FLUCLOXACILLIN 125 MG / 5ML POWDER FOR ORAL SOLUTION - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Flucloxacillin 125mg/5ml Powder For Oral Solution

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 5ml reconstituted solution contains Flucloxacillin Sodium equivalent to Flucloxacillin 125mg.

Excipient(s) with known effect

Contains 5.00 mg of Sodium Benzoate and 316.120 mg of Sucrose.

For a full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Powder for oral solution.

Pink free flowing powder.

4.1 Therapeutic indications

Flucloxacillin Sodium is indicated for the treatment of infections due to sensitive Gram-positive organisms, including ß-lactamase-producing staphylococci and streptococci. Typical indications include:

Skin and soft tissue infections:

Boils

Protection for skin grafts Carbuncles Furunculosis Infected wounds Impetigo

Cellulitis

Infected burns

Abscesses

Infected skin conditions, e.g. ulcer, eczema, and acne

Respiratory tract infections: Pneumonia

Lung abscess

Empyema

Sinusitis

Pharyngitis

Otitis media and externa

Tonsillitis

Quinsy

Other infections caused by Flucloxacillin-sensitive organisms: Osteomyelitis

Urinary tract infection

Enteritis

Meningitis

Endocarditis

Septicaemia

Flucloxacillin Sodium is also indicated for use as a prophylactic agent during major surgical procedures such as 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 age, weight and renal function of the patient, as well as the severity of the infection.

Adults (including the elderly)

Oral: 250mg four times daily

In serious infections, the dosage may be doubled.

Paediatric population

2–10 years: 125mg four times daily

Under 2 years: 2.5ml (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 patients with renal insufficiency, excretion of flucloxacillin is slowed. In the presence of severe renal insufficiency (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 1g 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.

Endocarditis or osteomyelitis

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.

Method of administration

Oral:

Flucloxacillin powder for oral solution should be taken at least 1 hour before or 2 hours after meals.

A full glass of water (250 ml) should be taken afterwards, to reduce the risk of oesophageal pain (see section 4.8). Patients should not lay down immediately after Flucloxacillin powder for oral solution intake.

4.3 Contraindications

Hypersensitivity to the active substance, to any of the excipients listed in section 6.1, to ß-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 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.

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 or patients with 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 posttreatment. 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.

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 previous hypersensitivity reactions to P-lactams. Cross-sensitivity between penicillins and cephalosporins is well documented. Serious and occasionally fatai hypersensitivity reactions (anaphyiaxis) have been reported in patients receiving P—lactam antibiotics. Although anaphylaxis is more frequent following parenteral therapy, it has occurred in patients on orai therapy. These reactions are more iikeiy to occur in individuals with a history of P-lactam hypersensitivity. 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.

During prolonged treatments (e.g. osteomyelitis, endocarditis), regular monitoring of hepatic and renal functions is 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).

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).

Patients with rare hereditary problems of fructose intolerance, glucose galactose malabsorption or sucrose-isomaltase insufficiency should not take this medicine.

This medicinal product contains 10.72mg sodium per 5ml, equivalent to 0.54% of the WHO recommended maximum daily intake of 2g sodium for an adult.

This medicine contains 5mg sodium benzoate in each dosage unit equivalent to 5ml volume.

4.5 Interaction with other medicinal products and other forms of interaction

Probenecid and sulfinpyrazone slow down the excretion of flucloxacillin by decreasing tubular secretion.

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.

Bacteriostatic drugs may interfere with the bactericidal action of flucloxacillin.

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.

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. Flucloxacillin preparations have been in clinical use since 1970 and the limited number of reported cases of use in human pregnancy has 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 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 or operate 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.

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

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).

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

Very rare: Hepatitis and cholestatic jaundice. (See Section 4). Changes in liver function laboratory test results (reversible when treatment is discontinued). These reactions are related to neither the dose nor to the route of administration.

Hepatitis and cholestatic jaundice may be delayed for up to two months posttreatment; 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: 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

Very rare: Arthralgia 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 more than 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 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.

5 PHARMACOLOGICAL PROPERTIES

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 ß-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) 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

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 250mg by the oral route (in fasting subjects): Approximately 8.8mg/l.

– After 500mg by the oral route (in fasting subjects): Approximately 14.5mg/l.

– After 500mg by the IM route: Approximately 16.5mg/l.

The total quantity absorbed by the oral route represents approximately 79% of the quantity administered.

Distribution

Flucloxacillin diffuses well into most tissue. Specifically, active concentrations of flucloxacillin have been recovered in bones: 11.6mg/l (compact bone) and 15.6mg/l (spongy bone), with a mean serum level of 8.9mg/l.

Crossing the meningeal barrier: Flucloxacillin diffuses in only small proportion into the cerebrospinal fluid of subjects whose meninges are not inflamed.

Crossing into mothers' milk: Flucloxacillin is excreted in small quantities in mothers' 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%.

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 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium Benzoate (E211)

Disodium Edetate

Saccharin Sodium

Mono-Ammonium-Glycyrrhizinate

Sodium Citrate Anhydrous (E331)

Flavour Pineapple

Flavour Menthol

Erythrosine (E127)

Sucrose

6.2 Incompatibilities

As for Penicillin. Incompatible with Colistin Polymixin B Sulphate. Loss of potency after mixing with Streptomycin has also been reported.

6.3 Shelf life

Unopened: 3 years

After reconstitution or when the container is opened for the first time: 7 days

6.4 Special precautions for storage

Unopened bottle: Do not store above 25°C. Store in the original container. Keep the container tightly closed.

Reconstituted solution: Store at 2–8°C.

6.5 Nature and contents of container

Nature: 150ml amber glass Beatson Clark container with polypropylene screw cap or 150ml high density polyethylene bottle with child resistant closure with expanded polyethylene wad: 100ml

6.6 Special precautions for disposal

To reconstitute, add 58ml of water, replace the lid and shake the bottle well.

7 MARKETING AUTHORISATION HOLDER

Milpharm Limited

Ares

Odyssey Business Park

West End Road

South Ruislip

HA4 6QD

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 16363/0043

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION

06/11/2001