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SERETIDE ACCUHALER 50 MICROGRAM /250 MICROGRAM /DOSE INHALATION POWDER PRE-DISPENSED

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

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Transcript
SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Seretide Accuhaler 50 microgram /250 microgram /dose inhalation powder, predispensed.

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each single inhalation provides a delivered dose (the dose leaving the mouthpiece) of
47 micrograms of salmeterol (as salmeterol xinafoate) and 231 micrograms of
fluticasone propionate. This corresponds to a pre-dispensed dose of 50 micrograms of
salmeterol (as salmeterol xinafoate) and 250 micrograms fluticasone propionate.
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Inhalation powder, pre-dispensed.
Moulded plastic device containing a foil strip with 28 or 60 regularly placed blisters.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Asthma
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 longacting β2 agonist

Note: Seretide 50 microgram /100 microgram strength is not appropriate in adults and
children with severe asthma.

Chronic Obstructive Pulmonary Disease (COPD)
Seretide is indicated for the symptomatic treatment of patients with COPD, with a
FEV1 <60% predicted normal (pre-bronchodilator) and a history of repeated
exacerbations, who have significant symptoms despite regular bronchodilator therapy.

4.2

Posology and method of administration
Posology
Route of administration: Inhalation use.
Patients should be made aware that Seretide Accuhaler 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 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. If an individual
patient should require dosages outside the recommended regimen, appropriate
doses of β2 agonist and/or corticosteroid should be prescribed.
Recommended Doses:
Asthma
Adults and adolescents 12 years and older:
- One inhalation of 50 micrograms salmeterol and 100 micrograms
fluticasone propionate twice daily.
or
- One inhalation of 50 micrograms salmeterol and 250 micrograms
fluticasone propionate twice daily.

or
- One inhalation of 50 micrograms salmeterol and500 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 one inhalation of 50 micrograms salmeterol and
100 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 50 microgram/100 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:
- One inhalation of 50 micrograms salmeterol and 100 micrograms
fluticasone propionate twice daily.
The maximum licensed dose of fluticasone propionate delivered by Seretide
Accuhaler in children is 100 microgram twice daily.
There are no data available for use of Seretide in children aged under 4 years.
COPD
Adults:
- One inhalation of 50 micrograms salmeterol and 500 micrograms
fluticasone propionate twice daily.
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.
Using the Accuhaler

The device is opened and primed by sliding the lever. The mouthpiece is then placed
in the mouth and the lips closed round it. The dose can then be inhaled and the device
closed.

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 Accuhaler 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.
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 Accuhaler 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.
Seretide contains lactose up to 12.5 milligram /dose. This amount does not
normally cause problems in lactose intolerant people.
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).
There was an increased reporting of lower respiratory tract infections
(particularly pneumonia and bronchitis) in the TORCH study in patients with
COPD receiving Seretide 50/500 micrograms bd compared with placebo as
well as in studies SCO40043 and SCO100250 comparing the lower nonapproved COPD dose of Seretide, 50/250 micrograms bd, to salmeterol 50
micrograms bd only (see section 4.8 and section 5.1). A similar incidence of
pneumonia in the Seretide group was seen across all studies In TORCH, 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 Seretide should be re-evaluated.
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.
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 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 longterm 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 15-fold 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 Accuhaler 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
children)

Not Known

Psychiatric
Disorders

System Organ
Class
Nervous System
Disorders

Eye Disorders

Cardiac Disorders

Respiratory,
Thoracic &
Mediastinal
Disorders

Adverse Event

Frequency

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
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; occasional symptoms or SABA use or less than 80% predicted lung
function plus 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 lung function, 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
Accuhaler 50/500 micrograms bd, salmeterol Accuhaler 50 micrograms bd,
fluticasone propionate (FP) Accuhaler 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
Seretide 50/500 vs
N/A
components (CIs)
p value

Salmeterol
50
N = 1521

FP 500
N = 1534

Seretide
50/500
N = 1533

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

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

193
(12.6%)
0.825
(0.68, 1.00 )
0.0521

0.932
(0.77, 1.13)
0.481

0.774
(0.64, 0.93)
0.007

N/A

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.
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
Relative Risk
endpoint events /number of (95% confidence
patients
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 27/7,049
17/7,041
1.60 (0.87, 2.93)
steroids
African-American patients
20/2,366
5/2,319
4.10
(1.54,
10.90)
Patient group

(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
/number of patients
salmeterol placebo
Respiratory-related death

Relative Risk
(95% confidence
intervals)

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)
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 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 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.
5.2

Pharmacokinetic properties
For pharmacokinetic purposes 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 or
COPD 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
In a population pharmacokinetic analysis utilizing data from 9 controlled
clinical trials with different devices (Diskus, metered dose inhaler) that
included 350 patients with asthma aged 4 to 77 years (174 patients 4 to 11
years of age) higher fluticasone propionate systemic exposure following
treatment with Seretide Diskus 50/100 compared to fluticasone propionate
Diskus 100 were seen.
Geometric Mean Ratio [90% CI] for the Salmeterol/fluticasone propionate vs.
fluticasone propionate Diskus Comparison in Children and Adolescent/Adult
Populations
Treatment (test vs. ref)

Populatio
n

AUC

Cmax

Salmeterol/ fluticasone
propionate Diskus 50/100
fluticasone propionate
Diskus 100
Salmeterol/fluticasone
propionate Diskus 50/100
fluticasone propionate
Diskus 100

Children
(4–11yr)

1.20 [1.06 –
1.37]

1.25 [1.11 – 1.41]

Adolescent 1.52 [1.08 –
/Adult
2.13]
( ≥12yr)

1.52 [1.08 – 2.16]

The effect of 21 days of treatment with Seretide Inhaler 25/50 micrograms (2
inhalations twice daily with or without a spacer) or Seretide Diskus 50/100
micrograms (1 inhalation twice daily) was evaluated in 31 children aged 4 to
11 years with mild asthma. 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). 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]).

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.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Excipient: Lactose monohydrate (which contains milk proteins).

6.2

Incompatibilities
Not applicable.

6.3

Shelf life
2 years.

6.4

Special precautions for storage
Do not store above 30°C.

6.5

Nature and contents of container
The inhalation powder is contained in blisters held on a formed PVC coated
base, with a peelable foil laminate lid. The strip is contained in a moulded
purple plastic device.
The plastic devices are available in cardboard containers, which hold:

or
or
or
or

1 x 28 dose Accuhaler
1 x 60 dose Accuhaler
2 x 60 dose Accuhaler
3 x 60 dose Accuhaler
10 x 60 dose Accuhaler

Not all pack sizes may be marketed.

6.6

Special precautions for disposal
The Accuhaler releases a powder which is inhaled into the lungs. A dose indicator on
the Accuhaler indicates the number of doses left. For detailed instructions for use see
the Patient Information Leaflet.

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 10949/0315

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
Date of first authorisation: 1 February 1999
Date of latest renewal: 3 December 2008

10

DATE OF REVISION OF THE TEXT
22/01/2016

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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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