FLUCLOXACILLIN 500 MG POWDER FOR SOLUTION FOR INJECTION - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Flucloxacillin 500 mg, powder for solution for injection.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains 500 mg of flucloxacillin (equivalent to 544 mg of flucloxacillin sodium).

Excipient with known effect: sodium 1.10 mmol/vial.

3 PHARMACEUTICAL FORM

Powder for solution for injection.

Flucloxacillin sodium is supplied as a white or almost white powder.

4 CLINICAL PARTICULARS

Flucloxacillin is an isoxazolyl penicillin of the ß-lactam group of antibiotics which exerts a bactericidal effect upon many Gram-positive organisms including ß -lactamase-producing staphylococci and streptococci.

4.1 Therapeutic indications

Flucloxacillin is indicated for the treatment of the following infections in adults and children caused by flucloxacillin-sensitive gram positive organisms (see section 5.1):

-Osteomyelitis

-Endocarditis

Treatment of patients with bacteraemia that occurs in association with, or is suspected to be associated with, any of the infections listed above.

Flucloxacillin may also be used in the peri-operative prophylaxis for surgical procedures when appropriate: for example cardiothoracic and orthopaedic surgery.

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

4.2 Posology and method of administration

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)

Intramuscular – 250 mg four times a day.

Intravenous – 250 mg to 1 g four times a day.

The above systemic dosages may be doubled where necessary.

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:

2–10 years: half adult dose

Under 2 years: quarter 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 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.

Hepatic impairment:

No dose reduction is necessary in patients with reduced hepatic function

Method of administration

For intravenous or intramuscular injection or infusion

For instructions on preparation of the solution for administration, see section 6.6

4.3 Contraindications

Flucloxacillin should not be given to patients with a history of hypersensitivity to ß-lactam antibiotics (e.g. penicillins, cephalosporins).

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

Ocular or subconjunctival administration is contraindicated.

4.4 Special warnings and precautions for use

Before initiating therapy with flucloxacillin, careful enquiry should be made concerning previous hypersensitivity reactions to P-lactams.

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.

The occurrence at the treatment initiation of a feverish generalized erythema associated with pustula may be a symptom of acute generalized exanthematous pustulosis (AGEP) (see section 4.8). In case of AGEP diagnosis, flucloxacillin should be discontinued and any subsequent administration of flucloxacillin contra-indicated.

Flucloxacillin should be used with caution in patients with evidence of hepatic dysfunction, patients > 50 years and those with serious underlying disease. In these patients, hepatic events may be severe, and in very rare circumstances, deaths have been reported (see section 4.8).

Care is necessary if very high doses of flucloxacillin are given, especially if renal function is poor, because of the risk of nephrotoxicity. Care is also necessary if large doses of sodium salts are given to patients with impaired renal function or heart failure.

Care is required when treating some patients with spirochacte infections such as syphilis or leptospirosis because the Jarisch-Herxheimer reaction may occur shortly after treatment with a penicillin is started.

Contact with flucloxacillin should be avoided since skin sensitization may occur.

Caution is advised in patients with porphyria.

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).

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.

Prolonged use may occasionally result in overgrowth of non-susceptible organisms.

In case of sever and persistent diarrhea, the possibility of pseudomembranous colitis should be considered; flucloxacillin therapy should be discontinued.

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.

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).

Flucloxacillin contains approximately 1,10 mmol sodium per vial. To be taken into consideration by patients on a controlled sodium diet.

4.5 Interaction with other medicinal products and other forms of interaction

Other antibacterials:

Since bacteriostatic drugs such as chloramphenicol and tetracycline may interfere with the bactericidal effect of penicillins in the treatment of meningitis or in other situations in which a rapid bactericidal effect is necessary, it is best to avoid concurrent therapy.

Immunosuppressants:

There is reduced excretion of methotrexate (increased risk of toxicity).

Oral contraceptives:

Flucloxacillin may decrease the efficacy of oestrogen-containing oral contraceptives.

Uricosuric agents:

Plasma concentrations of flucloxacillin are enhanced if probenecid is given concurrently.

Interference with diagnostic tests:

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.

Paracetamol

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 risks factors. (see section 4.4)

4.6 Fertility, pregnancy and lactation

Pregnancy

Data on a limited number of exposed pregnancies indicate no adverse effects of flucloxacillin on pregnancy or on the health of the foetus/new-born child. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development.

Caution should be exercised when prescribing to pregnant women.

Breastfeeding

Flucloxacillin diffuses into breast milk in a limited amount and in rare cases this can lead to diarrhoea and/or fungal colonisation of the mucosa in the infant. The possibility of sensitisation of the infant to beta-lactam drugs should be considered.

Fertility

There are no data available on fertility.

4.7 Effects on ability to drive and use machines

Not relevant.

4.8 Undesirable effects

Adverse reactions listed below are classified according to frequency and System Organ Class (SOC).

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.

1. These are reversible when treatment is discontinued.

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

3. If pseudomembranous colitis develops, flucloxacillin treatment should be discontinued and appropriate therapy, e.g. oral vancomycin should be initiated.

4. Hepatitis and cholestatic jaundice may be delayed for up to two months posttreatment. In some cases the course has been protracted and lasted for several months. Hepatic events may be severe, and in very rare circumstances, deaths have been reported. Most reports of deaths have been in patients > 50 years of age and in patients with serious underlying disease.

5. 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.

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 to The Medicines Authority at the following contact details: the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard

4.9 Overdose

Symptoms

Gastrointestinal effects such as nausea, vomiting and diarrhoea may be evident. With high parenteral doses of penicillins, neurotoxicity (e.g. convulsions, encephalopathy), blood disorders (e.g. neutropenia, haemolytic anaemia, prolongation of bleeding time, defective platelet function) or electrolyte disturbances may occur.

Treatment

Treatment is symptomatic.

Flucloxacillin is not removed from the circulation by haemodialysis.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antibacterials for systemic use, Beta-lactamase resistant penicillins, ATC code: J01CF05

Flucloxacillin is a narrow-spectrum antibiotic of the group of isoxazolyl penicillins; it is not inactivated by staphylococcal P-lactamases.

Mechanism of action

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.

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 p-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 is 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:

Pharmacokinetic/phar­macodynamic relationship

The time above the minimum inhibitory concentration (T>MIC) is considered to be the major determinant of efficacy for flucloxacillin.

5.2 Pharmacokinetic properties

Absorption

After the intramuscular administration of a single 250 or 500mg dose of flucloxacillin to volunteers, mean peak concentrations of the drug in serum were approximately 10.5 and 16mg.l-1 respectively. High serum levels of the drug are achieved when administered by intravenous bolus injection or by slow intravenous infusion: 30 minutes and 2 hours after a single 500mg intravenous bolus injection of flucloxacillin the mean serum concentration of the drug was 38 and 7.5mg.l-1, respectively; 30 minutes and 3 hours after a single 1g intravenous bolus injection of flucloxacillin, the mean serum concentrations were 60 and 4mg.l-1respectively. The administration of 2g flucloxacillin by intravenous infusion over 20 minutes resulted in mean serum concentrations of 244 and 27.7mg.l-1 15 minutes and 120 minutes respectively after the end of the infusion.

Distribution

Protein binding: the serum protein-binding rate is 95%. 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.

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 creatinin clearance <10 ml/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

There are no preclinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

6.1

None.

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

Flucloxacillin should not be mixed with blood products or other proteinaceous fluids (e.g. protein hydrolysates) or with intravenous lipid emulsions.

If Flucloxacillin is prescribed concurrently with an aminoglycoside, the two antibiotics should not be mixed in the syringe, intravenous fluid container or giving set; precipitation may occur.

6.3 Shelf life

36 months

Reconstituted solution: From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C unless reconstitution/ dilution has taken place in controlled and validated aseptic conditions.

6.4 Special precautions for storage

Flucloxacillin does not require any special storage conditions.

6.5 Nature and contents of container

Clear Type III glass vials with Chlorobutyl or bromobutyl rubber stopper and aluminium seal with a flip off cap.

Pack of 1,10, 25 and 50 vials.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Reconstituted solutions for IM or direct IV injection should normally be administered within 30 minutes of preparation.

Flucloxacillin may be added to most intravenous fluids:

Water for Injections

Sodium chloride 0.9%

Glucose 5%

Sodium chloride 0.18% with glucose 4%

Administration

Intramuscular: Add 2 ml Water for Injections to 500 mg vial contents.

Intravenous: Dissolve 250–500 mg in 5–10 ml Water for Injections. Administer by slow intravenous injection (three to four minutes). Flucloxacillin may also be added to infusion fluids or injected, suitably diluted, into the drip tube over a period of three to four minutes.

Intrapleural: Dissolve 250 mg in 5–10 ml Water for Injections.

Intra-articular: Dissolve 250–500 mg in up to 5 ml Water for Injections or 0.5% lidocaine hydrochloride solution.

Reconstitution of Flucloxacillin and preparation of Flucloxacillin must be carried out under appropriate aseptic conditions if the extended storage periods are required.

Flucloxacillin is not suitable for multi-dose use.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

PANPHARMA

Z.I. du Clairay

35133 Luitré

FRANCE

8 MARKETING AUTHORISATION NUMBER(S)

PL 44124/0005