Flucloxacillin Capsules BP

Name of Medicinal Product

Flucloxacillin Capsules BP

Pharmaceutical form – Strength and Pack size

Pharmaceutical form: CAPSULES

Description: White powder filled in ‘0’ size hard gelatin capsule having cylindrical opaque dark green colour body and cap.

Strength: Flucloxacillin Sodium BP equivalent to Flucloxacillin …. 250mg, per Capsule

Therapeutic Category

Penicillin Anti-Bacterial

Indications

• Flucloxacillin Sodium is indicated for the treatment of infections due to sensitive Gram-positive organisms, including β-lactamase-producing staphylococci and streptococci.
• Typical indications include:

Skin and soft tissue infections:

• Boils, cellulitis, infected burns, abscesses, infected skin conditions (e.g. ulcer, eczema, and acne), protection for skin grafts, carbuncles, furunculosis, infected wounds and impetigo

Respiratory tract infections:

• Pneumonia, lung abscess, empyema, sinusitis, pharyngitis, otitis media and externa, tonsillitis and quinsy.

Other infections caused by flucloxacillin-sensitive organisms:

• Osteomyelitis, urinary tract infection, enteritis, meningitis, endocarditis 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.

Contra-indications

• Flucloxacillin should not be given to patients with a history of hypersensitivity to β-lactam antibiotics (e.g. penicillins, cephalosporins) or excipients.
• Flucloxacillin is contra-indicated in patients with a previous history of flucloxacillin associated jaundice/hepatic dysfunction.

Precautions / Warnings

• The occurrence at the treatment initiation of a feverish generalised erythema associated with pustula may be a symptom of acute generalised exanthematous pustulosis (AGEP). 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 post-treatment. In several cases, the course of the reactions has been protracted and lasted for some months.
• 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 the overgrowth of non-susceptible organisms.
• Before initiating therapy with flucloxacillin, careful inquiry should be made concerning previous hypersensitivity reactions to β-lactams. Cross-sensitivity between penicillins and cephalosporins is well documented. Serious and occasionally fatal hypersensitivity reactions (anaphylaxis) have been reported in patients receiving β-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 β-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 nebulized bronchodilators may also be required.
• 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 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 flucloxacillin and paracetamol, 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.
• 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 dysfunction). 

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.

Fertility:

• 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.

Side effects / Adverse reactions

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, <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data).

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), angioneurotic oedema.

If any hypersensitivity reaction occurs, the treatment should be discontinued.

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.

Not Known: Oesophageal pain and related events *

* oesophagitis, burn oesophageal, throat irritation, oropharyngeal pain or oral pain.

Hepato-biliary disorders

Very rare: Hepatitis and cholestatic jaundice. 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 ≥50 years and in patients with serious underlying disease.

Skin and subcutaneous tissue disorders

*Uncommon: Rash, urticaria and purpura.

Very rare: Erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis.

Frequency not known: AGEP – acute generalized exanthematous pustulosis

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.

Metabolism and nutrition disorders

Post-marketing experience: very rare case of high anion gap metabolic acidosis, when flucloxacillin is used concomitantly with paracetamol, generally in the presence of risk factors.

Not known: Hypokalaemia

Drug Interactions

• 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 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.

Dosage & Administration

The dosage depends on the age, weight and renal function of the patient, as well as on the severity of the infection.

Usual adult dosage (Including elderly patients)

Oral – 250mg four times a day

In serious infections, the dosage may be doubled.

Osteomyelitis, endocarditis – Up to 8g daily, in divided doses six to eight hourly.

Paediatric population

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 usage in patients with renal impairment does not usually require dosage reduction. However, in the presence of severe renal failure (creatinine clearance <10ml/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.

Administration:

Oral: This medicine should be taken on an empty stomach.

Flucloxacillin capsules should be taken at least 1 hour before or 2 hours after meals.

The capsules should be taken with a full glass of water (250 ml), to reduce the risk of oesophageal pain. Patients should not lay down immediately after Flucloxacillin capsule intake.

Method of administration

• Flucloxacillin is for oral use.
• Absorption of amoxicillin is impaired by food.
• Therapy can be started parenterally according to the dosing recommendations of the intravenous formulation and continued with an oral preparation.
• Swallow with water without opening capsule.

Over dosage

Gastrointestinal effects such as nausea, vomiting and diarrhoea may be evident and should be treated symptomatically.

Effects on ability to drive and use machines

Flucloxacillin has no or negligible influence on the ability to drive and use machines.

Shelf life

24 months from the date of manufacturing

Special precautions for storage

Store in a cool and dry place. Protect from light, heat, and moisture.

Keep out of reach of Children.

Mechanism of Action

• Flucloxacillin is a narrow-spectrum, semisynthetic isoxazolyl penicillin with antibacterial activity. Floxacillin binds to and inactivates penicillin-binding proteins (PBPs) located on the inner membrane of the bacterial cell wall. Inactivation of PBPs interferes with the cross-linkage of peptidoglycan chains necessary for bacterial cell wall strength and rigidity. This interrupts bacterial cell wall synthesis and results in the weakening of the bacterial cell wall, eventually causing cell lysis.

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.

1. After 250mg by the oral route (in fasting subjects): Approximately 8.8mg/l
2. After 500mg by the oral route (in fasting subjects): Approximately 14.5mg/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:l1.6mg/1 (compact bone) and l5.6mg/l (spongy bone), with a mean serum level of 8.9mg/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.

Protein Binding:

The serum protein-binding rate is 95%.

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. 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.