FLUCLOXACILLIN Powder for solution for injection / infusion Ref.[8149] Active ingredients: Floxacillin

Flucloxacillin should be given with caution to patients with a history of allergy, especially to drugs. Before initiating therapy with flucloxacillin, careful enquiry should be made concerning previous hypersensitivity reactions to ß-lactams. Cross sensitivity between penicillins and cephalosporins is well documented.

Serious and occasionally fatal hypersensitivity reactions (anaphylaxis) have been reported in patients receiving ß-lactam antibiotics. These reactions are more likely to occur in individuals with a history of ß-lactam hypersensitivity. Desensitisation may be necessary if treatment is essential. If any hypersensitivity reaction occurs, the treatment should be discontinued.

Care is necessary if very high doses of flucloxacillin are given, especially if renal function is poor, because of the risk of nephrotoxicity and/or neurotoxicity. The intrathecal route should be avoided. Care is also necessary if large doses of sodium salts are given to patients with impaired renal function or heart failure.

Flucloxacillin should be used with caution in patients with evidence of hepatic dysfunction (see section 4.8). Renal, hepatic and haematological status should be monitored during prolonged and high-dose therapy (e.g. osteomyelitis, endocarditis). Prolonged use may occasionally result in overgrowth of non-susceptible organisms.

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

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

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

Caution is advised in patients with porphyria.

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.

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.

Sodium content: Flucloxacillin for Injection 250mg contains approximately 0.57mmol sodium per vial. This should be included in the daily allowance of patients on sodium restricted diets.

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).

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.

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.)

Pregnancy

There has been no evidence of a teratogenic effect in animals or untoward effect in humans. However, use in pregnancy should be reserved for essential cases.

Breastfeeding

Trace quantities of penicillin can be detected in breast milk with the potential for hypersensitivity reactions (e.g. drug rashes) in the breast-fed neonate or acute alterations in the neonatal bowel flora with resultant diarrhoea.

Not relevant.

Blood and lymphatic system disorders: Transient leucopenia, thrombocytopenia, haemolytic anaemia, agranulocytosis and neutropenia (which might have some immunological basis); prolongation of bleeding time and defective platelet function are generally associated with large intravenous doses of flucloxacillin or impaired renal function.

Immune system disorders: The most common adverse effects are sensitivity reactions including urticaria, maculo-papular rashes, pruritus, fever, joint pains and angioedema.

Anaphylaxis occasionally occurs and has sometimes been fatal. Late sensitivity reactions may include serum sickness-like reactions (featuring symptoms such as arthralgia, rash, urticaria, fever, angioedema, lymphadenopathy), haemolytic anaemia, nephropathy and acute interstitial nephritis, which is reversible when treatment is discontinued.

Some patients with spirochaete infections such as syphilis or leptospirosis may experience a Jarisch-Herxheimer reaction shortly after treatment with a penicillin is started. Symptoms include fever, chills, headache and reaction at the site of lesions. The reaction can be dangerous in cardiovascular syphilis or where there is a serious risk of increased local damage such as with optic atrophy.

Metabolism and nutrition disorders: Electrolyte disturbances, such as hypokalaemia, due to administration of large amounts of sodium (see Section 4.4), are generally associated with large intravenous doses of flucloxacillin or impaired renal function.

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.)

Psychiatric disorders: Hallucinations.

Nervous system disorders: Convulsions and other signs of central nervous system toxicity are generally associated with large intravenous doses of flucloxacillin or impaired renal function. Encephalopathy has been reported following intrathecal administration and can be fatal. Coma may develop with high doses of flucloxacillin.

Respiratory, thoracic and mediastinal disorders: Acute, severe dyspnoea; bronchospasm.

Gastrointestinal disorders: Diarrhoea, nausea and vomiting, reported with flucloxacillin, commonly occur after oral or parenteral administration. Pseudomembranous colitis has been reported with most antibiotics. Prolonged use of penicillins may lead to the development of oral candidiasis.

Hepatobiliary disorders: Changes in liver function test results may occur, but are reversible when treatment is discontinued. Hepatitis and cholestatic jaundice have been reported. These reactions are related neither to the dose nor to the route of administration; administration for more than two weeks and increasing age are risk factors. 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. In very rare cases, a fatal outcome has been reported, almost always 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: Erythema multiforme; Stevens-Johnson syndrome; toxic epidermal necrolysis (Lyell’s syndrome); erythema nodosum; pemphigoid reactions; non-thrombocytopenic purpura; vasculitis.

Frequency not known: AGEP – acute generalized exanthematous pustulosis (see section 4.4).

Congenital, familial and genetic disorders: Acute attacks of porphyria (refer to section 4.4).

General disorders and administration site conditions: Phlebitis has followed intravenous infusion.

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 www.mhra.gov.uk/yellowcard.

Flucloxacillin may be administered in combination with other antibiotics including ampicillin to produce a wider spectrum of antibacterial activity. If used concurrently with an aminoglycoside the two antibiotics should not be mixed in the syringe, container or giving set as precipitation may occur.

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

The following drugs are incompatible with flucloxacillin: amiodarone, atropine sulphate, buprenorphine, calcium gluconate, chlorpromazine hydrochloride, ciprofloxacin, clarithromycin, diazepam, dobutamine, hydrochloride, erythromycin lactobionate, gentamicin sulphate, metoclopramide hydrochloride, morphine sulphate, netilmicin sulphate, ofloxacin, papaveretum, pethidine hydrochloride, prochlorperazine edisylate, promethazine hydrochloride, tobramycin and verapamil hydrochloride.