Seretide Diskus Mite 50 mikrogram/100 mikrogram/dos Inhalationspulver, avdelad dos

Sverige - svenska - Läkemedelsverket (Medical Products Agency)

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Bipacksedel Bipacksedel (PIL)

27-08-2020

Produktens egenskaper Produktens egenskaper (SPC)

22-03-2018

Aktiva substanser:
flutikasonpropionat; salmeterolxinafoat
Tillgänglig från:
Orifarm AB
ATC-kod:
R03AK06
INN (International namn):
fluticasone propionate; salmeterol
Dos:
50 mikrogram/100 mikrogram/dos
Läkemedelsform:
Inhalationspulver, avdelad dos
Sammansättning:
salmeterolxinafoat 72,5 mikrog Aktiv substans; flutikasonpropionat 100 mikrog Aktiv substans; laktosmonohydrat Hjälpämne
Klass:
Apotek
Receptbelagda typ:
Receptbelagt
Terapiområde:
Salmeterol och flutikason
Produktsammanfattning:
Förpacknings: Inhalator, 60 doser; Inhalator, 180 (3 x 60) doser
Bemyndigande status:
Avregistrerad
Godkännandenummer:
50921
Tillstånd datum:
2014-10-15

Dokument på andra språk

Bipacksedel Bipacksedel - engelska

27-08-2020

Produktens egenskaper Produktens egenskaper - engelska

27-08-2020

Offentlig bedömningsrapport Offentlig bedömningsrapport - engelska

03-11-2016

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PACKAGE LEAFLET

Package leaflet: Information for the user

Seretide Diskus mite 50 microgram/100 microgram/ dose inhalation powder, pre-dispensed

Seretide Diskus 50 microgram/250 microgram/ dose inhalation powder, pre-dispensed

Seretide Diskus forte 50 microgram/500 microgram/ dose inhalation powder, pre-dispensed

[To be completed nationally]

salmeterol/fluticasone propionate

Read all of this leaflet carefully before you start taking this medicine

because it contains

important information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor or pharmacist.

This medicine has been prescribed for you only. Do not pass it on to others. It may harm them,

even if their symptoms and signs of illness are the same as yours.

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side

effects not listed in this leaflet. See section 4.

What is in this leaflet

What Seretide is and what it is used for

What you need to know before you use Seretide

How to use Seretide

Possible side effects

How to store Seretide

Contents of the pack and other information

1.

What Seretide is and what it is used for

Seretide contains two medicines, salmeterol and fluticasone propionate:

Salmeterol is a long-acting bronchodilator. Bronchodilators help the airways in the lungs to stay

open. This makes it easier for air to get in and out. The effects last for at least 12 hours.

Fluticasone propionate is a corticosteroid which reduces swelling and irritation in the lungs.

The doctor has prescribed this medicine to help prevent breathing problems such as:

Asthma

Chronic Obstructive Pulmonary Disease (COPD). Seretide Diskus, at a dose of 50/500

micrograms, reduces the number of flare ups of COPD symptoms.

You must use Seretide every day as directed by your doctor. This will make sure that it works

properly in controlling your asthma or COPD.

Seretide helps to stop breathlessness and wheeziness coming on. However Seretide should not be

used to relieve a sudden attack of breathlessness or wheezing. If this happens you need to use a

fast-acting ‘reliever’ (‘rescue’) inhaler, such as salbutamol. You should always have your fast-

acting 'rescue' inhaler with you.

2.

What you need to know before you use Seretide

Do not take Seretide:

If you are allergic to salmeterol, fluticasone propionate or to the other ingredient lactose

monohydrate.

Warnings and precautions

Talk to your doctor before using Seretide if you have:

Heart disease, including an irregular or fast heart beat

Overactive thyroid gland

High blood pressure

Diabetes mellitus (Seretide may increase your blood sugar)

Low potassium in your blood

Tuberculosis (TB) now or in the past, or other lung infections

Contact your doctor if you experience blurred vision or other visual disturbances.

Other medicines and Seretide

Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other

medicines including medicines for asthma or any medicines obtained without a prescription. This is

because Seretide may not be suitable to be taken with some other medicines.

Tell your doctor if you are taking the following medicines, before starting to use Seretide:

blockers (such as atenolol, propranolol and sotalol).

blockers are mostly used for high blood

pressure or other heart conditions.

Medicines to treat infections (such as ketoconazole, itraconazole and erythromycin) including

some medicines for HIV treatment (such as ritonavir, cobicistat containing products). Some of

these medicines may increase the amount of fluticasone propionate or salmeterol in your body.

This can increase your risk of experiencing side effects with Seretide, including irregular heart

beats, or may make side effects worse. Your doctor may wish to monitor you carefully if you are

taking these medicines.

Corticosteroids (by mouth or by injection). If you have had these medicines recently, this might

increase the risk of this medicine affecting your adrenal gland.

Diuretics, also known as ‘water tablets’ used to treat high blood pressure.

Other bronchodilators (such as salbutamol).

Xanthine medicines. These are often used to treat asthma.

Pregnancy and breastfeeding

If you are pregnant or breastfeeding, think you may be pregnant or are planning to have a baby, ask

your doctor or pharmacist for advice before taking this medicine.

Driving and using machines

Seretide is not likely to affect your ability to drive or use machines.

Seretide contains lactose

Seretide Diskus contains up to 12.5 milligrams of lactose monohydrate in each dose. The amount of

lactose in this medicine does not normally cause problems in people who are lactose intolerant. The

excipient lactose contains small amounts of milk proteins, which may cause allergic reactions.

3.

How to use Seretide

Always use this medicine exactly as your doctor or pharmacist has told you. Check with your doctor

or pharmacist if you are not sure.

Use your Seretide every day until your doctor advises you to stop. Do not take more than the

recommended dose. Check with your doctor or pharmacist if you are not sure.

Do not stop taking Seretide or reduce the dose of Seretide without talking to your doctor first.

Seretide should be inhaled through the mouth into the lungs.

You may not be able to taste or feel the powder on your tongue, even if you have used the Diskus

correctly.

For asthma

Adults and adolescents aged 12 years and over

Seretide 50/100 Diskus - One inhalation twice a day

Seretide 50/250 Diskus - One inhalation twice a day

Seretide 50/500 Diskus - One inhalation twice a day

Children 4 to 12 years of age

Seretide 50/100 Diskus - One inhalation twice a day

Seretide is not recommended for use in children below 4 years of age.

For adults with Chronic Obstructive Pulmonary Disease (COPD)

Seretide 50/500 Diskus - One inhalation twice a day

Your symptoms may become well controlled using Seretide twice a day. If so, your doctor may decide

to reduce your dose to once a day. The dose may change to:

once at night - if you have

night-time

symptoms

once in the morning - if you have

daytime

symptoms.

It is very important to follow your doctor’s instructions on how many inhalations to take and how

often to take your medicine.

If you are using Seretide for asthma, your doctor will want to regularly check your symptoms.

If your asthma or breathing

gets worse

tell your doctor straight away

. You may find that you feel

more wheezy, your chest feels tight more often or you may need to use more of your fast-acting

‘reliever’ medicine. If any of these happen, you should continue to take Seretide but do not increase

the number of puffs you take. Your chest condition may be getting worse and you could become

seriously ill. See your doctor as you may need additional treatment.

Instructions for use

Your doctor, nurse or pharmacist should show you how to use your inhaler. They should check

how you use it from time to time. Not using the Seretide Diskus properly or as prescribed may

mean that it will not help your asthma or COPD as it should.

The Diskus device holds blisters containing Seretide as a powder.

There is a counter on top of the Diskus which tells you how many doses are left. It counts down to

0. The numbers 5 to 0 will appear in red to warn you when there are only a few doses left. Once

the counter shows 0, your inhaler is empty.

Using your inhaler

To open your Diskus, hold the outer case in one hand and put the thumb of your other hand on the

thumbgrip. Push your thumb away from you as far as it will go. You will hear a click. This will

open a small hole in the mouthpiece.

Hold your Diskus with the mouthpiece towards you. You can hold it in either your right or left

hand. Slide the lever away from you as far as it will go. You will hear a click. This places a dose

of your medicine in the mouthpiece.

Every time the lever is pulled back a blister is opened inside and the powder made ready for you to

inhale. Do not play with the lever as this opens the blisters and wastes medicine.

Hold the Diskus away from your mouth, breathe out as far as is comfortable. Do not breathe into

your Diskus.

Put the mouthpiece to your lips; breathe in steadily and deeply through the Diskus, not through

your nose.

Remove the Diskus from your mouth.

Hold your breath for about 10 seconds or for as long as is comfortable.

Breathe out slowly.

Afterwards rinse your mouth with water and spit it out, and/or brushing your teeth. This may help

to stop you getting thrush and becoming hoarse.

To close the Diskus, slide the thumbgrip back towards you, as far as it will go. You will hear a

click.

The lever will return to its original position and is reset.

Your Diskus is now ready for you to use again.

As with all inhalers, caregivers should ensure that children prescribed Seretide Diskus use correct

inhalation technique, as described above.

Cleaning your inhaler

Wipe the mouthpiece of the Diskus with a dry tissue to clean it.

If you use more Seretide than you should

It is important to use the inhaler as instructed. If you accidentally take a larger dose than

recommended, talk to your doctor or pharmacist. You may notice your heart beating faster than usual

and that you feel shaky. You may also have dizziness, a headache, muscle weakness and aching joints.

If you have used larger doses for a long period of time, you should talk to your doctor or pharmacist

for advice. This is because larger doses of Seretide may reduce the amount of steroid hormones

produced by the adrenal gland.

If you forget to use Seretide

Do not take a double dose to make up for a forgotten dose. Just take your next dose at the usual time.

If you stop using Seretide

It is very important that you take your Seretide every day as directed.

Keep taking it until your

doctor tells you to stop. Do not stop or suddenly reduce your dose of Seretide

. This could make

your breathing worse.

In addition, if you suddenly stop taking Seretide or reduce your dose of Seretide this may (very rarely)

cause you to have problems with your adrenal gland (adrenal insufficiency) which sometimes causes

side effects.

These side effects may include any of the following:

Stomach pain

Tiredness and loss of appetite, feeling sick

Sickness and diarrhoea

Weight loss

Headache or drowsiness

Low levels of sugar in your blood

Low blood pressure and seizures (fits)

When your body is under stress such as from fever, trauma (such as a car accident), infection, or

surgery, adrenal insufficiency can get worse and you may have any of the side effects listed above.

If you get any side effects, talk to your doctor or pharmacist. To prevent these symptoms occurring,

your doctor may prescribe extra corticosteroids in tablet form (such as prednisolone).

If you have any further questions on the use of this medicine, ask your doctor, nurse or pharmacist.

4.

Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. To reduce

the chance of side effects, your doctor will prescribe the lowest dose of Seretide to control your

asthma or COPD.

Allergic reactions: you may notice your breathing suddenly gets worse immediately after using

Seretide

. You may be very wheezy and cough or be short of breath. You may also notice itching, a

rash (hives) and swelling (usually of the face, lips, tongue or throat), or you may suddenly feel that

your heart is beating very fast or you feel faint and light headed (which may lead to collapse or loss of

consciousness).

If you get any of these effects or if they happen suddenly after using Seretide,

stop using Seretide and tell your doctor straight away

. Allergic reactions to Seretide are

uncommon (they affect less than 1 person in 100).

Pneumonia (infection of the lung) in COPD patients. (Common side effect)

Tell your doctor

if you have any of the following while taking Seretide they could be symptoms of a

lung infection:

fever or chills

increased mucus production, change in mucus colour

increased cough or increased breathing difficulties

Other side effects are listed below:

Very Common (affects more than 1 person in 10

Headache - this usually gets better as treatment continues.

Increased number of colds have been reported in patients with COPD.

Common

(affects less than 1 person in 10)

Thrush (sore, creamy-yellow, raised patches) in the mouth and throat. Also sore tongue and

hoarse voice and throat irritation. Rinsing your mouth out with water and spitting it out

immediately and/or brushing your teeth after taking each dose of your medicine may help. Your

doctor may prescribe an anti-fungal medication to treat the thrush.

Aching, swollen joints and muscle pain.

Muscle cramps

The following side effects have also been reported in patients with Chronic Obstructive Pulmonary

Disease (COPD):

Bruising and fractures.

Inflammation of sinuses (a feeling of tension or fullness in the nose, cheeks and behind the eyes,

sometimes with a throbbing ache).

A reduction in the amount of potassium in the blood (you may get an uneven heart beat, muscle

weakness, cramp).

Uncommon

(affects less than 1 person in 100)

Increases in the amount of sugar (glucose) in your blood (hyperglycaemia). If you have diabetes,

more frequent blood sugar monitoring and possibly adjustment of your usual diabetic treatment

may be required.

Cataract (cloudy lens in the eye).

Very fast heart beat (tachycardia).

Feeling shaky (tremor) and fast or uneven heart beat (palpitations) - these are usually harmless

and get less as treatment continues.

Chest pain

Feeling worried (this effect mainly occurs in children).

Disturbed sleep

Allergic skin rash

Rare (affects less than 1 person in 1000)

Breathing difficulties or wheezing that get worse straight after taking Seretide.

If this

happens

stop using your Seretide inhaler

. Use your fast acting ‘reliever’ inhaler to help your

breathing and

tell your doctor straight away

Seretide may affect the normal production of steroid hormones in the body, particularly if you

have taken high doses for long periods of time. The effects include:

Slowing of growth in children and adolescents,

Thinning of the bones

Glaucoma

Weight gain

Rounded (moon shaped) face (Cushing’s Syndrome)

Your doctor will check you regularly for any of these side effects and make sure you are taking

the lowest dose of Seretide to control your asthma.

Behavioural changes, such as being unusually active and irritable (these effects mainly occur in

children).

Uneven heart beat or heart gives an extra beat (arrhythmias). Tell your doctor, but do not stop

taking Seretide unless the doctor tells you to stop.

A fungal infection in the oesophagus (gullet), which might cause difficulties in swallowing.

Frequency not known, but may also occur:

Depression or aggression. These effects are more likely to occur in children.

Blurred vision.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects

not listed in this leaflet.

You can also report side effects directly via the national reporting system listed in Appendix V. By

reporting side effects you can help provide more information on the safety of this medicine.

5.

How to store Seretide

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the label and carton after EXP.

The expiry date refers to the last day of that month.

Do not store above 30

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to

throw away medicines you no longer use. These measures will help protect the environment.

6.

Contents of the pack and other information

What Seretide contains

Each pre-dispensed dose contains 50 micrograms of salmeterol (as salmeterol xinafoate)

and 100,

250 or 500 micrograms of fluticasone propionate.

The other ingredient is lactose monohydrate (which contains milk proteins).

What Seretide looks like and contents of the pack

The Seretide Diskus contains a foil strip. The foil protects the powder for inhalation from the

effects of the atmosphere.

Each dose is pre-dispensed.

The devices are packed in cartons which hold:

1 x Diskus 28 inhalations

or 1, 2, 3 or 10 x Diskus each containing 60 inhalations

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder:

[To be completed nationally]

Manufacturer:

Glaxo Operations UK Ltd (trading as Glaxo Wellcome Operations),

Priory Street, Ware, Hertfordshire SG12 ODJ, United Kingdom.

Tel: +44 (0)1920 463993; Fax: +44 (0)1920 864000

Glaxo Wellcome Production

Zone Industrielle No.2, 23 Rue Lavoisier, la madeleine, 27000 Evreux, France.

Tel: +33 2 3223 5500; Fax: +33 2 3223 5558

Aspen Bad Oldesloe GmbH

Industriestrasse 32-36, 23843 Bad Oldesloe, Germany

This medicinal product is authorised in the Member States of the EEA under the following

names:

Austria

Seretide Diskus

Belgium

Seretide Diskus

Croatia

Seretide Diskus

Cyprus

Seretide Diskus

Czech Republic

Seretide Diskus

Denmark

Seretide

Estonia

Seretide Diskus

Finland

Seretide Diskus

France

Seretide Diskus

Germany

atmadisc Diskus

Greece

Seretide Diskus

Hungary

Seretide Diskus

Iceland

Seretide

Ireland

Seretide Diskus

Italy

Seretide Diskus

Luxembourg

Seretide Diskus

Malta

Seretide Diskus

The Netherlands

Seretide Diskus

Portugal

Seretaide Diskus

Romania

Seretide Diskus

Slovakia

Seretide Diskus

Spain

Seretide Accuhaler

Sweden

Seretide Diskus

United Kingdom

Seretide Accuhaler

This leaflet was last revised in

23 July 2020.

[To be completed nationally]

[Detailed information on this medicine is available on the web site of {MA/Agency}]

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SUMMARY OF PRODUCT CHARACTERISTICS

NAME OF THE MEDICINAL PRODUCT

Seretide Diskus mite 50 microgram/100 microgram/ dose inhalation powder, pre-dispensed.

Seretide Diskus 50 microgram/250 microgram/ dose inhalation powder, pre-dispensed.

Seretide Diskus forte 50 microgram/500 microgram/ dose inhalation powder, pre-dispensed.

[To be completed nationally]

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 92, 231 or 460 micrograms of fluticasone propionate. This

corresponds to a pre-dispensed dose of 50 micrograms of salmeterol (as salmeterol xinafoate) and

100, 250 or 500 micrograms fluticasone propionate.

Excipients with known effect:

Each delivered dose contains up to 12.5 mg of lactose (as monohydrate).

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

agonist

and inhaled corticosteroid) is

appropriate:

patients not adequately controlled with inhaled corticosteroids and ‘as needed’ inhaled

short-acting

agonist

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

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 FEV

<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 Diskus 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.

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

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.

One inhalation of 50

micrograms salmeterol and 250 micrograms fluticasone propionate twice

daily.

One inhalation of 50 micrograms salmeterol and500 micrograms fluticasone propionate twice

daily.

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

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.

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 Diskus 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 Diskus:

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

4.4

Special warnings and precautions for use

Deterioration of disease

Seretide Diskus 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 life-threatening and the

patient should undergo urgent medical assessment.

Consideration should be given to increasing

corticosteroid therapy.

Once asthma symptoms are controlled, consideration may be given to gradually reducing the dose of

Seretide. Regular review of patients as treatment is stepped down is important. The lowest effective

dose of Seretide should be used (see section 4.2).

For patients with COPD experiencing exacerbations, treatment with systemic corticosteroids is

typically indicated, therefore patients should be instructed to seek medical attention if symptoms

deteriorate with Seretide

Treatment with Seretide should not be stopped abruptly in patients with asthma due to risk of

exacerbation. Therapy should be down-titrated under physician supervision. For patients with COPD

cessation of therapy may also be associated with symptomatic decompensation and should be

supervised by a physician.

As with all inhaled medication containing

corticosteroids, Seretide should be administered with

caution in patients with active or quiescent pulmonary tuberculosis and fungal, viral or other

infections of the airway. Appropriate treatment should be promptly instituted, if indicated.

Cardiovascular effects

Rarely, Seretide may cause cardiac arrhythmias e.g. supraventricular tachycardia, extrasystoles and

atrial fibrillation, and a mild transient reduction in serum potassium at high therapeutic doses.

Seretide should be used with caution in patients with severe cardiovascular disorders or heart rhythm

abnormalities and in patients with diabetes mellitus,

thyrotoxicosis,

uncorrected hypokalaemia or

patients predisposed to low levels of serum potassium.

Hyperglycaemia

There have been very rare reports of increases in blood glucose levels (see section 4.8) and this

should be considered when prescribing to patients with a history of diabetes mellitus.

Paradoxical bronchospasm

As with other inhalation therapy paradoxical bronchospasm may occur with an immediate increase in

wheezing and shortness of breath after dosing. Paradoxical bronchospasm responds to a rapid-acting

bronchodilator and should be treated straightaway. Seretide Diskus should be discontinued

immediately, the patient assessed and alternative therapy instituted if necessary.

The pharmacological side effects of

agonist treatment, such as tremor, palpitations and headache,

have been reported, but tend to be transient and reduce with regular therapy.

Excipients

Seretide contains lactose monohydrate up to 12.5 milligram /dose. This amount does not normally

cause problems in lactose intolerant people. The excipient lactose contains small amounts of milk

proteins, which may cause allergic reactions.

Systemic corticosteroid effects

Systemic effects may occur with any inhaled corticosteroid, particularly at high doses prescribed for

long periods. These effects are much less likely to occur than with oral corticosteroids. Possible

systemic effects include

Cushing’s syndrome, Cushingoid features, adrenal suppression, decrease in

bone mineral density, cataract and glaucoma and more rarely, a range of psychological or behavioural

effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression

(particularly in children) (see Paediatric population sub-heading below for information on the

systemic effects of inhaled corticosteroids in children and adolescents).

It is important, therefore,

that the patient is reviewed regularly and the dose of inhaled corticosteroid is reduced to the

lowest dose at which effective control of asthma is maintained.

Prolonged treatment of patients with high doses of inhaled corticosteroids may result in adrenal

suppression and acute adrenal crisis. Very rare cases of adrenal suppression and acute adrenal crisis

have also been described with doses of fluticasone propionate between 500 and less than 1000

micrograms. Situations, which could potentially trigger acute adrenal crisis include trauma, surgery,

infection or any rapid reduction in dosage. Presenting symptoms are typically vague and may include

anorexia, abdominal pain, weight loss, tiredness, headache, nausea, vomiting, hypotension, decreased

level of consciousness, hypoglycaemia, and seizures. Additional systemic corticosteroid cover should

be considered during periods of stress or elective surgery.

The benefits of inhaled fluticasone propionate therapy should minimise the need for oral steroids, but

patients transferring from oral steroids may remain at risk of impaired adrenal reserve for a

considerable time. Therefore these patients should be treated with special care and adrenocortical

function regularly monitored. Patients who have required high dose emergency corticosteroid therapy

in the past may also be at risk. This possibility of residual impairment should always be borne in mind

in emergency and elective situations likely to produce stress, and appropriate corticosteroid treatment

must be considered.

The extent of the adrenal impairment may require specialist advice before

elective procedures.

Ritonavir can greatly increase the concentration of fluticasone propionate in plasma. Therefore,

concomitant use should be avoided, unless the potential benefit to the patient outweighs the risk of

systemic corticosteroid side effects. There is also an increased risk of systemic side effects when

combining fluticasone propionate with other potent CYP3A inhibitors (see section 4.5).

Pneumonia in patients with COPD

An increase in the incidence of pneumonia, including pneumonia requiring hospitalisation, has been

observed in patients with COPD receiving inhaled corticosteroids. There is some evidence of an

increased risk of pneumonia with increasing steroid dose but this has not been demonstrated

conclusively across all studies.

There is no conclusive clinical evidence for intra-class differences in the magnitude of the pneumonia

risk among inhaled corticosteroid products.

Physicians should remain vigilant for the possible development of pneumonia in patients with COPD

as the clinical features of such infections overlap with the symptoms of COPD exacerbations.

Risk factors for pneumonia in patients with COPD include current smoking, older age, low body mass

index (BMI) and severe COPD.

Interactions with potent CYP3A4 inhibitors

Concomitant use of systemic ketoconazole significantly increases systemic exposure to salmeterol.

This may lead to an increase in the incidence of systemic effects (e.g. prolongation in the QTc interval

and palpitations). Concomitant treatment with ketoconazole or other potent CYP3A4 inhibitors should

therefore be avoided unless the benefits outweigh the potentially increased risk of systemic side

effects of salmeterol treatment (see section 4.5).

Visual disturbance

Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents

with symptoms such as blurred vision or other visual disturbances, the patient should be considered

for referral to an ophthalmologist for evaluation of possible causes, which may include cataract,

glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported

after use of systemic and topical corticosteroids.

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

adrenergic blockers may weaken or antagonise the effect of salmeterol. Both non-selective and

selective

blockers should be avoided unless there are compelling reasons for their use. Potentially

serious hypokalaemia may result from

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

adrenergic containing drugs can have a potentially additive effect.

Fluticasone Propionate

Under normal circumstances, low plasma concentrations of fluticasone propionate are achieved after

inhaled dosing, due to extensive first pass metabolism and high systemic clearance mediated by

cytochrome CYP3A4 in the gut and liver. Hence, clinically significant drug interactions mediated by

fluticasone propionate are unlikely.

In an interaction study in healthy subjects with intranasal fluticasone propionate, ritonavir (a highly

potent cytochrome CYP3A4 inhibitor) 100 mg b.i.d. increased the fluticasone propionate plasma

concentrations several hundred fold, resulting in markedly reduced serum cortisol concentrations.

Information about this interaction is lacking for inhaled fluticasone propionate, but a marked increase

in fluticasone propionate plasma levels is expected. Cases of Cushing’s syndrome and adrenal

suppression have been reported. The combination should be avoided unless the benefit outweighs the

increased risk of systemic glucocorticoid side effects.

In a small study in healthy volunteers, the slightly less potent CYP3A inhibitor ketoconazole

increased the exposure of fluticasone propionate after a single inhalation by 150%. This resulted in a

greater reduction of plasma cortisol as compared with fluticasone propionate alone. Co-treatment with

other potent CYP3A inhibitors, such as itraconazole and cobicistat-containing products, and moderate

CYP3A inhibitors, such as erythromycin, is also expected to increase the systemic fluticasone

propionate exposure and the risk of systemic side effects. Combinations should be avoided unless the

benefit outweighs the potential increased risk of systemic corticosteroid side-effects, in which case

patients should be monitored for systemic corticosteroid side-effects.

Salmeterol

Potent CYP3A4 inhibitors

Co-administration of ketoconazole (400 mg orally once daily) and salmeterol (50 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 C

and 1.2-fold AUC). Co-administration with

erythromycin was not associated with any serious adverse effects.

4.6

Fertility, pregnancy and lactation

Fertility

There are no data in humans. However, animal studies showed no effects of salmeterol or fluticasone

propionate on fertility.

Pregnancy

A large amount of data on pregnant women (more than 1000 pregnancy outcomes) indicates no

malformative or feto/neonatal toxicity related to Seretide. Animal studies have shown reproductive

toxicity after administration of

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 Diskus 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

Adverse Event

Frequency

Infections &

Infestations

Candidiasis of the mouth and throat

Pneumonia (in COPD patients)

Bronchitis

Oesophageal candidiasis

Common

Common

1,3,5

Common

Rare

Immune System

Disorders

Hypersensitivity reactions with the following

manifestations:

Cutaneous hypersensitivity reactions

Angioedema (mainly facial and oropharyngeal

oedema)

Respiratory symptoms (dyspnoea)

Respiratory symptoms (bronchospasm)

Anaphylactic reactions including anaphylactic shock

Uncommon

Rare

Uncommon

Rare

Rare

Endocrine Disorders

Cushing’s syndrome, Cushingoid features,

Adrenal

suppression, Growth retardation in children and

adolescents, Decreased bone mineral density

Rare

Metabolism &

Nutrition Disorders

Hypokalaemia

Hyperglycaemia

Common

Uncommon

Psychiatric Disorders

Anxiety

Sleep disorders

Behavioural changes, including psychomotor

hyperactivity and irritability (predominantly in

children)

Depression, aggression (predominantly in children)

Uncommon

Uncommon

Rare

Not known

System Organ Class

Adverse Event

Frequency

Nervous System

Disorders

Headache

Tremor

Very Common

Uncommon

Eye Disorders

Cataract

Glaucoma

Vision, blurred

Uncommon

Rare

Not known

Cardiac Disorders

Palpitations

Tachycardia

Cardiac arrhythmias (including supraventricular

tachycardia and extrasystoles).

Atrial fibrillation

Angina pectoris

Uncommon

Uncommon

Rare

Uncommon

Uncommon

Respiratory, Thoracic

& Mediastinal

Disorders

Nasopharyngitis

Throat irritation

Hoarseness/dysphonia

Sinusitis

Paradoxical bronchospasm

Very Common

Common

Common

Common

Rare

Skin and

subcutaneous tissue

disorders

Contusions

Common

Musculoskeletal &

Connective Tissue

Disorders

Muscle cramps

Traumatic fractures

Arthralgia

Myalgia

Common

Common

Common

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

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 Diskus 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 the Seretide Diskus.

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 national reporting system

listed in Appendix V

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

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)

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

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)

Low dose ICS

≤500 micrograms BDP

or equivalent/day)

Medium dose ICS

(>500 to 1000

micrograms BDP or equivalent/day)

Pooled results across the 3 treatment

levels

*Well controlled asthma; less than or equal to 2 days with symptom score greater than 1 (symptom

score 1 defined as ‘symptoms for one short period during the day’), SABA use on less than or equal to

2 days and less than or equal to 4 occasions/week, greater than or equal to 80% predicted morning

peak expiratory flow, no night-time awakenings, no exacerbations and no side effects enforcing a

change in therapy

**Total control of asthma; no symptoms, no SABA use, greater than or equal to 80% predicted

morning peak expiratory flow, no night-time awakenings, no exacerbations and no side effects

enforcing a change in therapy

The results of this study suggest

that Seretide 50/100 micrograms bd may be considered as initial

maintenance therapy in patients with moderate persistent asthma for whom rapid control of asthma is

deemed essential (see section 4.2).

A double blind, randomised, parallel group study in 318 patients with persistent asthma aged ≥18

years evaluated the safety and tolerability of administering two inhalations twice daily (double dose)

of Seretide for two weeks. The study showed that doubling the inhalations of each strength of Seretide

for up to 14 days resulted in a small increase in

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

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 Diskus 50/500 micrograms

bd, salmeterol Diskus 50 micrograms bd, fluticasone propionate (FP) Diskus 500 micrograms bd or

placebo on all-cause mortality in patients with COPD. COPD patients with a baseline

(pre-bronchodilator) FEV

<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

Salmeterol 50

N = 1521

FP 500

N = 1534

Seretide

50/500

N = 1533

All cause mortality at 3 years

Number of deaths

(15.2%)

(13.5%)

(16.0%)

(12.6%)

Hazard Ratio vs

Placebo (CIs)

p value

0.879

(0.73, 1.06)

0.180

1.060

(0.89, 1.27)

0.525

0.825

(0.68, 1.00 )

0.052

Hazard Ratio

Seretide 50/500 vs

components (CIs)

p value

0.932

(0.77, 1.13)

0.481

0.774

(0.64, 0.93)

0.007

1. Non significant P value after adjustment for 2 interim analyses on the primary efficacy

comparison from a log-rank analysis stratified by smoking status

There was a trend towards improved survival in subjects treated with Seretide compared with placebo

over 3 years however this did not achieve the statistical significance level p≤0.05.

The percentage of patients who died within 3 years due to COPD-related causes was 6.0% for

placebo, 6.1% for salmeterol, 6.9% for FP and 4.7% for Seretide.

The mean number of moderate to severe exacerbations per year was significantly reduced with

Seretide as compared with treatment with salmeterol, FP and placebo (mean rate in the Seretide group

0.85 compared with 0.97 in the salmeterol group, 0.93 in the FP group and 1.13 in the placebo). This

translates to a reduction in the rate of moderate to severe exacerbations of 25% (95% CI: 19% to

31%; p<0.001) compared with placebo, 12% compared with salmeterol (95% CI: 5% to 19%,

p=0.002) and 9% compared with FP (95% CI: 1% to 16%, p=0.024). Salmeterol and FP significantly

reduced exacerbation rates compared with placebo by 15% (95% CI: 7% to 22%; p<0.001) and 18%

(95% CI: 11% to 24%; p<0.001) respectively.

Health Related Quality of Life, as measured by the St George’s Respiratory Questionnaire (SGRQ)

was improved by all active treatments in comparison with placebo. The average improvement over

three years for Seretide compared with placebo was -3.1 units (95% CI: -4.1 to -2.1; p<0.001),

compared with salmeterol was -2.2 units (p<0.001) and compared with FP was -1.2 units (p=0.017). A

4-unit decrease is considered clinically relevant.

The estimated 3-year probability of having pneumonia reported as an adverse event was 12.3% for

placebo, 13.3% for salmeterol, 18.3% for FP and 19.6% for Seretide (Hazard ratio for Seretide vs

placebo: 1.64, 95% CI: 1.33 to 2.01, p<0.001). There was no increase in pneumonia related deaths;

deaths while on treatment that were adjudicated as primarily due to pneumonia were 7 for placebo, 9

for salmeterol, 13 for FP and 8 for Seretide. There was no significant difference in probability of bone

fracture (5.1% placebo, 5.1% salmeterol, 5.4% FP and 6.3% Seretide; Hazard ratio for Seretide vs

placebo: 1.22, 95% CI: 0.87 to 1.72, p=0.248.

Placebo-controlled clinical trials, over 6 and 12 months, have shown that regular use of Seretide

50/500 micrograms improves lung function and reduces breathlessness and the use of relief

medication.

Studies SCO40043 and SCO100250 were randomised, double-blind, parallel-group, replicate studies

comparing the effect of Seretide 50/250 micrograms bd (a dose not licensed for COPD treatment in

the European Union) with salmeterol 50 micrograms bd on the annual rate of moderate/severe

exacerbations in subjects with COPD with FEV

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 open-label 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 (

agonist and anticholinergic), ipratropium/salbutamol combination products, oral

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) FEV

significantly favoured Seretide 50/250 micrograms bd over salmeterol. Adverse event profiles were

similar with the exception of a higher incidence of pneumonias and known local side effects

(candidiasis and dysphonia) in the Seretide 50/250 micrograms bd group compared with salmeterol.

Pneumonia-related events were reported for 55 (7%) subjects in the Seretide 50/250 micrograms bd

group and 25 (3%) in the salmeterol group. The increased incidence of reported pneumonia with

Seretide 50/250 micrograms bd appears to be of similar magnitude to the incidence reported following

treatment with Seretide 50/500 micrograms bd in TORCH.

Asthma

The Salmeterol Multi-center Asthma Research Trial (SMART)

The Salmeterol Multi-center Asthma Research Trial (SMART) was a 28-week US study that

evaluated the safety of salmeterol compared to placebo added to usual therapy in adult and adolescent

subjects. Although there were no significant differences in the primary endpoint of the combined

number of respiratory-related deaths and respiratory-related life-threatening experiences, the study

showed a significant increase in asthma-related deaths in patients receiving salmeterol (13 deaths out

of 13,176 patients treated with salmeterol versus 3 deaths out of 13,179 patients on placebo). The

study was not designed to assess the impact of concurrent inhaled corticosteroid use, and only 47% of

subjects reported ICS use at baseline.

Safety and efficacy of salmeterol-FP versus FP alone in asthma

Two multi-centre 26-week studies were conducted to compare the safety and efficacy of salmeterol-

FP versus FP alone, one in adult and adolescent subjects (AUSTRI trial), and the other in paediatric

subjects 4-11 years of age (VESTRI trial). For both studies, enrolled subjects had moderate to severe

persistent asthma with history of asthma-related hospitalisation or asthma exacerbation in the

previous year. The primary objective of each study was to determine whether the addition of LABA to

ICS therapy (salmeterol-FP) was non-inferior to ICS (FP) alone in terms of the risk of serious asthma

related events (asthma-related hospitalisation, endotracheal intubation, and death). A secondary

efficacy objective of these studies was to evaluate whether ICS/LABA (salmeterol-FP) was superior

to ICS therapy alone (FP) in terms of severe asthma exacerbation (defined as deterioration of asthma

requiring the use of systemic corticosteroids for at least 3 days or an in-patient hospitalisation or

emergency department visit due to asthma that required systemic corticosteroids).

A total of 11,679 and 6,208 subjects were randomized and received treatment in the AUSTRI and

VESTRI trials, respectively. For the primary safety endpoint, non-inferiority was achieved for both

trials (see Table below).

Serious Asthma-Related Events in the 26-Week AUSTRI and VESTRI Trials

AUSTRI

VESTRI

Salmeterol-FP

(n = 5,834)

FP Alone

(n = 5,845)

Salmeterol-FP

(n = 3,107)

FP Alone

(n = 3,101)

Composite endpoint

(Asthma-related

hospitalisation,

endotracheal intubation, or

death)

34 (0.6%)

33 (0.6%)

27 (0.9%)

21 (0.7%)

Salmeterol-FP/FP Hazard

ratio (95% CI)

1.029

(0.638-1.662)

1.285

(0.726-2.272)

Death

Asthma-related

hospitalisation

Endotracheal intubation

If the resulting upper 95% CI estimate for the relative risk was less than 2.0, then non-inferiority

was concluded.

If the resulting upper 95% CI estimate for the relative risk was less than 2.675, then non-inferiority

was concluded.

For the secondary efficacy endpoint, reduction in time to first asthma exacerbation for salmeterol-FP

relative to FP was seen in both studies, however only AUSTRI met statistical significance:

AUSTRI

VESTRI

Salmeterol-FP

(n = 5,834)

FP Alone

(n = 5,845)

Salmeterol-FP

(n = 3,107)

FP Alone

(n = 3,101)

Number of subjects with an

asthma exacerbation

480 (8%)

597 (10%)

265 (9%)

309 (10%)

Salmeterol-FP/FP Hazard

ratio (95% CI)

0.787

(0.698, 0.888)

0.859

(0.729, 1.012)

Paediatric population:

In trial SAM101667, in 158 children aged 6 to 16 years with symptomatic asthma, the combination of

salmeterol/fluticasone propionate is equally efficacious to doubling the dose of fluticasone propionate

regarding symptom control and lung function. This study was not designed to investigate the effect on

exacerbations.

In a 12 week trial of children aged 4 to 11 years [n=257] treated with either salmeterol/fluticasone

propionate 50/100 or salmeterol 50 micrograms + fluticasone propionate 100 micrograms both twice

daily, both treatment arms experienced a 14% increase in peak expiratory flow rate as well as

improvements in symptom score and rescue salbutamol use. There were no differences between the 2

treatment arms. There were no differences in safety parameters between the 2 treatment arms.

In a 12 week trial of children 4 to 11 years of age [n=203] randomized in a parallel-group study with

persistent asthma and who were symptomatic on inhaled corticosteroid, safety was the primary

objective. Children received either salmeterol/fluticasone propionate (50/100 micrograms) or

fluticasone propionate (100 micrograms) alone twice daily. Two children on salmeterol/fluticasone

propionate and 5 children on fluticasone propionate withdrew because of worsening asthma. After 12

weeks no children in either treatment arm had abnormally low 24 hour urinary cortisol excretion.

There were no other differences in safety profile between the treatment arms.

Fluticasone propionate containing medications in asthma during pregnancy

An observational retrospective epidemiological cohort study utilising electronic health records from

the United Kingdom was conducted to evaluate the risk of MCMs following first trimester exposure

to inhaled FP alone and salmeterol-FP relative to non-FP containing ICS. No placebo comparator was

included in this study.

Within the asthma cohort of 5362 first trimester ICS-exposed pregnancies, 131 diagnosed MCMs

were identified; 1612 (30%) were exposed to FP or salmeterol-FP of which 42 diagnosed MCMs were

identified. The adjusted odds ratio for MCMs diagnosed by 1 year was 1.1 (95%CI: 0.5 – 2.3) for FP

exposed vs non-FP ICS exposed women with moderate asthma and 1.2 (95%CI: 0.7 – 2.0) for women

with considerable to severe asthma. No difference in the risk of MCMs was identified following first

trimester exposure to FP alone versus salmeterol-FP. Absolute risks of MCM across the asthma

severity strata ranged from 2.0 to 2.9 per 100 FP-exposed pregnancies which is comparable to results

from a study of 15,840 pregnancies unexposed to asthma therapies in the General Practice Research

Database (2.8 MCM events per 100 pregnancies).

5.2

Pharmacokinetic properties

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 presystemic 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)

Population

AUC

C

max

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]

Salmeterol/fluticasone

propionate Diskus 50/100

fluticasone propionate Diskus

100

Adolescent/Adult

( ≥12yr)

1.52 [1.08 – 2.13]

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. Neither salmeterol xinafoate or fluticasone

propionate have shown any potential for genetic toxicity.

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

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

1 x 28 dose Diskus

1 x 60 dose Diskus

2 x 60 dose Diskus

3 x 60 dose Diskus

10 x 60 dose Diskus

Not all pack sizes may be marketed.

6.6

Special precautions for disposal and other handling

The Diskus releases a powder which is inhaled into the lungs. A dose indicator on the Diskus

indicates the number of doses left. For detailed instructions for use see the Patient Information

Leaflet.

7.

MARKETING AUTHORISATION HOLDER

[To be completed nationally]

8.

MARKETING AUTHORISATION NUMBER(S)

[To be completed nationally]

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation:

[To be completed nationally]

Date of latest renewal:

[To be completed nationally]

10.

DATE OF REVISION OF THE TEXT

23 July 2020

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