Document: spc-doc_PL 17907-0460 change

• spc-doc_PL 17907-0053
• spc-doc_PL 17907-0460

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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Flucloxacillin 500mg Capsules

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains 500 mg flucloxacillin as flucloxacillin sodium.

For the full list of excipients, see Section 6.1.

3    PHARMACEUTICAL FORM

Capsules

Blue cap/blue body capsule printed with “F 500” and containing a white, free flowing powder.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Flucloxacillin is an isoxazolyl penicillin of the P-lactam group of antibiotics which exerts a bactericidal effect upon many Gram-positive organisms including P-lactamase-producing staphylococci and streptococci. Flucloxacillin Capsules are indicated for the treatment of infections due to flucloxacillin sensitive gram-positive organisms, including P-lactamase-producing staphyloccoci and streptococci. Typical indications include:

Skin and soft tissue infections:
Boils	Cellulitis	Infected burns
Abscesses	Infected skin conditions, e.g.	Protection for skin
	ulcer, eczema, and acne	grafts
Carbuncles	Impetigo
Furunculosis	Infected wounds

Respiratory tract infections:
Pneumonia	Lung abscess	Empyema
Sinusitis	Pharyngitis	Otitis media and
Tonsillitis	Quinsy	externa
Other infections caused by flucloxacillin-sensitive organisms:
Osteomyelitis	Urinary tract infection	Enteritis
Meningitis	Endocarditis	Septicaemia

Flucloxacillin is also indicated for use as a prophylactic agent during major surgical procedures when 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 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

Premature infants, neonates, sucklings and infants

Not Recommended. Other pharmaceutical forms/strengths may be more appropriate for administration to this population.

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)

Oral - 250 mg four times a day.

In serious infections, the above systemic dosage may be doubled.

Endocarditis or osteomyelitis

Upto 8g daily in divided doses six to eight hourly.

Surgical prophylaxis

1 to 2g IV at induction of anaesthesia followed by 500mg six hourly IV, IM or orally for upto 72 hours.

Usual children's dosage 2-10 years: half the adult dose Under 2 years: quarter the 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 case of severe renal impairment (creatinine clearance <10ml/min) a reduction in dosage or an extension of dose interval may be necessary. 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. 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

Oral. Oral doses should be administered half to one hour before meals.

4.3 Contraindications

Flucloxacillin should not be given to patients with a history of hypersensitivity to flucloxacillin, other P-lactam antibiotics (e.g. penicillins, cephalosporins) or any of the excipients in the capsule.

Flucloxacillin is contraindicated 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 (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 of age 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 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).

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

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

Prolonged use 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 fatal hypersensitivity reactions (anaphylaxis) have been reported in patients receiving P-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 P-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.

Sodium Content: flucloxacillin capsules contain approximately 51 mg sodium per g of flucloxacillin. This should be included in the daily allowance of patients on sodium restricted diets.

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.

4.5 Interaction with other medicinal products and other forms of interaction

Probenecid decreases the renal tubular secretion of flucloxacillin. Concurrent administration of probenecid and sulfinpyrazone delay/slow down the renal excretion of flucloxacillin.

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.

In common with other antibiotics, flucloxacillin may affect the gut flora, leading to lower oestrogen reabsorption and reduced efficacy of combined oral contraceptives.

Bacteriostatic drugs may interfere with the bactericidal action of flucloxacillin.

4.6    Fertility, pregnancy and lactation

Pregnancy: Animal studies with flucloxacillin 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 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 breast-feeding 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

Adverse effects on the ability to drive or operate machinery have not been observed.

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, <1/1000), 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.

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 special Warnings and precautions for use), angioneurotic oedema.

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.

Hepato-biliary disorders

Very rare:    Hepatitis and cholestatic jaundice. (See Section

4.4 Special Warnings and Precautions for Use).

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 cases, 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.

(See also Immune system disorders).

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). It is not active against methicillin-resistant staphylococci.

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 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.

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 mothers' milk: flucloxacillin is excreted in small quantities in mothers' milk.

Metabolism: 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.

Excretion: excretion occurs mainly through the kidney. About 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 preclinical data of relevance to the prescriber, which are additional to those already included in other sections of the SmPC.

PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Magnesium stearate Capsule Shell Titanium dioxide (E171)

Indigo carmine (E132)

Gelatin

Methyl hydroxybenzoate (E218) Propyl hydroxybenzoate (E216) Printing ink Shellac

Titanium dioxide (E171)

6.2 Incompatibilities

Not applicable

6.3 Shelf life

24 months

6.4 Special precautions for storage

Do not store above 25^oC.

Store in the original package.

6.5 Nature and contents of container

PVC/PVDC/Aluminium foil blisters, packs of 28 and 56 capsules. Not all pack sizes may be marketed.