Flucloxacillin Capsules Bp 500mg
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Flucloxacillin Capsules BP 500 mg
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each capsule contains 500 mg Flucloxacillin (as Flucloxacillin Sodium) Excipient with known effect:
Each capsule contains approximately 46.6mg sodium per g. (See section 4.4). For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Capsule
Blue/Blue size 0 gelatin capsule, containing powder. Overprinted with “fluc” and “500”.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Treatment of infections due to sensitive gram-positive organisms, including P-lactamase-producing staphylococci and streptococci.
Typical indications include:
Respiratory tract infections such as pneumonia, pharyngitis, tonsillitis, lung abscess, empyema, sinusitis, quinsy.
Otitis media and externa.
Skin and soft tissue infections such as boils, carbuncles, skin ulcers, eczema, abscesses and acne. Furunculosis, cellulitis, infected wounds and burns, skin-graft protection, impetigo.
Other infections due to Flucloxacillin - sensitive organisms such as enteritis, endocarditis, meningitis, osteomyelitis, septicaemia and urinary tract infections.
Prophylaxis during major surgery, where 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
The dosage depends on the age, weight and renal function of the patient, as well as the severity of the infection.
Usual adult dosage (including the elderly)
250mg four times daily, administered 0.5-1 hour before meals. In serious infections, these dosages may be doubled where necessary.
Osteomyelitis and endocarditis: Up to 8g daily, in divided doses six to eight hourly.
Paediatric population
This preparation (500mg capsule) is not suitable for children who should be given Flucloxacillin elixir BP 125mg/5ml, based on the following schedule.
Under 2 years: 62.5mg four times daily
2-10 years: 125mg four times daily or 50mg/kilo body weight per 24 hours, divided into four doses, half to one hour before food. In serious infections the dosage may be doubled.
Renal impairment: The use of Flucloxacillin (like other penicillins) in patients with renal impairment does not usually require dosage reduction. However, in the presence of severe renal failure (creatinine clearance less than 10ml/min), a reduction in dose or an extension of dose interval should be considered. 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.
Surgical prophylaxis
1 to 2g IV at induction of anaesthesia followed by 500mg six hourly IV, IM or orally for up to 72 hours.
Method of administration
For oral use only. This medicine should be taken on an empty stomach. This means an hour before food or two hours after food.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the ingredients listed in section 6.1.
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 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 and those with serious 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 these patients, hepatic events may be severe, and in very rare circumstances, deaths have 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 flucloxacillin careful enquiry should be made concerning any previous hypersensitivity to P-lactams. Patients receiving P-lactam antibiotics have been reported to experience serious and occasionally fatal hypersensitivity reactions (anaphylaxis). Although anaphylaxis is more frequent following parenteral therapy, it has occurred in patients on oral therapy. Patients with a history of P-lactam hypersensitivity are more likely to experience these reactions.
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.
Regular monitoring of hepatic and renal functions is recommended during prolonged treatments (e.g. osteomyelitis, endocarditis).
Overgrowth of non-susceptible organisms may occasionally result after prolonged use.
This medicinal product contains approximately 46.6mg sodium per g. To be taken into consideration by patients on a controlled sodium diet.
4.5 Interaction with other medicinal products and other forms of interaction
Probenecid and sulfinpyrazone delays the renal tubular secretion of Flucloxacillin upon concurrent administration.
Other drugs, such as piperacillin, which are excreted via renal tubular secretion, may interfere with flucloxacillin elimination.
In common with other antibiotics, flucloxacillin may affect the gut flora, leading to lower oestrogen reabsorption and reduced efficacy of combined oral contraceptives.
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.
4.6 Fertility, pregnancy and lactation
Pregnancy: The product has been in clinical use since 1970. Animal studies have shown no evidence of teratogenic effects and the limited number of reports of use in human pregnancy have shown no evidence of untoward effects. Flucloxacillin should only be used in pregnancy when the potential benefits outweigh the potential risks associated with treatment.
Breast-feeding: 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
Flucloxacillin has no or negligible influence on the ability to drive and use machines.
4.8 Undesirable effects
The following convention has been utilised 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).
Unless otherwise stated, the frequency of the adverse events has been derived from more than 30 years of post-marketing reports.
|
System Organ Class |
Frequency |
Adverse Events |
|
Blood and lymphatic system disorders |
Very rare: |
Neutropenia (including agranulocytosis) and thrombocytopenia. These are reversible when |
|
treatment is discontinued. Haemolytic anaemia. | ||
|
Immune system disorders |
Very rare: |
Anaphylactic shock (exceptional with oral administration) (see section 4.4), angioneuroticoedema. 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). 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. The onset of these 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. 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). | |
|
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 at www.mhra.gov.uk/yellowcard.
4.9 Overdose
Problems of overdose with this capsule presentation are unlikely, but if encountered they may be treated symptomatically.
With high doses, mainly after parenteral administration, 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
ATC code: J01C F05
Pharmacotherapeutic group - Beta-lactamase resistant penicillins.
Properties: Flucloxacillin is a narrow-spectrum antibiotic of the group of isoxazolyl penicillins; it is not inactivated by staphylococcal P-lactamases.
The drug is stable in an acidic medium. Flucloxacillin is markedly resistant to cleavage by penicillinase. It is less effective than benzylpenicillin or phenoxymethylpenicillin against non-penicillinase-producing staphylococci or other gram positive cocci.
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), and staphylococci. It is not active against methicillin-resistant staphylococci.
Risk of hepatic injury
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.
5.2 Pharmacokinetic properties
Absorption: Flucloxacillin provides good absorption after oral administration (30-80% absorbed from GI tract). Absorption of the drug is more efficient when taken on an empty stomach. Peak plasma levels are attained at 1 hour after administration and 1G dose provides peak plasma level of 15mcg/ml. The drug is rapidly excreted by the kidney, about 50% within 6 hours of administration T^=30-60 minutes.
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:
- After 250mg by the oral route (in fasting subjects): Approximately 8.8mg/l.
- After 500mg by the oral route (in fasting subjects): Approximately 14.5mg/l.
- After 500mg by the IM route: Approximately 16.5mg/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: 11.6mg/l (compact bone) and 15.6mg/l (spongy bone), with a mean serum level of 8.9mg/l.
Crossing the meningeal barrier: flucloxacillin diffuses in only small proportions into the cerebrospinal fluid of subjects whose meninges are not inflamed.
Crossing into mother's milk: flucloxacillin is excreted in small quantities in mothers' 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.
Protein binding: About 95% of Flucloxacillin in the circulation is bound to plasma proteins.
5.3 Preclinical safety data
No data of relevance which is additional to that already included in other sections of the SPC.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Magnesium stearate
Capsule Shell:
Gelatin
Indigo Carmine (E132) Titanium Dioxide (E171) Printing ink:
Titanium Dioxide (E171) Shellac
Polysorbate 80
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
24 months.
6.4 Special precautions for storage
Store in a dry place, below 25°C.
6.5 Nature and contents of container
1. HDPE tablet containers with HDPE lids.
2. PVC/PVdC-Aluminium blister pack (250 micron PVC externally with 40 gsm PVdC, 20 micron hard tempered aluminium).
3. PVC/PVdC/Aluminium blister pack (250 micron PVC externally with 40 gsm PVdC, 20 micron hard tempered aluminium) - “Burgopak” packaging format.
Pack sizes: 4, 28, 100, 250, 500 and 1000 capsules.
Not all pack sizes may be marketed.
4. For bulk supply only, packs of 5,000 and 10,000 capsules will be available (supplied in polybags, free from additives, inside a cardboard outer container.
6.6 Special precautions for disposal
No special requirements for use/handling.
7 MARKETING AUTHORISATION HOLDER
Special Concept Development (UK) Ltd
Units 1-7 Colonial Way
Watford
Hertfordshire
WD24 4YR
8 MARKETING AUTHORISATION NUMBER(S)
PL 36722/0011
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
18/02/1999
10 DATE OF REVISION OF THE TEXT
18/07/2016