Flucloxacillin 1000 mg powder for solution for injection or infusion

Ireland - English - HPRA (Health Products Regulatory Authority)

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Active ingredient:
FLUCLOXACILLIN SODIUM PH. EUR.
Available from:
Riemser Pharma GmbH
ATC code:
J01CF; J01CF05
INN (International Name):
FLUCLOXACILLIN SODIUM PH. EUR.
Dosage:
1000 milligram(s)
Pharmaceutical form:
Powder for solution for injection/infusion
Therapeutic area:
Beta-lactamase resistant penicillins; flucloxacillin
Authorization number:
PA22709/001/002
Authorization date:
2019-08-13

Package leaflet: Information for the patient

Flucloxacillin 500 mg and 1000 mg

powder for solution for injection or infusion

Flucloxacillin sodium

Flucloxacillin 500 mg and 1000 mg

powder for solution for injection or infusion

Flucloxacillin sodium

190 x 410 mm

190 x 410 mm

The following information is intended for medical or healthcare

professionals only:

Incompatibilities

This medicinal product must not be mixed with other medicinal products

except those mentioned below.

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.

Preparation and

administration of

Flucloxacillin reconstituted

solutions

Routes of administration: intramuscular, intravenous, intrapleural, intra-

articular and inhalation.

Flucloxacillin may be added to most intravenous fluids (e.g. Water for

Injections, sodium chloride 0.9%, glucose 5%, sodium chloride 0.18%

with glucose 4%, Hartmann's solution, Dextran 40 (10%) Intravenous

Infusion

NaCl

(0.9%)

intravenous

infusion,

Dextran

(10%)

Intravenous Infusion in glucose (5%) intravenous infusion).

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

3.0 ml Water for Injections to 1 g vial contents

Intravenous: Dissolve 250-500 mg in 5-10 ml Water for Injections.

Dissolve 1g in 20 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

Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2;

Tel: +353 1 6764971;

Fax: +353 1 6762517.

Website: www.hpra.ie;

E-mail: medsafety@hpra.ie.

By reporting side effects you can help provide more information on the

safety of this medicine.

5. How to store Flucloxacillin

Keep this medicine out of the sight and reach of children.

Do not store above 25 C.

Do not use this medicine after the expiry date which is stated on the vial

and outer carton after the abbreviation EXP. The expiry date refers to the

last day of that month.

Reconstituted solutions for IM or direct IV injection should normally be

administered within 30 minutes of preparation.

Do not throw away any medicines via wastewater or household waste.

Ask your pharmacist how to throw away medicines you no longer use.

These measures will help protect the environment.

6. Contents of the pack and other information

What Flucloxacillin contains

-The active substance is flucloxacillin. Each vial contains either 500 mg

or 1000 mg flucloxacillin as flucloxacillin sodium.

-There are no other ingredients.

What Flucloxacillin looks like and contents of the pack

Flucloxacillin 500 mg and 1000 mg powder for solution for injection or

infusion is a fine white powder. Flucloxacillin is supplied in packs of 10

vials in a carton with a package leaflet.

Marketing Authorisation Holder for UK:

Intrapharm Laboratories Ltd

The Courtyard Barns,

Choke Lane

Maidenhead

Berkshire SL6 6PT

Marketing Authorisation Holder for Ireland:

RIEMSER Pharma GmbH

An der Wiek 7

17493 Greifswald – Insel Riems

Germany

Manufacturer:

Antibiotice SA

1 Valea Lupului Street, 707410 Iasi, Romania

This leaflet was last revised in February 2019.

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

1.0% lidocaine hydrochloride solution.

Nebuliser solution: Dissolve 125-250 mg of the vial contents in 3 ml

sterile water.

Any unused product or waste should be disposed of in accordance with

local requirements.

How to store

Reconstituted solutions for IM or direct IV injection should normally be

administered within 30 minutes of preparation.

Posology and method of administration

The usual adult dosage (including the elderly) is as follows:

By slow intravenous injection or by infusion: 250 mg to 1 g every six

hours. These doses may be doubled in severe infections.

Osteomyelitis: Up to 8 g daily divided in 3 to 4 divided doses

Endocarditis: 8 g daily in four divided doses in patients weighing up to

85 kg, and 12 g daily in 6 divided doses may be used in those weighing

more.

During surgical prophylaxis, 1 to 2 g intravenously at induction of

anaesthesia

followed

hourly

intravenously

intramuscularly for up to 48 hours.

By intramuscular injection: 250 mg four times daily.

By intrapleural injection: 250 mg once daily.

By nebuliser: 125 to 250 mg four times daily.

By intra-articular injection: 250 to 500 mg once daily.

No single bolus injection or infusion should exceed 2 g.

The maximum dose of 12 g per day should not be exceeded.

Paediatric population:

Children under 14 years of age

25 to 50 mg/kg/24 hours administered in three to four equally divided

doses by i.m. or i.v. injection.

Children aged 10 to 14 years usually receive a daily dose of 1.5 g to 2 g

and children aged 6 to 10 years 0.75 g to 1.5 g, divided into three to four

equal doses.

In cases of severe infections: Up to 100 mg/kg/24 hours in three to four

divided doses.

No single bolus injection or infusion should exceed 33 mg/kg.

Renal impairment

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.

The maximum recommended dose is 1 g every 8 to 12 hours.

Flucloxacillin is not significantly removed by dialysis and hence no

supplementary dosages need be administered either during, or at the

end of the dialysis period.

Hepatic impairment

Dose

reduction

patients

with

reduced

hepatic

function

necessary.

Read all of this leaflet carefully before you start using this medicine

because it contains important information for you.

-Keep this leaflet. You may need to read it again.

-If you have any further questions, ask your doctor or pharmacist.

-This medicine has been prescribed for you only. Do not pass it on to

others. It may harm them, even if their signs of illness are the same as

yours.

-If you get any side effects, talk to your doctor or pharmacist.

This

includes any possible side effects not listed in this leaflet. See section 4.

The full name of this product is Flucloxacillin 500 mg or 1000mg,

powder for solution for injection or infusion, but within the leaflet it

will be referred to as Flucloxacillin.

What is in this leaflet

1. What Flucloxacillin is and what it is used for

2. What you need to know before you use Flucloxacillin

3. How to use Flucloxacillin

4. Possible side effects

5. How to store Flucloxacillin

6. Contents of the pack and other information

1. What Flucloxacillin is and what it is used for

Flucloxacillin is an antibiotic used to treat infections by killing the

bacteria that cause them. It belongs to a group of antibiotics called

“penicillins”.

Flucloxacillin is available in two strengths. Each vial contains 500mg or

1000mg flucloxacillin powder for reconstitution for injection.

Flucloxacillin is used for the treatment of a range of bacterial infections

including bone infections (osteomyelitis) and infections within the lining

of the heart (endocarditis). Flucloxacillin can also be used to prevent

infections that can occur during major surgical operations, such as heart

(cardiothoracic

surgery)

bone,

joint

muscle

operations

(orthopaedic surgery).

2. What you need to know before you use Flucloxacillin

You should not be given Flucloxacillin:

-if you are allergic to flucloxacillin

-if you are allergic to penicillins, cephalosporins and other antibiotics

-if you have had jaundice (yellow skin and white of eyes) or liver

problems when you have been given flucloxacillin previously

You must tell your doctor or nurse if any of these apply to you.

Flucloxacillin should not be given into the eye or under the eye lids.

Warnings and precautions

Talk to your doctor or pharmacist before you are given flucloxacillin,

-if you have ever had a skin rash or swelling of the face or neck when

taking an antibiotic

-if you ever had a serious complaint when taking an antibiotic

-if you are being treated for liver problems

-if you are being treated for kidney problems or gout

-if you are on a low sodium diet

-if you are 50 years old or over

-if you have porphyria

-if you have any serious illness, other than this infection

-if you are giving this medicine to a newborn child

-if you are taking or will be taking paracetamol. When flucloxacillin is

used together with paracetamol there is an increased risk of a blood

abnormality called high anion gap metabolic acidosis, a condition in

which the body produces too much acid or the kidneys do not remove

enough acid from the body. Patients at increased risk are those with poor

kidney function, blood poisoning, poor nutrition and especially when the

maximum daily doses of paracetamol are used. (Your doctor will need to

do a blood test to confirm this) High anion gap metabolic acidosis is a

serious disease that must have urgent treatment.

If any of the above applies to you, your doctor may prescribe a different

medicine or a different dose of flucloxacillin.

Other medicines and Flucloxacillin

Tell your doctor or nurse if you are taking, have recently taken, or might

take any other medicines, including medicines obtained without a

prescription. Especially:

methotrexate,

reduced

excretion

occur

with

flucloxacillin

(increased risk of toxicity)

probenecid (used to treat gout)

please tell your doctor if you are taking other antibiotics when

prescribed flucloxacillin, as it may affect the action of flucloxacillin.

Pregnancy and, breast-feeding and fertility

If you are pregnant or breast-feeding, think you may be pregnant or are

planning to have a baby, ask your doctor or nurse for advice before

taking this medicine.

Driving and using machines

There should be no effect on the ability to drive or operate machinery.

Tests

Regular monitoring of liver and kidney function should be performed

during prolonged treatments. Tell your doctor that you are taking

flucloxacillin if you are having liver function tests as flucloxacillin may

affect the results. If you are having a blood test, you should mention to

the doctor or nurse that you are taking flucloxacillin because the

antibiotic might affect the blood test results.

Flucloxacillin contains sodium

This medicinal product contains approximately 51 mg sodium per g. This

should be included in the daily allowance of patients on a sodium

restricted diet.

3. How to use Flucloxacillin

Your doctor or nurse will give you this medicine by injection into a muscle

(intramuscular) or injection into a vein (intravenous). It can also be given

to you by injection into a joint (intra-articular) or injection into the lining of

the lung (intrapleural), or by breathing in the medicine from a mask

(nebuliser).

Your doctor will decide on the dose and the duration of treatment. This

will depend on the severity and type of infection you have.

If you have severe kidney failure you may be give a lower dose or you

may receive your doses less frequently.

The recommended dose for treating infections intramuscularly or

intravenously is:

Adults and adolescents over 14 years:

The usual dose is 250 mg to 1 g every six hours.

For severe infections: up to 8 g daily can be given, administered in three

to four infusions (over 20-30 minutes).

Doses of up to 8 g a day may be required for infections of the bones and

joints (osteomyelitis) or the heart (endocarditis).

To prevent infections after an operation the usual dose is 1 to 2 g before

the operation when you are given your anaesthetic. This is then followed

by 500 mg four times a day for up to three days after your operation.

Children under 14 years:

25-50 mg per kg body weight in 24 hours. This will be given in three or

four divided doses.

Children aged 10-14 years usually receive a daily dose of 1.5 g – 2 g in

three to four divided doses. Children aged 6-10 years usually receive a

daily dose of 0.75 g – 1.5 g in three to four divided doses. For severe

infections: Up to 100 mg per kg body weight in 24 hours. This will be

given in three or four divided doses each day.

Flucloxacillin may be administered by other routes, together with

systemic therapy:

-by injection into the lining of the lung (intrapleural): 250 mg once daily,

-by injection into a joint (intra-articular): up to 250 - 500 mg once daily,

-inhalation by nebulizer: 125 mg – 250 mg four times a day.

If you are given more Flucloxacillin than you should

As this medicine will normally be given to you by a nurse or a doctor, it is

unlikely you will be given too much, but if you think you have been given

too much flucloxacillin tell your doctor or nurse immediately. Signs may

be nausea, vomiting and diarrhoea.

If you think you have missed a dose of Flucloxacillin

As this medicine will normally be given to you by a nurse or a doctor, it is

unlikely you will miss a dose, but if you have any concerns discuss this

with your doctor or nurse.

If you have any further questions on the use of this medicine, ask your

doctor or healthcare professional.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not

everybody gets them.

Prolonged treatment with flucloxacillin may result in increased growth of

resistant organisms.

If you notice any of the following side effects soon after receiving

this medicine, tell your doctor or nurse immediately. If you get them

you may have had a serious allergic reaction or other type of

reaction to this medicine. You may need urgent medical attention, if

you have:

Stomach pain or diarrhoea (possibly with bleeding)

Your skin or the white of your eyes turn yellow

Your urine becomes darker or your faeces become paler

Any unexplained bleeding, bruising or skin discolouration

Skin rash and itching

Blistering of the skin, mouth, eyes and genitals

Any sudden wheeziness, difficulty in breathing or dizziness

Any swelling of the face, neck, or tongue

Serious skin reactions

A red, scaly rash with bumps under the skin and blisters (exanthematous

pustulosis)

Severe bloody diarrhoea (pseudomembranous colitis)

Some of these reactions can be delayed for several weeks after

finishing treatment.

Common side effects (may affect up to 1 in 10 people):

- stomach upset or diarrhoea

Very rare (may affect up to 1 in 10,000 people):

Reduction in blood cell counts which makes infections more likely

Inflammation of the kidney which can cause swollen ankles or high

blood pressure

Joint pain, muscle pain or fever. This may develop after 2 days or more

from the start of treatment.

Convulsions (“fits”) in patients taking high doses.

High anion gap metabolic acidosis in patients taking flucloxacillin

together with paracetamol (see section 2).

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This

includes any possible side effects not listed in this leaflet.

UK patients can report side effects directly to MHRA via the Yellow Card

Scheme. Website: www.mhra.gov.uk/yellowcard.

Irish

patients

report

side

effects

directly

HPRA

Health Products Regulatory Authority

14 August 2019

CRN008LJT

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Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Flucloxacillin 1000 mg powder for solution for injection or infusion

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains 1000 mg flucloxacillin as flucloxacillin sodium and 2 mmol sodium per vial.

3 PHARMACEUTICAL FORM

Powder for solution for injection/infusion

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

4 CLINICAL PARTICULARS

4.1 Therapeutic Indications

Flucloxacillin is an isoxazolyl penicillin of the β-lactam group of antibiotics which exerts a bactericidal effect upon many

Gram-positive organisms including β-lactamase-producing staphylococci and streptococci.

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 or orthopaedic surgery.

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

4.2 Posology and method of administration

Posology

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

The usual adult dosage (including the elderly) is as follows:

By slow intravenous injection or by infusion: 250 mg to 1 g every six hours. These doses may be doubled in severe

infections. Doses of up to 8 g daily divided in 3 to 4 divided doses have been suggested for osteomyelitis; in endocarditis a

dose of 8 g daily in four divided doses in patients weighing up to 85 kg, and 12 g daily in 6 divided doses may be used in those

weighing more.

During surgical prophylaxis, 1 to 2 g intravenously at induction of anaesthesia followed by 500 mg six hourly intravenously or

intramuscularly.

By intramuscular injection: 250 mg four times daily.

By intrapleural injection: 250 mg once daily.

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By nebuliser: 125 to 250 mg four times daily.

By intra-articular injection: 250 to 500 mg once daily.

No single bolus injection or infusion should exceed 2 g.

The maximum dose of 12 g per day should not be exceeded.

Paediatric population

Children under 14 years of age

25 to 50 mg/kg/24 hours administered in three to four equally divided doses by i.m. or i.v. injection.

Children aged 10 to 14 years usually receive a daily dose of 1.5 g to 2 g and children aged 6 to 10 years 0.75 g to 1.5 g, divided

into three to four equal doses.

In cases of severe infections: Up to 100 mg/kg/24 hours in three to four divided doses.

No single bolus injection or infusion should exceed 33 mg/kg.

Renal impairment

Incommon 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. The maximum recommended dose is 1 g every 8 to 12 hours.

Flucloxacillin is not significantly removed by dialysis and hence no supplementary dosages need be administered either during,

or at the end of the dialysis period.

Hepatic impairment

Dose reduction in patients with reduced hepatic function is not necessary.

Method of administration

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.

Flucloxacillin may also be administered by intra-articular, intrapleural or intramuscular injection or by nebuliser.

For instructions on reconstitution of flucloxacillin before administration, see section 6.6.

4.3 Contraindications

Flucloxacillin should not be given to patients with a history of hypersensitivity to β-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

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 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.

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If anaphylaxis occurs, flucloxacillin should be discontinued and the appropriate therapy instituted. Serious anaphylactic

reactions may require immediate emergency treatment with adrenaline (epinephrine). Oxygen, i.v. steroids, and airway

management, including intubation, may also be required.

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).

Dosage should be adjusted in renal impairment (see section 4.2).

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.

Caution is advised in patients with porphyria.

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 severe and persistent diarrhoea, the possibility of pseudomembranous colitis should be considered; flucloxacillin

therapy should be discontinued.

Flucloxacillin injection contains approximately 51 mg sodium per g. This should be included in the daily allowance of patients

on sodium restricted diets.

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.

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).

Paediatric population

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.

4.5 Interaction with other medicinal products and other forms of interactions

Probenecid decreases the renal tubular secretion of flucloxacillin. Concurrent administration of probenecid delays the renal

excretion of flucloxacillin.

Bacteriostatic drugs (chloramphenicol, erthromycins, sulphonamides, and tetracyclines) may interfere with the bactericidal

action of flucloxacillin.

Methotrexate, reduced excretion may occur with flucloxacillin (increased risk of toxicity).

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.

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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.)

4.6 Fertility, pregnancy and lactation

Pregnancy

Animal studies with flucloxacillin have shown no teratogenic effects. Limited information is available on the use of flucloxacillin

in human pregnancy. Flucloxacillin should only be used in pregnancy when the potential benefits outweigh the potential risks

associated with treatment.

Breastfeeding

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.

Fertility

The impact on male or female fertility has not been investigated.

4.7 Effects on ability to drive and use machines

Adverse effects on the ability to drive or operate machinery have not been observed.

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, <1/1000),very rare (<1/10,000).

Unless otherwise stated, the frequency of theadverse events has been derived from more than 30 years of post-marketing

reports.

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)

(see Item 4.4

Warnings),

angioneurotic

oedema

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

also Skin and subcutaneous tissue disorders).

Nervous system disorders

Very rare:

In patients suffering

from renal failure,

neurological

disorders with

convulsions are

possible with the I.V.

injection of high

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doses

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.

Metabolism and nutrition disorders

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.)

Hepato-biliary disorders

Very rare:

Hepatitis and

cholestatic jaundice.

(See Section 4.4

Special Warnings

and Special

Precautions for Use).

Changes in liver

function laboratory

test results

(reversible when

treatment is

discontinued).

Hepatitis and cholestatic jaundice may be delayed for up to two months post-treatment. 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.

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.

Not known:

AGEP – acute

generalized

exanthematous

pustulosis (see

section 4.4)

(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 treatment.

Renal and urinary disorders

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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 HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517.

Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

4.9 Overdose

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

Pharmacotherapeutic group: β-lactamase resistant penicillins, ATC code: J01 CF05.

Flucloxacillin is a semisynthetic penicillin (beta-lactam antibiotic; isoxazolylpenicillin) with a narrow spectrum of activity

primarily against Gram-positive organisms, including β-lactamase-producing strains.

Mechanism of action

Flucloxacillin inhibits one or more enzymes (often referred to as penicillin-binding proteins, PBPs) in the biosynthetic pathway

of bacterial peptidoglycan, which is an integral structural component of the bacterial cell wall. Inhibition of peptidoglycan

synthesis leads to weakening of the cell wall, which is usually followed by cell lysis and death.

PK/PD relationship

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

flucloxacillin.

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 cefalosporins.

Methicillin-resistant staphylococci generally have low susceptibility for all beta-lactam antibiotics.

Antimicrobial activity

Flucloxacillin is active against both β-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:

Micro-organisms

MIC (mg/l)

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Staphylococcus aureus

0.1 to 0.25

Staphylococcus aureus (beta-lactamase +)

0.25 to 0.5

Streptococcus pneumoniae

0.25

Streptococcus pyogenes (Group A beta-haemolytic) (*)

Streptococcus viridans group

Clostridium tetani

0.25

Clostridium welchii

0.25

Neisseria meningitidis

Neisseria gonorrhoeae

Neisseria gonorrhoeae(beta-lactamase +)

(*) The Group A beta-haemolytic streptococci are less sensitive to

the isoxazolyl penicillins than to penicillin G or penicillin V.

5.2 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:

- After 250 mg by the oral route (in fasting subjects): Approximately 8.8 mg/l.

- After 500 mg by the oral route (in fasting subjects): Approximately 14.5mg/l.

- After 500 mg by the IM route: Approximately 16.5 mg/l.

The total quantity absorbed by the oral route represents approximately 79% of the quantity administered.

Distribution

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.

Paediatric population

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 creatinine clearance <10 ml/min (see section 4.2).

Patients with hepatic impairment

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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 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

None

6.2 Incompatibilities

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.

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

6.3 Shelf life

Unopened product: 3 years

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

6.4 Special precautions for storage

Do not store above 25

For storage conditions after reconstitution of the medicinal product, see section 6.3.

6.5 Nature and contents of container

The product is presented in colourless glass vials sealed with a bromobutyl rubber stopper and aluminium cap with plastic lid.

Pack size: 10 vials/carton

6.6 Special precautions for disposal and other handling

Instructions for preparation of reconstituted solutions:

Flucloxacillin may be added to most intravenous fluids (e.g. Water for Injections, sodium chloride 0.9%, glucose 5%, sodium

chloride 0.18% with glucose 4%, Hartmann's solution, Dextran 40 (10%) Intravenous Infusion in NaCl (0.9%) intravenous

infusion, Dextran 40 (10%) Intravenous Infusion in glucose (5%) intravenous infusion).

Intramuscular: Add 2 ml Water for Injections to 500 mg vial contents. Add 3.0 ml Water for Injections to 1 g vial contents

Intravenous: Dissolve 250-500 mg in 5-10 ml Water for Injections. Dissolve 1g in 20 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 1.0% lidocaine hydrochloride solution.

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Nebuliser solution: Dissolve 125-250 mg of the vial contents in 3 ml sterile water.

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

7 MARKETING AUTHORISATION HOLDER

Riemser Pharma GmbH

An der Wiek 7

17493 Greifswald – Insel Riems

Germany

8 MARKETING AUTHORISATION NUMBER

PA22709/001/002

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 13

August 2019

10 DATE OF REVISION OF THE TEXT

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