Sandoz Flucloxacillin 250 mg Hard gelatin capsules.

Infections caused by susceptible Gram-positive organisms, including beta-lactamase producing staphylococci and streptococci:

• Skin and soft tissue infections
• Infected wounds and burns
• Otitis media
• Urinary tract infections
• Respiratory tract infections caused by penicillinase producing organisms
• Orthopaedic infections
• Septicaemia
• Meningitis
• Endocarditis
• Enterocolitis

Posology

Usual adult dose: 250 mg every six hours, one hour before meals. Doses may be doubled in severe infections; up to 8 g daily in three or four divided doses may be given for endocarditis and osteomyelitis.

Special populations

Renal impairment: For patients with a creatinine clearance value 10 mL / min, no dose adjustment is necessary.

Paediatric population

SANDOZ FLUCLOXACILLIN 250 is indicated for adults and must not be prescribed to children. Safety and efficacy has not been established in children.

SANDOZ FLUCLOXACILLIN should not be given to patients with a history of hypersensitivity to u03b2-lactam antibiotics (e.g., penicillins, cephalosporins) or any of the excipients. SANDOZ FLUCLOXACILLIN is contraindicated in patients with a previous history of flucloxacillin associated jaundice/hepatic dysfunction.

The use of this antibiotic may lead to the appearance of resistant strains of organisms, and sensitivity testing should therefore be carried out whenever possible to ensure the appropriateness of the therapy. Oral administration can cause gastrointestinal symptoms such as diarrhoea, nausea, heartburn and colic, pruritus ani, and disturbances of electrolyte balance, which are dose related and a result of local irritation. It should be given with caution to patients with known histories of allergy. Cholestatic hepatitis has been reported rarely. 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, SANDOZ FLUCLOXACILLIN should be discontinued and any subsequent administration of flucloxacillin contraindicated. The use of SANDOZ 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 10 ml/min), however, a reduction in dose or an extension of dose interval should be considered because of the risk of neurotoxicity. SANDOZ 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. SANDOZ FLUCLOXACILLIN should be used with caution in patients who are older than 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 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 (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 SANDOZ FLUCLOXACILLIN, careful enquiry should be made concerning previous hypersensitivity reactions to u03b2-lactams. Cross-sensitivity between penicillins and cephalosporins is well documented. Serious and occasionally fatal hypersensitivity reactions (anaphylaxis) have been reported in patients receiving u03b2-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 u03b2-lactam hypersensitivity. If anaphylaxis occurs, SANDOZ 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, SANDOZ 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 SANDOZ 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 SANDOZ FLUCLOXACILLIN is administered concomitantly with paracetamol due to the increased risk of high anion gap metabolic acidosis (HAGMA). Patients at high risk of 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 SANDOZ 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 SANDOZ 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 SANDOZ FLUCLOXACILLIN maintaining the clinical picture of HAGMA (see section 4.5). Hypokalaemia (potentially life threatening) can occur with the use of SANDOZ FLUCLOXACILLIN, especially in high doses. Hypokalaemia caused by SANDOZ FLUCLOXACILLIN can be resistant to potassium supplementation. Regular measurements of potassium levels are recommended during the therapy with higher doses of SANDOZ FLUCLOXACILLIN. Attention for this risk is warranted also when combining SANDOZ FLUCLOXACILLIN with hypokalemia-inducing diuretics or when other risk factors for the development of hypokalemia are present (e.g. malnutrition, renal tubule disfunction).

• Probenecid and sulfinpyrazone slow down the excretion of flucloxacillin by decreasing tubular secretion.
• Other medicines, 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 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 INR should be carefully monitored during addition or withdrawal of flucloxacillin.
• Bacteriostatic medicines 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.)
• Flucloxacillin (CYP450 inducer) has been reported to significantly decrease plasma voriconazole concentrations. If concomitant administration of flucloxacillin with voriconazole cannot be avoided, monitor for potential loss of voriconazole effectiveness (e.g. by therapeutic drug monitoring); increasing the dose of voriconazole may be needed.

Pregnancy

Safety and efficacy has not been established in pregnant women taking SANDOZ FLUCLOXACILLIN. SANDOZ FLUCLOXACILLIN should not be used by pregnant women.

Lactation

Trace quantities of SANDOZ FLUCLOXACILLIN can be detected in breast milk. The possibility of hypersensitivity reactions must be considered in breastfeeding infants. Safety and efficacy has not been established in women who are breastfeeding and taking SANDOZ FLUCLOXACILLIN. SANDOZ FLUCLOXACILLIN should not be used by women who are breastfeeding.

Adverse effects on the ability to drive or operate machinery have not been observed. No studies on the effects on the ability to drive and use machines have been performed. Patients should be instructed that if they experience sedation or dizziness, they should avoid potentially hazardous tasks such as driving or operating machinery.

Allergic reactions may occur, presenting as a pruritic skin rash, an erythematous skin reaction or urticaria, fever, eosinophilia, joint pains, angioneurotic oedema, or exfoliative dermatitis. Should a serious anaphylactic reaction occur, SANDOZ FLUCLOXACILLIN should be discontinued, and the patient treated with the usual agents: adrenalin, corticosteroids and antihistamines.

Blood and lymphatic system disorders: Less frequent: Neutropenia (including agranulocytosis) and thrombocytopenia. These are reversible when treatment is discontinued. haemolytic anaemia.

Immune system disorders: Less frequent: 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).

Gastrointestinal disorders: Frequent: Minor gastrointestinal disturbances. Less Frequent: Pseudomembranous colitis. If pseudomembranous colitis develops, SANDOZ FLUCLOXACILLIN treatment should be discontinued and appropriate therapy, e.g. oral vancomycin should be initiated. Not known: Abdominal pain, vomiting. Not Known: Oesophageal pain and related events * * oesophagitis, burn oesophageal, throat irritation, oropharyngeal pain or oral pain.

Hepatobiliary disorders: Less frequent: Hepatitis and cholestatic jaundice (see section 4.4). 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 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 circumstances a fatal outcome has been reported. Most reports of deaths have been in patients u2265 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: Less frequent: Rash, urticaria and purpura. Very rare: Erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis. (See also Immune system disorders). Frequency not known: AGEP u2013 acute generalized exanthematous pustulosis (see section 4.4).

Musculoskeletal and connective tissue disorders: Less frequent: Arthralgia and myalgia sometimes develop more than 48 hours after the start of the treatment.

Renal and urinary disorders: Less frequent: Interstitial nephritis. This is reversible when treatment is discontinued.

General disorders and administration site conditions: Less frequent: Fever sometimes develops more than 48 hours after the start of the treatment.

Metabolism and nutrition disorders: Post marketing experience: very rare case of high anion gap metabolic acidosis, when SANDOZ FLUCLOXACILLIN is used concomitantly with paracetamol, generally in the presence of risk factors (see section 4.4.) Not known: Hypokalaemia.

(See section 4.4 and 4.8). Treatment is symptomatic and supportive. With high doses (mainly parenteral) neurotoxicity may develop. Gastrointestinal effects such as nausea, vomiting and diarrhoea may be evident and should be treated symptomatically with attention to water/electrolyte balance. SANDOZ FLUCLOXACILLIN is not removed from the circulation by haemodialysis.