FLIXOTIDE ACCUHALER 50 MCG
Active substance(s): FLUTICASONE PROPIONATE
NAME OF THE MEDICINAL PRODUCT
Flixotide Accuhaler 50 micrograms
QUALITATIVE AND QUANTITATIVE COMPOSITION
Flixotide Accuhaler is a moulded plastic device containing a foil strip with 28
or 60 regularly placed blisters each containing a mixture of microfine
fluticasone propionate (50 micrograms) and larger particle size lactose.
Excipient with known effect:
Multi-dose dry powder inhalation device.
Fluticasone propionate given by inhalation offers preventative treatment for asthma.
At recommended doses it has a potent glucocorticoid anti-inflammatory action within
the lungs, with a lower incidence and severity of adverse effects than those observed
when corticosteroids are administered systemically.
Flixotide Accuhaler 50 micrograms is recommended for any child who requires
prophylactic medication for asthma, including patients not controlled on currently
available prophylactic medication.
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
Flixotide Accuhaler is for oral inhalation use only. Flixotide Accuhaler is
suitable for many patients, including those who cannot use a metered-dose
inhaler successfully. The dose may be increased until control is achieved or
reduced to the minimum effective dose, according to the individual response.
Patients should be made aware of the prophylactic nature of therapy with
Flixotide Accuhaler and that it should be taken regularly even when they are
asymptomatic. The onset of therapeutic effect is within 4 to 7 days.
Typical starting doses for children
over 4years 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.
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.
Patients should be given a starting dose of inhaled fluticasone propionate
which is appropriate to the severity of their disease.
The dose should be titrated down to the lowest dose at which effective control
of asthma is maintained.
Hypersensitivity to the active substance or any of the excipients listed in
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.
Flixotide Accuhaler 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.
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
Fluticasone propionate is not for use in acute asthma attacks, but for routine
long-term management. Patients will require a fast- and short-acting inhaled
bronchodilator to relieve acute asthmatic symptoms.
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
There have been very rare reports of increases in blood glucose levels, in
patients with or without a history of diabetes mellitus (See section 4.8). 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 Accuhaler 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 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.
Certain individuals can show greater susceptibility to the effects of inhaled
corticosteroid than do most patients.
Because of the possibility of impaired adrenal response, patients transferring
from oral steroid therapy to inhaled fluticasone propionate therapy should be
treated with special care, and adrenocortical function regularly monitored.
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
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.
When changing from a dry powder inhaler to a metered dose inhaler,
administration of high doses, above 1000 mcg daily, is recommended through
a spacer to reduce side effects in the mouth and throat. However, this may
increase drug delivery to the lungs. As systemic absorption is largely through
the lungs, there may be an increase in the risk of systemic adverse effects. A
lower dose may be required.
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 section 4.5).
Treatment with Flixotide Accuhaler should not be stopped abruptly.
For the transfer of patients being treated with oral corticosteroids: The
transfer of oral steroid-dependent patients to Flixotide Accuhaler 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
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
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,
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 section 4.5).
Patients with rare hereditary problems of galactose intolerance, the Lapp
lactase deficiency or glucose-galactose malabsorption should not take this
Visual disturbance may be reported with systemic and topical corticosteroid
use. If a patient presents with symptoms such as blurred vision or other visual
disturbances, the patient should be considered for referral to an
ophthalmologist for evaluation of possible causes, which may include cataract,
glaucoma or rare diseases such as central serous chorioretinopathy (CSCR)
which have been reported after use of systemic and topical corticosteroids.
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.
Fertility, pregnancy and lactation
There is inadequate evidence of safety of fluticasone propionate in human
pregnancy. 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 Accuhaler
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.
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.
Effects on ability to drive and use machines
Fluticasone propionate is unlikely to produce an effect.
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.
Candidiasis of the mouth and throat
Pneumonia (in COPD patients)
Hypersensitivity reactions with the following
Cutaneous hypersensitivity reactions
Angioedema (mainly facial and oropharyngeal
Respiratory symptoms (dyspnoea and/or
Cushing’s syndrome, Cushingoid features,
adrenal suppression, growth retardation in
children and adolescents, decreased bone
mineral density, cataract, glaucoma
Vision, blurred (see section 4.4)
Hyperglycaemia (see section 4.4)
Anxiety, sleep disorders, behavioural changes,
including hyperactivity and irritability
(predominantly in children)
Depression, aggression (predominantly in
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, (see
As with other inhalation therapy, paradoxical bronchospasm may occur (see
section 4.4). 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 or search for MHRA Yellow Card in the
Google Play or Apple App Store.
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
Patients receiving higher than approved doses should be managed closely and
the dose reduced gradually.
Fluticasone propionate given by inhalation at recommended doses has a potent
glucocorticoid anti-inflammatory action within the lungs, resulting in reduced
symptoms and exacerbations of asthma, with a lower incidence and severity of
adverse effects than those observed when corticosteroids are administered
Systemic absolute bioavailability of fluticasone propionate is estimated at 12-26% of
an inhaled dose, dependent on presentation. Systemic absorption occurs mainly
through the lungs and is initially rapid then prolonged. 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 major metabolite.
After an intravenous dose, fluticasone propionate is extensively distributed in the
body. The very high clearance rate indicates extensive hepatic clearance.
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 nonsensitising in animal models.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
18 months when not stored above 30°C.
Special Precautions for Storage
Do not store above 30°C (86°F). Store in a dry place.
Flixotide Accuhaler is sealed in a foil overwrap which should only be opened when it
is to be used for the first time. Once opened the foil overwrap should be discarded.
Nature and contents of container
The powder mix of fluticasone propionate and lactose is filled into a blister strip
consisting of a formed base foil with a peelable foil laminate lid. The foil strip is
contained within the Accuhaler device.
Flixotide Accuhaler is packaged within a foil overwrap.
Special precautions for disposal and other handling
The powdered medicine is inhaled through the mouth into the lungs.
The Accuhaler device contains the medicine in individual blisters which are
opened as the device is manipulated.
For detailed instructions for use refer to the Patient Information Leaflet in
MARKETING AUTHORISATION HOLDER
Glaxo Wellcome UK Ltd,
Stockley Park West,
Middlesex, UB11 1BT
MARKETING AUTHORISATION NUMBER(S)
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
25 April 1995
DATE OF REVISION OF THE TEXT