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SERETIDE EVOHALER 25 MICROGRAM /125 MICROGRAM PER METERED DOSE PRESSURISED INHALATION SUSPENSION

Active substance(s): FLUTICASONE PROPIONATE MICRONISED / SALMETEROL XINAFOATE MICRONISED

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Seretide Evohaler 25 microgram /125 microgram per metered dose pressurised
inhalation, suspension.

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each metered dose (ex valve) contains:
25 micrograms of salmeterol (as salmeterol xinafoate) and 125 micrograms of
fluticasone propionate. This is equivalent to a delivered dose (ex actuator) of 21
micrograms of salmeterol and 110 micrograms of fluticasone propionate.
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Pressurised inhalation, suspension.
The canister contains a white to off white suspension.
The canisters are fitted into purple plastic actuators incorporating an atomising orifice
and fitted with dustcaps.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Seretide is indicated in the regular treatment of asthma where use of a
combination product (long-acting β2 agonist and inhaled corticosteroid) is
appropriate:
or
-

patients not adequately controlled with inhaled corticosteroids and
‘as needed’ inhaled short- acting β2 agonist
patients already adequately controlled on both inhaled
corticosteroid and long-acting β2 agonist

4.2

Posology and method of administration
Posology
Route of administration: Inhalation use.
Patients should be made aware that Seretide Evohaler must be used daily for optimum
benefit, even when asymptomatic.
Patients should be regularly reassessed by a doctor, so that the strength of Seretide
they are receiving remains optimal and is only changed on medical advice. The dose
should be titrated to the lowest dose at which effective control of symptoms is
maintained. Where the control of symptoms is maintained with the lowest strength of
the combination given twice daily then the next step could include a test of inhaled
corticosteroid alone. As an alternative, patients requiring a long-acting 2 agonist
could be titrated to Seretide given once daily if, in the opinion of the prescriber, it
would be adequate to maintain disease control. In the event of once daily dosing
when the patient has a history of nocturnal symptoms the dose should be given at
night and when the patient has a history of mainly daytime symptoms the dose should
be given in the morning.
Patients should be given the strength of Seretide containing the appropriate
fluticasone propionate dosage for the severity of their disease. Note: Seretide 25
microgram/50 microgram strength is not appropriate for adults and children with
severe asthma. If an individual patient should require dosages outside the
recommended regimen, appropriate doses of 2 agonist and/or corticosteroid should
be prescribed.
Recommended Doses:
Adults and adolescents 12 years and older:
Two inhalations of 25 micrograms salmeterol and 50 micrograms fluticasone
propionate twice daily.
or
Two inhalations of 25 micrograms salmeterol and 125 micrograms
fluticasone propionate twice daily.
or
Two inhalations of 25 micrograms salmeterol and 250 micrograms
fluticasone propionate twice daily.
A short-term trial of Seretide may be considered as initial maintenance therapy in
adults or adolescents with moderate persistent asthma (defined as patients with daily
symptoms, daily rescue use and moderate to severe airflow limitation) for whom

rapid control of asthma is essential. In these cases, the recommended initial dose is
two inhalations of 25 micrograms salmeterol and 50 micrograms fluticasone
propionate twice daily. Once control of asthma is attained treatment should be
reviewed and consideration given as to whether patients should be stepped down to
an inhaled corticosteroid alone. Regular review of patients as treatment is stepped
down is important.
A clear benefit has not been shown as compared to inhaled fluticasone propionate
alone used as initial maintenance therapy when one or two of the criteria of severity
are missing. In general inhaled corticosteroids remain the first line treatment for most
patients. Seretide is not intended for the initial management of mild asthma. Seretide
25 micrograms/50 micrograms strength is not appropriate in adults and children with
severe asthma; it is recommended to establish the appropriate dosage of inhaled
corticosteroid before any fixed-combination can be used in patients with severe
asthma.
Paediatric population
Children 4 years and older:
Two inhalations of 25 micrograms salmeterol and 50 micrograms fluticasone
propionate twice daily.
The maximum licensed dose of fluticasone propionate delivered by Seretide inhaler
in children is 100 microgram twice daily.
There are no data available for use of Seretide inhaler in children aged under 4 years.
Children <12 years old may have difficulties synchronising aerosol actuation with
inspiration of breath. Use of a spacer device with Seretide inhaler is recommended in
patients who have, or are likely to have difficulties to coordinate actuation with
inspiration. A recent clinical study has shown that paediatric patients using a spacer
achieved exposure similar to adults not using spacer and paediatric patients using
Diskus, confirming that spacers compensate for poor inhaler technique (see section
5.2).
Either the Volumatic or AeroChamber Plus spacer device can be used (depending on
National Guidance). Limited data are available that demonstrate an increase in
systemic exposure when the AeroChamber Plus spacer device is used compared with
the Volumatic spacer device (see section 4.4).
Patients should be instructed in the proper use and care of their inhaler and spacer and
their technique checked to ensure optimum delivery of the inhaled drug to the lungs.
Patients should continue to use the same make of spacer device as switching between
spacer devices can result in changes in the dose delivered to the lungs (see section
4.4).

Re-titration to the lowest effective dose should always follow the introduction or
change of a spacer device.
Special patient groups
There is no need to adjust the dose in elderly patients or in those with renal
impairment. There are no data available for use of Seretide in patients with hepatic
impairment.
Instructions for Use
Patients should be instructed in the proper use of their inhaler (see patient information
leaflet)
During inhalation, the patient should preferably sit or stand. The inhaler has been
designed for use in a vertical position.
Testing the inhaler:
Before using for the first time patients should remove the mouthpiece cover by gently
squeezing the sides of the cover, shake the inhaler well, hold the inhaler between the
fingers and thumb with their thumb on the base, below the mouthpiece and release
puffs into the air until the counter reads 120 to make sure that it works. The inhaler
should be shaken immediately before releasing each puff. If the inhaler has not been
used for a week or more the mouthpiece cover should be removed, the patient should
shake the inhaler well and should release two puffs into the air. Each time the inhaler
is activated the number on the counter will count down by one.
Use of the inhaler:
1.

Patients should remove the mouthpiece cover by gently squeezing the sides of
the cover

2.

Patients should check inside and outside of the inhaler including the
mouthpiece for the presence of loose objects.

3.

Patients should shake the inhaler well to ensure that any loose objects are
removed and that the contents of the inhaler are evenly mixed

4.

Patients should hold the inhaler upright between fingers and thumb with their
thumb on the base, below the mouthpiece.

5.

Patients should breathe out as far as is comfortable and then place the
mouthpiece in their mouth between their teeth and close their lips around it,
Patients should be instructed not to bite the mouth piece.

6.

Just after starting to breathe in through their mouth, patients should press
firmly down on the top of the inhaler to release Seretide, while still breathing
in steadily and deeply.

7.

While holding their breath, patients should take the inhaler from their mouth
and take their finger from the top of the inhaler. Patients should continue
holding their breath for as long as is comfortable.

8.

To take a second inhalation, patients should keep the inhaler upright and wait
about half a minute before repeating steps 3 to 7.

9.

Patients should immediately replace the mouthpiece cover in the correct
orientation by firmly pushing and snapping the cap into position. This does
not require excessive force, the cover should click into position.

IMPORTANT
Patients should not rush stages 5, 6 and 7. It is important that patients start to breathe
in as slowly as possible just before operating their inhaler. Patients should practise in
front of a mirror for the first few times. If they see "mist" coming from the top of
their inhaler or the sides of their mouth they should start again from stage 3.
Patients should rinse their mouth out with water and spit out, and/or brush their teeth
after each dose of medicine, in order to minimise the risk of oropharyngeal
candidiasis and hoarseness.
Patients should consider getting a replacement when the counter shows the number
020. The counter will stop at 000 when all the recommended puffs have been used.
Replace the inhaler when the counter reads 000.
Patients should never try to alter the numbers on the counter or detach the counter
from the metal canister. The counter cannot be reset and is permanently attached to
the canister.
Cleaning (also detailed in patient information leaflet):
Your inhaler should be cleaned at least once a week.

1.

Remove the mouth piece cover.

2.

Do not remove the canister from the plastic casing.

3.

Wipe the inside and outside of the mouthpiece and the plastic casing with a
dry cloth or tissue.

4.

Replace the mouthpiece cover in the correct orientation. This does not require
excessive force, the cover should click into position.

DO NOT PUT THE METAL CANISTER IN WATER

4.3

Contraindications
Hypersensitivity to any of the active substances or to any of the excipients listed in
section 6.1.

4.4

Special warnings and precautions for use
Deterioration of disease
Seretide Evohaler should not be used to treat acute asthma symptoms for
which a fast- and short- acting bronchodilator is required. Patients should be
advised to have their inhaler to be used for relief in an acute asthma attack
available at all times.
Patients should not be initiated on Seretide during an exacerbation, or if they
have significantly worsening or acutely deteriorating asthma.
Serious asthma-related adverse events and exacerbations may occur during
treatment with Seretide. Patients should be asked to continue treatment but to
seek medical advice if asthma symptoms remain uncontrolled or worsen after
initiation on Seretide.
Increased requirements for use of reliever medication (short-acting
bronchodilators), or decreased response to reliever medication indicate
deterioration of control and patients should be reviewed by a physician.
Sudden and progressive deterioration in control of asthma is potentially lifethreatening and the patient should undergo urgent medical assessment.
Consideration should be given to increasing corticosteroid therapy.
Once asthma symptoms are controlled, consideration may be given to
gradually reducing the dose of Seretide. Regular review of patients as
treatment is stepped down is important. The lowest effective dose of Seretide
should be used (see section 4.2).

For patients with COPD experiencing exacerbations, treatment with systemic
corticosteroids is typically indicated, therefore patients should be instructed to
seek medical attention if symptoms deteriorate with Seretide.
Treatment with Seretide should not be stopped abruptly in patients with
asthma due to risk of exacerbation. Therapy should be down-titrated under
physician supervision. For patients with COPD cessation of therapy may also
be associated with symptomatic decompensation and should be supervised by
a physician.
As with all inhaled medication containing corticosteroids, Seretide should be
administered with caution in patients with active or quiescent pulmonary
tuberculosis and fungal, viral or other infections of the airway. Appropriate
treatment should be promptly instituted, if indicated.
Cardiovascular effects
Rarely, Seretide may cause cardiac arrhythmias e.g. supraventricular
tachycardia, extrasystoles and atrial fibrillation, and a mild transient reduction
in serum potassium at high therapeutic doses. Seretide should be used with
caution in patients with severe cardiovascular disorders or heart rhythm
abnormalities and in patients with diabetes mellitus, thyrotoxicosis,
uncorrected hypokalaemia or patients predisposed to low levels of serum
potassium.
Hyperglycaemia
There have been very rare reports of increases in blood glucose levels (see
section 4.8) and this should be considered when prescribing to patients with a
history of diabetes mellitus.
Paradoxical bronchospasm
As with other inhalation therapy paradoxical bronchospasm may occur with an
immediate increase in wheezing and shortness of breath after dosing.
Paradoxical bronchospasm responds to a rapid-acting bronchodilator and
should be treated straightaway. Seretide Evohaler should be discontinued
immediately, the patient assessed and alternative therapy instituted if
necessary.
The pharmacological side effects of β2 agonist treatment, such as tremor,
palpitations and headache, have been reported, but tend to be transient and
reduce with regular therapy.
Excipients
Seretide contains lactose monohydrate up to 12.5 milligram /dose. This
amount does not normally cause problems in lactose intolerant people. The

excipient lactose contains small amounts of milk proteins, which may cause
allergic reactions.
Systemic corticosteroid effects
Systemic effects may occur with any inhaled corticosteroid, particularly at
high doses prescribed for long periods. These effects are much less likely to
occur than with oral corticosteroids. Possible systemic effects include
Cushing’s syndrome, Cushingoid features, adrenal suppression, 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)
(see Paediatric population sub-heading below for information on the systemic
effects of inhaled corticosteroids in children and adolescents). It is important,
therefore, that the patient is reviewed regularly and the dose of inhaled
corticosteroid is reduced to the lowest dose at which effective control of
asthma is maintained.
Prolonged treatment of patients with high doses of inhaled corticosteroids may
result in adrenal suppression and acute adrenal crisis. Very rare cases of
adrenal suppression and acute adrenal crisis have also been described with
doses of fluticasone propionate between 500 and less than 1000 micrograms.
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, hypotension, decreased level of
consciousness, hypoglycaemia, and seizures. Additional systemic
corticosteroid cover should be considered during periods of stress or elective
surgery.
The benefits of inhaled fluticasone propionate therapy should minimise the
need for oral steroids, but patients transferring from oral steroids may remain
at risk of impaired adrenal reserve for a considerable time. Therefore these
patients should be treated with special care and adrenocortical function
regularly monitored. Patients who have required high dose emergency
corticosteroid therapy in the past may also be at risk. This possibility of
residual impairment should always be borne in mind in emergency and
elective situations likely to produce stress, and appropriate corticosteroid
treatment must be considered. The extent of the adrenal impairment may
require specialist advice before elective procedures.
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).
Pneumonia in patients with COPD

An increase in the incidence of pneumonia, including pneumonia requiring
hospitalisation, has been observed in patients with COPD receiving inhaled
corticosteroids. There is some evidence of an increased risk of pneumonia
with increasing steroid dose but this has not been demonstrated conclusively
across all studies.
There is no conclusive clinical evidence for intra-class differences in the
magnitude of the pneumonia risk among inhaled corticosteroid products.
Physicians should remain vigilant for the possible development of pneumonia
in patients with COPD as the clinical features of such infections overlap with
the symptoms of COPD exacerbations.
Risk factors for pneumonia in patients with COPD include current smoking,
older age, low body mass index (BMI) and severe COPD.
Interactions with potent CYP3A4 inhibitors

Concomitant use of systemic ketoconazole significantly increases systemic
exposure to salmeterol. This may lead to an increase in the incidence of
systemic effects (e.g. prolongation in the QTc interval and palpitations).
Concomitant treatment with ketoconazole or other potent CYP3A4 inhibitors
should therefore be avoided unless the benefits outweigh the potentially
increased risk of systemic side effects of salmeterol treatment (see section
4.5).
Paediatric population
Children and adolescents <16 years taking high doses of fluticasone
propionate (typically ≥ 1000 micrograms/day) may be at particular risk.
Systemic effects may occur, particularly at high doses prescribed for long
periods. Possible systemic effects include Cushing’s syndrome, Cushingoid
features, adrenal suppression, acute adrenal crisis and growth retardation in
children and adolescents and more rarely, a range of psychological or
behavioural effects including psychomotor hyperactivity, sleep disorders,
anxiety, depression or aggression. Consideration should be given to referring
the child or adolescent to a paediatric respiratory specialist.
It is recommended that the height of children receiving prolonged treatment
with inhaled corticosteroid is regularly monitored. The dose of inhaled
corticosteroid should be reduced to the lowest dose at which effective
control of asthma is maintained.
4.5

Interaction with other medicinal products and other forms of interaction

β adrenergic blockers may weaken or antagonise the effect of salmeterol. Both
non-selective and selective β blockers should be avoided in patients with
asthma, unless there are compelling reasons for their use. Potentially serious
hypokalaemia may result from β2 agonist therapy. Particular caution is
advised in acute severe asthma as this effect may be potentiated by
concomitant treatment with xanthine derivatives, steroids and diuretics.
Concomitant use of other β adrenergic containing drugs can have a potentially
additive effect.
Fluticasone Propionate
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 CYP3A4 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 CYP3A4 inhibitor) 100 mg
b.i.d. increased the fluticasone propionate plasma concentrations several
hundred fold, resulting in markedly reduced serum cortisol concentrations.
Information about this interaction is lacking for inhaled fluticasone propionate,
but a marked increase in fluticasone propionate plasma levels is expected.
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 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 and cobicistat-containing products,
and moderate CYP3A inhibitors, such as erythromycin, is also expected to
increase the systemic fluticasone propionate exposure and the risk of systemic
side effects. 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.
Salmeterol
Potent CYP3A4 inhibitors
Co-administration of ketoconazole (400 mg orally once daily) and salmeterol
(50 microgram inhaled twice daily) in 15 healthy subjects for 7 days resulted
in a significant increase in plasma salmeterol exposure (1.4-fold Cmax and 15fold AUC). This may lead to an increase in the incidence of other systemic
effects of salmeterol treatment (e.g. prolongation of QTc interval and
palpitations) compared with salmeterol or ketoconazole treatment alone (see
section 4.4).

Clinically significant effects were not seen on blood pressure, heart rate, blood
glucose and blood potassium levels. Co-administration with ketoconazole did
not increase the elimination half-life of salmeterol or increase salmeterol
accumulation with repeat dosing.
The concomitant administration of ketoconazole should be avoided, unless the
benefits outweigh the potentially increased risk of systemic side effects of
salmeterol treatment. There is likely to be a similar risk of interaction with
other potent CYP3A4 inhibitors (e.g. itraconazole, telithromycin, ritonavir).
Moderate CYP 3A4 inhibitors
Co-administration of erythromycin (500 mg orally three times a day) and
salmeterol (50 micrograms inhaled twice daily) in 15 healthy subjects for 6
days resulted in a small but non-statistically significant increase in salmeterol
exposure (1.4-fold Cmax and 1.2-fold AUC). Co-administration with
erythromycin was not associated with any serious adverse effects.
4.6

Fertility, pregnancy and lactation
Fertility
There are no data in humans. However, animal studies showed no effects of
salmeterol or fluticasone propionate on fertility.
Pregnancy
A large amount of data on pregnant women (more than 1000 pregnancy
outcomes) indicates no malformative or feto/neonatal toxicity related to
Seretide. Animal studies have shown reproductive toxicity after administration
of β2 adrenoreceptor agonists and glucocorticosteroids (see section 5.3).
Administration of Seretide to pregnant women should only be considered if
the expected benefit to the mother is greater than any possible risk to the fetus.
The lowest effective dose of fluticasone propionate needed to maintain
adequate asthma control should be used in the treatment of pregnant women.
Breastfeeding
It is unknown whether salmeterol and fluticasone propionate/metabolites are
excreted in human milk.
Studies have shown that salmeterol and fluticasone propionate, and their
metabolites, are excreted into the milk of lactating rats.
A risk to breastfed newborns/infants cannot be excluded. A decision must be
made whether to discontinue breastfeeding or to discontinue Seretide therapy
taking into account the benefit of breastfeeding for the child and the benefit of
therapy for the woman.

4.7

Effects on ability to drive and use machines
Seretide Evohaler has no or negligible influence on the ability to drive and use
machines.

4.8

Undesirable effects
As Seretide contains salmeterol and fluticasone propionate, the type and
severity of adverse reactions associated with each of the compounds may be
expected. There is no incidence of additional adverse events following
concurrent administration of the two compounds.
Adverse events which have been associated with salmeterol/fluticasone
propionate are given below, listed by system organ class and frequency.
Frequencies are defined as: very common (≥1/10), common (≥1/100 to <1/10),
uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000) and not known
(cannot be estimated from the available data). Frequencies were derived from
clinical trial data. The incidence in placebo was not taken into account.

System Organ
Class
Infections &
Infestations

Immune System
Disorders

Endocrine
Disorders

Adverse Event

Frequency

Candidiasis of the mouth and throat

Common

Pneumonia

Common1, 3, 5

Bronchitis

Common1, 3

Oesophageal candidiasis

Rare

Hypersensitivity reactions with the following
manifestations:
Cutaneous hypersensitivity reactions

Uncommon

Angioedema (mainly facial and oropharyngeal
oedema)

Rare

Respiratory symptoms (dyspnoea)

Uncommon

Respiratory symptoms (bronchospasm)

Rare

Anaphylactic reactions including anaphylactic
shock

Rare

Cushing’s syndrome, Cushingoid features,
Adrenal suppression, Growth retardation in

Rare4

System Organ
Class

Adverse Event

Frequency

children and adolescents, Decreased bone
mineral density
Metabolism &
Nutrition Disorders

Psychiatric
Disorders

Nervous System
Disorders

Eye Disorders

Cardiac Disorders

Respiratory,
Thoracic &
Mediastinal
Disorders

Hypokalaemia

Common3

Hyperglycaemia

Uncommon4

Anxiety

Uncommon

Sleep disorders

Uncommon

Behavioural changes, including psychomotor
hyperactivity and irritability (predominantly in
children)

Rare

Depression, aggression (predominantly in
children)

Not Known

Headache

Very Common1

Tremor

Uncommon

Cataract

Uncommon

Glaucoma

Rare4

Palpitations

Uncommon

Tachycardia

Uncommon

Cardiac arrhythmias (including supraventricular
tachycardia and extrasystoles).

Rare

Atrial fibrillation

Uncommon

Angina pectoris

Uncommon

Nasopharyngitis

Very Common2,
3

Throat irritation
Common
Hoarseness/dysphonia
Common
Sinusitis
Common1, 3
Paradoxical bronchospasm

Skin and

Contusions

Rare4
Common1, 3

System Organ
Class
subcutaneous tissue
disorders
Musculoskeletal &
Connective Tissue
Disorders

1.
2.
3.
4.
5.

Adverse Event

Frequency

Muscle cramps

Common

Traumatic fractures

Common1, 3

Arthralgia

Common

Myalgia

Common

Reported commonly in placebo
Reported very commonly in placebo
Reported over 3 years in a COPD study
See section 4.4
See section 5.1.

Description of selected adverse reactions
The pharmacological side effects of β2 agonist treatment, such as tremor,
palpitations and headache, have been reported, but tend to be transient and
reduce with regular therapy.
As with other inhalation therapy paradoxical bronchospasm may occur with an
immediate increase in wheezing and shortness of breath after dosing.
Paradoxical bronchospasm responds to a rapid-acting bronchodilator and
should be treated straightaway. Seretide Accuhaler should be discontinued
immediately, the patient assessed and alternative therapy instituted if
necessary.
Due to the fluticasone propionate component, hoarseness and candidiasis
(thrush) of the mouth and throat and, rarely, of the oesophagus can occur in
some patients. Both hoarseness and incidence of candidiasis may be relieved
by rinsing the mouth with water and/or brushing the teeth after using the
product. Symptomatic mouth and throat candidiasis can be treated with topical
anti-fungal therapy whilst still continuing with the Seretide Accuhaler.
Paediatric population
Possible systemic effects include Cushing’s syndrome, Cushingoid features,
adrenal suppression and growth retardation in children and adolescents (see
section 4.4). Children may also experience anxiety, sleep disorders and
behavioural changes, including hyperactivity and irritability.
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
There are no data available from clinical trials on overdose with Seretide, however
data on overdose with both drugs are given below:
The signs and symptoms of salmeterol overdose are dizziness, increases in systolic
blood pressure, tremor, headache and tachycardia. If Seretide therapy has to be
withdrawn due to overdose of the β agonist component of the drug, provision of
appropriate replacement steroid therapy should be considered. Additionally,
hypokalaemia can occur and therefore serum potassium levels should be monitored.
Potassium replacement should be considered.
Acute: Acute inhalation of fluticasone propionate doses in excess of those
recommended may lead to temporary suppression of adrenal function. This does not
need emergency action as adrenal function is recovered in a few days, as verified by
plasma cortisol measurements.
Chronic overdose of inhaled fluticasone propionate: Adrenal reserve should be
monitored and treatment with a systemic corticosteroid may be necessary. When
stabilised, treatment should be continued with an inhaled corticosteroid at the
recommended dose. Refer to section 4.4: risk of adrenal suppression.
In cases of both acute and chronic fluticasone propionate overdose, Seretide therapy
should be continued at a suitable dosage for symptom control.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic Group: Adrenergics in combination with corticosteroids
or other drugs, excl. Anticholinergics.
ATC Code:

R03AK06

Mechanism of action and pharmacodynamic effects
Seretide contains salmeterol and fluticasone propionate which have differing
modes of action. The respective mechanisms of action of both drugs are
discussed below:

Salmeterol:
Salmeterol is a selective long-acting (12 hour) β2 adrenoceptor agonist with a
long side chain which binds to the exo-site of the receptor.
Salmeterol produces a longer duration of bronchodilation, lasting for at least
12 hours, than recommended doses of conventional short-acting β2 agonists.
Fluticasone propionate:
Fluticasone propionate given by inhalation at recommended doses has a
glucocorticoid anti-inflammatory action within the lungs, resulting in reduced
symptoms and exacerbations of asthma, with less adverse effects than when
corticosteroids are administered systemically.
Clinical efficacy and safety
Seretide Asthma clinical trials
A twelve month study (Gaining Optimal Asthma ControL, GOAL), in 3416
adult and adolescent patients with persistent asthma, compared the safety and
efficacy of Seretide versus inhaled corticosteroid (Fluticasone Propionate)
alone to determine whether the goals of asthma management were achievable.
Treatment was stepped up every 12 weeks until **total control was achieved
or the highest dose of study drug was reached. GOAL showed more patients
treated with Seretide achieved asthma control than patients treated with ICS
alone and this control was attained at a lower corticosteroid dose.
*Well controlled asthma was achieved more rapidly with Seretide than with
ICS alone. The time on treatment for 50% of subjects to achieve a first
individual well controlled week was 16 days for Seretide compared to 37 days
for the ICS group. In the subset of steroid naive asthmatics the time to an
individual well controlled week was 16 days in the Seretide treatment
compared to 23 days following treatment with ICS.
The overall study results showed:
Percentage of Patients Attaining *Well Controlled (WC) and **Totally
Controlled (TC) Asthma over 12 months
Salmeterol/FP
FP
Pre-Study Treatment
WC
TC
WC
TC
No ICS (SABA alone)
78%
50%
70%
40%
Low dose ICS ( ≤500 micrograms
75%
44%
60%
28%
BDP or equivalent/day)
Medium dose ICS (>500 to 1000
62%
29%
47%
16%
micrograms BDP or equivalent/day)
71%
41%
59%
28%
Pooled results across the 3
treatment levels

*Well controlled asthma; less than or equal to 2 days with symptom score greater than 1
(symptom score 1 defined as ‘symptoms for one short period during the day’), SABA use on
less than or equal to 2 days and less than or equal to 4 occasions/week, greater than or equal to
80% predicted morning peak expiratory flow, no night-time awakenings, no exacerbations and
no side effects enforcing a change in therapy
**Total control of asthma; no symptoms, no SABA use, greater than or equal to 80%
predicted morning peak expiratory flow, no night-time awakenings, no exacerbations and no
side effects enforcing a change in therapy

The results of this study suggest that Seretide 50/100 micrograms bd may be
considered as initial maintenance therapy in patients with moderate persistent
asthma for whom rapid control of asthma is deemed essential (see section 4.2).
A double blind, randomised, parallel group study in 318 patients with
persistent asthma aged ≥18 years evaluated the safety and tolerability of
administering two inhalations twice daily (double dose) of Seretide for two
weeks. The study showed that doubling the inhalations of each strength of
Seretide for up to 14 days resulted in a small increase in β agonist-related
adverse events (tremor; 1 patient [1%] vs 0, palpitations; 6 [3%] vs 1 [<1%],
muscle cramps; 6[3%] vs 1 [<1%]) and a similar incidence of inhaled
corticosteroid-related adverse events (e.g. oral candidiasis; 6 [6%] vs 16 [8%],
hoarseness; 2 [2%] vs 4 [2%]) compared to one inhalation twice daily. The
small increase in β agonist-related adverse events should be taken into account
if doubling the dose of Seretide is considered by the physician in adult patients
requiring additional short-term (up to 14 days) inhaled corticosteroid therapy.
Seretide COPD clinical trials
TORCH was a 3-year study to assess the effect of treatment with Seretide
Evohaler 50/500 micrograms bd, salmeterol Evohaler 50 micrograms bd,
fluticasone propionate (FP) Evohaler 500 micrograms bd or placebo on allcause mortality in patients with COPD. COPD patients with a baseline
(pre-bronchodilator) FEV1 <60% of predicted normal were randomised to
double-blind medication. During the study, patients were permitted usual
COPD therapy with the exception of other inhaled corticosteroids, long-acting
bronchodilators and long-term systemic corticosteroids. Survival status at 3
years was determined for all patients regardless of withdrawal from study
medication. The primary endpoint was reduction in all cause mortality at 3
years for Seretide vs Placebo.
Placebo
N = 1524
All cause mortality at 3 years
231
Number of deaths
(%)
(15.2%)
Hazard Ratio vs
Placebo (CIs)
N/A
p value
Hazard Ratio
N/A

Salmeterol
50
N = 1521

FP 500
N = 1534

Seretide
50/500
N = 1533

205
(13.5%)
0.879
(0.73, 1.06)
0.180
0.932

246
(16.0%)
1.060
(0.89, 1.27)
0.525
0.774

193
(12.6%)
0.825
(0.68, 1.00 )
0.0521
N/A

Seretide 50/500 vs
components (CIs)
p value

(0.77, 1.13)
0.481

(0.64, 0.93)
0.007

1. Non-significant P value after adjustment for 2 interim analyses on the primary efficacy
comparison from a log-rank analysis stratified by smoking status

There was a trend towards improved survival in subjects treated with Seretide
compared with placebo over 3 years however this did not achieve the
statistical significance level p≤0.05.
The percentage of patients who died within 3 years due to COPD-related
causes was 6.0% for placebo, 6.1% for salmeterol, 6.9% for FP and 4.7% for
Seretide.
The mean number of moderate to severe exacerbations per year was
significantly reduced with Seretide as compared with treatment with
salmeterol, FP and placebo (mean rate in the Seretide group 0.85 compared
with 0.97 in the salmeterol group, 0.93 in the FP group and 1.13 in the
placebo). This translates to a reduction in the rate of moderate to severe
exacerbations of 25% (95% CI: 19% to 31%; p<0.001) compared with
placebo, 12% compared with salmeterol (95% CI: 5% to 19%, p=0.002) and
9% compared with FP (95% CI: 1% to 16%, p=0.024). Salmeterol and FP
significantly reduced exacerbation rates compared with placebo by 15% (95%
CI: 7% to 22%; p<0.001) and 18% (95% CI: 11% to 24%; p<0.001)
respectively.
Health Related Quality of Life, as measured by the St George’s Respiratory
Questionnaire (SGRQ) was improved by all active treatments in comparison
with placebo. The average improvement over three years for Seretide
compared with placebo was -3.1 units (95% CI: -4.1 to -2.1; p<0.001),
compared with salmeterol was -2.2 units (p<0.001) and compared with FP was
-1.2 units (p=0.017). A 4-unit decrease is considered clinically relevant.
The estimated 3-year probability of having pneumonia reported as an adverse
event was 12.3% for placebo, 13.3% for salmeterol, 18.3% for FP and 19.6%
for Seretide (Hazard ratio for Seretide vs placebo: 1.64, 95% CI: 1.33 to 2.01,
p<0.001). There was no increase in pneumonia-related deaths; deaths while on
treatment that were adjudicated as primarily due to pneumonia were 7 for
placebo, 9 for salmeterol, 13 for FP and 8 for Seretide. There was no
significant difference in probability of bone fracture (5.1% placebo, 5.1%
salmeterol, 5.4% FP and 6.3% Seretide; Hazard ratio for Seretide vs placebo:
1.22, 95% CI: 0.87 to 1.72, p=0.248.
Placebo-controlled clinical trials, over 6 and 12 months, have shown that
regular use of Seretide 50/500 micrograms improves lung function and
reduces breathlessness and the use of relief medication.
Studies SCO40043 and SCO100250 were randomised, double blind, parallel
group, replicate studies comparing the effect of Seretide 50/250 micrograms
bd (a dose not licensed for COPD treatment in the European Union) with

salmeterol 50 micrograms bd on the annual rate of moderate/severe
exacerbations in subjects with COPD with FEV1 less than 50% predicted and a
history of exacerbations. Moderate/ severe exacerbations were defined as
worsening symptoms that required treatment with oral corticosteroids and/or
antibiotics or in-patient hospitalisation.
The trials had a 4 week run-in period during which all subjects received openlabel salmeterol/ FP 50/250 to standardize COPD pharmacotherapy and
stabilise disease prior to randomisation to blinded study medication for 52
weeks. Subjects were randomised 1:1 to salmeterol/ FP 50/250 (total ITT
n=776) or salmeterol (total ITT n=778). Prior to run-in, subjects discontinued
use of previous COPD medications except short-acting bronchodilators. The
use of concurrent inhaled long-acting bronchodilators (β2 agonist and
anticholinergic), ipratropium/salbutamol combination products, oral β2
agonists, and theophylline preparations were not allowed during the treatment
period. Oral corticosteroids and antibiotics were allowed for the acute
treatment of COPD exacerbations with specific guidelines for use. Subjects
used salbutamol on an as-needed basis throughout the studies.
The results of both studies showed that treatment with Seretide 50/250 resulted
in a significantly lower annual rate of moderate/severe COPD exacerbations
compared with salmeterol (SCO40043: 1.06 and 1.53 per subject per year,
respectively, rate ratio of 0.70, 95% CI: 0.58 to 0.83, p<0.001; SCO100250:
1.10 and 1.59 per subject per year, respectively, rate ratio of 0.70, 95% CI:
0.58 to 0.83, p<0.001). Findings for the secondary efficacy measures (time to
first moderate/severe exacerbation, the annual rate of exacerbations requiring
oral corticosteroids, and pre-dose morning (AM) FEV1) significantly favoured
Seretide 50/250 micrograms bd over salmeterol. Adverse event profiles were
similar with the exception of a higher incidence of pneumonias and known
local side effects (candidiasis and dysphonia) in the Seretide 50/250
micrograms bd group compared with salmeterol. Pneumonia-related events
were reported for 55 (7%) subjects in the Seretide 50/250 micrograms bd
group and 25 (3%) in the salmeterol group. The increased incidence of
reported pneumonia with Seretide 50/250 micrograms bd appears to be of
similar magnitude to the incidence reported following treatment with Seretide
50/500 micrograms bd in TORCH.
Asthma
The Salmeterol Multi-center Asthma Research Trial (SMART)
The Salmeterol Multi-center Asthma Research Trial (SMART) was a 28-week
US study that evaluated the safety of salmeterol compared to placebo added to
usual therapy in adult and adolescent subjects. Although there were no
significant differences in the primary endpoint of the combined number of
respiratory-related deaths and respiratory-related life-threatening experiences,
the study showed a significant increase in asthma-related deaths in patients
receiving salmeterol (13 deaths out of 13,176 patients treated with salmeterol
versus 3 deaths out of 13,179 patients on placebo). The study was not designed

to assess the impact of concurrent inhaled corticosteroid use and only 47 % of
subjects reported ICS use at baseline.
Safety and efficacy of salmeterol-FP versus FP alone in asthma
Two multi-centre 26-week studies were conducted to compare the safety and
efficacy of salmeterol-FP versus FP alone, one in adult and adolescent subjects
(AUSTRI trial), and the other in paediatric subjects 4-11 years of age
(VESTRI trial). For both studies, enrolled subjects had moderate to severe
persistent asthma with history of asthma-related hospitalisation or asthma
exacerbation in the previous year. The primary objective of each study was to
determine whether the addition of LABA to ICS therapy (salmeterol-FP) was
non-inferior to ICS (FP) alone in terms of the risk of serious asthma related
events (asthma-related hospitalisation, endotracheal intubation, and death). A
secondary efficacy objective of these studies was to evaluate whether
ICS/LABA (salmeterol-FP) was superior to ICS therapy alone (FP) in terms of
severe asthma exacerbation (defined as deterioration of asthma requiring the
use of systemic corticosteroids for at least 3 days or an in-patient
hospitalisation or emergency department visit due to asthma that required
systemic corticosteroids).
A total of 11,679 and 6,208 subjects were randomized and received treatment
in the AUSTRI and VESTRI trials, respectively. For the primary safety
endpoint, non-inferiority was achieved for both trials (see Table below).
Serious Asthma-Related Events in the 26-Week AUSTRI and VESTRI Trials
AUSTRI
VESTRI

Composite endpoint
(Asthma-related
hospitalisation,
endotracheal intubation,
or death)
Salmeterol-FP/FP Hazard
ratio (95% CI)
Death

Salmeterol-FP
(n = 5,834)
34 (0.6%)

1.029
(0.638-1.662)a
0

FP Alone
(n = 5,845)
33 (0.6%)

Salmeterol-FP
(n = 3,107)
27 (0.9%)

FP Alone
(n = 3,101)
21 (0.7%)

0

1.285
(0.726-2.272)b
0

0

Asthma-related
34
33
27
21
hospitalisation
Endotracheal intubation
0
2
0
0
a
If the resulting upper 95% CI estimate for the relative risk was less than 2.0, then
non-inferiority was concluded.
b
If the resulting upper 95% CI estimate for the relative risk was less than 2.675, then
non-inferiority was concluded.
For the secondary efficacy endpoint, reduction in time to first asthma exacerbation for
salmeterol-FP relative to FP was seen in both studies, however only AUSTRI met
statistical significance:

AUSTRI

Number of subjects with
an asthma exacerbation
Salmeterol-FP/FP Hazard
ratio (95% CI)

Salmeterol-FP
(n = 5,834)
480 (8%)

FP Alone
(n = 5,845)
597 (10%)

0.787
(0.698, 0.888)

VESTRI

Salmeterol-FP
(n = 3,107)
265 (9%)

FP Alone
(n = 3,101)
309 (10%)

0.859
(0.729, 1.012)

Paediatric population
In trial SAM101667, in 158 children aged 6 to 16 years with symptomatic
asthma, the combination of salmeterol/fluticasone propionate is equally
efficacious to doubling the dose of fluticasone propionate regarding symptom
control and lung function. This study was not designed to investigate the effect
on exacerbations.
In a 12 week trial of children aged 4 to 11 years [n=257] treated with either
salmeterol/fluticasone propionate 50/100 or salmeterol 50 micrograms +
fluticasone propionate 100 micrograms both twice daily, both treatment arms
experienced a 14% increase in peak expiratory flow rate as well as
improvements in symptom score and rescue salbutamol use. There were no
differences between the 2 treatment arms. There were no differences in safety
parameters between the 2 treatment arms.
In a 12 week trial of children 4 to 11 years of age [n=203] randomized in a
parallel-group study with persistent asthma and who were symptomatic on
inhaled corticosteroid, safety was the primary objective. Children received
either salmeterol/fluticasone propionate (50/100 micrograms) or fluticasone
propionate (100 micrograms) alone twice daily. Two children on
salmeterol/fluticasone propionate and 5 children on fluticasone propionate
withdrew because of worsening asthma. After 12 weeks no children in either
treatment arm had abnormally low 24 hour urinary cortisol excretion. There
were no other differences in safety profile between the treatment arms.
Fluticasone propionate containing medications in asthma during pregnancy
An observational retrospective epidemiological cohort study utilising
electronic health records from the United Kingdom was conducted to evaluate
the risk of MCMs following first trimester exposure to inhaled FP alone and
salmeterol-FP relative to non-FP containing ICS. No placebo comparator was
included in this study.
Within the asthma cohort of 5362 first trimester ICS-exposed pregnancies, 131
diagnosed MCMs were identified; 1612 (30%) were exposed to FP or
salmeterol-FP of which 42 diagnosed MCMs were identified. The adjusted
odds ratio for MCMs diagnosed by 1 year was 1.1 (95%CI: 0.5 – 2.3) for FP

exposed vs non-FP ICS exposed women with moderate asthma and 1.2
(95%CI: 0.7 – 2.0) for women with considerable to severe asthma. No
difference in the risk of MCMs was identified following first trimester
exposure to FP alone versus salmeterol-FP. Absolute risks of MCM across the
asthma severity strata ranged from 2.0 to 2.9 per 100 FP-exposed pregnancies
which is comparable to results from a study of 15,840 pregnancies unexposed
to asthma therapies in the General Practice Research Database (2.8 MCM
events per 100 pregnancies).
5.2

Pharmacokinetic properties
When salmeterol and fluticasone propionate were administered in combination by the
inhaled route, the pharmacokinetics of each component were similar to those
observed when the drugs were administered separately. For pharmacokinetic
purposes therefore each component can be considered separately.
Salmeterol
Salmeterol acts locally in the lung therefore plasma levels are not an indication of
therapeutic effects. In addition there are only limited data available on the
pharmacokinetics of salmeterol because of the technical difficulty of assaying the
drug in plasma due to the low plasma concentrations at therapeutic doses
(approximately 200 picogram/mL or less) achieved after inhaled dosing.
Fluticasone propionate
The absolute bioavailability of a single dose of inhaled fluticasone propionate in
healthy subjects varies between approximately 5 to 11% of the nominal dose
depending on the inhalation device used. In patients with asthma a lesser degree of
systemic exposure to inhaled fluticasone propionate has been observed.
Systemic absorption occurs mainly through the lungs and is initially rapid then
prolonged. The remainder of the inhaled dose may be swallowed but contributes
minimally to systemic exposure due to the low aqueous solubility and pre-systemic
metabolism, resulting in oral availability of less than 1%. There is a linear increase in
systemic exposure with increasing inhaled dose.
The disposition of fluticasone propionate is characterised by high plasma clearance
(1150 mL/min), a large volume of distribution at steady-state (approximately 300 L)
and a terminal half-life of approximately 8 hours.
Plasma protein binding is 91%.
Fluticasone propionate is cleared very rapidly from the systemic circulation. The
main pathway is metabolism to an inactive carboxylic acid metabolite, by the

cytochrome P450 enzyme CYP3A4. Other unidentified metabolites are also found in
the faeces.
The renal clearance of fluticasone propionate is negligible. Less than 5% of the dose
is excreted in urine, mainly as metabolites. The main part of the dose is excreted in
faeces as metabolites and unchanged drug.
Paediatric population
The effect of 21 days of treatment with Seretide Inhaler 25/50 microgram
(2 inhalations twice daily with or without a spacer) or Seretide Diskus 50/100
microgram (1 inhalation twice daily) was evaluated in 31 children aged 4 to 11 years
with mild asthma. Systemic exposure to fluticasone propionate was similar for
Seretide Inhaler with spacer (107 pg hr/mL [95% CI: 45.7, 252.2]) and Seretide
Diskus (138 pg hr/mL [95% CI: 69.3, 273.2]), but lower for Seretide Inhaler (24 pg
hr/mL [95% CI: 9.6, 60.2]). Systemic exposure to salmeterol was similar for Seretide
Inhaler, Seretide Inhaler with spacer, and Seretide Diskus (126 pg hr/mL [95% CI:
70, 225], 103 pg hr/mL [95% CI: 54, 200], and 110 pg hr/mL [95% CI: 55, 219],
respectively).

5.3

Preclinical safety data
The only safety concerns for human use derived from animal studies of
salmeterol and fluticasone propionate given separately were effects associated
with exaggerated pharmacological actions.
In animal reproduction studies, glucocorticosteroids have been shown to
induce malformations (cleft palate, skeletal malformations). However, these
animal experimental results do not seem to be relevant for man given
recommended doses. Animal studies with salmeterol have shown embryofetal
toxicity only at high exposure levels. Following co-administration, increased
incidences of transposed umbilical artery and incomplete ossification of
occipital bone were found in rats at doses associated with known
glucocorticoid-induced abnormalities. Neither salmeterol xinafoate or
fluticasone propionate have shown any potential for genetic toxicity.
The non-CFC propellant, norflurane, 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.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Propellant: norflurane (HFA 134a).

6.2

Incompatibilities
Not applicable.

6.3

Shelf life
2 years

6.4

Special precautions for storage
Do not store above 25°C.

The canister contains a pressurised liquid. Do not expose to temperatures
higher than 50°C, protect from direct sunlight. Do not pierce or burn the
canister even when empty.
As with most inhaled medicinal products in pressurised canisters, the
therapeutic effect of this medicinal product may decrease when the canister is
cold.

6.5

Nature and contents of container
The suspension is contained in an internally lacquered, 8 mL aluminium alloy
pressurised canister sealed with a metering valve. The canisters are fitted into purple
plastic actuators incorporating an atomising mouthpiece and fitted with dustcaps. The
canister has a counter attached to it, which shows how many actuations of medicine
are left. The number will show through a window in the back of the plastic actuator.
One pressurised canister delivers 120 actuations.
The devices are available in cardboard containers, which hold:

1 x 120 actuations Inhaler
or

3 x 120 actuations Inhaler

or

10 x 120 actuations Inhaler - hospital/pharmacy use only (for
dispensing purposes)

Not all pack sizes may be marketed.

6.6

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

7

MARKETING AUTHORISATION HOLDER
Glaxo Wellcome UK Ltd
trading as GlaxoSmithKline UK
Stockley Park West
Uxbridge
Middlesex UB11 1BT

8

MARKETING AUTHORISATION NUMBER(S)
PL 10949/0338

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
25/08/2010

10

DATE OF REVISION OF THE TEXT
30/01/2018

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