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FLIXOTIDE 50 MICROGRAMS EVOHALER

Active substance(s): FLUTICASONE PROPIONATE / FLUTICASONE PROPIONATE / FLUTICASONE PROPIONATE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Flixotide 50 micrograms Evohaler

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Flixotide 50 micrograms Evohaler is a pressurised inhalation, suspension,
delivering 50 micrograms of fluticasone propionate per actuation.

3

PHARMACEUTICAL FORM
Pressurised inhalation, suspension
Flixotide 50 micrograms Evohaler does not contain any chlorofluorocarbons
(CFCs).

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Fluticasone propionate given by inhalation offers prophylactic treatment for
asthma.
Adults:
Mild asthma: Patients requiring intermittent symptomatic bronchodilator
asthma medication on a regular daily basis.
Moderate asthma: Patients with unstable or worsening asthma despite
prophylactic therapy or bronchodilator alone.
Severe asthma: Patients with severe chronic asthma and those who are
dependent on systemic corticosteroids for adequate control of symptoms. On
introduction of inhaled fluticasone propionate many of these patients may be
able to reduce significantly or to eliminate their requirement for oral
corticosteroids.
Children: Any child who requires prophylactic medication, including patients
not controlled on currently available prophylactic medication

4.2

Posology and method of administration

Patients should be made aware of the prophylactic nature of therapy with inhaled
fluticasone propionate and that it should be taken regularly even when they are
asymptomatic.
If patients find that relief with short-acting bronchodilator treatment becomes less
effective or they need more inhalations than usual, medical attention must be sought.
Flixotide Evohaler is for oral inhalation use only. Flixotide Evohaler may be used
with a Volumatic spacer device by patients who find it difficult to synchronise
aerosol actuation with inspiration of breath.
Patients should be made aware of the prophylactic nature of therapy with Flixotide
Evohaler and that it should be taken regularly even when they are asymptomatic. The
onset of therapeutic effect is within 4 to 7 days.
Adults and children over 16 years: 100 to 1,000 micrograms twice daily, usually as
two twice daily inhalations.
Prescribers should be aware that fluticasone propionate is as effective as other inhaled
steroids approximately at half the microgram daily dose. For example, a 100mcg of
fluticasone propionate is approximately equivalent to 200mcg dose of beclometasone
dipropionate (CFC containing) or budesonide.
Due to the risk of systemic effects, doses above 500 micrograms twice daily should
be prescribed only for adult patients with severe asthma where additional clinical
benefit is expected, demonstrated by either an improvement in pulmonary function
and/or symptom control, or by a reduction in oral corticosteroid therapy (see 4.4
Special Warnings and Precautions for Use and 4.8 Undesirable Effects).
Patients should be given a starting dose of inhaled fluticasone propionate which is
appropriate to the severity of their disease.
The dose may be increased until control is achieved or reduced to the minimum
effective dose, according to the individual response.
Typical Adult Starting Doses:
For patients with mild asthma, a typical starting dose is 100 micrograms twice daily.
In moderate and more severe asthma, starting doses may need to be 250 to 500
micrograms twice daily. Where additional clinical benefit is expected, doses of up to
1000 micrograms twice daily may be used. Initiation of such doses should be
prescribed only by a specialist in the management of asthma (such as a consultant
physician or general practitioner with appropriate experience).
The dose should be titrated down to the lowest dose at which effective control of
asthma is maintained
Typical starting doses for children over 4 years of age:

50 to 100 micrograms twice daily.

Many children’s asthma will be well controlled using the 50 to 100 microgram twice
daily dosing regime. For those patients whose asthma is not sufficiently controlled,
additional benefit may be obtained by increasing the dose up to 200 micrograms
twice daily. The maximum licensed dose in children is 200 micrograms twice daily.
The starting dose should be appropriate to the severity of the disease.
The dose should be titrated down to the lowest dose at which effective control of
asthma is maintained
Should this particular Flixotide presentation not offer the exact paediatric dose
prescribed by the physician, please see data sheets of alternative Flixotide
presentation (Accuhaler, Nebules)
Administration of doses above 1000 micrograms (500 micrograms twice daily)
should be via a spacer device to help reduce side-effects in the mouth and throat (See
Section 4.4)
Special patient groups:
There is no need to adjust the dose in elderly patients or those with hepatic or renal
impairment.

4.3.

Contra-indications
Hypersensitivity to any ingredient of the preparation.

4.4

Special warnings and precautions for use
The management of asthma should follow a stepwise programme, and patient
response should be monitored clinically and by lung function tests.
Patients’ inhaler technique should be checked regularly to make sure that
inhaler actuation is synchronised with inspiration to ensure optimum
delivery to the lungs. During inhalation, the patient should preferably sit
or stand. The inhaler has been designed for use in a vertical position.
Sudden and progressive deterioration in asthma control is potentially lifethreatening and consideration should be given to increasing corticosteroid
dosage. In patients considered at risk, daily peak flow monitoring may be
instituted.
Flixotide Evohaler is not designed to relieve acute symptoms for which an
inhaled short-acting bronchodilator is required. Patients should be advised
to have such rescue medication available.
Severe asthma requires regular medical assessment, including lung-function
testing, as patients are at risk of severe attacks and even death. Increasing use
of short-acting inhaled β2-agonists to relieve symptoms indicates deterioration
of asthma control. If patients find that short-acting relief bronchodilator

treatment becomes less effective, or they need more inhalations than usual,
medical attention must be sought. In this situation patients should be
reassessed and consideration given to the need for increased anti-inflammatory
therapy (e.g. higher doses of inhaled corticosteroids or a course of oral
corticosteroids). Severe exacerbations of asthma must be treated in the normal
way.
There have been very rare reports of increases in blood glucose levels, in
patients with or without a history of diabetes mellitus (See 4.8 ‘Undesirable
Effects’). This should be considered in particular when prescribing to patients
with a history of diabetes mellitus.
As with other inhalation therapy, paradoxical bronchospasm may occur with
an immediate increase in wheezing after dosing. Flixotide Evohaler should be
discontinued immediately, the patient assessed and alternative therapy
instituted if necessary.
Systemic effects of inhaled corticosteroids may occur, particularly at high
doses prescribed for prolonged periods. These effects are much less likely to
occur than with oral corticosteroids. Possible systemic effects include
Cushing’s syndrome, Cushingoid features, adrenal suppression, growth
retardation in children and adolescents, decrease in bone mineral density,
cataract and glaucoma and more rarely, a range of psychological or
behavioural effects including psychomotor hyperactivity, sleep disorders,
anxiety, depression or aggression (particularly in children). It is important
therefore that the dose of inhaled corticosteroid is reviewed regularly and
reduced to the lowest dose at which effective control of asthma is maintained.
Prolonged treatment with high doses of inhaled corticosteroids may result in
adrenal suppression and acute adrenal crisis. Children aged < 16 years taking
higher than licensed doses of fluticasone (typically ≥1000mcg/day) may be at
particular risk. Situations, which could potentially trigger acute adrenal crisis,
include trauma, surgery, infection or any rapid reduction in dosage. Presenting
symptoms are typically vague and may include anorexia, abdominal pain,
weight loss, tiredness, headache, nausea, vomiting, decreased level of
consciousness, hypoglycaemia, and seizures. Additional systemic
corticosteroid cover should be considered during periods of stress or elective
surgery.
It is recommended that the height of children receiving prolonged treatment
with inhaled corticosteroids is regularly monitored. If growth is slowed,
therapy should be reviewed with the aim of reducing the dose of inhaled
corticosteroid, if possible, to the lowest dose at which effective control of
asthma is maintained. In addition, consideration should be given to referring
the patient to a paediatric respiratory specialist.
Certain individuals can show greater susceptibility to the effects of inhaled
corticosteroid than do most patients.

Administration of high doses, above 1000 mcg daily is recommended through
a spacer to reduce side effects in the mouth and throat. However, as systemic
absorption is largely through the lungs, the use of a spacer plus metered dose
inhaler may increase drug delivery to the lungs. It should be noted that this
could potentially lead to an increase in the risk of systemic adverse effects. A
lower dose may be required. (See section 4.2)
The benefits of inhaled fluticasone propionate should minimise the need for
oral steroids. However, patients transferred from oral steroids, remain at risk
of impaired adrenal reserve for a considerable time after transferring to inhaled
fluticasone propionate. The possibility of adverse effects may persist for some
time. These patients may require specialised advice to determine the extent of
adrenal impairment before elective procedures. The possibility of residual
impaired adrenal response should always be considered in emergency (medical
or surgical) and elective situations likely to produce stress, and appropriate
corticosteroid treatment considered.
Lack of response or severe exacerbations of asthma should be treated by
increasing the dose of inhaled fluticasone propionate and, if necessary, by
giving a systemic steroid and/or an antibiotic if there is an infection.
Replacement of systemic steroid treatment with inhaled therapy sometimes
unmasks allergies such as allergic rhinitis or eczema previously controlled by
the systemic drug. These allergies should be symptomatically treated with
antihistamine and/or topical preparations, including topical steroids.
As with all inhaled corticosteroids, special care is necessary in patients with
active or quiescent pulmonary tuberculosis.
During post-marketing use, there have been reports of clinically significant
drug interactions in patients receiving fluticasone propionate and ritonavir,
resulting in systemic corticosteroid effects including Cushing's syndrome and
adrenal suppression. Therefore,concomitant use of fluticasone propionate and
ritonavir should be avoided, unless the potential benefit to the patient
outweighs the risk of systemic corticosteroid side-effects (See Interactions).

Treatment with Flixotide Evohaler should not be stopped abruptly.
For the transfer of patients being treated with oral corticosteroids: The
transfer of oral steroid-dependent patients to Flixotide Evohaler and their
subsequent management needs special care as recovery from impaired
adrenocortical function, caused by prolonged systemic steroid therapy,
may take a considerable time.
Patients who have been treated with systemic steroids for long periods of time
or at a high dose may have adrenocortical suppression. With these patients
adrenocortical function should be monitored regularly and their dose of
systemic steroid reduced cautiously.

After approximately a week, gradual withdrawal of the systemic steroid is
commenced. Decrements in dosages should be appropriate to the level of
maintenance systemic steroid, and introduced at not less than weekly
intervals. For maintenance doses of prednisolone (or equivalent) of 10mg
daily or less, the decrements in dose should not be greater than 1mg per
day, at not less than weekly intervals. For maintenance doses of
prednisolone in excess of 10mg daily, it may be appropriate to employ
cautiously, larger decrements in dose at weekly intervals.
Some patients feel unwell in a non-specific way during the withdrawal phase
despite maintenance or even improvement of the respiratory function. They
should be encouraged to persevere with inhaled fluticasone propionate and to
continue withdrawal of systemic steroid, unless there are objective signs of
adrenal insufficiency.
Patients weaned off oral steroids whose adrenocortical function is still
impaired should carry a steroid warning card indicating that they need
supplementary systemic steroid during periods of stress, e.g. worsening
asthma attacks, chest infections, major intercurrent illness, surgery,
trauma, etc.

Ritonavir can greatly increase the concentration of fluticasone propionate in
plasma. Therefore, concomitant use should be avoided, unless the potential
benefit to the patient outweighs the risk of systemic corticosteroid side-effects.
There is also an increased risk of systemic side effects when combining
fluticasone propionate with other potent CYP3A inhibitors (see 4.5 Interaction
with Other Medicinal Products and Other Forms of Interaction).

4.5

Interaction with other medicinal products and other forms of interaction
Under normal circumstances, low plasma concentrations of fluticasone
propionate are achieved after inhaled dosing, due to extensive first pass
metabolism and high systemic clearance mediated by cytochrome P450 3A4 in
the gut and liver. Hence, clinically significant drug interactions mediated by
fluticasone propionate are unlikely.
In an interaction study in healthy subjects with intranasal fluticasone
propionate, ritonavir (a highly potent cytochrome P450 3A4 inhibitor) 100 mg
b.i.d. increased the fluticasone propionate plasma concentrations several
hundred fold, resulting in markedly reduced serum cortisol concentrations.
Cases of Cushing’s syndrome and adrenal suppression have been reported.
The combination should be avoided unless the benefit outweighs the increased
risk of systemic glucocorticoid side-effects.
In a small study using inhaled fluticasone propionate in healthy volunteers, the
slightly less potent CYP3A inhibitor ketoconazole increased the exposure of
fluticasone propionate after a single inhalation by 150%. This resulted in a
greater reduction of plasma cortisol as compared with fluticasone propionate

alone. Co-treatment with other potent CYP3A inhibitors, such as itraconazole,
is also expected to increase the systemic fluticasone propionate exposure and
the risk of systemic side-effects. Caution is recommended and long-term
treatment with such drugs should if possible be avoided.
Co-treatment with other potent CYP3A inhibitors, including cobicistatcontaining products, is expected to increase the risk of systemic side-effects.
Other inhibitors of CYP3A4 produce negligible (erythromycin) and minor
(ketoconazole) increases in systemic exposure to fluticasone propionate
without notable reductions in serum cortisol concentrations. Combinations
should be avoided unless the benefit outweighs the potential increased risk of
systemic corticosteroid side-effects, in which case patients should be
monitored for systemic corticosteroid side-effects.
4.6

Fertility, pregnancy and lactation
Pregnancy
There is inadequate evidence of safety of fluticasone propionate in human
pregnancy. Data on a limited (200) of exposed pregnancies indicate no adverse
effects of Flixotide Evohaler on pregnancy or the health of the foetus/new
born child. To date no other relevant epidemiological data are available.
Administration of corticosteroids to pregnant animals can cause abnormalities
of fetal development, including cleft palate and intra-uterine growth
retardation. There may therefore be a very small risk of such effects in the
human fetus. It should be noted, however, that the fetal changes in animals
occur after relatively high systemic exposure. Because Flixotide Evohaler
delivers fluticasone propionate directly to the lungs by the inhaled route it
avoids the high level of exposure that occurs when corticosteroids are given by
systemic routes. Administration of fluticasone propionate during pregnancy
should only be considered if the expected benefit to the mother is greater than
any possible risk to the fetus.
Breast-feeding
The secretion of fluticasone propionate in human breast milk has not been
investigated. Subcutaneous administration of fluticasone propionate to
lactating laboratory rats produced measurable plasma levels and evidence of
fluticasone propionate in the milk. However, plasma levels in humans after
inhalation at recommended doses are likely to be low. When fluticasone
propionate is used in breast-feeding mothers the therapeutic benefits must be
weighed against the potential hazards to mother and baby.

4.7.

Effects on Ability to Drive and Use Machines
Fluticasone propionate is unlikely to produce an effect.

4.8

Undesirable Effects

Adverse events are listed below by system organ class and frequency.
Frequencies are defined as: very common (≥1/10), common (≥1/100 and
<1/10), uncommon (≥1/1000 and <1/100), rare (≥1/10,000 and <1/1000), very
rare (<1/10,000) including isolated reports and not known (cannot be
estimated from the available data). Very common, common and uncommon
events were generally determined from clinical trial data. Rare and very rare
events were generally determined from spontaneous data.
System Organ
Class
Infections &
Infestations

Immune System
Disorders

Endocrine
Disorders

Metabolism &
Nutrition
Disorders
Psychiatric
Disorders

Respiratory,
Thoracic &
Mediastinal
Disorders
Gastrointestinal
Disorders
Skin &
Subcutaneous
Tissue Disorders
Musculoskeletal
& Connective
Tissue Disorders

Adverse Event

Frequency

Candidiasis of the mouth and throat

Very
Common

Pneumonia (in COPD patients)
Oesophageal candidiasis
Hypersensitivity reactions with the following
manifestations:

Common
Rare

Cutaneous hypersensitivity reactions

Uncommon

Angioedema (mainly facial and oropharyngeal
oedema),
Respiratory symptoms (dyspnoea and/or
bronchospasm),
Anaphylactic reactions
Cushing’s syndrome, Cushingoid features,
adrenal suppression, growth retardation in
children and adolescents, decreased bone
mineral density, cataract, glaucoma
Hyperglycaemia (see 4.4 ‘Special Warnings and
Precautions for Use’)

Very Rare

Anxiety, sleep disorders, behavioural changes,
including hyperactivity and irritability
(predominantly in children)

Very Rare

Depression, aggression (predominantly in
children)
Hoarseness/dysphonia

Not known

Paradoxical bronchospasm

Very Rare

Epistaxis
Dyspepsia

Not known
Very Rare

Contusions

Common

Arthralgia

Very Rare

Very Rare
Very Rare
Very Rare

Very Rare

Common

Hoarseness and candidiasis of the mouth and throat (thrush) occurs in some
patients. Such patients may find it helpful to rinse out their mouth with water
after using the Accuhaler. Symptomatic candidiasis can be treated with
topical anti-fungal therapy whilst still continuing with the Flixotide Accuhaler.
Possible systemic effects include Cushing’s syndrome, Cushingoid features,
adrenal suppression, growth retardation, decreased bone mineral density,
cataract, glaucoma (see 4.4 Special Warnings and Special Precautions for
Use).
As with other inhalation therapy, paradoxical bronchospasm may occur (see
4.4 ‘Special Warnings and Precautions for Use’). This should be treated
immediately with a fast-acting inhaled bronchodilator. Flixotide Accuhaler
should be discontinued immediately, the patient assessed, and if necessary
alternative therapy instituted.
There was an increased reporting of pneumonia in studies of patients with
COPD receiving FLIXOTIDE 500 micrograms. Physicians should remain
vigilant for the possible development of pneumonia in patients with COPD as
the clinical features of pneumonia and exacerbation frequently overlap.
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
Acute: Inhalation of the drug in doses in excess of those recommended may
lead to temporary suppression of adrenal function. This does not necessitate
emergency action being taken. In these patients treatment with fluticasone
propionate by inhalation should be continued at a dose sufficient to control
asthma adrenal function recovers in a few days and can be verified by
measuring plasma cortisol.
If higher than approved doses are continued over prolonged periods,
significant adrenocortical suppression is possible. There have been very rare
reports of acute adrenal crisis occurring in children exposed to higher than
approved doses (typically 1000 micrograms daily and above), over prolonged
periods (several months or years); observed features included hypoglycaemia
and sequelae of decreased consciousness and/or convulsions. Situations which
could potentially trigger acute adrenal crisis include exposure
to trauma, surgery, infection or any rapid reduction in dosage.

Chronic: refer to section 4.4: risk of adrenal suppression.

Monitoring of adrenal reserve may be indicated. Treatment with inhaled
fluticasone propionate should be continued at a dose sufficient to control
asthma.
Treatment
Patients receiving higher than approved doses should be managed closely and
the dose reduced gradually.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Fluticasone propionate given by inhalation at recommended doses has a potent
glucocorticoid anti-inflammatory action within the lungs, resulting in a
reduction of both symptoms and exacerbations of asthma, with a lower
incidence and severity of adverse effects than those observed when
corticosteroids are administered systemically.

5.2.

Pharmacokinetic Properties
In healthy subjects the mean systemic bioavailability of Flixotide Evohaler is
28.6%. In patients with asthma (FEV1 < 75% predicted) the mean systemic
absolute bioavailability was reduced by 62 %. Systemic absorption occurs
mainly through the lungs and has been shown to be linearly related to dose
over the dose range 500 to 2000 micrograms. Absorption is initially rapid
then prolonged and the remainder of the dose may be swallowed.
Absolute oral bioavailability is negligible (< 1%) due to a combination of
incomplete absorption from the GI tract and extensive first-pass metabolism.
87-100% of an oral dose is excreted in the faeces, up to 75% as parent
compound. There is also a non-active metabolite.
After an intravenous dose, fluticasone propionate is extensively distributed in
the body. The very high clearance rate indicates extensive hepatic clearance.

5.3.

Preclinical Safety Data
Toxicology has shown only those class effects typical of potent
corticosteroids, and these only at doses greatly in excess of that proposed for
therapeutic use. No novel effects were identified in repeat dose toxicity tests,
reproductive studies or teratology studies. Fluticasone propionate is devoid of
mutagenic activity in vitro and in vivo and showed no tumorigenic potential in
rodents. It is both non-irritant and non-sensitising in animal models.

The non-CFC propellant, HFA 134a, has been shown to have no toxic effect at
very high vapour concentrations, far in excess of those likely to be
experienced by patients, in a wide range of animal species exposed daily for
periods of two years.
The use of HFA 134a as a propellant has not altered the toxicity profile of
fluticasone propionate compared to that using the conventional CFC
propellant.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
HFA 134a

6.2.

Incompatibilities
None reported.

6.3.

Shelf Life
24 months

6.4

Special precautions for storage
Do not store above 30°C (86°F). Do not refrigerate or freeze. Protect from
frost and direct sunlight.
As with most medicines in pressurised canisters, the therapeutic effect of this
medication may decrease when the canister is cold.
The canister should not be punctured, broken or burnt even when apparently
empty.
Replace the mouthpiece cover firmly and snap it into position.

6.5.

Nature and Contents of Container
An inhaler comprising an aluminium alloy can sealed with a metering valve,
actuator and dust cap. Each canister contains 120 metered actuations of 50
micrograms of fluticasone propionate.(60 metered actuation hospital packs are
available).

6.6

Special precautions for disposal and other handling
The aerosol spray is inhaled through the mouth into the lungs. After shaking
the inhaler the patient should exhale, the mouthpiece should be placed in the
mouth and the lips closed around it. The actuator is depressed to release a
spray, which must coincide with inspiration of breath.
For detailed instructions for use refer to the Patient Information Leaflet in
every pack.

7

MARKETING AUTHORISATION HOLDER
Glaxo Wellcome UK Ltd,
Stockley Park West,
Uxbridge,
Middlesex, UB11 1BT

8.

MARKETING AUTHORISATION NUMBER(S)
PL 10949/0324

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
12/10/2005

10

DATE OF REVISION OF THE TEXT
30/03/2017

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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