Abriff 250 mikrogram/10 mikrogram/puff Inhalationsspray, suspension

Sverige - svenska - Läkemedelsverket (Medical Products Agency)

Bipacksedel Bipacksedel (PIL)

14-03-2019

Produktens egenskaper Produktens egenskaper (SPC)

11-04-2019

Aktiva substanser:
flutikasonpropionat; formoterolfumaratdihydrat
Tillgänglig från:
Mundipharma AB
ATC-kod:
R03AK11
INN (International namn):
fluticasone propionate; formoterol
Dos:
250 mikrogram/10 mikrogram/puff
Läkemedelsform:
Inhalationsspray, suspension
Sammansättning:
flutikasonpropionat 250 mikrog Aktiv substans; formoterolfumaratdihydrat 10 mikrog Aktiv substans; etanol, vattenfri Hjälpämne
Receptbelagda typ:
Receptbelagt
Produktsammanfattning:
Förpacknings: Inhalator, 120 puffar
Bemyndigande status:
Godkänd
Godkännandenummer:
58824
Tillstånd datum:
2019-04-11

Dokument på andra språk

Bipacksedel Bipacksedel - engelska

15-07-2021

Produktens egenskaper Produktens egenskaper - engelska

14-03-2019

Läs hela dokumentet

PACKAGE LEAFLET

Package leaflet: Information for the user

Abriff 50 microgram /5 microgram per actuation pressurised inhalation, suspension

Abriff 125 microgram /5 microgram per actuation pressurised inhalation, suspension

Abriff 250 microgram /10 microgram per actuation pressurised inhalation, suspension

fluticasone propionate/formoterol fumarate dihydrate

Read all of this leaflet carefully before you start using 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 <or nurse>.

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 <or nurse>. This includes any possible

side effects not listed in this leaflet. See section 4.

What is in this leaflet

What

Abriff

is and what it is used for

What you need to know before you use

Abriff

How to use

Abriff

Possible side effects

How to store

Abriff

Contents of the pack and other information

1.

What Abriff is and what it is used for

Please note:-

Abriff

pressurised inhalation, suspension is the product name, however throughout this leaflet it is

shortened to

Abriff

inhaler. Sometimes this may refer to a specific strength.

Abriff

is an inhaler (a pressurised inhalation suspension) which contains two active ingredients:

Fluticasone propionate which belongs to a group of medicines called steroids. Steroids help to reduce

swelling and inflammation in the lungs.

Formoterol fumarate dihydrate which belongs to a group of medicines called long-acting beta

agonists.

Long-acting beta

agonists are long-acting bronchodilators which help the airways in your lungs to stay

open, making it easier for you to breathe.

Together these two active ingredients help to improve your breathing. It is advised that you should use this

medicine every day as directed by your doctor.

This medicine

helps to prevent breathing problems such as asthma and helps to stop you becoming

breathless and wheezy

. However, it does not work if you are already having an asthma attack i.e. you are

already breathless and wheezing. You will need to use a fast- acting ‘reliever’ medicine such as salbutamol

if this happens.

2.

What you need to know before you use Abriff

Do not use Abriff

if you:

are allergic to fluticasone propionate, formoterol fumarate or any of the other ingredients of this

medicine (listed in section 6).

Warnings and precautions

Talk to your doctor <,or> pharmacist <or nurse> before using this inhaler

Before treatment with this inhaler tell your doctor<, or> pharmacist <or nurse> if you have:

tuberculosis (TB) now or in the past. Symptoms include a persistent cough often with blood streaked

phlegm, fever, tiredness, loss of appetite, loss of weight and night sweats;

an infection of the lungs or chest;

heart problems such as problems with the blood flow to your heart or narrowing of one of your heart

valves (the aortic valve), heart failure which can cause shortness of breath or ankle swelling, a condition

where the heart muscle is enlarged (hypertrophic obstructive cardiomyopathy), an irregular heart beat

(cardiac arrhythmias) or if you have been told that your heart trace is abnormal (prolongation of the QTc

interval);

an abnormal bulging of a blood vessel wall (an aneurysm);

diabetes;

high blood pressure;

an overactive thyroid gland which can cause increased appetite, weight loss or sweating

(thyrotoxicosis);

low blood levels of potassium which can cause muscle weakness, twitching or abnormal heart rhythm

(hypokalaemia);

poor adrenal gland function (if your adrenal gland is not working properly you may have symptoms such

as headaches, weakness, tiredness, abdominal pain, loss of appetite, weight loss, dizziness, very low

blood pressure, diarrhoea, feeling or being sick or fits) or a tumor of the adrenal gland

(phaeochromocytoma);

liver problems.

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

If you are going to have an operation or are extremely stressed, please tell your doctor as you may need

additional steroid treatment to control your asthma.

Other medicines and Abriff

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

including medicines obtained without a prescription.. If you use this inhaler with some other medicines the

effect of this inhaler or the other medicine may be altered.

Tell your doctor or pharmacist if you are taking:

medicines known as beta blockers (such as atenolol to treat high blood pressure, sotalol to treat an

irregular heart beat, metoprolol to treat a fast heart beat or timolol eye drops to treat glaucoma);

certain other medicines used to treat asthma or breathing conditions (such as theophylline or

aminophylline);

medicines containing adrenaline or related substances (including other beta agonists like salbutamol or

beta antagonists including atenolol, metoprolol, propranolol, timolol). Additional long-acting beta

agonists should not be used together with this inhaler. If your asthma becomes worse between doses of

Abriff

then you should use your quick acting ‘reliever’ inhaler for immediate relief;

medicines to treat allergic reactions (antihistamines);

medicines to treat high blood pressure or fluid build up by increasing the amount of urine produced

(diuretics);

medicines used to treat heart failure (such as digoxin);

medicines to treat abnormal heart rhythms (such as quinidine, disopyramide, procainamide);

medicines to treat symptoms of depression or mental disorders such as monoamine oxidase inhibitors

(for example phenelzine and isocarboxazid), tricyclic antidepressants (for example amitriptyline and

imipramine), or you have taken any of these types of medicine in the last two weeks;

medicines used to treat psychiatric or mental disorders (phenothiazines or antipsychotics);

other medicines containing steroids;

antifungal medicines (such as ketaconazole or itraconazole);

some medicines may increase the effects of Abriff and your doctor may wish to monitor you carefully if

you are taking these medicines (including some medicines for HIV: ritonavir, atazanavir, indinavir,

nelfinavir, saquinavir or cobicistat);

antibiotics (such as clarithromycin, telithromycin or furazolidone);

medicine to treat Parkinson’s disease (levodopa);

medicine to treat an underactive thyroid gland (levothyroxine);

medicine to treat Hodgkin’s disease (procarbazine);

medicine to induce labour (oxytocin).

If you are going to have an operation under a general anaesthetic, please tell the doctor at the hospital that you

are using this inhaler.

Pregnancy and breastfeeding

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

doctor or pharmacist for advice about using your inhaler. Your doctor will advise you if you should take

this medicine.

Driving and using machines

This medicine is unlikely to affect your ability to drive or use machines.

Abriff contains ethanol (alcohol) and sodium cromoglicate

This medicine contains 2 mg of alcohol in each dose (2 inhalations). The amount in each dose is equivalent

to less than 1 ml of beer or 1 ml of wine. The small amount of alcohol in this medicine will not have any

noticeable effects. It also contains a very small amount of sodium cromoglicate however patients who are

currently taking cromoglicate (used to treat asthma, allergic rhinitis and allergic conjunctivitis) should

continue as normal.

3.

How to use Abriff

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

pharmacist if you are not sure. You should use your inhaler regularly i.e. two actuations (puffs) in the

morning and two actuations (puffs) in the evening every day to get the most benefit from your inhaler,

unless your doctor tells you otherwise or advises you to stop. Do not take more than the prescribed dose.

Your doctor may have prescribed your inhaler for a different indication other than asthma/or at a different

dose from that normally prescribed and as described in this leaflet. You should always use your inhaler

exactly as your doctor has advised. If you are not sure about how much to take or how often to use your

inhaler please check with your doctor or pharmacist.

Adults, adolescents and children aged 5 years and above

The usual dose is two inhalations twice a day, that is two puffs (actuations) in the morning and two in the

evening. Your doctor will prescribe the dose required to treat your asthma.

Only adults should use the

highest strength inhaler (Abriff 250 microgram /10 microgram).

Only adults and adolescents over 12 years of age should use the medium strength inhaler (Abriff

125 microgram /5 microgram).

Abriff should not be used in children under 5 years of age.

Instructions for use

Read this leaflet very carefully prior to use and follow the instructions for use in the text and diagrams

below. Your doctor, or pharmacist will show you how to use your inhaler properly. The medicine is

contained in an aerosol can (see Diagram 1) which sits inside a plastic dispenser (also known as an

actuator). The actuator also has a counter to tell you how many puffs (actuations) are left after it has been

primed. This counter is colour coded. It starts off green then, when there are less than 50 puffs (actuations)

left it changes to yellow and when there are less than 30 puffs (actuations) left it changes to red. When this

is getting near to zero, you should contact your doctor for a replacement inhaler. Do not use your inhaler

when the counter reads zero.

Before you use your inhaler for the first time or if it hasn’t been used for more than 3 days or if it has

been exposed to freezing conditions

If your inhaler is new or it hasn’t been used for more than 3 days then it must be ‘primed’ to ensure it works

properly and gives you the correct dose.

If your inhaler has been exposed to freezing temperatures it must be allowed to warm at room temperature

for 30 minutes then it must be ‘primed’ to ensure it works properly and gives you the correct dose.

To prime the inhaler

Remove the mouthpiece cover and shake the inhaler well.

Point the mouthpiece away from you and release one puff (actuation) by pressing down on the aerosol

can. This step should be performed 4 times.

Your inhaler should always be shaken immediately before use.

Using your inhaler

If you feel you are getting breathless or wheezy while using

Abriff

, you should continue to use

Abriff

go to see your doctor as soon as possible, as you may need additional treatment. Once your asthma is well

controlled your doctor may consider it appropriate to gradually reduce the dose of

Abriff

Perform steps 2 to 5 below, slowly.

Remove the mouthpiece cover (see Diagram 2) and check that your inhaler is clean and free from any

dust.

The inhaler should be shaken immediately before releasing each puff (actuation) to ensure the contents

of your inhaler are evenly mixed.

Sit upright or stand. Breathe out as far as is comfortable and as slowly and as deeply as possible.

Hold your inhaler upright (as shown in Diagram 3) and put the mouthpiece in your mouth with your lips

around it. Hold the inhaler with your thumb(s) on the base of the mouthpiece and forefinger/index

finger(s) on the top of the inhaler. Do not bite the mouthpiece.

Breathe in slowly and deeply through your mouth and, at the same time, press down on the aerosol can

to release one puff (actuation). Continue to breathe in steadily and deeply (ideally for about 2-3 seconds

in children or 4-5 seconds in adults).

While holding your breath, remove the inhaler from your mouth. Continue to hold your breath for as

long as is comfortable. Do not breathe out into the inhaler.

For the second puff (actuation), keep the inhaler in a vertical position, then repeat steps 2 to 6.

Replace the mouthpiece cover.

You can practise in front of a mirror. If you see a ‘mist’ from the top of the inhaler or around your mouth

when you use your inhaler then you may not have inhaled your medicine properly. Take another dose by

repeating from Step 2 above.

Always rinse your mouth out, gargle with water or brush your teeth after you have taken your inhaler and

spit out the residue. This may help prevent you developing a sore mouth and throat or a hoarse voice.

If you have weak hands it may be easier to hold the inhaler in both hands placing both index fingers on the

aerosol can and both thumbs on the base of the inhaler.

If you have difficulty using your inhaler your doctor may give you a device called an

AeroChamber Plus

®

Flow-Vu

®

spacer device, to help you to breathe your medicine into your lungs properly. Your doctor or

pharmacist will advise you how to use the

AeroChamber Plus

®

Flow-Vu

®

spacer device with your inhaler.

AeroChamber Plus

®

Flow-Vu

®

will come with instructions for use and with care and cleaning

instructions which you must read carefully.

Caring for your inhaler

It is important that you follow these instructions carefully and clean your inhaler weekly. To clean your

inhaler:

Remove the mouthpiece cover.

Do not remove the aerosol can from the actuator.

Wipe the inside and outside of the mouthpiece and the actuator with a clean, dry cloth or tissue.

Replace the mouthpiece cover.

Do not put the metal canister into water

If you use more Abriff than you should

It is important that you take your dose as stated on the pharmacist’s label or as advised by your doctor. You

should not increase or decrease your dose without seeking medical advice

.

If you take more of your medicine than you should, contact your doctor or pharmacist for advice. You may

suffer from severe chest pain (angina), high or low blood pressure, a headache, muscle cramps, difficulty in

sleeping, nervousness, a dry mouth, a loss of appetite, seizures, fits or convulsions. You may feel shaky,

light headed, faint, tired, sick or generally unwell. You may also notice changes in the rate of your heart

beat and your blood may have low levels of potassium or an increase in the amount of sugar in your blood.

You may also suffer from symptoms such as abdominal pain, being sick, weight loss, decreased level of

consciousness (which could make you feel drowsy or confused) or a low blood sugar level.

If you have taken more than the prescribed dose for a long period of time, you should talk to your doctor or

pharmacist for advice. This is because large doses may reduce the amount of steroid hormones produced

normally by your adrenal glands (see section 4).

If you forget to use Abriff

If you forget to take a dose, take it as soon as you remember

However, if it is nearly time for your next

dose, skip the missed dose. Do not take a double dose to make up for a forgotten dose.

If you stop using Abriff

It is very important that you take this inhaler every day as directed by your doctor even if you feel well as it

will help to control your asthma. If you want to stop using your inhaler talk to your doctor first. Your

doctor will tell you how to do this, usually by decreasing the dose gradually so that you do not trigger an

asthma attack.

4.

Possible side effects

Like all medicines, this inhaler

can cause side effects, although not everybody gets them. Your doctor will

prescribe the lowest dose necessary to control your asthma which may reduce the possibility of side effects

occurring.

All medicines can cause allergic reactions, although serious allergic reactions are reported rarely. Tell your

doctor immediately if you get any sudden swelling of the eyelids, face, throat, tongue or lips, rash or itching

especially those covering your whole body, symptoms such as dizziness, light-headedness or fainting or any

sudden changes in your breathing pattern such as increased wheezing or shortness of breath.

As with other inhalers, your breathing may worsen immediately after using your inhaler. You may notice an

increase in wheezing and shortness of breath. If this happens stop using your

Abriff

inhaler and use your

quick acting ‘reliever’ inhaler. Contact your doctor straight away. Your doctor will assess you and may

start you on a different course of treatment. You should carry your ‘reliever’ inhaler with you at all times.

Uncommon:

may affect up to 1 in 100 people

Worsening of asthma.

Headache.

Shaking.

An irregular heartbeat or palpitations.

Dizziness.

Difficulty in sleeping.

Alteration in voice/hoarse voice.

Dry mouth, sore or irritated throat.

Rash.

Rare:

may affect up to 1 in 1,000 people

An increase in the amount of sugar in your blood. If you are diabetic you may need to check your blood

sugar more often and adjust your usual diabetic treatment. Your doctor may need to monitor you more

closely.

Thrush or other fungal infections in the mouth and throat.

Inflammation of the sinuses (sinusitis).

Fast heartbeat.

Chest pain associated with heart disease.

Muscle spasms.

Coughing or shortness of breath.

Diarrhoea.

Indigestion.

Changes in taste.

A feeling of dizziness or ‘spinning’.

Abnormal dreams.

Agitation.

Itchy skin.

High blood pressure.

A feeling of unusual weakness.

Swelling of hands, ankles or feet.

Not known:

frequency cannot be estimated from the available data

Blurred vision.

Sleeping problems, depression or feeling worried, aggression, anxiety, restlessness, nervousness, over-

excitment or irritability. These effects are more likely to occur in children.

The following side effects are associated with formoterol fumarate but they have not been reported during

clinical trials with this inhaler:

Low blood levels of potassium which can cause muscle weakness, twitching or abnormal heart rhythm.

An abnormal heart trace potentially leading to an abnormal heart rhythm (QTc interval prolongation).

High levels of lactic acid in the blood.

Feeling sick.

Muscle pain.

Inhaled steroids can affect the normal production of steroid hormones in your body, particularly if you use

high doses for a long time. The effects include:

changes in bone mineral density (thinning of the bones);

cataracts (clouding of the lens in the eye);

glaucoma (increased pressure in the eye);

bruising or thinning of the skin;

an increased chance of catching an infection;

slowing of the rate of growth of children and adolescents;

a round (moon shaped) face;

an effect on the adrenal gland (a small gland next to the kidney) which means you may have

symptoms such such as weakness, tiredness, difficulty in coping with stress, abdominal pain, loss of

appetite, weight loss, headache, dizziness, very low blood pressure, diarrhoea, feeling or being sick or

fits.

These effects are much less likely to happen with inhaled steroids than with steroid tablets.

Reporting of side effects

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

effects not listed in this leaflet.

You can also report side effects directly via the national reporting system.

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

5.

How to store Abriff

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

Do not use this inhaler after the expiry date which is stated on the label, foil pouch and carton after EXP.

The expiry date refers to the last day of that month. EXP: 08-2020 means that you should not use the

inhaler after the last day of that month i.e. August 2020.

Do not store above 25°C. Do not refrigerate or freeze. If the inhaler is exposed to freezing conditions it

must be allowed to warm at room temperature for 30 minutes then primed before use (see section 3 “How to

use…”). Do not use the inhaler if it has been removed from the foil pouch for more than 3 months, or if the

dose indicator reads ‘0’.

Do not expose to temperatures higher than 50°C. The aerosol can contains a pressurised liquid so do not

puncture, break or burn the can even when apparently empty. 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 Abriff contains

The active substances are fluticasone propionate and formoterol fumarate dihydrate. There are three

different strengths of inhaler available.

50 microgram/5 microgram per actuation

pressurised inhalation, suspension – only

Each puff (actuation) contains 50 micrograms fluticasone propionate and 5 micrograms formoterol fumarate

dihydrate.

125 microgram/5 microgram per actuation

pressurised inhalation, suspension – only

Each puff (actuation) contains 125 micrograms fluticasone propionate and 5 micrograms formoterol

fumarate dihydrate.

250 microgram/10 microgram per actuation

pressurised inhalation, suspension – only

Each puff (actuation) contains 250 micrograms fluticasone propionate and 10 micrograms formoterol

fumarate dihydrate.

The other ingredients are:

Sodium cromoglicate

Ethanol

Apaflurane HFA 227 (propellant)

What Abriff looks like and the contents of the pack

These inhalers are small aerosol cans containing a white to off white liquid suspension fitted with a metering

valve. The aerosol cans are inserted into grey and white plastic dispensers (actuators) with a light grey

mouthpiece cover. Each inhaler contains 120 puffs (actuations). There is one inhaler in a pack.

Marketing Authorisation Holder and Manufacturer

<To be completed nationally>

05/2021

This medicinal product is authorised in the Member States of the EEA under the name Abriff:

Italy

Sweden

This leaflet was last revised in 2021-06-07*.

(*where date is day 90 of DCP application)

<To be completed nationally>

Trademark registration details: <To be completed Nationally.>

Abriff P0448-A R4V3 DCP 31-07-18

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SUMMARY OF PRODUCT CHARACTERISTICS

NAME OF THE MEDICINAL PRODUCT

Abriff 50 microgram/5 microgram per actuation pressurised inhalation, suspension.

Abriff 125 microgram/5 microgram per actuation pressurised inhalation, suspension.

Abriff 250 microgram/10 microgram per actuation pressurised inhalation, suspension.

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each metered dose (ex-valve) contains:

50 micrograms of fluticasone propionate and 5 micrograms of formoterol fumarate dihydrate. This is

equivalent to a delivered dose (ex-actuator) of approximately 46 microgram of fluticasone

propionate/4.5 microgram of formoterol fumarate dihydrate.

125 micrograms of fluticasone propionate and 5 micrograms of formoterol fumarate dihydrate. This is

equivalent to a delivered dose (ex-actuator) of approximately 115 microgram of fluticasone

propionate/4.5 microgram of formoterol fumarate dihydrate.

250 micrograms of fluticasone propionate and 10 micrograms of formoterol fumarate dihydrate. This is

equivalent to a delivered dose (ex-actuator) of approximately 230 microgram of fluticasone

propionate/9.0 microgram of formoterol fumarate dihydrate.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Pressurised inhalation, suspension

The canister contains white to off white liquid suspension. The canister is in a white actuator with a grey

integrated dose indicator and a light grey mouthpiece cover.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

This fixed-dose combination of fluticasone propionate and formoterol fumarate (<Invented name>) is

indicated in the regular treatment of asthma where the use of a combination product (an inhaled

corticosteroid and a long -acting β

agonist) is appropriate:

For patients not adequately controlled with inhaled corticosteroids and ‘as required’ inhaled short -acting

agonist.

For patients already adequately controlled on both an inhaled corticosteroid and a long-acting β

agonist.

<Invented name> 50 microgram

/

5 microgram per actuation

is indicated in adults, adolescents and children

aged 5 years and above.

<Invented name>

125 microgram/5 microgram per actuation is indicated in adults and adolescents aged 12

years and above.

<Invented name> 250 microgram

/

10 microgram per actuation is indicated in adults only.

4.2

Posology and method of administration

Posology

Patients will need to be trained on the use of the inhaler and their asthma should be regularly reassessed by a

doctor, so that the strength of <Invented name> 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.

Once control of asthma is achieved with the lowest strength of <Invented name>

administered twice daily treatment should be reviewed and consideration given as to whether patients

should be stepped down to an inhaled corticosteroid alone.

As a general principle the dose should be

titrated to the lowest dose at which effective control of symptoms is maintained.

Regular review of

patients as treatment is stepped down is extremely important.

There are no data available for use of <Invented name> in patients with COPD. <Invented name>

should not be used in patients with COPD.

Patients should be given the strength of <Invented name> containing the appropriate fluticasone propionate

dosage for the severity of their disease. Note: <Invented name> 50 microgram/5 microgram per actuation,

strength is not appropriate in adults and adolescents with severe asthma. Prescribers should be aware that,

in patients with asthma, fluticasone propionate is as effective as some other inhaled steroids when

administered at approximately half the total daily dose (in micrograms). If an individual patient should

require doses outside the recommended dose regimens, appropriate doses of the β

agonist and the inhaled

corticosteroid in separate inhalers, or appropriate doses of the inhaled corticosteroid alone, should be

prescribed.

<Invented name> is delivered by a press-and-breathe pressurised metered dose inhaler (pMDI) which also

contains an integrated dose indicator. Each inhaler will provide at least 120 actuations (60 doses).

<Invented name> 50 microgram/5 microgram per actuation pressurised inhalation, suspension – only

Recommended dose for adults, adolescents and children aged 5 years and above:

<Invented name> 50 microgram/5 microgram per actuation pressurised inhalation, suspension - two

inhalations (puffs) twice daily normally taken in the morning and in the evening.

For adults and adolescents

If the patient’s asthma remains poorly controlled the total daily dose of the inhaled corticosteroid can be

increased by administering a higher strength of this combination product – i.e. <Invented name> 125

microgram/5 micrograms per actuation pressurised inhalation, suspension - two inhalations (puffs) twice

daily. This strength should not be used in children under the age of 12 years.

For adults only:

The total daily dose can be further increased if asthma still remains poorly controlled by administering the

highest strength of this combination product – i.e. <Invented name> 250 micrograms/10 microgram per

actuation pressurised inhalation, suspension - two inhalations (puffs) twice daily. This highest strength is

for use in adults only; it should not be used in adolescents and children.

Children under 5 years:

Experience in children under the age of 5 years is limited (see sections 4.4, 4.8, 5.1 & 5.3). <Invented

name> pressurised inhalation, suspension in any strength is not recommended for use in children less than

5 years of age;

<Invented name> should not be used in this young age group.

<Invented name> 125 microgram/5 microgram per actuation

pressurised inhalation, suspension – only

Recommended dose for adults and adolescents aged 12 years and above:

<Invented name> 125 microgram/5 microgram per actuation pressurised inhalation, suspension - two

inhalations (puffs) twice daily normally taken in the morning and in the evening.

Patients may be transferred to the lowest strength of this combination product i.e. <Invented name> 50

microgram/5 microgram per actuation if their asthma is adequately controlled. A patient’s dose should be

titrated to the lowest dose at which effective control of symptoms is maintained.

For adults only:

The total daily dose can be further increased if asthma remains poorly controlled by administering the

highest strength of this combination product – i.e. <Invented name> 250 microgram/10 microgram per

actuation pressurised inhalation, suspension - two inhalations (puffs) twice daily. This highest strength is

for use in adults only; it should not be used in adolescents aged 12 years and above.

Children under 12 years:

No data are available for this strength of <Invented name> in children. Experience in children under the age

of 12 years is limited to the lowest strength (50 microgram/5 microgram) (see sections 4.4, 4.8, 5.1 & 5.3).

<Invented name> pressurised inhalation, suspension in this strength (125 microgram/5 microgram) is not

recommended for use in children less than 12 years of age;

<Invented name> 125 microgram/5

microgram per actuation should not be used in this young age group.

<Invented name> 250 microgram/10 microgram per actuation pressurised inhalation, suspension - only

Recommended dose for adults:

<Invented name> 250 microgram /10 microgram per actuation pressurised inhalation, suspension - two

inhalations (puffs) twice daily normally taken in the morning and in the evening.

Patients may be transferred to a lower strength of this combination product i.e. <Invented name> 125

microgram/5 microgram per actuation or ultimately <Invented name> 50 microgram/5 microgram per

actuation if their asthma is adequately controlled. A patient’s dose should be titrated to the lowest dose at

which effective control of symptoms is maintained.

Adolescents under 18 years and children:

No data are available for this strength of <Invented name> in children or adolescents. Experience in

children is limited to the lowest strength (50 microgram/5 microgram) (see sections 4.4, 4.8, 5.1 & 5.3).

<Invented name> pressurised inhalation, suspension in this strength (250 microgram/10 microgram)

is not recommended for use in adolescents or children; <Invented name> 250 microgram /10

microgram per actuation should not be used in this young age group.

<Invented name> 250 microgram/10 microgram per actuation should not be used in adolescents or

children.

However there are lower strengths available i.e. 50 microgram/5 microgram per actuation which

may be used in children or adolescents or 125 microgram/5 microgram per actuation which may be used in

adolescents.

Special patient groups:

There is no need to adjust the dose in elderly patients.

There are no data available for use of <Invented name>

in patients with hepatic or renal impairment (see

section 5.2). These patients should be regularly monitored by a physician to ensure titration to the lowest

dose at which effective control of symptoms is maintained. As the fractions of fluticasone and formoterol

which reach systemic circulation are primarily eliminated via hepatic metabolism, an increased exposure can

be expected in patients with severe hepatic impairment.

General information:

Inhaled corticosteroids alone are the first line of treatment for most patients. <Invented name> is not

intended for the initial treatment of mild asthma. For patients with severe asthma the inhaled corticosteroid

therapy should be established before prescribing a fixed-dose combination product.

Patients should be made aware that <Invented name> must be used daily for optimum benefit, even when

asymptomatic.

Patients using <Invented name> should not use additional long-acting β

agonists for any reason. If asthma

symptoms arise in the period between doses, an inhaled, short-acting β

agonist should be taken for

immediate relief.

For patients who are currently receiving medium to high doses of inhaled corticosteroid therapy, and whose

disease severity clearly warrants treatment with two maintenance therapies, the recommended starting dose

is two inhalations twice daily of <Invented name> 125 microgram/5 microgram per actuation.

Use of a spacer device with <Invented name> is recommended in patients who find it difficult to

synchronise aerosol actuation with inspiration of breath. The

AeroChamber Plus

Flow-Vu

is the

recommended spacer device.

Patients should be instructed in the proper use and care of their inhaler and spacer and their technique

checked to ensure optimum delivery of the inhaled drug to the lungs.

Re-titration to the lowest effective dose should always follow the introduction of a spacer device.

Method of administration

For inhalation use.

To ensure proper administration of the drug, the patient should be shown how to use the inhaler correctly by

a physician or other health professionals. The correct use of the pressurised metered dose inhaler (pMDI) is

essential for successful treatment. The patient should be advised to read the Patient Information Leaflet

carefully and follow the instructions for use and pictograms in the leaflet.

The actuator has an integrated counter which counts down the number of actuations (puffs) remaining. This

counter is also colour coded. It starts off green then, when there are less than 50 puffs (actuations) left it

changes to yellow and when there are less than 30 puffs (actuations) left it changes to red. The counter

counts down from 120 to 60 in intervals of 10, and from 60 to 0 in intervals of 5. When this is getting near

to zero the patient should be advised to contact their prescriber for a replacement inhaler. The inhaler must

not be used after the dose indicator reads “0”.

Priming the inhaler

Before using the inhaler for the first time, or if the inhaler has not been used for 3 days or more, or after

exposure to freezing or refrigerated conditions (see section 6.4) the inhaler must be primed before use:

Remove the mouthpiece cover and shake the inhaler well.

Actuate (puff) the inhaler whilst pointing it away from the face. This step must be performed 4 times.

The inhaler should always be shaken immediately before use.

Whenever possible patients should stand or sit in an upright position when inhaling from the inhaler.

Steps to follow when using the inhaler

:

Remove the mouthpiece cover and check that the mouthpiece is clean, and free from dust and dirt.

The inhaler should be shaken immediately before releasing each actuation (puff) to ensure that the

contents of the inhaler are evenly mixed.

Breathe out as far as is comfortable and as slowly and deeply as possible.

Hold the canister vertically with its body upwards and put the lips around the mouthpiece. Hold the

inhaler upright with a thumb(s) on the base of the mouthpiece and a forefinger/index finger(s) on the top

of the inhaler. Do not bite the mouthpiece.

Breathe in slowly and deeply through the mouth. After starting to breathe in press down on the top of

the inhaler to release one actuation (puff) and continue to breathe in steadily and deeply (optimally for

about 2-3 seconds for children and 4-5 seconds in adults).

While holding breath, remove the inhaler from mouth. Patients should continue to hold their breath for

as long as is comfortable. Do not breathe out into the inhaler.

For the second actuation (puff), keep the inhaler in a vertical position then repeat steps 2 to 6.

After use, replace the mouthpiece cover.

IMPORTANT: Do not perform steps 2 to 6 too quickly.

Patients may be advised to practise their technique in front of a mirror. If a mist appears following

inhalation, either from the inhaler or from the sides of the mouth, the procedure should be repeated from

step 2.

For patients with weak hands, it may be easier to hold the inhaler with both hands. Therefore the index

fingers should be placed on the top of the inhaler canister and both thumbs on the base of the inhaler.

Patients should rinse their mouth, gargle with water or brush the teeth after inhaling and spit out the residue

to minimise the risk of oral candidiasis or dysphonia.

Cleaning:

Patients should be advised to read the Patient Information Leaflet carefully for cleaning instructions:

The inhaler should be cleaned once a week.

Remove the mouthpiece cover.

Do not remove the canister from the plastic casing.

Wipe the inside and outside of the mouthpiece and the plastic casing with a dry cloth or tissue.

Replace the mouthpiece cover in the correct orientation.

Do not put the metal canister into water.

If a patient requires an

AeroChamber Plus

®

Flow-Vu

spacer device then they must be advised to read the

instructions provided by the manufacturer to ensure they use it and clean and maintain it properly.

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

The management of asthma should normally follow a stepwise programme and patients’ responses should be

monitored clinically and by lung function tests.

<Invented name> 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 medicine to be used for relief in an

acute asthma attack available at all times.

The prophylactic use of <Invented name> in exercise-induced asthma has not been studied. For such use, a

separate rapid-acting bronchodilator should be considered.

Patients should be reminded to take their <Invented name> maintenance dose as prescribed, even when

asymptomatic.

Patients should not be initiated on <Invented name> 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 <Invented name>.

Patients should be asked to continue treatment but to seek medical advice if asthma symptoms remain

uncontrolled or worsen after initiation on <Invented name>.

<Invented name> should not be used as the first treatment for asthma.

If increasing use of short-acting bronchodilators to relieve asthma is required, if short-acting bronchodilators

become less effective, or ineffective or if asthma symptoms persist, the patient should be reviewed by their

doctor as soon as possible as any of these may indicate a deterioration in asthma control and their treatment

may need to be changed.

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. The patient should also be medically reviewed when the current dosage of <Invented name> has

failed to give adequate control of asthma. Consideration should be given to additional corticosteroid

therapies.

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

<Invented name>. Regular review of patients as treatment is stepped down is important. The lowest

effective dose of <Invented name> should be used (see section 4.2).

Treatment with <Invented name> should not be stopped abruptly in patients with asthma due to risk of

exacerbation. Therapy should be down-titrated under the supervision of a prescriber.

An exacerbation of the clinical symptoms of asthma may be due to an acute respiratory tract bacterial

infection and treatment may require appropriate antibiotics, increased inhaled corticosteroids and a short

course of oral corticosteroids. A rapid-acting inhaled bronchodilator should be used as rescue medication.

As with all inhaled medication containing corticosteroids, <Invented name> should be administered with

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

infections of the airway. Any such infections must always be adequately treated if <Invented name> is

being used.

<Invented name> should be used with caution in patients with thyrotoxicosis, phaeochromocytoma, diabetes

mellitus, uncorrected hypokalaemia or patients predisposed to low levels of serum potassium, hypertrophic

obstructive cardiomyopathy, idiopathic subvalvular aortic stenosis, severe hypertension, aneurysm or other

severe cardiovascular disorders, such as ischaemic heart disease, cardiac arrhythmias or severe heart failure.

Potentially serious hypokalaemia may result from high doses of β

agonists. Concomitant treatment of β

agonists with drugs which can induce hypokalaemia or potentiate a hypokalaemic effect, e.g. xanthine

derivatives, steroids and diuretics, may add to a possible hypokalaemic effect of the β

agonist. Particular

caution is recommended in unstable asthma with variable use of rescue bronchodilators, in acute severe

asthma as the associated risk may be augmented by hypoxia and in other conditions when the likelihood for

hypokalaemia adverse effects is increased. It is recommended that serum potassium levels are monitored

during these circumstances.

Caution must be observed when treating patients with existing prolongation of the QTc interval. Formoterol

itself may induce prolongation of the QTc interval.

As for all β

agonists, additional blood sugar controls should be considered in diabetic patients.

Care should be taken when transferring patients to <Invented name> therapy, particularly if there is any

reason to suppose that adrenal function is impaired from previous systemic steroid 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

inhaled bronchodilator and should be treated straight away. <Invented name> should be discontinued

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

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.

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, growth retardation in children and

adolescents, decrease in bone mineral density, cataract glaucoma and more rarely, a range of psychological

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

aggression (particularly in children). 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. Children and adolescents <16 years taking high doses of fluticasone propionate

(typically ≥ 1000 micrograms/day) may be at particular risk. 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 treatment 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. 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. In situations of possible

impaired adrenal function hypothalamic pituitary adrenocortical (HPA) axis function should be monitored

regularly.

There is an increased risk of systemic side effects when combining fluticasone propionate with potent

CYP3A4 inhibitors (see section 4.5).

The patient should be made aware that this fixed-dose combination inhaler is a prophylactic therapy and as

such has to be used regularly even when asymptomatic for optimum benefit.

Use of a spacer device may lead to a possible increase in pulmonary deposition and a potential increase in

systemic absorption and systemic adverse events.

As the fractions of fluticasone and formoterol which reach systemic circulation are primarily eliminated via

hepatic metabolism, an increased exposure can be expected in patients with severe hepatic impairment.

Patients should be advised that <Invented name> contains a very small amount of ethanol (approximately

1.00 mg per actuation); however this amount of ethanol is negligible and does not pose a risk to patients.

Paediatric population

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

regularly monitored. If growth is slowed, therapy should be reviewed with the aim of reducing the dose of

inhaled corticosteroid, if possible, to the lowest dose at which effective control of asthma is maintained. In

addition, consideration should be given to referring the patient to a paediatric respiratory specialist.

Possible systemic effects as reported for the individual components of <Invented name> include Cushing's

syndrome, Cushingoid features, adrenal suppression and growth retardation in children and adolescents.

Children may also experience anxiety, sleep disorders and behavioural changes, including hyperactivity and

irritability (see section 4.8)

Limited data are available on the use of <Invented name> in children under 5 years of age. <Invented

name> is NOT recommended for use in children under 5 years of age.

4.5

Interaction with other medicinal products and other forms of interaction

No formal drug interaction studies have been performed with <Invented name>.

<Invented name> contains sodium cromoglicate at non-pharmacological levels. Patients should not

discontinue any cromoglicate containing medication.

Fluticasone propionate, an individual component of <Invented name>, is a substrate of CYP 3A4. Co-

treatment with CYP3A inhibitors (e.g. ritonavir, atazanavir, clarithromycin, indinavir, itraconazole,

nelfinavir, saquinavir, ketoconazole, telithromycin, cobicistat) is expected to increase the risk of systemic

side-effects. The combination should be avoided unless the benefit outweighs the increased risk of systemic

corticosteroid side-effects, in which case patients should be monitored for systemic corticosteroid side-

effects.

The ECG changes and/or hypokalaemia that may result from the administration of non-potassium sparing

diuretics (such as loop or thiazide diuretics) can be acutely worsened by β agonists, especially when the

recommended dose of the β agonist is exceeded. Although the clinical significance of these effects is not

known, caution is advised in the co-administration of a β agonist with non-potassium sparing diuretics.

Xanthine derivates and glucocorticosteroids may add to a possible hypokalaemic effect of the β agonists.

In addition L-Dopa, L-thyroxine, oxytocin and alcohol can impair cardiac tolerance towards β

sympathomimetics.

Concomitant treatment with monoamine oxidase inhibitors, including agents with similar properties such as

furazolidone and procarbazine, may precipitate hypertensive reactions.

There is an elevated risk of arrhythmias in patients receiving concomitant anaesthesia with halogenated

hydrocarbons.

Concomitant use of other β adrenergic drugs can have a potentially additive effect.

Hypokalaemia may increase the risk of arrhythmias in patients who are treated with digitalis glycosides.

Formoterol fumarate, as with other β

agonists, should be administered with caution to patients being treated

with tricyclic antidepressants or monoamine oxidase inhibitors, and during the immediate two week period

following their discontinuation, or other drugs known to prolong the QT

interval such as antipsychotics

(including phenothiazines), quinidine, disopyramide, procainamide, and antihistamines. Drugs that are

known to prolong the QT

interval can increase the risk of ventricular arrhythmias (see section 4.4).

If additional adrenergic drugs are to be administered by any route, they should be used with caution, because

the pharmacologically predictable sympathetic effects of formoterol may be potentiated.

Beta adrenergic receptor antagonists (β blockers) and formoterol fumarate may inhibit the effect of each

other when administered concurrently. Beta blockers may also produce severe bronchospasm in asthmatic

patients. Therefore, patients with asthma should not normally be treated with β blockers and this includes β

blockers used as eye drops for treatment of glaucoma. However, under certain circumstances, e.g. as

prophylaxis after myocardial infarction, there may be no acceptable alternatives to the use of β blockers in

patients with asthma. In this setting, cardioselective β blockers could be considered, although they should

be administered with caution.

4.6

Fertility, pregnancy and lactation

Pregnancy

There are limited data on the use of fluticasone propionate and formoterol fumarate, either administered

alone or together but administered from separate inhalers, or on the use of this fixed-dose combination,

<Invented name> in pregnant women. Studies in animals have shown reproductive toxicity (see section

5.3).

Administration of <Invented name> is not recommended during pregnancy, and should only be considered if

expected benefit to the mother is greater than any possible risk to the fetus. If this is the case, then the

lowest effective dose needed to maintain adequate asthma control should be used.

Because of the potential for β agonist interference with uterine contractility, use of <Invented name> for

management of asthma during labour should be restricted to those patients in whom the benefit outweighs

the risks.

Breastfeeding

It is not known whether fluticasone propionate or formoterol fumarate are excreted in human breast milk. A

risk to the suckling child cannot be excluded. Therefore, a decision must be made whether to discontinue

breastfeeding or to discontinue/abstain from <Invented name> therapy taking into account the benefit of

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

Fertility

There are no data available on effects on fertility following administration of <Invented name>. In animal

studies, no effects on fertility have been seen following administration of the individual active substances at

clinically relevant doses (see section 5.3).

4.7

Effects on ability to drive and use machines

<Invented name> has no or negligible influence on the ability to drive and use machines.

4.8

Undesirable effects

Undesirable effects which have been associated with <Invented name> during clinical development are

given in the table below, listed by system organ class. The following frequency categories form the basis for

classification of the undesirable effects as: very common (≥1/10), common (≥1/100 and <1/10), uncommon

(≥1/1,000 and <1/100), rare (≥1/10,000 < 1/1,000), very rare (<1/10,000) and not known (cannot be

estimated from the available data). Within each frequency grouping, undesirable effects are presented in

order of decreasing seriousness.

System Organ Class

Adverse Event

Frequency

Infections and Infestations

Oral candidiasis

Oral fungal infections

Sinusitis

Rare

Metabolism and Nutrition

Disorders

Hyperglycaemia

Rare

Sleep disorders including

insomnia

Uncommon

Abnormal dreams

Agitation

Rare

Psychiatric Disorders

Psychomotor hyperactivity,

anxiety, depression,

aggression, behavioural

changes (predominantly in

children)

Not known

Headache

Tremor

Dizziness

Uncommon

Nervous System Disorders

Dysgeusia

Rare

Eye disorders

Vision blurred

Not known

Ear and labyrinth disorders

Vertigo

Rare

Palpitations

Ventricular extrasystoles

Uncommon

Cardiac Disorders

Angina pectoris

Tachycardia

Rare

Vascular disorders

Hypertension

Rare

Exacerbation of asthma

Dysphonia

Throat irritation

Uncommon

Respiratory, Thoracic and

Mediastinal Disorders

Dyspnoea

Cough

Rare

Dry mouth

Uncommon

Gastrointestinal disorders

Diarrhoea

Dyspepsia

Rare

Rash

Uncommon

Skin and subcutaneous tissue

disorders

Pruritus

Rare

Musculoskeletal and

Connective Tissue Disorders

Muscle spasms

Rare

General disorders and

administration site conditions

Peripheral oedema

Asthenia

Rare

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

inhaled bronchodilator and should be treated straight away. <Invented name> should be discontinued

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

Since <Invented name> contains both fluticasone propionate and formoterol fumarate, the same pattern of

undesirable effects as reported for these substances may occur. The following undesirable effects are

associated with fluticasone propionate and formoterol fumarate, but have not been seen during the clinical

development of <Invented name>:

Fluticasone propionate: Hypersensitivity reactions including, urticaria, pruritus, angiooedema (mainly facial

and oropharyngeal), anaphylactic reactions. Systemic effects of inhaled corticosteroids may occur,

particularly at high doses prescribed for prolonged periods. These may include Cushing’s Syndrome,

Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decrease in bone

mineral density, cataract and glaucoma, contusion, skin atrophy and susceptibility to infections. The ability

to adapt to stress may be impaired. The systemic effects described, however, are much less likely to occur

with inhaled corticosteroids than with oral corticosteroids. Prolonged treatment with high doses of inhaled

corticosteroids may result in clinically significant adrenal suppression and acute adrenal crisis. Additional

systemic corticosteroid cover may be required during periods of stress (trauma, surgery, infection).

Formoterol fumarate: Hypersensitivity reactions (including hypotension, urticaria, angioneurotic oedema,

pruritus, exanthema), QTc interval prolongation, hypokalaemia, nausea, myalgia, increased blood lactate

levels. Treatment with β

agonists such as formoterol may result in an increase in blood levels of insulin,

free fatty acids, glycerol and ketone bodies.

Hypersensitivity reactions have been reported in patients using inhaled sodium cromoglicate as an active

ingredient. Whilst <Invented name> contains only a low concentration of sodium cromoglicate as an

excipient, it is unknown if hypersensitivity reactions are dose dependent.

In the unlikely event of a hypersensitivity reaction to <Invented name>, treatment should be initiated in

accordance with standard treatment for any other hypersensitivity reaction, which may include the use of

antihistamines and other treatment as required. <Invented name> may need to be discontinued immediately

and an alternative asthma therapy may need to be initiated if necessary.

Dysphonia and candidiasis may be relieved by gargling or rinsing the mouth with water or brushing the teeth

after using the product. Symptomatic candidiasis can be treated with topical anti-fungal therapy whilst

continuing the treatment with <Invented name>.

Paediatric population

Possible systemic effects as reported for the individual components of <Invented name> include Cushing's

syndrome, Cushingoid features, adrenal suppression and growth retardation in children and adolescents.

Children may also experience anxiety, sleep disorders and behavioural changes, including hyperactivity and

irritability. Studies conducted with <Invented name> demonstrated similar safety and tolerability profile as

compared to fluticasone monotherapy in children aged 5-12 years and fluticasone/salmeterol in children

aged 4-12. Long term treatment with <Invented name> for 24 weeks in 208 children did not show any

indication of growth retardation or adrenal suppression. Another pharmacodynamic study conducted in

children aged 5-12 years showed similar lower leg growth rate as measured by knemometry after treatment

with <Invented name> as compared to fluticasone monotherapy for 2 weeks.

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.

4.9

Overdose

There are no data available from clinical trials on overdose with <Invented name>, however, data on

overdose with both single drugs are given below:

Formoterol fumarate:

An overdose of formoterol would likely lead to an exaggeration of effects that are typical for β

agonists; in

which case the following adverse experiences may occur: angina, hypertension or hypotension, palpitations,

tachycardia, arrhythmia, prolonged QT

-interval, headache, tremor, nervousness, muscle cramps, dry mouth,

insomnia, fatigue, malaise, seizures, metabolic acidosis, hypokalaemia, hyperglycaemia, nausea and

vomiting.

Treatment of formoterol overdose consists of discontinuation of the medication together with institution of

appropriate symptomatic and/or supportive therapy. The judicious use of cardio selective β receptor

blockers may be considered, bearing in mind that such medication can induce bronchospasm. There is

insufficient evidence to determine if dialysis is beneficial in cases of formoterol overdose. Cardiac

monitoring is recommended.

If <Invented name> therapy has to be withdrawn due to overdose of the β agonist component of the drug,

provision of appropriate replacement steroid therapy should be considered. Serum potassium levels should

be monitored as hypokalaemia can occur. Potassium replacement should be considered.

Fluticasone propionate:

Acute overdose with fluticasone propionate usually does not constitute a clinical problem. The only harmful

effect after inhalation of a large amount of the drug over a short period is suppression of hypothalamic

pituitary adrenocortical (HPA) axis function. HPA axis function usually recovers in a few days, as verified

by plasma cortisol measurements. Treatment with the inhaled corticosteroid should be continued at the

recommended dose to control asthma.

There are reports of rare cases of acute adrenal crisis. Children and adolescents <16 years taking high doses

of fluticasone propionate: (typically ≥1000 microgram/day) may be at particular risk. Presenting symptoms

can be vague (anorexia, abdominal pain, weight loss, tiredness, headache, nausea, vomiting and

hypotension). Typical symptoms of an adrenal crisis are decreased level of consciousness, hypoglycaemia

and/or seizures.

Following chronic use of very high doses a degree of atrophy of the adrenal cortex and HPA axis

suppression may occur. Monitoring of adrenal reserve may be necessary. Possible systemic effects include

Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and

adolescents, decrease in bone mineral density, cataract and glaucoma (see section 4.4).

In the management of chronic overdose oral or systemic corticosteroids may be required in situations of

stress. All patients deemed to be chronically overdosed should be treated as if steroid dependent with a

suitable maintenance dose of a systemic corticosteroid. When stabilised, treatment should be continued

with an inhaled corticosteroid at the recommended dose for symptom control.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic Group: Drugs for obstructive airways, adrenergics in combination with corticosteroids

or other drugs excl. anticholinergics

ATC code: R03AK11

Mechanism of Action and Pharmacodynamic Effects

<Invented name> contains both fluticasone propionate and formoterol fumarate. The mechanisms of action

are described below for the individual components. These drugs represent two classes of medications (a

synthetic corticosteroid and a selective, long-acting β

adrenergic receptor agonist) and as with other inhaled

corticosteroid and long-acting β

adrenergic agonist combinations additive effects are seen in terms of a

reduction in asthma exacerbations.

Fluticasone propionate

Fluticasone propionate is a synthetic, trifluorinated glucocorticoid with potent anti-inflammatory activity in

the lungs when given by inhalation. Fluticasone propionate reduces symptoms and exacerbations of asthma

with less adverse effects than when corticosteroids are administered systemically.

Formoterol fumarate

Formoterol fumarate is a long-acting selective β

adrenergic receptor agonist. Inhaled formoterol fumarate

acts locally in the lung as a bronchodilator. The onset of bronchodilating effect is rapid, within 1 - 3

minutes, and the duration of effect is at least 12 hours after a single dose.

<Invented name>

In 12-week clinical trials in adults and adolescents, the addition of formoterol to fluticasone propionate

improved asthma symptoms and lung function and reduced exacerbations. Therapeutic effect of <Invented

name> exceeded that of fluticasone propionate alone. There are no long-term data comparing <Invented

name> with fluticasone propionate.

In an 8-week clinical trial the effect on lung function with <Invented name> was at least equal to that of the

combination of fluticasone propionate and formoterol fumarate when administered as separate inhalers.

Long-term comparative data of <Invented name> versus fluticasone propionate and formoterol fumarate are

not available. There were no signs of attenuation of therapeutic effects of <Invented name> in trials lasting

up to 12 months including adult and adolescent patients.

Dose-response trends for <Invented name> were evident for symptom-based endpoints, with incremental

benefits from high versus low dose <Invented name> being most likely in patients with more severe asthma.

Paediatric population

In a 12-week double-blind study 512 children aged 5 – 11 years were randomised to <Invented name> (2

inhalations of 50/5 micrograms twice daily), fluticasone/salmeterol or fluticasone monotherapy. <Invented

name> (2 inhalations of 50/5 micrograms twice daily) was superior to fluticasone monotherapy and non-

inferior to fluticasone/salmeterol with regards to change from baseline in pre-dose FEV1 to post dose FEV1

over 12-weeks and 4-hour FEV1 AUC at Week 12. <Invented name> (2 inhalations of 50/5 micrograms

twice daily) was not superior to fluticasone monotherapy in change in pre-dose FEV1 over the 12-week

treatment but was non-inferior to fluticasone/salmeterol on this endpoint.

In a second 12-week paediatric study including a 6-month extension phase 210 children aged 4 - 12 years

were treated with a maintenance dose of <Invented name> (2 inhalations of 50/5 micrograms twice daily) or

with fluticasone/salmeterol. <Invented name> (2 inhalations of 50/5 micrograms twice daily) was non-

inferior to fluticasone/salmeterol. Two hundred and five patients subsequently completed the 6 month

extension phase during which they received <Invented name> (2 inhalations of 50/5 micrograms twice

daily). <Invented name> was safe and well tolerated.

5.2

Pharmacokinetic properties

Fluticasone propionate:

Absorption

Following inhalation, systemic absorption of fluticasone propionate occurs mainly through the lungs and has

been shown to be linearly related to dose over the dose range 500 to 2000 micrograms. Absorption is

initially rapid then prolonged.

Published studies using oral dosing of labelled and unlabelled drug have demonstrated that the absolute oral

systemic bioavailability of fluticasone propionate is negligible (<1%) due to a combination of incomplete

absorption from the GI tract and extensive first-pass metabolism.

Distribution

Following intravenous administration, fluticasone propionate is extensively distributed in the body. The

initial disposition phase for fluticasone propionate is rapid and consistent with its high lipid solubility and

tissue binding. The volume of distribution averages 4.2 L/kg. The percentage of fluticasone propionate

bound to human plasma proteins averages 91%. Fluticasone propionate is weakly and reversibly bound to

erythrocytes and is not significantly bound to human transcortin.

Biotransformation

The total clearance of fluticasone propionate is high (average, 1,093 mL/min), with renal clearance

accounting for less than 0.02% of the total. The very high clearance rate indicates extensive hepatic

clearance. The only circulating metabolite detected in man is the 17β-carboxylic acid derivative of

fluticasone propionate, which is formed through the cytochrome P450 3A4 isoform subfamily (CYP 3A4)

pathway. This metabolite has less affinity (approximately 1/2000) than the parent drug for the

glucocorticoid receptor of human lung cytosol

in vitro

. Other metabolites detected

in vitro

using cultured

human hepatoma cells have not been detected in man.

Elimination

87 - 100% of an oral dose is excreted in the faeces, up to 75% as parent compound. There is also a

non-active major metabolite.

Following intravenous dosing, fluticasone propionate shows polyexponential kinetics and has a terminal

elimination half-life of approximately 7.8 hours. Less than 5% of a radiolabelled dose is excreted in the

urine as metabolites, and the remainder is excreted in the faeces as parent drug and metabolites.

Formoterol fumarate:

Data on the plasma pharmacokinetics of formoterol were collected in healthy volunteers after inhalation of

doses higher than the recommended range and in COPD patients after inhalation of therapeutic doses.

Absorption

Following inhalation of a single 120 microgram dose of formoterol fumarate by healthy volunteers,

formoterol was rapidly absorbed into plasma, reaching a maximum concentration of 91.6 pg/mL within

5 minutes of inhalation. In COPD patients treated for 12 weeks with formoterol fumarate 12 or

24 micrograms b.i.d. the plasma concentrations of formoterol ranged between 4.0 and 8.9 pg/mL and 8.0 and

17.3 pg/mL respectively at 10 minutes, 2 hours and 6 hours post inhalation.

Studies investigating the cumulative urinary excretion of formoterol and/or its (RR) and

(SS)-enantiomers, after inhalation of dry powder (12 - 96 micrograms) or aerosol formulations

(12-96 micrograms), showed that absorption increased linearly with the dose.

After 12 weeks administration of 12 micrograms or 24 micrograms formoterol powder b.i.d., the urinary

excretion of unchanged formoterol increased by 63 - 73% in adult patients with asthma, by 19 - 38% in adult

patients with COPD and by 18 - 84% in children, suggesting a modest and self-limiting accumulation of

formoterol in plasma after repeated dosing.

Distribution

The plasma protein binding of formoterol is 61 - 64% (34% primarily to albumin).

There is no saturation of binding sites in the concentration range reached with therapeutic doses.

The concentrations of formoterol used to assess the plasma protein binding were higher than those achieved

in plasma following inhalation of a single 120 microgram dose.

Biotransformation

Formoterol is eliminated primarily by metabolism, direct glucuronidation being the major pathway of

biotransformation, with O-demethylation followed by further glucuronidation being another pathway.

Minor pathways involve sulphate conjugation of formoterol and deformylation followed by sulphate

conjugation. Multiple isozymes catalyze the glucuronidation (UGT1A1, 1A3, 1A6, 1A7, 1A8, 1A9, 1A10,

2B7 and 2B15) and O-demethylation (CYP 2D6, 2C19, 2C9 and 2A6) of formoterol, and so consequently

the potential for metabolic drug-drug interaction is low. Formoterol did not inhibit cytochrome P450

isozymes at therapeutically relevant concentrations. The kinetics of formoterol is similar after single and

repeated administration, indicating no auto-induction or inhibition of metabolism.

Elimination

In asthmatic and COPD patients treated for 12 weeks with 12 or 24 micrograms formoterol fumarate b.i.d.,

approximately 10% and 7% of the dose, respectively, were recovered in the urine as unchanged formoterol.

In asthmatic children, approximately 6% of the dose was recovered in the urine as unchanged formoterol

after multiple dosing of 12 and 24 micrograms. The (R,R) and (S,S)-enantiomers accounted for 40% and

60% respectively of urinary recovery of unchanged formoterol, after single doses (12 to 120 micrograms) in

healthy volunteers and after single and repeated doses in asthma patients.

After a single oral dose of

H-formoterol, 59 - 62% of the dose was recovered in the urine and 32 - 34% in

the faeces. Renal clearance of formoterol is 150 mL/min.

After inhalation, plasma formoterol kinetics and urinary excretion rate data in healthy volunteers indicate a

biphasic elimination, with the terminal elimination half-lives of the (R, R) - and (S, S)-enantiomers being

13.9 and 12.3 hours, respectively. Peak excretion occurs rapidly, within 1.5 hours.

Approximately 6.4 - 8% of the dose was recovered in the urine as unchanged formoterol, with the (R,

R) - and (S, S)-enantiomers contributing 40% and 60%, respectively.

<Invented name> - (fluticasone propionate/formoterol fumarate combination)

A number of studies have examined the pharmacokinetic characteristics of fluticasone propionate and

formoterol fumarate from <Invented name>

compared with the individual components, given both together

and separately.

There is a high variability both within and between the pharmacokinetic studies however, in general there is

a trend for the systemic exposure of fluticasone and formoterol to be less from this fixed combination of

fluticasone propionate and formoterol fumarate

than from the individual components given together.

Pharmacokinetic equivalence between <Invented name> and the constituent monoproducts has not been

demonstrated. Long-term comparative data of <Invented name> versus fluticasone propionate and

formoterol fumarate are not available (see section 5.1).

Absorption

<Invented name> – fluticasone propionate

Following inhalation of a single 250 microgram dose of fluticasone propionate from 2 actuations of

<Invented name> 125 microgram/5 micrograms by healthy volunteers, fluticasone propionate was rapidly

absorbed into the plasma, reaching a mean maximum plasma fluticasone concentration of 32.8 pg/mL within

45 minutes of inhalation. In asthma patients who received single doses of fluticasone propionate from

<Invented name>, mean maximum plasma concentrations of 15.4 pg/mL and 27.4 pg/mL were achieved

within 20 minutes and 30 minutes for 100 microgram/10 microgram (2 actuations of <Invented name> 50

microgram/5 microgram) and 250 microgram/10 microgram (2 actuations of <Invented name> 125

microgram/5 microgram) doses respectively.

In multiple dose studies in healthy volunteers, <Invented name> doses of 100 microgram/10 micrograms,

250 microgram/10 micrograms and 500 microgram/20 micrograms resulted in mean maximum plasma

fluticasone concentrations of 21.4, 25.9 to 34.2 and 178 pg/mL respectively. The data for the

100 microgram/10 microgram and 250 microgram/10 microgram doses were generated by use of a device

without a spacer and the data for the 500 microgram/20 microgram dose were generated by use of a device

with a spacer. Use of an AeroChamber Plus® spacer increases mean systemic (which equates to pulmonary

absorption) bioavailability of fluticasone by 35% in healthy volunteers compared to administration of

<Invented name> via a pMDI alone.

<Invented name> – formoterol fumarate

Following a single dose of <Invented name> in healthy volunteers, a dose of 20 micrograms of formoterol

fumarate from 2 actuations of <Invented name> 250 microgram/10 microgram resulted in a mean maximum

plasma formoterol concentration of 9.92 pg/mL within 6 minutes of inhalation. Following multiple doses,

20 micrograms of formoterol fumarate from 2 actuations of <Invented name> 250 microgram/10 microgram

resulted in a mean maximum plasma formoterol concentration of 34.4 pg/mL.

Use of an

AeroChamber Plus

®

spacer decreases mean systemic bioavailability of formoterol by 25% in

healthy volunteers compared to administration of <Invented name> via a pMDI alone. This is likely to be

due to a reduction in absorption from the gastrointestinal tract when the spacer is used, offsetting the

expected corresponding increase in pulmonary absorption.

Distribution

There is currently no plasma protein binding information specific to fluticasone propionate or formoterol

fumarate from <Invented name>.

Biotransformation

There are currently no data relating to the metabolism of fluticasone propionate or formoterol fumarate

specifically from the inhalation of <Invented name>.

Elimination

Fluticasone propionate

Following inhalation of fluticasone propionate from 2 actuations of <Invented name> 250 microgram/10

microgram, fluticasone propionate has a terminal elimination half-life of approximately 14.2 h.

Formoterol fumarate

Following inhalation of formoterol fumarate from 2 actuations of <Invented name> 250 microgram/10

microgram, formoterol fumarate has a terminal elimination half-life of approximately 6.5 h. Less than 2%

of a single dose of formoterol fumarate from <Invented name> is excreted in the urine.

5.3

Preclinical safety data

The toxicity observed in animal studies with formoterol fumarate and fluticasone propionate, given in

combination or separately consisted mainly of effects associated with exaggerated pharmacological activity.

Effects on the cardiovascular system are related to formoterol administration and included hyperaemia,

tachycardia, arrhythmias and myocardial lesions. Neither increase in toxicity nor occurrence of unexpected

findings was observed upon administration of the combination.

Reproduction studies in rats and rabbits with <Invented name> confirmed the known embryo-fetal effects of

the two individual components including fetal growth retardation, incomplete ossification, embryo lethality,

cleft palate, oedema and skeletal variations. These effects were seen at lower exposures than those expected

by using the clinical maximum recommended dose. A somewhat reduced fertility in male rats was observed

at very high systemic exposure to formoterol.

Neither formoterol fumarate nor fluticasone propionate were found to be genotoxic in standard in vitro and

in vivo tests, when tested individually. No carcinogenicity studies have been performed with the

combination. No carcinogenic potential has been identified for fluticasone propionate. A slight increase in

the incidence of benign tumours was observed in the reproductive tract of female mice and rats following

administration of formoterol. This effect is looked upon as a class effect in rodents after long exposure to

high doses of β

agonists and does not suggest any potential risk of carcinogenicity in man.

Pre-clinical studies with HFA 227 reveal no special hazard for man based on studies of repeated-dose

toxicity, genotoxicity, carcinogenicity and toxicity to reproduction.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Sodium Cromoglicate

Ethanol Anhydrous

Apaflurane HFA 227

6.2

Incompatibilities

Not applicable

6.3

Shelf life

2 Years

In use shelf – life: 3 months after opening the foil pouch.

6.4

Special precautions for storage

Do not store above 25°C. Do not refrigerate or freeze. If the inhaler is exposed to freezing conditions then

the patient must be advised to allow the inhaler to warm at room temperature for 30 minutes then re-prime

the inhaler (see section 4.2).

The canister contains a pressurised liquid. Do not expose to temperatures higher than 50°C. Do not

puncture, break or burn, even when apparently empty.

6.5

Nature and contents of container

120 actuations per inhaler

The actuator is white with a grey integrated dose indicator and a light grey mouthpiece cover. The

suspension is contained in an aluminium pressurised canister crimped with a standard metering valve. This

canister is inserted into a press-and-breathe actuator fitted with a mouthpiece cover (both made of

polypropylene) and an integrated dose indicator which indicates the number of actuations (puffs) remaining.

Each container delivers 120 actuations. The assembled MDI inhaler is pouched in an aluminium foil

laminate and is packed in a cardboard carton.

6.6

Special precautions for disposal and other handling

No special requirements for disposal.

For detailed instructions on the use of the medicinal product see section 4.2.

7.

MARKETING AUTHORISATION HOLDER

<[To be completed nationally]>

{Name and address}

< {Tel}>

< {Fax}>

< {E-mail}>

8.

MARKETING AUTHORISATION NUMBER(S)

< [To be completed nationally]>

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

< {DD/MM/YYYY}> < {DD month YYYY}>

< [To be completed nationally]>

10.

DATE OF REVISION OF THE TEXT

2019-03-14

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