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SERETIDE EVOHALER 25 MICROGRAM /50 MICROGRAM PER METERED DOSE PRESSURISED INHALATION SUSPENSION

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

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Seretide Evohaler 25 microgram /50 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 50 micrograms of
fluticasone propionate. This is equivalent to a delivered dose (ex actuator) of 21
micrograms of salmeterol and 44 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:
patients not adequately controlled with inhaled corticosteroids and ‘as
needed’ inhaled short- acting β2 agonist
or
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 longacting β2 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 β2 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
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 asthma 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).
Treatment with Seretide should not be stopped abruptly due to risk of
exacerbation. Therapy should be down-titrated under physician supervision.
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
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.
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.

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.
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.
Systemic absorption of salmeterol and fluticasone propionate is largely
through the lungs. As the use of a spacer device with a 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. Single
dose pharmacokinetic data have demonstrated that the systemic exposure to
salmeterol and fluticasone propionate may be increased as much as two-fold
when the AeroChamber Plus spacer device is used with Seretide inhaler as
compared with the Volumatic spacer device.
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).
There was an increased reporting of lower respiratory tract infections
(particularly pneumonia and bronchitis) in a 3-year study in patients with
Chronic Obstructive Pulmonary Disease (COPD) receiving salmeterol and
fluticasone propionate as a fixed-dose combination administered via the
Diskus/Accuhaler compared with placebo (see section 4.8). In a 3-year COPD
study, older patients, patients with a lower body mass index (<25kg/m2) and
patients with very severe disease (FEV1<30% predicted) were at greatest risk
of developing pneumonia regardless of treatment. Physicians should remain
vigilant for the possible development of pneumonia and other lower
respiratory tract infections in patients with COPD as the clinical features of
such infections and exacerbation frequently overlap. If a patient with severe
COPD has experienced pneumonia the treatment with Seretide should be reevaluated. The safety and efficacy of Seretide Evohaler has not been
established in patients with COPD and therefore Seretide Evohaler is not
indicated for use in the treatment of patients with COPD.
Data from a large clinical trial (the Salmeterol Multi-Center Asthma Research
Trial, SMART) suggested African-American patients were at increased risk of
serious respiratory-related events or deaths when using salmeterol compared

with placebo (see section 5.1). It is not known if this was due to
pharmacogenetic or other factors. Patients of black African or Afro-Caribbean
ancestry should therefore be asked to continue treatment but to seek medical
advice if asthma symptoms remain uncontrolled or worsen whilst using
Seretide.
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 of
systemic effects. 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 nonselective 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 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. 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 moderate CYP3A inhibitors, such
as erythromycin, 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.
Salmeterol
Potent CYP3A4 inhibitors
Co-administration of ketoconazole (400 mg orally once daily) and salmeterol
(50 micrograms 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 moderate amount of data on pregnant women (between 300 to 1000
pregnancy outcomes) indicates no malformative or feto/neonatal toxicity of
salmeterol and fluticasone propionate. 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

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

Endocrine
Disorders

Cushing’s syndrome, Cushingoid features,
Adrenal suppression, Growth retardation in
children and adolescents, Decreased bone
mineral density

Rare4

Metabolism &
Nutrition 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

Not Known

Psychiatric
Disorders

System Organ
Class

Adverse Event

Frequency

children)
Nervous System
Disorders

Eye Disorders

Cardiac Disorders

Respiratory,
Thoracic &
Mediastinal
Disorders

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
subcutaneous tissue
disorders
Musculoskeletal &
Connective Tissue
Disorders

1.
2.
3.
4.
5.

Contusions

Rare4
Common1, 3

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
No ICS (SABA alone)
78%
50%
70%
Low dose ICS ( ≤500 microgram
75%
44%
60%
BDP or equivalent/day)
Medium dose ICS (>500 to 1000
62%
29%
47%
microgram BDP or equivalent/day)
71%
41%
59%
Pooled results across the 3
treatment levels

TC
40%
28%
16%
28%

*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 microgram 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.
The Salmeterol Multi-center Asthma Research Trial (SMART)

SMART was a multi-centre, randomised, double blind, placebo-controlled,
parallel group 28-week study in the US which randomised 13,176 patients to
salmeterol (50 micrograms twice daily) and 13,179 patients to placebo in
addition to the patients’ usual asthma therapy. Patients were enrolled if ≥12
years of age, with asthma and if currently using asthma medication (but not a
LABA). Baseline ICS use at study entry was recorded, but not required in the
study. The primary endpoint in SMART was the combined number of
respiratory-related deaths and respiratory-related life-threatening experiences.

Key findings from SMART: primary endpoint
Number of primary endpoint events
Patient group
/number of patients
salmeterol
placebo
All patients
50/13,176
36/13,179
Patients using inhaled 23/6,127
19/6,138
steroids
Patients
not
using 27/7,049
17/7,041
inhaled steroids
African-American
20/2,366
5/2,319
patients

Relative Risk
(95% confidence
intervals)
1.40 (0.91, 2.14)
1.21 (0.66, 2.23)
1.60 (0.87, 2.93)
4.10
10.90)

(1.54,

(Risk in bold is statistically significant at the 95% level.)

Key findings from SMART by inhaled steroid use at baseline: secondary
endpoints
Number of secondary endpoint Relative Risk
events /number of patients
(95% confidence
intervals)
salmeterol
placebo
Respiratory-related death
Patients using inhaled steroids
10/6127
5/6138
2.01 (0.69, 5.86)
Patients not using inhaled 14/7049
6/7041
2.28 (0.88, 5.94)
steroids
Combined asthma-related death or life-threatening experience
Patients using inhaled steroids
16/6127
13/6138
1.24 (0.60, 2.58)
Patients not using inhaled 21/7049
9/7041
2.39 (1.10, 5.22)
steroids
Asthma-related death
Patients using inhaled steroids
4/6127
3/6138
1.35 (0.30, 6.04)
Patients not using inhaled 9/7049
0/7041
*
steroids
(*=could not be calculated because of no events in placebo group. Risk in bold figures is
statistically significant at the 95% level. The secondary endpoints in the table above reached
statistical significance in the whole population.) The secondary endpoints of combined all
cause death or life-threatening experience, all cause death, or all cause hospitalisation did not
reach statistical significance in the whole population.

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 trial which randomized children aged 4 to 11 years [n=428],
salmeterol/fluticasone propionate Diskus (50/100 microgram, one inhalation twice
daily) was compared with salmeterol/fluticasone propionate MDI (25/50 microgram,
two inhalations twice daily) over a 12-week treatment period. The adjusted mean
change from baseline in mean morning peak expiratory flow over Weeks 1-12 was
37.7L/min in the Diskus group and 38.6L/min in the MDI group. Improvements were
also seen in both treatment groups on rescue and symptom free days and nights.

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.
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 10949/0337

9

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

10

DATE OF REVISION OF THE TEXT
06/08/2015

Expand Transcript

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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