store above 25°C. Keep the bottle tightly closed.

After reconstitution: Store in a refrigerator (2º C–8º C). Use within one week of preparation.

6.5 Nature and contents of container

Round HDPE bottles and PP/HDPE child resistant caps with EPE induction seal liner, containing 17 gm of granules (for pack size of 100 ml).

6.6 Special precautions for disposal and other handling

To reconstitute the granules to make the solution, add 88 ml of water and shake well until the powder is dissolved. When reconstituted the solution produced is essentially a clear solution.

7 MARKETING AUTHORISATION HOLDER

Crescent Pharma Limited

Units 3 & 4, Quidhampton Business Units

Polhampton Lane

Overton

Hampshire

RG25 3ED

8 MARKETING AUTHORISATION NUMBER(S)

PL 20416/0209

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

Date of first authorisation: 20 September 2011

10 DATE OF REVISION OF THE TEXT

04/04/2025