Fluterolo Easyhaler 50 mikrogram/500 mikrogram/dos Inhalationspulver

Sverige - svenska - Läkemedelsverket (Medical Products Agency)

Bipacksedel Bipacksedel (PIL)

11-06-2018

Produktens egenskaper Produktens egenskaper (SPC)

15-04-2019

Aktiva substanser:
flutikasonpropionat; salmeterolxinafoat
Tillgänglig från:
Orion Corporation
ATC-kod:
R03AK06
INN (International namn):
fluticasone propionate; salmeterol
Dos:
50 mikrogram/500 mikrogram/dos
Läkemedelsform:
Inhalationspulver
Sammansättning:
salmeterolxinafoat 73 mikrog Aktiv substans; flutikasonpropionat 500 mikrog Aktiv substans; laktosmonohydrat Hjälpämne
Receptbelagda typ:
Receptbelagt
Produktsammanfattning:
Förpacknings: Inhalator, 1 x 60 doser (utan fodral); Inhalator, 2 x 60 doser (utan fodral); Inhalator, 3 x 60 doser (utan fodral); Inhalator, 1 x 60 doser (med fodral); Inhalator, 2 x 60 doser (med fodral); Inhalator, 3 x 60 doser (med fodral)
Bemyndigande status:
Godkänd
Godkännandenummer:
56280
Tillstånd datum:
2018-06-08

Dokument på andra språk

Bipacksedel Bipacksedel - engelska

15-03-2018

Produktens egenskaper Produktens egenskaper - engelska

15-04-2019

Offentlig bedömningsrapport Offentlig bedömningsrapport - engelska

08-06-2018

Läs hela dokumentet

PACKAGE LEAFLET

QR code to www.oeh.fi/ xxxx [to be completed nationally].

Scan this code or visit www.oeh.fi/ xxxx [to be completed nationally] to see instructions on how to use

Easyhaler

Package leaflet: Information for the user

Fluterolo Easyhaler 50 microgram/250 microgram/dose, inhalation powder

Fluterolo Easyhaler 50 microgram/500 microgram/dose, inhalation powder

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 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 Fluterolo Easyhaler is and what it is used for

What you need to know before you use Fluterolo Easyhaler

How to use Fluterolo Easyhaler

Possible side effects

How to store Fluterolo Easyhaler

Contents of the pack and other information

1.

What Fluterolo Easyhaler is and what it is used for

Fluterolo Easyhaler 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). Fluterolo Easyhaler, at a dose of

50/500 micrograms, reduces the number of flare ups of COPD symptoms.

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

works properly in controlling your asthma or COPD.

Fluterolo Easyhaler helps to stop breathlessness and wheeziness coming on. However, Fluterolo

Easyhaler 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 Fluterolo Easyhaler

Do not take Fluterolo Easyhaler:

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

monohydrate (which contains small amounts of milk protein).

Warnings and precautions

Talk to your doctor before using Fluterolo Easyhaler if you have:

Heart disease, including an irregular or fast heart beat

Overactive thyroid gland

High blood pressure

Diabetes mellitus (Fluterolo Easyhaler 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 Fluterolo Easyhaler

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

medicines. This includes medicines for asthma or any medicines obtained without a prescription. This

is because Fluterolo Easyhaler may not be suitable to take with some other medicines.

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

Beta blockers (such as atenolol, propranolol and sotalol). Beta blockers are mostly used for high

blood pressure or other heart conditions.

Medicines to treat infections (including ketoconazole, itraconazole and erythromycin and some

medicines for HIV: ritonavir, cobicistat). Some of these medicines may increase the amount of

fluticasone propionate or salmeterol in your body. This can increase the effects of Fluterolo

Easyhaler and therefore increase your risk of experiencing side effects, including irregular

heartbeats. 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 Fluterolo Easyhaler 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

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

Fluterolo Easyhaler contains lactose

Fluterolo Easyhaler contains up to 17.1 milligrams of lactose in each dose. The amount of lactose in

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

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

3.

How to use Fluterolo Easyhaler

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 Fluterolo Easyhaler every day until your doctor advises you to stop. Do not take more

than the recommended dose.

Do not stop taking Fluterolo Easyhaler or reduce the dose of Fluterolo Easyhaler without talking

to your doctor first.

Fluterolo Easyhaler should be inhaled through the mouth into the lungs.

For asthma

Adults and adolescents aged 12 years and over

Fluterolo Easyhaler 50/250 - One inhalation twice a day

Fluterolo Easyhaler 50/500 - One inhalation twice a day

Children below 12 years of age

Fluterolo Easyhaler is not recommended for use in children below 12 years of age

For adults with Chronic Obstructive Pulmonary Disease (COPD)

Fluterolo Easyhaler 50/500 - One inhalation twice a day

Your symptoms may become well controlled using Fluterolo Easyhaler 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 Fluterolo Easyhaler 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 Fluterolo Easyhaler but do not

increase the number of doses you take. Your chest condition may be getting worse and you could

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

If you use more Fluterolo Easyhaler 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 Fluterolo Easyhaler may reduce the amount of steroid

hormones produced by the adrenal gland.

If you forget to use Fluterolo Easyhaler

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 Fluterolo Easyhaler

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

Keep taking it until

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

This could make your breathing worse.

In addition, if you suddenly stop taking Fluterolo Easyhaler or reduce your dose of Fluterolo Easyhaler

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.

The instructions how to use the inhaler are at the end of the leaflet.

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 Fluterolo Easyhaler to control

your asthma or COPD.

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

Fluterolo Easyhaler

. 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

Fluterolo Easyhaler, stop using Fluterolo Easyhaler and tell your doctor straight away

. Allergic

reactions to Fluterolo Easyhaler 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 Fluterolo Easyhaler, 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 (may affect more than 1 in 10 people

Headache - this usually gets better as treatment continues

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

Common

(may affect up to 1 in 10 people)

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 common 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

(may affect up to 1 in 100 people)

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 (may affect up to 1 in 1,000 people)

Breathing difficulties or wheezing that get worse straight after taking Fluterolo Easyhaler.

If this happens

stop using your Fluterolo Easyhaler inhaler

. Use your fast acting ‘reliever’

inhaler to help your breathing and

tell your doctor straight away

Fluterolo Easyhaler 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 Fluterolo Easyhaler 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 Fluterolo Easyhaler unless the doctor tells you to stop.

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

Frequency not known (cannot be estimated from the available data), 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 Fluterolo Easyhaler

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

Do not use this medicine after the expiry date that is stated on the carton, foil bag and label of

your inhaler after EXP. The expiry date refers to the last day of that month.

Replace Fluterolo Easyhaler 1 month (50/250) or 2 months (50 /500) after you opened the foil

bag. Write down the date you opened the bag to help you remember.

After opening the foil bag do not store above 25

C and store protected from moisture. It is

recommended to keep the Easyhaler in its protective cover.

If your Fluterolo Easyhaler gets damp you need to replace it with a new one.

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 to protect the

environment.

6.

Contents of the pack and other information

What Fluterolo Easyhaler contains

Each dose contains salmeterol xinafoate equivalent to 50 micrograms of salmeterol and 250 or

500 micrograms of fluticasone propionate.

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

What Fluterolo Easyhaler looks like and contents of the pack

Fluterolo Easyhaler is an inhaler containing your medicine. The inhalation powder is white. Each

inhaler contains 60 doses and has a white body with purple upper part.

Fluterolo Easyhaler is available in packs of 1, 2 or 3 inhaler(s).

Not all pack sizes may be marketed.

Your pack may contain a protective cover. If you need a protective cover, please contact the

Marketing Authorisation Holder (details given below).

Marketing Authorisation Holder

Orion Corporation

Orionintie 1

FI-02200 Espoo

Finland

Manufacturer

Orion Corporation Orion Pharma

Orionintie 1

FI-02200 Espoo

Finland

This leaflet was last revised on 15 March 2018

Detailed and updated information on this product is available by scanning this QR code (included also

on outer carton and inhaler label) with a smartphone. The same information is also available on the

following URL: www.oeh.fi/ xxxx [to be completed nationally].

QR code to www.oeh.fi/ xxxx [to be completed nationally].

How to use the Easyhaler inhaler

About your Easyhaler

Fluterolo Easyhaler may be different to inhalers you have used in the past. Therefore it is very

important that you use it properly as using incorrectly can lead to you not receiving the right amount

of medicine. This could make you very unwell or could lead to your asthma and COPD not being

treated as it should.

Your doctor, nurse or pharmacist will show you how to use your inhaler properly. Make sure you

understand the correct way to use the inhaler. If you are unsure contact your doctor, nurse or

pharmacist. As with all inhalers, caregivers should ensure that children prescribed Fluterolo Easyhaler

use correct inhalation technique, as described below. You can also use the instruction video at

www.oeh.fi/xxxx

When you first get your Easyhaler

The Easyhaler comes in a foil bag. Do not open the foil bag until

you are ready to start using the medicine as it helps to keep the

powder dry in the inhaler.

When you are ready to start treatment open the bag and record

the date e.g., in your calendar.

Use the inhaler within 1 month

(50/250)

or 2 months

(50/500)

removing from the foil bag.

HOW TO USE CORRECTLY

Step 1:

SHAKE

Remove the dustcap

Shake the inhaler

3

5

times

holding it in the

upright

position

SHAKE x 3-5

Important points to remember

It is important to keep the

inhaler in the upright position

If you accidentally click while

you shake the inhaler, empty the

powder from the mouthpiece as

shown below

Step 2

CLICK

Keep holding the inhaler

upright between your forefinger

and thumb

Press down until you hear a

click, and let the inhaler click

back again. This releases a dose

Only click down once

CLICK x 1

Important points to remember

The inhaler will not click if the

dustcap is still on

Only click down once

If you accidentally click more

than once, empty the powder

from the mouthpiece, see below

Click to release dose before

you inhale, not at the same time

Keep the inhaler

upright

when

you click it and when you inhale

the dose. If you tip it, the

powder could fall out before

you are able to inhale it

Step 3

INHALE

Keep holding the inhaler

upright

Breathe out normally

Place the mouthpiece in

your mouth between your

teeth and close your lips

tightly around the

mouthpiece

Take a strong and deep

breath in

Take the inhaler out of your

mouth, hold breath

for at

least 5 seconds

, then breathe

out normally.

INHALE

Important points to

remember

Make sure the whole

mouthpiece is well inside

your mouth, so that the

medication gets into your

lungs

Make sure your lips make a

good seal around the

mouthpiece

Do not breathe out into the

inhaler. This is important: it

could clog up the inhaler. If

you breathed out into the

inhaler, empty the powder

from mouthpiece, see below

After you have used the inhaler:

Put the dust cap back on the mouthpiece. It stops the inhaler going off by accident.

After you have taken the dose, rinse your mouth with water, and spit it out and/or brush your teeth.

This may help to stop you getting thrush and becoming hoarse.

How to empty the powder from the mouthpiece

If you click the inhaler by accident, or if you might have

clicked it more than once, or if you breathe out into it,

empty the mouthpiece.

Tap the mouthpiece to empty the powder onto a table top,

or the palm of your hand.

Then start again with steps Shake-Click-Inhale.

Cleaning the Easyhaler

Keep your inhaler dry and clean. If necessary you may wipe the mouthpiece of your inhaler with a dry

cloth or tissue. Do not use water: the powder in the Easyhaler is sensitive to moisture.

Using the Easyhaler with a protective cover

You may use a protective cover with your inhaler.This helps to

improve durability of the product. When you first insert your

inhaler in the protective cover make sure the dustcap is on the

inhaler as this stops it going off by accident. You can use the

inhaler without removing it from the protective cover.

Follow the same instructions as above,

1. Shake – 2. Click – 3.

Inhale.

Remember to:

Keep the

inhaler in the upright position when clicking it

Replace the dustcap after taking the dose as this stops the

inhaler going off by accident.

When to switch to a new Easyhaler

The dose counter shows the number of remaining doses.

The counter turns after every 5th click. When the dose

counter starts turning red, there are 20 doses left.

If you do not already have a new Easyhaler, contact your

doctor for a new prescription. When the counter reaches

0 (zero), you need to replace the Easyhaler.

If you use the protective cover, you can keep it and insert

your new inhaler into it.

Remember

1. Shake – 2. Click – 3. Inhale.

After you have taken the dose, rinse your mouth with water and spit it out and/or brush your

teeth.

Do not get your inhaler wet, protect it from moisture.

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

Läs hela dokumentet

SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT

Fluterolo Easyhaler 50 microgram/250 microgram/dose, inhalation powder

Fluterolo Easyhaler 50 microgram/500 microgram/dose, inhalation powder

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Fluterolo Easyhaler 50 microgram/250 microgram: Each delivered dose (the dose that leaves the

mouthpiece) contains salmeterol xinafoate corresponding to 48 micrograms of salmeterol and

238 micrograms fluticasone propionate.

This corresponds to a metered dose of salmeterol xinafoate corresponding to 50 micrograms of

salmeterol and 250 micrograms fluticasone propionate.

Fluterolo Easyhaler 50 microgram/500 microgram: Each delivered dose (the dose that leaves the

mouthpiece) contains salmeterol xinafoate corresponding to 48 micrograms of salmeterol and

476 micrograms fluticasone propionate.

This corresponds to a metered dose of salmeterol xinafoate corresponding to 50 micrograms of

salmeterol and 500 micrograms fluticasone propionate.

Excipient with known effect: Lactose monohydrate 17 mg per delivered dose

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Inhalation powder in a device metered inhaler (Easyhaler)

White powder.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Asthma

Fluterolo Easyhaler is indicated in the regular treatment of asthma in adults and adolescents 12 years

and over 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.

Chronic Obstructive Pulmonary Disease (COPD)

Fluterolo Easyhaler 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

Patients should be made aware that Fluterolo Easyhaler must be used daily for optimum benefit, even

when asymptomatic.

Patients should be regularly reassessed by a doctor, so that the strength of Fluterolo Easyhaler 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.

For dosages which cannot

be achieved with Fluterolo Easyhaler (i.e. 50 micrograms salmeterol and 100 micrograms fluticasone

propionate) other fixed-dose combination products containing these two active ingredients are

available.

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 Fluterolo Easyhaler 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 Fluterolo Easyhaler 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 250 micrograms fluticasone propionate twice daily.

One inhalation of 50 micrograms salmeterol and 500 micrograms fluticasone propionate twice daily.

A short-term trial of salmeterol/fluticasone propionate 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, a strength which is available for

other similar fixed-dose combination products containing these two active ingredients. 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. Fluterolo Easyhaler is not intended for

the initial management of mild asthma. Salmeterol/fluticasone propionate

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

Fluterolo Easyhaler should not be used in children younger than 12 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 Fluterolo Easyhaler in patients with hepatic impairment.

Method of administration

Inhalation use.

Instructions for correct use of Fluterolo Easyhaler:

The inhaler is inspiratory flow-driven, which means that when the patient inhales through the

mouthpiece, the substance will follow the inspired air into the airways.

Note

:

It is important to instruct the patient

To carefully read the instructions for use in the patient information leaflet which is packed

together with each Fluterolo Easyhaler

To hold the inhaler upright, gripping it between finger and thumb

To vigorously shake the inhaler up and down 3 to 5 times before actuation

To actuate (click) the inhaler before inhalation

To breathe in forcefully and deeply through the mouthpiece to ensure that an optimal dose is

delivered to the lungs

To hold breath after inhaling for at least 5 seconds

Never to breathe out through the mouthpiece as this will result in a reduction in the delivered

dose. Should this happen the patient is instructed to tap the mouthpiece onto a table top or the

palm of a hand to empty the powder, and then to repeat the dosing procedure.

Never to actuate the device more than once without inhalation of the powder. Should this happen

the patient is instructed to tap the mouthpiece onto a table top or the palm of a hand to empty the

powder, and then to repeat the dosing procedure.

To always replace the dust cap (and, if in use, close the protective cover) after use to prevent

accidental actuation of the device (which could result in either overdosing or under dosing the

patient when subsequently used)

To rinse the mouth out with water and/or brush teeth after inhaling the maintenance dose to

minimise the risk of oropharyngeal thrush.

Water should never be used for cleaning the inhaler because the powder is sensitive to moisture

To replace Fluterolo Easyhaler when the counter reaches zero even though powder could still be

observed within the inhaler.

4.3

Contraindications

Hypersensitivity

to the active substances or to the excipient listed in section 6.1 (lactose, which

contains small amounts of milk protein).

4.4

Special warnings and precautions for use

Deterioration of disease

Fluterolo Easyhaler 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 Fluterolo Easyhaler 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 Fluterolo

Easyhaler. Patients should be asked to continue treatment but to seek medical advice if asthma

symptoms remain uncontrolled or worsen after initiation on Fluterolo Easyhaler.

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

Fluterolo Easyhaler. Regular review of patients as treatment is stepped down is important. The lowest

effective dose of Fluterolo Easyhaler 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 Fluterolo Easyhaler.

Treatment with Fluterolo Easyhaler 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, Fluterolo Easyhaler 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, Fluterolo Easyhaler may cause cardiac arrhythmias e.g. supraventricular tachycardia,

extrasystoles and atrial fibrillation, and a mild transient reduction in serum potassium at high

therapeutic doses. Fluterolo Easyhaler 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. Fluterolo Easyhaler 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.

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

1,000 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).

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.

Pneumonia in patients with COPD

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

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

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

conclusively across all studies.

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

risk among inhaled corticosteroid products.

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

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

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

index (BMI) and severe COPD.

Interactions with potent CYP3A4 inhibitors

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

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

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

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

effects of salmeterol treatment (see section 4.5).

Paediatric population

Children and adolescents <16 years taking high doses of fluticasone propionate (typically

1000 micrograms/day) may be at particular risk. Systemic effects may occur, particularly at high

doses prescribed for long periods. Possible systemic effects include Cushing’s syndrome, Cushingoid

features

,

adrenal suppression, acute adrenal crisis and growth retardation in children and adolescents

and more rarely, a range of psychological or behavioural effects including psychomotor hyperactivity,

sleep disorders, anxiety, depression or aggression. Consideration should be given to referring the

child or adolescent to a paediatric respiratory specialist.

It is recommended that the height of children receiving prolonged treatment with inhaled

corticosteroid is regularly monitored.

The dose of inhaled corticosteroid should be reduced to the

lowest dose at which effective control of asthma is maintained.

Excipients

Fluterolo Easyhaler contains lactose up to 17.1 mg /dose as an excipient. 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.

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 CYP3A inhibitors, including 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 C

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 CYP3A4 inhibitors

Co-administration of erythromycin (500 mg orally three times a day) and salmeterol (50 micrograms

inhaled twice daily) in 15 healthy subjects for 6 days resulted in a small but non-statistically

significant increase in salmeterol exposure (1.4-fold C

and 1.2-fold AUC). Co-administration with

erythromycin was not associated with any serious adverse effects.

4.6

Fertility, pregnancy and lactation

Pregnancy

A large amount of data on pregnant women (more than 1,000 pregnancy outcomes) indicates no

malformative or feto/neonatal toxicity related to salmeterol and fluticasone propionate. Animal

studies have shown reproductive toxicity after administration of

adrenoreceptor agonists and

glucocorticosteroids (see section 5.3).

Administration of Fluterolo Easyhaler 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 Fluterolo Easyhaler therapy taking into account the

benefit of breastfeeding for the child and the benefit of therapy for the woman.

Fertility

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

propionate on fertility.

4.7

Effects on ability to drive and use machines

Fluterolo Easyhaler has no or negligible influence on the ability to drive and use machines.

4.8

Undesirable effects

As Fluterolo Easyhaler 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 (

1/1,000 to

1/100), rare (

1/10,000 to <1/1,000) 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:

System Organ Class

Adverse Event

Frequency

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

Nervous System

Disorders

Headache

Tremor

Very Common

Uncommon

Eye Disorders

Cataract

Glaucoma

Vision, blurred (see also section 4.4)

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

Nasopharyngitis

Very Common

System Organ Class

Adverse Event

Frequency

Disorders

Throat irritation

Hoarseness/dysphonia

Sinusitis

Paradoxical bronchospasm

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. Fluterolo Easyhaler 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 Fluterolo Easyhaler.

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 Fluterolo Easyhaler, 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 Fluterolo Easyhaler 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 Fluterolo Easyhaler therapy should

be continued at a suitable dosage for symptom control.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic Group: Drugs for obstructive airway diseases, adrenergics in combination with

corticosteroids or other drugs, excl. anticholinergics.

ATC Code: R03AK06

Mechanism of action and pharmacodynamic effects

Fluterolo Easyhaler 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

Asthma clinical trials

A twelve month study (Gaining Optimal Asthma ControL, GOAL), in 3,416 adult and adolescent

patients with persistent

asthma, compared the safety and efficacy of salmeterol/fluticasone propionate

(FP) versus inhaled corticosteroid (FP) alone to determine whether the goals of asthma management

were achievable. Treatment was stepped up every 12 weeks until **

total control

was achieved or the

highest dose of study drug was reached. GOAL showed more patients treated with salmeterol/FP

achieved asthma control than patients treated with ICS alone and this control was attained at a lower

corticosteroid dose.

*Well controlled

asthma was achieved more rapidly with salmeterol/FP than with ICS alone. The time

on treatment for 50% of subjects to achieve a first individual

well controlled

week was 16 days for

salmeterol/FP compared to 37 days for the ICS group. In the subset of steroid naive asthmatics the

time to an individual

well controlled

week was 16 days in the salmeterol/FP 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 salmeterol/FP 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.

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

≥18 years evaluated the safety and tolerability of administering two inhalations twice daily (double

dose) of salmeterol/FP for two weeks. The study showed that doubling the inhalations of each

strength of salmeterol/FP 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 Fluterolo Easyhaler is considered by the physician in adult patients requiring additional

short-term (up to 14 days) inhaled corticosteroid therapy.

COPD clinical trials

TORCH was a 3-year study to assess the effect of treatment with salmeterol/FP 50/500 micrograms

bd, salmeterol 50 micrograms bd, FP 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 salmeterol/FP vs Placebo.

Placebo

N = 1,524

Salmeterol 50

N = 1,521

FP 500

N = 1,534

Salmeterol/FP

50/500

N = 1,533

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

salmeterol/FP

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 salmeterol/FP 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 salmeterol/FP.

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

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

salmeterol/FP 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 salmeterol/FP 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 salmeterol/FP (Hazard ratio for

salmeterol/FP 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 salmeterol/FP. There was no significant difference

in probability of bone fracture (5.1% placebo, 5.1% salmeterol, 5.4% FP and 6.3% salmeterol/FP;

Hazard ratio for salmeterol/FP 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 salmeterol/FP

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 salmeterol/FP 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 salmeterol/FP 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 salmeterol/FP 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 salmeterol/FP 50/250 micrograms bd group compared with

salmeterol. Pneumonia-related events were reported for 55 (7%) subjects in the salmeterol/FP

50/250 micrograms bd group and 25 (3%) in the salmeterol group. The increased incidence of

reported pneumonia with salmeterol/FP 50/250 micrograms bd appears to be of similar magnitude to

the incidence reported following treatment with salmeterol/FP 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

Fluterolo Easyhaler is not recommended for use in children aged less than 12 years. The safety and

efficacy of Fluterolo Easyhaler in this young population have not been established.

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 5,362 first trimester ICS-exposed pregnancies, 131 diagnosed MCMs

were identified; 1,612 (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 (1,150 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

Fluterolo Easyhaler is not recommended for use in children aged less than 12 years. The safety and

efficacy of Fluterolo Easyhaler in this young population have not been established.

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

Lactose monohydrate (which contains milk proteins)

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

As packaged for sale: 2 years.

After first opening the foil bag: 1 month [50/250 strength], 2 months [50/500 strength]. Do not store

above 25°C. Protect from moisture.

6.4

Special precautions for storage

This medicinal product does not require any special storage conditions.

For storage conditions after first opening of the medicinal product, see section 6.3.

6.5

Nature and contents of container

The multidose powder inhaler consists of seven plastic parts and a stainless steel spring. The plastic

materials of the inhaler are: polybutylene terepthalate, low density polyethylene, polycarbonate,

styrene butadiene, polypropylene. The inhaler is sealed in a foil bag and packed with or without a

protective cover (polypropylene and thermoplastic elastomer) in a cardboard box.

Packages:

1, 2, or 3 inhalers containing 60 doses, with or without protective cover.

Not all pack sizes may be marketed.

6.6

Special precautions for disposal and other handling

No special requirements.

7.

MARKETING AUTHORISATION HOLDER

Orion Corporation

Orionintie 1

FI-02200 Espoo

Finland

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

15.04.2019

Liknande Produkter

Sök varningar relaterade till denna produkt

Visa dokumenthistorik

Dela den här informationen