FLUCLOXACILLIN CAPSULES BP 500 MG - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Flucloxacillin Capsules BP 500mg

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Flucloxacillin Sodium BP 500mg equivalent to 500mg Flucloxacillin.

3 PHARMACEUTICAL FORM

Capsules

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Flucloxacillin Sodium is used for the treatment of infections due to staphylococci resistant to benzylpenicillin. It is also used for mixed streptococcal and staphylococcal, infections when the staphylococci are penicillin-resistant.

Typical indications include: skin and soft tissue infections (boils, abscesses, carbuncles, furunculosis, cellulitis, infected skin conditions e.g. ulcer, eczema, and acne, infected wounds, infected burns, protection for skin grafts, Impetigo), respiratory tract infections (pneumonia, lung abscess, empyema, sinusitis, pharyngitis, tonsillitis, quinsy otitis media and externa). Other infections include: osteomyelitis, enteritis, endocarditis, urinary tract infections, meningitis and septicaemia.

Flucloxacillin Sodium 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 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

Adults (including the elderly):

(Dosage for all indications except osteomyelitis, endocarditis, and surgical prophylaxis).

The equivalent of 250mg (1 × 250mg capsule) of flucloxacillin by mouth 4 times a day. However dose may be doubled in severe infections (1 × 500mg capsules 4 times a day).

Osteomyelitis, endocarditis: Up to 8g daily in divided doses 6–8 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

Children:

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, Flucloxacillin Sodium 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. 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

This oral medicine should be taken on an empty stomach, meaning the, dosage should be taken half to one hour before food or two hours after food.

4.3 Contraindications

Hypersensitivity to the active substance, to any of the excipients listed in section 6.1, or to P-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 sensitization 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 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.

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).

This medicinal product contains 45.25 mg sodium (main component of cooking/table salt) in each 500 mg capsule. This is equivalent to 2.3% of the recommended maximum daily dietary intake of sodium for an adult.

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. 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.)

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.

Lactation: 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

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

4.8 Undesirable effects

The following convention has been utilized 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.

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.)

Immune system disorders

Very rare: Anaphylactic shock (exceptional with oral administration) (see Section 4.4 special Warnings and special 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 Special 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.

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.

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).

Frequency not known: AGEP – acute generalised 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.

*The incidence of these AEs was 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 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

Flucloxacillin Sodium, like other isoxazolyl penicillins, is a potent inhibitor of the growth of most penicillinase-producing staphylococci. This agent, in general, is less effective against micro-organisms susceptible to penicillin G and are not as useful against gram-negative bacteria.

Flucloxacillin Sodium is bactericidal. It is considered to act by inhibiting transpeptidase, the enzyme responsible for cross-linking of peptidoglycan during the final stages of synthesis of the bacterial cell wall and so exerts its effects against dividing bacteria. It is active against most gram-positive organisms and neisseria spp.

On the basis of minimum inhibitory concentrations, its activity against both penicillin-resistant and penicillin-sensitive staphylococci is 4 to 8 times that of methicillin sodium, but against penicillin-sensitive staphylococci, its activity is only about one quarter that of benzylpenicillin or phenoxymethyl-penicillin.

A minimum inhibitory concentration against penicillin-resistant staphylococci of 0.25–0.5pg/ml has been reported. Its activity against streptococci is less than that of benzylpenicillin but sufficient to be useful when these organisms are present with penicillin-resistant staphylococci.

Resistance to Flucloxacillin has developed in both penicillinase and nonpenicillinase producing staphylococci with cross resistance to other penicillins, including the penicillinase-resistant penicillins such as cloxacillin, nafcillin and oxacillin; to the cephalosporins and to other antibiotics including chloramphenicol, erythromycin, tetracycline, kanamycin, streptomycin, and lincomycin. This resistance is intrinsic and unrelated to penicillin production

5.2 Pharmacokinetic properties

Flucloxacillin Sodium is better absorbed from the gastrointestinal tract than cloxacillin sodium but absorption is also reduced by food in the stomach or small intestine. After an oral dose of 250mg to 500mg, in fasting subjects, peak serum concentrations in about 1 hour may range from 3 to 27rig per ml with mean peak concentrations of about 11 to 15rig per ml. A therapeutic concentration persists for about 4 hours. Doubling the dose can double the plasma concentration. Some 50% of a dose by mouth is excreted in the urine within 6 hours, serum concentrations are enhanced if probenecid is given concomitantly.

About 90–95% of Flucloxacillin in the circulation is bound to plasma albumin to a greater extent, none is removed from the circulation to a significant degree by haemodialysis.

The isoxazolyl penicillins, like Flucloxacillin, are rapidly excreted by the kidney. There is also significant hepatic elimination of these agents in the bile. The half life of Flucloxacillin is between 30–60 minutes.

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

Magnesium Stearate

Colloidal Anhydrous Silica

Capsule Shell Components:

Body:

Red Iron Oxide E172

Yellow Iron Oxide E172

Methyl Paraben E218

Propyl Paraben E216

Titanium Dioxide E171

Gelatin

Cap:

Black Iron Oxide E172

Titanium Dioxide E171

Methyl Paraben E218

Propyl Paraben E216

Gelatin

Ink components:

Titanium Dioxide

Shellac

Isopropyl Alcohol

Alcohol

Industrial Methylated Spirits

Purified Water

N-butyl Alcohol

Soya Lecithin

Antifoam DC 1510

6.2 Incompatibilities

None stated

6.3 Shelf life

24 months: HDPE containers

24 months: blister strips

6.4 Special precautions for storageBlister pack

Store below 25°C. Store in the original package.

Bottle pack

Store below 25°C. Store in the original package, keep the bottle tightly closed.

6.5 Nature and contents of container

HDPE Containers: 14, 28, 100, 250, 500 and 1000 capsules.

Blister Strips: 7,14 and 28 capsules.

6.6 Special precautions for disposal

Nothing Stated

7 MARKETING AUTHORISATION HOLDER

Pharmaclarity Limited

Bemin House Cox Lane,

Chessington Industrial Estate

Chessington

Surrey

England

KT9 1SG

8 MARKETING AUTHORISATION NUMBER(S)

PL 48134/0019

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION

9th August 1991 / 7th October 1996