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It is intended that each prescribed dose is given by a

minimum of two inhalations.

FLIXOTIDE™ In patients who find co-ordination of a pressurised

PHARMA CODE N° 5508


metered dose inhaler difficult a spacer may be used with
FLIXOTIDE inhaler.
EVOHALER™ ASTHMA
The onset of therapeutic effect is four to seven days,
Fluticasone propionate although some benefit may be apparent as soon as
24 hours for patients who have not previously received
inhaled steroids.
QUALITATIVE AND QUANTITATIVE COMPOSITION
If patients find that relief with short-acting
Fluticasone propionate 50, 125 and 250 micrograms.
bronchodilator treatment becomes less effective or they
FLIXOTIDE 50 Evohaler, 125 Evohaler and 250 Evohaler need more inhalations than usual, medical attention
are pressurised metered-dose inhalers which deliver must be sought.
50 micrograms, 125 micrograms and 250 micrograms of
2 fluticasone propionate per actuation into the
mouthpiece of a specially designed actuator.
• Adults and children over 16 years of age
100 to 1000 micrograms twice daily.
Patients should be given a starting dose of inhaled
62000000004309 PHARMACEUTICAL FORM FLIXOTIDE which is appropriate for the severity of their
Pressurised metered-dose aerosol. disease:
Each canister of FLIXOTIDE 50 Evohaler supplies Mild asthma: - 100 to 250 micrograms twice daily.
GSK-ESP-Aranda-ESARA 120 actuations. Moderate asthma: - 250 to 500 micrograms twice daily.
Severe asthma: - 500 to 1000 micrograms twice
Each canister of FLIXOTIDE 125 Evohaler and
daily.
250 Evohaler supplies 60 or 120 actuations.
*Multi-Market Central-GEXP The dose may then be adjusted until control is achieved
CLINICAL PARTICULARS or reduced to the minimum effective dose, according to
the individual response.
Flixotide Indications
Alternatively, the starting dose of fluticasone propionate
ASTHMA may be gauged at half the total daily dose of
FLIXOTIDE has a marked anti-inflammatory effect in the beclomethasone dipropionate or equivalent as
N/A lungs. administered by metered-dose inhaler.
It reduces symptoms and exacerbations of asthma in • Children 4 years of age and over
02-01-XX-273-11 patients previously treated with bronchodilator alone or 50 to 200 micrograms twice daily.
with other prophylactic therapy.
Many children’s asthma will be well controlled using the
Severe asthma requires regular medical assessment as 50 to 100 micrograms twice daily dosing regime. For
N/A death may occur. Patients with severe asthma have those patients whose asthma is not sufficiently
constant symptoms and frequent exacerbations, with controlled, additional benefit may be obtained by
limited physical capacity, and PEF values below increasing the dose up to 200 micrograms twice daily.
N/A 60% predicted at baseline with greater than
Children should be given a starting dose of inhaled
30% variability, usually not returning entirely to normal
FLIXOTIDE that is appropriate for the severity of the
1 after a bronchodilator. These patients will require high
disease.
dose inhaled (see Dosage and Administration) or oral
corticosteroid therapy. Sudden worsening of symptoms The dose may then be adjusted until control is achieved,
K or reduced to the minimum effective dose, according to
may require increased corticosteroid dosage which
should be administered under urgent medical individual response.
supervision. • Children 4 years of age and over
0 • Adults It should be noted that only the 50 microgram device is
Prophylactic management in: suitable for the administration of this dose.

- Mild asthma (PEF values greater than 80% predicted This presentation of FLIXOTIDE may not offer the
at baseline with less than 20% variability): Patients required paediatric dose, in which case an alternative
requiring intermittent symptomatic bronchodilator presentation of FLIXOTIDE should be considered (e.g.
asthma medication on more than an occasional basis. dry powder inhalers).
0 - Moderate asthma (PEF values 60-80% predicted at • Children aged 1 to 4 years
baseline with 20-30% variability): Patients requiring Inhaled FLIXOTIDE is of benefit to younger children in
regular asthma medication and patients with the control of frequent and persistent asthma symptoms.
unstable or worsening asthma on currently available Clinical trials in 1 to 4 year old children have shown that
prophylactic therapy or bronchodilator alone. the optimal control of asthma symptoms is achieved
- Severe asthma (PEF values less than 60% predicted at with 100 micrograms twice daily, administered via a
baseline with greater than 30% variability): Patients paediatric spacer device with a face mask (such as the
with severe chronic asthma. On introduction of BABYHALER ™).
inhaled FLIXOTIDE many patients who are dependent The diagnosis and treatment of asthma should be kept
on systemic corticosteroids for adequate control of under regular review.
symptoms may be able to reduce significantly or to
eliminate their requirement for oral corticosteroids. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)

• Children • Adults
Any child who requires preventative asthma medication, 500 micrograms twice daily used as an adjunct to
including patients not controlled on currently available long-acting bronchodilators (e.g. LABAs).
prophylactic medication. Medication must be used daily for optimum benefit
which may take three to six months. If there is no
CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)
improvement after three to six months then the patient
FLIXOTIDE is indicated for the management of COPD should undergo medical assessment.
when used in combination with long-acting
Only the 250 microgram device is suitable for the
bronchodilators (e.g. long-acting beta antagonists
administration of this dose.
(LABAs)).
• Special patient groups
Dosage and Administration
There is no need to adjust the dose in elderly patients or
Patients should be made aware of the prophylactic in those with hepatic or renal impairment.
nature of therapy with inhaled FLIXOTIDE and that it
should be taken regularly even when they are Contraindications
asymptomatic. Hypersensitivity to any ingredient of the preparation.
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Warnings and Precautions Interactions
Increasing use of short-acting inhaled beta2-agonists to Under normal circumstances, low plasma concentrations
control asthma symptoms indicates deterioration of of fluticasone propionate are achieved after inhaled
asthma control. Under these conditions, the patient’s dosing, due to extensive first pass metabolism and high
therapy plan should be reassessed. systemic clearance mediated by cytochrome P450 3A4 in
Sudden and progressive deterioration in asthma control the gut and liver. Hence, clinically significant drug
is potentially life-threatening and consideration should interactions mediated by fluticasone propionate are
be given to increasing corticosteroid dosage. In patients unlikely.
considered at risk, daily peak flow monitoring may be A drug interaction study in healthy subjects has shown
instituted. that ritonavir (a highly potent cytochrome P450 3A4
There was an increased reporting of pneumonia in inhibitor) can greatly increase fluticasone propionate
studies of patients with COPD receiving FLIXOTIDE plasma concentrations, resulting in markedly reduced
500 micrograms (see Adverse Reactions). Physicians serum cortisol concentrations. During post-marketing
should remain vigilant for the possible development of use, there have been reports of clinically significant drug
pneumonia in patients with COPD as the clinical features interactions in patients receiving intranasal or inhaled

2 of pneumonia and exacerbation frequently overlap.


Systemic effects may occur with any inhaled
fluticasone propionate and ritonavir, resulting in
systemic corticosteroid effects including Cushing’s
syndrome and adrenal suppression. Therefore,
corticosteroid, particularly at high doses prescribed for concomitant use of fluticasone propionate and ritonavir
62000000004309 long periods; these effects are much less likely to occur should be avoided, unless the potential benefit to the
than with oral corticosteroids (see Overdose). Possible patient outweighs the risk of systemic corticosteroid
systemic effects include Cushing’s syndrome, Cushingoid side-effects.
GSK-ESP-Aranda-ESARA features, adrenal suppression, growth retardation in
children and adolescents, decrease in bone mineral Studies have shown that other inhibitors of cytochrome
density, cataract and glaucoma. It is important, P450 3A4 produce negligible (erythromycin) and minor
therefore, that the dose of inhaled corticosteroid is (ketoconazole) increases in systemic exposure to
*Multi-Market Central-GEXP fluticasone propionate without notable reductions in
titrated to the lowest dose at which effective control is
maintained (see Adverse Reactions). serum cortisol concentrations. Nevertheless, care is
advised when co-administering potent cytochrome
Flixotide It is recommended that the height of children receiving P450 3A4 inhibitors (e.g. ketoconazole) as there is
prolonged treatment with inhaled corticosteroid is potential for increased systemic exposure to fluticasone
regularly monitored. propionate.
N/A Because of the possibility of impaired adrenal response,
patients transferring from oral steroid therapy to inhaled Pregnancy and Lactation
FLIXOTIDE therapy should be treated with special care, Fertility
02-01-XX-273-11 and adrenocortical function regularly monitored. There are no data on human fertility. Animal studies
Following introduction of inhaled FLIXOTIDE, indicate no effects of fluticasone propionate on male or
withdrawal of systemic therapy should be gradual and female fertility.
N/A patients encouraged to carry a steroid warning card Pregnancy
indicating the possible need for additional therapy in There are limited data in pregnant women.
times of stress. Administration of FLIXOTIDE during pregnancy should
N/A The possibility of impaired adrenal response should only be considered if the expected benefit to the mother
always be considered in emergency situations (including is greater than any possible risk to the foetus.
1 surgery), and also in elective situations likely to produce Results from a retrospective epidemiological study did
stress, especially in patients taking high doses for an not find an increased risk of major congenital
K extended duration of time. Additional corticosteroid malformations (MCMs) following exposure to fluticasone
treatment appropriate to a given clinical situation must propionate when compared to other inhaled
be considered (see Overdose). corticosteoroids, during the first trimester of pregnancy
Similarly replacement of systemic steroid treatment with (see Clinical Studies).
0 inhaled therapy may unmask allergies such as allergic Reproductive studies in animals have shown only those
rhinitis or eczema previously controlled by the systemic effects characteristic of glucocorticosteroids at systemic
drug. exposures in excess of those seen at the recommended
Treatment with FLIXOTIDE should not be stopped inhaled therapeutic dose.
abruptly. Lactation
There have been very rare reports of increases in blood The excretion of fluticasone propionate into human
0
glucose levels (see Adverse Reactions) and this should be breast milk has not been investigated. When
considered when prescribing to patients with a history measurable plasma levels were obtained in lactating
of diabetes mellitus. laboratory rats following subcutaneous administration
As with all inhaled corticosteroids, special care is there was evidence of fluticasone propionate in the
necessary in patients with active or quiescent pulmonary breast milk. However, plasma levels in patients
tuberculosis. following inhaled application of fluticasone propionate
During post-marketing use, there have been reports of at recommended doses are likely to be low.
clinically significant drug interactions in patients Administration during lactation should only be
receiving fluticasone propionate and ritonavir, resulting considered if the expected benefit to the mother is
in systemic corticosteroid effects including Cushing’s greater than any possible risk to the child.
syndrome and adrenal suppression. Therefore,
Effects on Ability to Drive and Use Machines
concomitant use of fluticasone propionate and ritonavir
should be avoided, unless the potential benefit to the FLIXOTIDE is unlikely to produce an effect.
patient outweighs the risk of systemic corticosteroid Adverse Reactions
side-effects (see Interactions).
Adverse events are listed below by system organ class and
As with other inhalation therapy, paradoxical frequency. Frequencies are defined as: very common
bronchospasm may occur with an immediate increase in (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to
wheezing after dosing. This should be treated <1/100), rare (≥1/10,000 to <1/1000) and very rare
immediately with a fast-acting inhaled bronchodilator. (<1/10,000) including isolated reports. Very common,
FLIXOTIDE Evohaler should be discontinued immediately, common and uncommon events were generally
the patient assessed, and alternative therapy instituted determined from clinical trial data. Rare and very rare
if necessary (see Adverse Reactions). events were generally determined from spontaneous data.
Patients’ inhaler technique should be checked to make
sure that inhaler actuation is synchronised with inspiration
to ensure optimum delivery of the drug to the lungs.

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Infections and infestations Diskhaler (9.0%) and fluticasone propionate Evohaler
Very common: Candidiasis of mouth and throat. (10.9%) respectively. In patients with asthma or COPD a
lesser degree of systemic exposure to inhaled fluticasone
Candidiasis of the mouth and throat (thrush) occurs in
propionate has been observed. Systemic absorption
some patients. Such patients may find it helpful to rinse
occurs mainly through the lungs and is initially rapid
out their mouth with water after using their medication.
then prolonged. The remainder of the inhaled dose may
Symptomatic candidiasis can be treated with topical
be swallowed but contributes minimally to systemic
anti-fungal therapy whilst still continuing with FLIXOTIDE.
exposure due to the low aqueous solubility and
Common: Pneumonia (in COPD patients). pre-systemic metabolism, resulting in oral availability of
Rare: Oesophageal candidiasis less than 1%. There is a linear increase in systemic
exposure with increasing inhaled dose.
Immune system disorders
Hypersensitivity reactions with the following Distribution
manifestations have been reported: Fluticasone propionate has a large volume of
Uncommon: Cutaneous hypersensitivity reactions. distribution at steady-state (approximately 300 l). Plasma
protein binding is moderately high (91%).
Very rare: Angioedema (mainly facial and oropharyngeal
2 oedema), respiratory symptoms (dyspnoea and/or Metabolism
bronchospasm) and anaphylactic reactions. Fluticasone propionate is cleared very rapidly from the
Endocrine disorders systemic circulation, principally by metabolism to an
62000000004309
inactive carboxylic acid metabolite, by the cytochrome
Possible systemic effects include (see Warnings and
P450 enzyme CYP3A4. Care should be taken when
Precautions):
co-administering known CYP3A4 inhibitors, as there is
GSK-ESP-Aranda-ESARA Very rare: Cushing’s syndrome, Cushingoid features, potential for increased systemic exposure to fluticasone
adrenal suppression, growth retardation, decreased propionate.
bone mineral density, cataract, glaucoma.
*Multi-Market Central-GEXP Elimination
Metabolism and nutrition disorders
The disposition of fluticasone propionate is characterised
Very rare: Hyperglycaemia.
by high plasma clearance (1150 ml/min) and a terminal
Flixotide Psychiatric disorders half-life of approximately 8 hours. The renal clearance of
Very rare: Anxiety, sleep disorders and behavioural fluticasone propionate is negligible (less than 0.2%) and
changes, including hyperactivity and irritability less than 5% as the metabolite.
N/A (predominantly in children). Clinical Studies

Respiratory, thoracic and mediastinal disorders COPD


02-01-XX-273-11 Common: Hoarseness. There is a significant reduction of symptoms of COPD
and an improvement in lung function regardless of
In some patients inhaled FLIXOTIDE may cause patient age, gender, lung base line function, smoking
hoarseness. It may be helpful to rinse out the mouth status or atopy status. This can result in a significant
N/A with water immediately after inhalation. improvement in the quality of life.
Very rare: Paradoxical bronchospasm (see Warnings and Fluticasone propionate containing medications in
Precautions). asthma during pregnancy
N/A
Skin and subcutaneous tissue disorders An observational retrospective epidemiological cohort
1 Common: Contusions. study utilising electronic health records from the United
Kingdom was conducted to evaluate the risk of MCMs
Overdose following first trimester exposure to inhaled fluticasone
K
Acute inhalation of FLIXOTIDE doses in excess of those propionate (FP) alone and salmeterol-FP combination
approved may lead to temporary suppression of the relative to non-FP containing ICS. No placebo
hypothalamic-pituitary-adrenal axis. This does not comparator was included in this study.
0 usually require emergency action, as normal adrenal Within the asthma cohort of 5362 first trimester
function typically recovers within a few days. ICS-exposed pregnancies, 131 diagnosed MCMs were
If higher than approved doses are continued over identified; 1612 (30%) were exposed to FP or
prolonged periods, significant adrenocortical salmeterol-FP of which 42 diagnosed MCMs were
suppression is possible. There have been very rare identified. The adjusted odds ratio for MCMs diagnosed
reports of acute adrenal crisis occurring in children by 1 year was 1.1 (95%CI: 0.5 – 2.3) for FP exposed vs
exposed to higher than approved doses (typically non-FP ICS exposed women with moderate asthma and
0
1000 micrograms daily and above), over prolonged 1.2 (95%CI: 0.7 – 2.0) for women with considerable to
periods (several months or years); observed features severe asthma. No difference in the risk of MCMs was
included hypoglycaemia and sequelae of decreased identified following first trimester exposure to FP alone
consciousness and/or convulsions. Situations which could versus salmeterol-FP combination. Absolute risks of
potentially trigger acute adrenal crisis include exposure MCM across the asthma severity strata ranged from
to trauma, surgery, infection or any rapid reduction in 2.0 to 2.9 per 100 FP-exposed pregnancies which is
dosage. comparable to results from a study of 15,840
Patients receiving higher than approved doses should be pregnancies unexposed to asthma therapies in the
managed closely and the dose reduced gradually. General Practice Research Database (2.8 MCM events per
100 pregnancies).
PHARMACOLOGICAL PROPERTIES
Pre-clinical Safety Data
Pharmacodynamics Toxicology has shown only those class effects typical of
potent corticosteroids, and these only at doses in excess
Pharmacodynamic Properties
of those proposed for therapeutic use. No novel effects
FLIXOTIDE given by inhalation at recommended doses were identified in repeat dose toxicity tests,
has a potent glucocorticoid anti-inflammatory action reproductive studies or teratology studies.
within the lungs, resulting in reduced symptoms and
Fluticasone propionate is devoid of mutagenic activity
exacerbations of asthma.
in-vitro and in-vivo and showed no tumorigenic
Pharmacokinetics potential in rodents. It is both non-irritant and
non-sensitising in animal models.
Absorption
The non-CFC propellant, HFA134a, has been shown to
The absolute bioavailability of fluticasone propionate have no toxic effect at very high vapour concentrations,
for each of the available inhaler devices has been far in excess of those likely to be experienced by
estimated from within and between study comparisons patients, in a wide range of animal species exposed daily
of inhaled and intravenous pharmacokinetic data. In for periods of two years.
healthy adult subjects the absolute bioavailability has
been estimated for fluticasone propionate
TEXT SIZE CONTAINED IN THIS ARTWORK Accuhaler/Diskus (7.8%), fluticasone propionate
62000000004309
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PHARMACEUTICAL PARTICULARS
List of Excipients
Hydroxyfluoroalkane 134a, 1, 1, 1, 2-tetrafluoroethane
(HFA 134a).
Incompatibilities
None reported.
Shelf-Life
The expiry date is indicated on the packaging.
6. Just after starting to 7. While holding your
Special Precautions for Storage
breathe in through breath, take the
Replace the mouthpiece cover firmly and snap it into your mouth press inhaler from your
position. down on the top of mouth and take your
FLIXOTIDE Evohaler should not be stored above 30°C. the inhaler to release finger from the top
2 Protect from frost and direct sunlight. FLIXOTIDE while still
breathing in steadily
of the inhaler.
Continue holding
As with most inhaled medications in pressurised
PHARMA CODE N° 5508

and deeply. your breath for as


canisters, the therapeutic effect of this medication may
62000000004309 long as is
decrease when the canister is cold. comfortable.
The canister should not be punctured, broken or burnt
8. If you are to take further puffs keep the inhaler
GSK-ESP-Aranda-ESARA even when apparently empty.
upright and wait about half a minute before
Nature and Contents of Container repeating steps 3 to 7.
FLIXOTIDE Evohaler comprises a suspension of 9. Afterwards, rinse your mouth with water and spit it
*Multi-Market Central-GEXP fluticasone propionate in the non-CFC propellant HFA out.
134a. The suspension is contained in an aluminium alloy 10. Replace the mouthpiece cover by firmly pushing and
can sealed with a metering valve. The canisters are fitted snapping the cap into position.
Flixotide into plastic actuators incorporating an atomising orifice
and fitted with dustcaps. IMPORTANT:
Do not rush stages 5, 6 and 7. It is important that you
N/A Instructions for Use/Handling
start to breathe in as slowly as possible just before
Instructions for use of your FLIXOTIDE Evohaler operating your inhaler. Practise in front of a mirror for
the first few times. If you see “mist” coming from the
02-01-XX-273-11 Testing your inhaler: top of your inhaler or the sides of your mouth you
Before using for the first time or if your inhaler has not should start again from stage 2.
been used for a week or more remove the mouthpiece If your doctor has given you different instructions for
N/A cover by gently squeezing the sides of the cover, shake using your inhaler, please follow them carefully. Tell
the inhaler well, and release two puffs into the air to your doctor if you have any difficulties.
make sure that it works.
N/A Cleaning:
Using your inhaler:
Your inhaler should be cleaned at least once a week.
1 1. Remove the mouthpiece cover.
2. Do not remove the canister from the plastic casing.
K
3. Wipe the inside and outside of the mouthpiece with
a dry cloth or tissue.
4. Replace the mouthpiece cover.
0 DO NOT PUT THE METAL CANISTER INTO WATER.
Manufactured by:
Glaxo Wellcome, S.A.,* Aranda de Duero, Spain
*Member of the GlaxoSmithKline group of companies
1. Remove the 3. Shake the inhaler
FLIXOTIDE, EVOHALER and BABYHALER are trade marks
mouthpiece cover by well to ensure that
0 of the GlaxoSmithKline group of companies.
gently squeezing the any loose objects are
sides of the cover. removed and that the © 2015 GlaxoSmithKline group of companies. All rights
contents of the reserved
2. Check inside and
outside of the inhaler inhaler are evenly Version number: GDS32/IPI10
including the mixed.
Date of issue: 30 March 2015
mouthpiece for the
presence of loose
objects.

4. Hold the inhaler 5. Breathe out as far as


upright between is comfortable and
fingers and thumb then place the
with your thumb on mouthpiece in your
the base, below the mouth between your
mouthpiece. teeth and close your
lips around it but do
not bite it.

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