FLUCIL®

Flucloxacillin (as flucloxacillin sodium) Powder for Injection 500 mg AUST R 90879
1g AUST R 90878

PRODUCT INFORMATION

DESCRIPTION

FLUCIL® (flucloxacillin sodium) is the sodium salt of (2S, 5R, 6R)–6-[3-(2-chloro-6-

fluorophenyl)-5-methylisoxazole-4-carboxamido]-3,3-dimethyl-7-oxo-4-thia-1-
azabicyclo[3.2.0]heptane-2-carboxylic acid. It is a member of the beta-lactamase-stable
group of penicillins derived from the penicillin nucleus, 6-amino-penicillanic acid.
Flucloxacillin sodium has the following structure:

Cl9Hl6CIFN3NaO5S,H20

Flucloxacillin sodium has a molecular weight of 493.9 and a CAS registry number,
1847-24-1. Each vial contains 95.0 to 105.0% of the stated amount of flucloxacillin. Each
one gram of monograph substance represents 2 mmol of sodium.
FLUCIL® Powder for Injection is a fine white to off-white homogeneous powder, soluble in
water. The injection is prepared by the addition of the appropriate volume of Water for
Injections to give the desired concentration of flucloxacillin.
FLUCIL® Powder for Injection contains no antiseptics or buffering agents nor are there any
excipients.

PHARMACOLOGY

Microbiology
FLUCIL® is a narrow spectrum antibiotic with considerable activity against the following
Gram-positive organisms:

Beta-lactamase-producing Staphylococcus aureus

Penicillin sensitive Staphylococcus aureus
Streptococcus pyogenes
Streptococcus pneumoniae

It is less active than benzylpenicillin against organisms which are sensitive to

benzylpenicillin.

It is not active against Gram-negative bacilli, methicillin resistant Staphylococcus aureus

(MRSA), nor Streptococcus faecalis.

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Susceptibility tests
Dilution or diffusion techniques – either quantitative (MIC) or breakpoint, should be used
following a regularly updated, recognised and standardised method (e.g. NCCLS).
Standardised susceptibility test procedures require the use of laboratory control
microorganisms to control the technique aspects of the laboratory procedures.
A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the
antimicrobial compound in the blood reaches the concentrations achievable. A report of
“Intermediate” indicates that the result should be considered equivocal, and if the
microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should
be repeated. This category implies possible clinical applicability in body sites where the drug
is physiologically concentrated or in situations where high dosage of drug can be used. This
category also provides a buffer zone, which prevents small-uncontrolled technical factors
from causing major discrepancies in interpretation. A report of “Resistant” indicates that the
pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the
concentrations usually achievable; other therapy should be selected.
Note: The prevalence of resistance may vary geographically for selected species and local
information on resistance is desirable, particularly when treating severe infections.

Pharmacokinetics
Flucloxacillin is well absorbed following intramuscular injection. The major route of excretion is
renal (by both glomerular filtration and tubular secretion) and high levels of active antibiotic are
produced in the urine. At least 10% of the dose is excreted as an active metabolite which can
rise to as high as 50% in renal failure.
The concurrent administration of probenecid delays the excretion of flucloxacillin resulting in
higher and more prolonged blood levels of the antibiotic.
Flucloxacillin, in common with other isoxazolylpenicillins, is highly bound to serum proteins.
However, the low minimum inhibitory concentrations of flucloxacillin against Gram-positive cocci
and the free antibiotic levels achieved ensure that the preparation is fully active against
susceptible pathogens.

INDICATIONS

For the treatment of confirmed or suspected Staphylococcal and other Gram-positive coccal
infections. Indications include pneumonia, osteomyelitis, skin and skin structure and wound
infections, infected burns and cellulitis.

CONTRAINDICATIONS

History of flucloxacillin associated jaundice or hepatic dysfunction.

History of a hypersensitivity reaction to beta-lactam antibiotics, e.g. penicillins.

Use in the eye

PRECAUTIONS

Hepatic Toxicity
Flucloxacillin can cause severe hepatitis and cholestatic jaundice, which may be
protracted. This reaction is more frequent in older patients and those who take the drug
for prolonged periods (see ADVERSE REACTIONS).

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Serious, and occasionally fatal, hypersensitivity reactions (anaphylaxis) have been reported in
patients receiving beta-lactam antibiotics, e.g. penicillins. Although anaphylaxis is more
frequent following parenteral therapy, it has occurred in patients on oral therapy. Before
commencing therapy with any beta-lactam antibiotic, careful enquiry should be made
concerning previous hypersensitivity reactions to penicillins, cephalosporins or other allergens.
If a hypersensitivity reaction occurs, appropriate therapy should be instituted and FLUCIL®
therapy discontinued.

Serious anaphylactoid reactions require emergency treatment with adrenaline. Oxygen,

intravenous steroids and airway management including intubation, should also be administered
as indicated.

Antibiotic associated pseudomembranous colitis has been reported with many antibiotics
including flucloxacillin.

A toxin produced by Clostridium difficile appears to be the primary cause. The severity of the
colitis may range from mild to life threatening. It is important to consider this diagnosis in
patients who develop diarrhoea or colitis in association with antibiotic use (this may occur up to
several weeks after cessation of antibiotic therapy). Mild cases usually respond to drug
discontinuation alone. However in moderate to severe cases, appropriate therapy with a
suitable oral antibacterial agent effective against Clostridium difficile should be considered.
Fluids, electrolytes and protein replacement should be provided when indicated. Drugs which
delay peristalsis, e.g. opiates and diphenoxylate with atropine (Lomotil) may prolong and/or
worsen the condition and should not be used.

Caution should be exercised in the treatment of patients with an allergic diathesis.

FLUCIL® should be used with caution in patients with evidence of hepatic dysfunction even
though the latter is not a recognised predisposing factor to hepatic reactions to the drug.

Hepatitis, predominantly of a cholestatic type, has been reported (see ADVERSE

REACTIONS). Reports have been more frequent with increasing age (particularly over 55 years
of age) or following prolonged treatment (more than 14 days). Jaundice may appear several
weeks after therapy: in some cases the course of the reactions has been protracted and lasted
for several months. Resolution has occurred with time in most cases. In rare cases, deaths
have been reported, nearly always in patients with serious underlying disease or receiving
concomitant medication.

Use in Pregnancy: Category B1

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 effect. The use of flucloxacillin in pregnancy should be
reserved for cases considered essential by the clinician.

Use in lactation

Flucloxacillin is excreted in breast milk in trace amounts. An alternative feeding method is

recommended to avoid any possible sensitisation of the newborn.

Use in Neonates

Animal studies show that high doses of flucloxacillin reduce albumin-bound bilirubin to 50 to
70% of the base line concentration. The drug should therefore be used with extreme caution in
jaundiced neonates or premature infants.

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Interactions with other drugs

Probenecid decreases the renal tubular secretion of flucloxacillin. Concurrent use with FLUCIL®
may result in increased and prolonged blood levels of flucloxacillin.

In common with other antibiotics, patients should be warned that FLUCIL® may reduce the
effectiveness of oral contraceptives.

It is recommended that flucloxacillin sodium for injection and aminoglycosides are not to be
mixed together in the same solution for injection, due to possible precipitation and the
gradual inactivation of the aminoglycosides under these circumstances.

Flucloxacillin sodium for injections should not be mixed with blood products or other proteinases
fluids (e.g. Protein hydrolysates).

Drug incompatibilities
Flucloxacillin sodium for injection is incompatible with aminoglycosides, amiodarone, atropine,
buprenorphine, calcium gluconate, chlorpromazine, ciprofloxacin, diazepam, dobutamine,
erythromycin lactobionate, metoclopramide, morphine sulphate, pefloxacin, pethidine,
prochlorperazine edisylate and verapamil.

ADVERSE REACTIONS

As with all penicillins, the possibility of hypersensitivity reactions should always be considered.
Reactions are more likely to occur in those with an allergic diathesis. Anaphylactic shock is
most likely to occur with injected penicillins (see PRECAUTIONS).

The following adverse reactions have been reported as associated with the use of flucloxacillin:

HEPATIC: Hepatitis and cholestatic jaundice (occasionally severe) have been reported with a
frequency of about 1 in 15,000 exposures (see PRECAUTIONS).

GASTROINTESTINAL: Nausea, vomiting, diarrhoea, and dyspepsia. As with other antibiotics,

pseudomembraneous colitis has been reported rarely (see PRECAUTIONS).

HYPERSENSITIVITY REACTIONS: Erythematous maculopapular rashes, urticaria, purpura,

eosinophilia, and angioneurotic oedema. Anaphylaxis and erythema multiforme have been
reported rarely. Certain reactions (fever, arthralgia and myalgia) sometimes develop more than
48 hours after the start of treatment. Whenever such reactions occur, the administration of
FLUCIL® should be discontinued. (Note: urticaria, other skin rashes and serum sickness-like
reactions may be controlled with antihistamines and, if necessary, systemic corticosteroids).

RENAL: Isolated cases of nephritis and haematuria have been reported.

HAEMIC and LYMPHATIC: Haemolytic anaemia has been reported during therapy with
flucloxacillin. Reactions such as anaemia, thrombocytopenia, thrombocytopenic purpura,
eosinophilia, leucopenia and agranulocytosis have been reported during therapy with penicillins.
These reactions are usually reversible on discontinuation of therapy and are believed to be
hypersensitivity phenomena.

CNS: Adverse effects have been reported rarely. They include dizziness and convulsions.
Convulsions may occur in patients with impaired renal function or in those receiving high doses.

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As the blood brain barrier becomes more permeable in meningitis, toxic symptoms may be
precipitated by lower levels of flucloxacillin in patients with meningitis.

OTHER: Vaginal or oral moniliasis may occur following the use of antibiotics.

INJECTION SITE: Pain may be experienced at the site of intramuscular injection and phlebitis
at the site of intravenous injection.

Amongst the adverse events spontaneously reported to ADRAC, 61% were dermatological
effects, 17% were jaundice, 16% were gastrointestinal reactions and 2.5% were CNS related.

DOSAGE AND ADMINISTRATION

Usual adult dose

Intramuscular 250 mg, 6-hourly
Intravenous 250 mg to 1 g, 6-hourly
Intrapleural 250 mg once daily
Intra-articular 250 mg to 500 mg once daily

Note: Systemic doses may be doubled where necessary in severe infections.

Usual children's dose

2 to 10 years Half of the adult dose
under 2 years Quarter of the adult dose

Note: In severe infections the dosage may be increased.

Dosage in patients with impaired liver function

Adjustment of dosage may not be necessary as flucloxacillin is not metabolised in the liver to
any appreciable extent. However, during prolonged treatment it is advisable to check
periodically for hepatic dysfunction (see PRECAUTIONS).

Dosage in patients with impaired renal function

As flucloxacillin is excreted to a large extent by the kidney, the dose or dose interval may need
modification in patients with renal failure, as the half life in patients with renal failure is
increased. However dosage recommendations for various plasma creatinine levels for patients
with impaired renal function are not available. Flucloxacillin is not significantly removed by
haemodialysis.

Preparation of Injections

INTRAMUSCULAR: Dissolve the 500 mg vial contents in 2.0 mL Water for Injections, or the 1 g
vial contents in 2.5 mL Water for Injections.

INTRAVENOUS: Dissolve the 500 mg vial contents in 10 mL Water for Injections, or the 1 g
vial contents in 15 mL to 20 mL Water for Injections. Administer by slow IV injection (3 to 4
minutes). FLUCIL® may also be added to infusion fluids or injected, suitably diluted, into the
drip tube over a period of 3 to 4 minutes.

INTRAPLEURAL: Dissolve the 500 mg vial contents in 10 mL Water for Injections.

INTRA-ARTICULAR: Dissolve the 500 mg vial contents in up to 5 mL Water for Injections or in

0.5% lignocaine hydrochloride solution.

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The following tables (Tables 1 and 2) may be used as a guide to assist in the preparation of
fractional doses of FLUCIL®.

Table 1: 500 mg Powder for Injection

For concentration of: 100 125 200 250 mg per mL

Add to 500 mg powder: 4.6 3.6 2.1 1.6 mL Water for Injections

Table 2: 1 g Powder for Injection

For concentration of: 100 200 250 500 mg per mL

Add to 1 g powder: 9.3 4.3 3.3 1.3 mL Water for Injections

When FLUCIL® is reconstituted with Water for Injections, it must be used immediately to reduce
microbiological hazard. FLUCIL® is for one dose in one patient only. Discard any remaining
contents.

OVERDOSAGE

No information is available, but it could be anticipated that overdosage with FLUCIL® would
cause gastrointestinal and CNS symptoms (see ADVERSE REACTIONS). As the blood brain
barrier becomes more permeable in meningitis, toxic symptoms may be precipitated by lower
levels of flucloxacillin in patients with meningitis.

Flucloxacillin is not significantly removed from the circulation by haemodialysis. General

supportive measures should be instituted.

STABILITY AND STORAGE

Stability in Solution

FLUCIL® Powder for Injection 500 mg, after reconstitution in different infusion liquids to a final
concentration of 1 mg/mL, retained the flucloxacillin content reported in Table 3. However, to
avoid microbiological hazards, FLUCIL® Powder for Injection should be used immediately
following reconstitution. As FLUCIL® Powder for Injection does not contain an antimicrobial
preservative, the reconstituted injection solution should be used only once and any residue
discarded.

Table 3: Stability of FLUCIL® Powder for Injection 500 mg in 500 mL of different infusion
fluids at 2-8°C

Intravenous Fluid Residual Potency after 24 hours

(% of initial value)
Normal saline 97
Glucose saline 94
5% Glucose 99
M/6 Sodium lactate 96

If up to 24 hour storage of FLUCIL® at 2-8°C is required in one of the above intravenous fluids
at a concentration of 1 mg/mL, reconstitution should be carried out under appropriate aseptic
conditions to avoid microbiological hazards.

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Storage

FLUCIL® Powder for Injection should be stored in a dry place, protected from light, at less than
25°C.

FLUCIL® Powder for Injection should be used immediately following reconstitution.

PRESENTATION

FLUCIL® Powder for Injection 500 mg vials contain flucloxacillin sodium equivalent to 500 mg of
flucloxacillin. The 500 mg vials are stored in cartons of 5.

FLUCIL® Powder for Injection 1 g vials contain flucloxacillin sodium equivalent to 1 g of

flucloxacillin. The 1 g vials are stored in cartons of 5.

SPONSOR

Aspen Pharmacare Australia Pty Limited

ABN 51 096 236 985
34-36 Chandos Street
St Leonards 2065 NSW
Australia

Date of TGA Approval: 23 January 2008

FLUCIL® is a registered tradename of Aspen Pharmacare Australia Pty Ltd.

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