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SIRDUPLA 25 MICROGRAM/250 MICROGRAM PER METERED DOSE PRESSURISED INHALATION SUSPENSION

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

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Transcript
SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Sirdupla 25 microgram/250 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 250 micrograms of
fluticasone propionate. This is equivalent to a delivered dose (ex actuator) of 21
micrograms of salmeterol and 220 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 white plastic actuators incorporating an atomising orifice
and fitted with burgundy dustcaps.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Sirdupla 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

-

4.2

patients already adequately controlled on both inhaled corticosteroid and
long-acting β2 agonist

Posology and method of administration
Sirdupla is indicated in adults 18 years of age and older only.
Sirdupla is not indicated for use in children, 12 years of age and younger or
adolescents, 13 to 17 years of age.

Posology
Route of administration: Inhalation use.
Patients should be made aware that Sirdupla must be used daily for optimum benefit,
even when asymptomatic.

Patients should be regularly reassessed by a doctor, so that the strength of Sirdupla
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. To Note: Sirdupla is only available in two strengths, it is not
available in a lower strength product containing salmeterol 25 microgram and
fluticasone propionate 50 microgram, a strength which is available for other
similar fixed-dose combination products containing these two actives and
currently available on the market. Therefore, when it is appropriate to titrate down
to a dose of inhaled corticosteroid below 125 micrograms, a change to an alternative
fixed-dose combination of salmeterol and fluticasone propionate containing a lower
dose of the inhaled corticosteroid is required.

When long-term control of symptoms is maintained with the lowest strength of
such an alternative fixed-dose combination given twice daily, then the next step
could include a test of inhaled corticosteroid alone. As an alternative, patients
requiring a long-acting β2 agonist rather than treatment with an inhaled corticosteroid
alone, could be titrated to once daily use of this alternative lowest strength
combination product 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.

Sirdupla should not be used for patients with mild asthma. Sirdupla could be
considered for use in patients with moderate persistent asthma but only where control
of symptoms cannot be maintained with a lower strength product containing a lower
dose of the corticosteroid

Patients should be given the strength of Sirdupla containing the appropriate
fluticasone propionate dosage for the severity of their disease. 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 18 years and older:
- Two inhalations of 25 micrograms salmeterol and 250 micrograms
fluticasone propionate twice daily.
A short term trial of salmeterol/fluticasone propionate may be considered as
initial maintenance therapy in adults 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. To Note:
Sirdupla is not available in the lowest strength of this combination as
currently available on the market and therefore an alternative fixed-dose
combination of salmeterol and fluticasone propionate containing a lower
dose of the inhaled corticosteroid would need to be prescribed for the
initial maintenance therapy in adults with moderate persistent asthma.
The dose of the inhaled corticosteroid may need to be increased to achieve
control of asthma symptoms but once control is attained treatment should be
reviewed and the dose of the inhaled corticosteroid titrated downwards to the
lowest dose at which effective control of symptoms is maintained.
Consideration may be given as to whether patients should be stepped down to
an inhaled corticosteroid alone from the lowest strength combination product.
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. Sirdupla is not intended for the initial
management of mild 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:
The safety and efficacy of Sirdupla in children, 12 years and younger and
adolescents, 13-17 years of age have not been established. No data are
available. Sirdupla is not recommended for use in children and adolescents
under 18 years of age.
Use of an AeroChamber Plus® spacer device with Sirdupla is recommended in
patients who have, or are likely to have, difficulties in coordinating actuation
with inspiration. Only the AeroChamber Plus® spacer device should be
used with Sirdupla. Other spacing devices should not be used with
Sirdupla and patients should not switch from one spacer device to
another.

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 use the recommended spacer device as
switching to another spacer device can result in changes in the dose
delivered to the lungs (see section 4.4).
Re-titration to the lowest effective dose should always be carried out when
patients who have previously used an alternative product and spacer device are
then transferred to Sirdupla with or without the AeroChamber Plus® 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 Sirdupla 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 the inhaler for the first time patients should test that it is working.
Patients should remove the mouthpiece cover by gently squeezing the sides of
the cover, hold the inhaler between the fingers and thumb with their thumb on
the base, below the mouthpiece. To make sure that the inhaler works, the
patient should shake it well, point the mouthpiece away from them and press
the canister firmly to release a puff into the air. These steps should be
repeated at least three times, shaking the inhaler before releasing each puff,
until the counter reads 120.
If the inhaler has not been used for a week or more, or the inhaler gets very
cold (below 0ºC) 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 mouthpiece.
6. Just after starting to breathe in through their mouth, patients should press
firmly down on the top of the inhaler to release the medicine, while still
breathing in steadily and deeply.

7.

8.
9.

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.
To take a second inhalation, patients should keep the inhaler upright and
wait about half a minute before repeating steps 3 to 7.
Patients should immediately replace the mouthpiece cover 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 20. The counter will stop at 0 when all the recommended puffs have
been used. Replace the inhaler when the counter reads 0.
Patients should never try to alter the numbers on the counter or detach the
counter from the actuator. The counter cannot be reset and is permanently
attached inside the actuator.
Cleaning (also detailed in patient information leaflet):
Your inhaler should be cleaned at least once a week.
1. Remove the mouthpiece 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. This does not require excessive force, the
cover should click into position.
DO NOT WASH OR PUT ANY PARTS OF THE INHALER IN WATER.
4.3

Contraindications
Sirdupla is contraindicated in patients with hypersensitivity (allergy) 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
Sirdupla should not be used to treat acute asthma symptoms for which a fastand 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 Sirdupla 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 Sirdupla. Patients should be asked to continue treatment but to

seek medical advice if asthma symptoms remain uncontrolled or worsen after
initiation on Sirdupla.
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 Sirdupla. Regular review of patients as
treatment is stepped down is important. The lowest effective dose of the
combination of salmeterol and fluticasone propionate (which may mean a
change to an alternative fixed-dose combination of salmeterol and fluticasone
propionate containing a lower dose of the inhaled corticosteroid) should be
used (see section 4.2).
Treatment with Sirdupla 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, Sirdupla 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, Sirdupla may cause cardiac arrhythmias e.g. supraventricular
tachycardia, extrasystoles and atrial fibrillation, and a mild transient reduction
in serum potassium at high therapeutic doses. Sirdupla 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. Sirdupla 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 a fixed-dose
combination of salmeterol and fluticasone propionate 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 (<25
kg/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 Sirdupla should
be re-evaluated. The safety and efficacy of Sirdupla has not been established

in patients with COPD and therefore Sirdupla 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
Sirdupla.
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. To Note: Sirdupla is only available in
two strengths, it is not available in a lower strength product containing
salmeterol 25 microgram and fluticasone propionate 50 microgram, the
strength which would be prescribed for use in children. Furthermore the
safety and efficacy of Sirdupla in children, 12 years and younger and
adolescents, 13-17 years of age have not been established. No data are
available. Sirdupla is not recommended for use in children and
adolescents under 18 years of age at this time (see section 4.2).
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 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 CYP3A4 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) indicate 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 Sirdupla 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 Sirdupla 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
Sirdupla has no or negligible influence on the ability to drive and use machines.

4.8

Undesirable effects
As Sirdupla 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

Adverse Event

Frequency

Infections &
Infestations

Candidiasis of the mouth and throat

Common

Pneumonia

Common1,3

Bronchitis

Common1,3

Oesophageal candidiasis

Rare

Immune System
Disorders

Endocrine Disorders

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 children and
adolescents, Decreased bone mineral density

Rare4

Common3

Metabolism & Nutrition Hypokalaemia
Disorders
Hyperglycaemia

Uncommon4

Psychiatric Disorders

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

Respiratory, Thoracic & Nasopharyngitis
Mediastinal Disorders

Very
Common2,3

Nervous System
Disorders
Eye disorder
Cardiac Disorders

Throat irritation

Common

Hoarseness/dysphonia

Common

Sinusitis

Common1,3

Paradoxical bronchospasm

Rare4

Skin and subcutaneous
tissue disorders

Contusions

Common1,3

Musculoskeletal &
Connective Tissue
Disorders

Muscle cramps

Common

Traumatic fractures

Common1,3

Arthralgia

Common

Myalgia

Common

1.

Reported commonly in placebo
Reported very commonly in placebo
3.
Reported over 3 years in a COPD study
4.
See section 4.4
2.

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. Sirdupla 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 mouth and throat 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 Sirdupla.
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 Sirdupla,
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 Sirdupla 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, Sirdupla
therapy should be continued at a suitable dosage for symptom control.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic Group: Adrenergics and other anti-asthmatics.
ATC Code: R03AK06
Mechanism of action and pharmacodynamic effects
Sirdupla 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
Salmeterol/fluticasone propionate 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 salmeterol/fluticasone propionate 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 salmeterol/fluticasone propionate
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
salmeterol/fluticasone propionate than with ICS alone. The time on treatment
for 50% of subjects to achieve a first individual well controlled week was 16

days for salmeterol/fluticasone propionate 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 salmeterol/fluticasone propionate
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

78%

50%

70%

40%

Low dose ICS ( 500 microgram BDP 75%
or equivalent/day)

44%

60%

28%

Medium dose ICS (>500 to 1000
microgram BDP or equivalent/day)

29%

47%

16%

No ICS (SABA alone)

62%

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 salmeterol/fluticasone propionate 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
salmeterol/fluticasone propionate for two weeks. The study showed that
doubling the inhalations of each strength of salmeterol/fluticasone propionate
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 corticosteroidrelated 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 salmeterol/fluticasone propionate 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
Relative Risk
/number of patients
(95% confidence
intervals)
salmeterol
placebo
All patients

50/13,176

36/13,179

1.40 (0.91, 2.14)

Patients using inhaled steroids

23/6,127

19/6,138

1.21 (0.66, 2.23)

Patients not using inhaled steroids

27/7,049

17/7,041

1.60 (0.87, 2.93)

African-American patients

20/2,366

5/2,319

4.10 (1.54, 10.90)

(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 events
Relative Risk
/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 steroids

14/7049

6/7041

2.28 (0.88, 5.94)

16/6127

13/6138

1.24 (0.60, 2.58)

21/7049

9/7041

2.39 (1.10, 5.22)

4/6127

3/6138

1.35 (0.30, 6.04)

Combined asthma-related death or life-threatening experience
Patients using inhaled steroids
Patients
steroids

not

using

inhaled

Asthma-related death
Patients using inhaled steroids

Patients not using inhaled steroids
9/7049
0/7041
(*=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 salmeterol/fluticasone propionate
inhaler 25/50 microgram (2 inhalations twice daily with or without a spacer)
or salmeterol/fluticasone propionate 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
salmeterol/fluticasone propionate Inhaler with spacer (107 pg hr/mL [95% CI:
45.7, 252.2]) and salmeterol/fluticasone propionate Diskus® (138 pg hr/mL
[95% CI: 69.3, 273.2]), but lower for salmeterol/fluticasone propionate Inhaler
(24 pg hr/mL [95% CI: 9.6, 60.2]). Systemic exposure to salmeterol was
similar for salmeterol/fluticasone propionate Inhaler, salmeterol/fluticasone
propionate Inhaler with spacer, and salmeterol/fluticasone propionate 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)
ethanol, anhydrous

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, 16 mL aluminium
alloy pressurised canister sealed with a metering valve. The canisters are
fitted into white plastic actuators incorporating an atomising mouthpiece and
fitted with burgundy dustcaps. The actuator has an integrated dose counter
attached to it, which shows how many metered doses of medicine are left. The
number shows through a window in the back of the plastic actuator. One
pressurised canister delivers 120 metered doses.
The devices are available in cardboard containers, which hold:
1x120 metered doses inhaler

6.6

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

7

MARKETING AUTHORISATION HOLDER
Generics [UK] Limited t/a Mylan
Station Close
Potters Bar
Hertfordshire
EN6 1TL
UK

8

MARKETING AUTHORISATION NUMBER(S)
PL 04569/1450

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
15/05/2015

10

DATE OF REVISION OF THE TEXT
15/05/2015

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Source: Medicines and Healthcare Products Regulatory Agency

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

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