Duohal 25 mikrogram/250 mikrogram/dos Inhalationsspray, suspension

Sverige - svenska - Läkemedelsverket (Medical Products Agency)

Bipacksedel Bipacksedel (PIL)

25-02-2020

Produktens egenskaper Produktens egenskaper (SPC)

25-07-2019

Aktiva substanser:
flutikasonpropionat; salmeterolxinafoat
Tillgänglig från:
Cipla Europe NV,
ATC-kod:
R03AK06
INN (International namn):
fluticasone propionate; salmeterol
Dos:
25 mikrogram/250 mikrogram/dos
Läkemedelsform:
Inhalationsspray, suspension
Sammansättning:
flutikasonpropionat 250 mikrog Aktiv substans; salmeterolxinafoat 36,32 mikrog Aktiv substans
Receptbelagda typ:
Receptbelagt
Produktsammanfattning:
Förpacknings: Spraybehållare, 10 x 120 doser (sjukhusförpackning); Spraybehållare, 2 x 120 doser; Spraybehållare, 3 x 120 doser; Spraybehållare, 120 doser
Bemyndigande status:
Godkänd
Godkännandenummer:
53792
Tillstånd datum:
2016-12-22

Dokument på andra språk

Bipacksedel Bipacksedel - engelska

31-03-2020

Produktens egenskaper Produktens egenskaper - engelska

25-07-2019

Offentlig bedömningsrapport Offentlig bedömningsrapport - engelska

27-02-2017

Läs hela dokumentet

Package leaflet: Information for the patient

Duohal 25 micrograms /125 micrograms /dose pressurised inhalation, suspension

Duohal 25 micrograms /250 micrograms /dose pressurised inhalation, suspension

Salmeterol/fluticasone propionate

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, 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 Duohal is and what it is used for

What you need to know before you use Duohal

How to use Duohal

Possible side effects

How to store Duohal

Contents of the pack and other information

1.

What Duohal

is and what it is used for

Duohal 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.

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

controlling your asthma.

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

relieve a sudden attack of breathlessness or wheezing. If that 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 Duohal

Do not take Duohal:

If you are allergic to salmeterol, fluticasone propionate or any of the other ingredients

of this medicine (listed in section 6).

Warnings and precautions

Talk to your doctor, pharmacist or nurse before using Duohal if you have:

heart disease, including an irregular or fast heart beat

overactive thyroid gland

high blood pressure

diabetes mellitus (Duohal 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 Duohal

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

includes medicine for asthma or any medicines obtained without a prescription. This is because Duohal may

not be suitable to be taken with some other medicines.

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

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 (such as ketoconazole, itraconazole and erythromycin). Some of these

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

increase your risk of experiencing side effects with

Duohal including irregular heart beats, or may

make side effects worse.

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

increase the risk of this medicine affecting your adrenal gland.

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

Other bronchodilators (such as salbutamol).

Xanthine medicines. These are often used to treat asthma.

Medicines to treat viruses (including some medicines for HIV: ritonavir, cobicistat). Your doctor

may wish to monitor you carefully if you are taking these medicines.

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant or are planing to have a baby, ask your

doctor or pharmacist for advice before taking this medicine.

Driving and using machines

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

3. How to use Duohal

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

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

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

Duohal should be inhaled through the mouth into the lungs.

Adults and adolescents aged 12 years and over

Duohal 25 micrograms /125 micrograms /dose - 2 puffs twice a day

Duohal 25 micrograms /250 micrograms /dose - 2 puffs twice a day

Use in children and adolescents

Duohal is not recommended for use in children below 12 years of age.

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

Where the control of symptoms is maintained with the lowest strength of Duohal (25/125 micrograms), the

next step could include a switch to a different inhaled salmeterol fluticasone product available in a lower

strength (25/50 micrograms).

Your symptoms may become well controlled using Duohal 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 Duohal 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 Duohal but do not increase the number of puffs

you take. Your chest condition may be getting worse and you could become seriously ill. See your doctor as

you may need additional treatment.

Instructions for use

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

use it from time to time. Not using the Duohal properly or as prescribed may mean that it will not help

your asthma as it should.

The medicine is contained in a pressurised canister in a plastic casing with a mouthpiece.

There is an indicator in front of the inhaler which tells you how many doses are left. As you use the

inhaler the dose indicator will typically rotate during every five to seven puffs towards next decreasing

number. The dose indicator will show the approximate no of puffs remaining in the inhaler

Take care not to drop the Inhaler as this may cause the indicator to count down.

Testing your inhaler

When using the inhaler for the first time, test that it is working. Remove the mouthpiece cover by gently

squeezing the sides with your thumb and forefinger and pull apart.

To make sure that it works, shake it well, point the mouthpiece away from you and press the canister to

release four puffs into the air. The dose indicator will show the number ‘120’ indicating the number of

puffs in the inhaler. If you have not used your inhaler for a week or more, shake well and release two

puffs of medicine into the air.

Using your inhaler

It is important to start to breathe as slowly as possible just before using inhaler.

Stand or sit upright when using your inhaler.

Remove the mouthpiece cover. Check inside and outside to make sure that the mouthpiece is clean and

free of loose objects (figure A).

Shake the inhaler for 4 or 5 times to ensure that any loose objects are removed and that the contents of

the inhaler are evenly mixed (figure B).

Hold the inhaler upright with your thumb on the base, below the mouthpiece. Breathe out as far as is

comfortable (figure C).

Place the mouthpiece in your mouth between your teeth. Close your lips around it. Do not bite (figure

Breathe in through your mouth slowly and deeply. Just after starting to breathe in, press firmly down on

the top of the canister to release a puff of medicine. Do this while still breathing in steadily and deeply

(figure D).

Hold your breathe, take the inhaler from your mouth and your finger from the top of the inhaler.

Continue holding your breathe for a few seconds, or as long as is comfortable (figure E).

Wait about half a minute between taking each puff of medicine and then repeat steps 3 to 7.

Afterwards, 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.

After use always replace the mouthpiece cover straight away to keep out dust. When the mouthpiece

cover is fitted correctly it will ‘click’ into position. If it does not ‘click’ into place, turn the mouthpiece

cover the other way round and try again. Do not use too much force.

Do not rush steps 4, 5, 6 and 7. It is important that you breathe in as slowly as possible just before using your

inhaler. You should use your inhaler whilst standing in front of a mirror for the first few times. If you see

"mist" coming from the top of your inhaler or the sides of your mouth, you should start again from step 3.

As with all inhalers, caregivers should ensure that adolescents prescribed Duohal use correct inhalation

technique, as described above.

If you find it difficult to use the inhaler, a spacer device may be used such as the Volumatic or AeroChamber

Plus or other spacer devices (depending on National Guidance). Before starting to use a spacer device for the

first time or if you need to change your make of spacer device, talk to your doctor, nurse or pharmacist.

You should get a replacement when the indicator shows the number ‘40’ and the color on the dose indicator

will change from green to red. Stop using the Inhaler when the indicator shows ‘0’ as any puffs left in the

device may not be enough to give you a full dose. Never try to alter the numbers on the indicator or detach

the indicator from the actuator. The indicator cannot be reset and is permanently attached to the actuator.

Cleaning your inhaler

To stop your inhaler blocking, it is important to clean it at least once a week.

To clean your inhaler:

Remove the mouthpiece cover.

Do not remove the metal canister from the plastic casing at any time.

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

tissue.

Replace the mouthpiece cover. It will ‘click’ into place when fitted correctly. If it does not

‘click’ into place, turn the mouthpiece cover the other way round and try again. Do not use

too much force.

Do not put the metal canister in water.

If you use more Duohal

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 Duohal may reduce the amount of steroid hormones produced by the

adrenal gland.

If you forget to use Duohal

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 Duohal

It is very important that you take your Duohal every day as directed. Keep taking it until your

doctor tells

you to stop. Do not stop or suddenly reduce your dose of Duohal. This could make

your breathing problem

worse.

In addition, if you suddenly stop taking Duohal or reduce your dose of Duohal 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 or pharmacist.

4.

Possible side effects

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

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

control your asthma.

Allergic reactions:

you may notice your breathing suddenly gets worse immediately after using Duohal.

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 these

effects or if they happen suddenly after using Duohal, stop using Duohal and tell your doctor straight away.

Allergic reactions to Duohal are uncommon (may affect up to 1 in 100 people).

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 antifungal medication

to treat the thrush.

Aching, swollen joints and muscle pain.

Muscle cramps

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

Pulmonary Disease (COPD):

Pneumonia (infection of the lung).

Tell your doctor if you have any of the following while taking Duohal

they could be symptoms of a lung

infection:

fever or chills,

increased mucus production, change in mucus colour

increased cough or increased breathing difficulties.

Throat irritation. Rinsing your mouth out with water and spitting it out immediately after taking each puff

may help

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 heartbeat, 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.

Cloudy lens in the eye (cataract)

Very fast heartbeat (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 1000 people)

Breathing difficulties or wheezing that get worse straight after taking Duohal. If this happens stop using

your Duohal. Use your fast-acting ‘reliever’ inhaler to help your breathing and tell your doctor straight away.

Duohal 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

damage to eye’s optic nerve (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 Duohal to control your asthma.

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

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

Duohal unless they tell you to stop.

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

Not known (frequency cannot be estimated from the available data):

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

Blurred vision

Reporting of side effects

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

not listed in this leaflet. You can also report the 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 Duohal

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

Straight after use, replace the mouthpiece cover firmly and click it into position. Do not use

excessive force.

Do not expose to temperatures higher than 50°C. Do not store Duohal in a cold place, as your medicine

may not work as well.

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

expiry date refers to the last day of that month.

The metal canister contains a pressurised liquid. Do not pierce the canister.

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 Duohal contains

Each metered dose of Duohal provides:

25 micrograms of salmeterol (as salmeterol xinafoate) and 125 or 250 micrograms of fluticasone propionate

(delivered from the valve). This is equivalent to 21 micrograms of salmeterol and 110 or 220 micrograms of

fluticasone propionate delivered from the actuator (delivered dose).

The other ingredient is norflurane (HFA 134a).

What Duohal looks like and contents of the pack

Aluminium canister with a suitable metering valve and a polypropylene actuator with dust cap having

dose indicator in a sealed pouch containing desiccant.

Each container is filled to deliver 120 doses.

Pack sizes:

1, 2 (bundled package 2x1) or 3 (bundled package 3x1) canisters containing 120 doses.

10 (bundled package 10x1) canisters containing 120 doses -hospital/pharmacy use only

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder

[To be completed nationally]

Manufacturer

S&D Pharma CZ, spol. s r.o,

Theodor 28, 273 08

Pchery (Pharmos a.s. facility),

Ceská Republika.

Arrow Generiques

26 Avenue Tony Garnier

69007 LYON

France

Cipla Europe NV

De Keyserlei 58-60, Box-19,

2018 Antwerp,

Belgium

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

Sweden

Duohal

Bulgaria

Салметерол и флутиказон Сипла 25 микрограма/ 125 микрограма на впръскване,

суспензия под налягане за инхалация

Салметерол и флутиказон Сипла 25 микрограма/ 250 микрограма на впръскване,

суспензия под налягане за инхалация

France

PROPIONATE DE FLUTICASONE/SALMETEROL ARROW 125

microgrammes/25 microgrammes/ dose, suspension pour inhalation en flacon

pressurisé

PROPIONATE DE FLUTICASONE/SALMETEROL ARROW 250

microgrammes/25 microgrammes/ dose, suspension pour inhalation en flacon

pressurisé

This leaflet was last revised in:

2020-03-27

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SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT

Duohal 25 micrograms/125 micrograms /dose pressurised inhalation, suspension

Duohal 25 micrograms/250 micrograms /dose pressurised inhalation, suspension

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each metered dose of Duohal provides:

25 micrograms of salmeterol (as salmeterol xinafoate) and 125 or 250 micrograms of fluticasone

propionate (delivered from the valve). This is equivalent to 21 micrograms of salmeterol and 110

or 220 micrograms of fluticasone propionate delivered from the actuator (delivered dose).

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Pressurised inhalation, suspension.

The canister contains a white homogeneous suspension.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Duohal is indicated in the regular treatment of asthma where use of a combination product (long-

acting β

agonist and inhaled corticosteroid) is appropriate:

patients not adequately controlled with inhaled corticosteroids and 'as needed' inhaled short

acting β

agonist

patients already adequately controlled on both inhaled corticosteroids and long-acting β

agonist.

4.2

Posology and method of administration

Posology

Duohal is for inhalation use only.

Patients should be made aware that Duohal must be used daily for optimum benefit, even when

asymptomatic.

Patients should be regularly reassessed by a doctor, so that the strength of Duohal they are

receiving remains optimal and is only changed on medical advice.

The dose should be titrated

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

Where the control of symptoms is maintained with the lowest strength of Duohal (25/125

microgram), the next step could include a swap to a different inhaled salmeterol fluticasone

product available in a lower strength (25/50 micrograms).

As an alternative, patients requiring a long-acting β

agonist could be titrated to

salmeterol/fluticasone propionate 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 a salmeterol/fluticasone propionate product containing

the appropriate fluticasone propionate dosage for the severity of their disease. Prescribers should

be aware that, in patients with asthma, fluticasone propionate is as effective as other inhaled

steroids at approximately half the microgram daily dose. If an individual patient should require

dosages outside the recommended regimen, appropriate doses of β

agonist and/or corticosteroid

should be prescribed.

Note: If a higher than 250 micrograms dose of fluticasone propionate is required, an alternative

product must be used.

Recommended doses

Adults and adolescents 12 years and older

Two inhalations of 25 micrograms salmeterol and 125 micrograms fluticasone propionate

twice daily.

Two inhalations of 25 micrograms salmeterol and 250 micrograms fluticasone propionate

twice daily.

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. Duohal is not intended for

the initial management of mild asthma.

Use of a spacer device with Duohal is recommended in patients who have, or are likely to have

difficulties to coordinate actuation with inspiration.

A spacer device such as the Volumatic or AeroChamber Plus or other spacer devices can be used

(depending on National Guidance). Single dose pharmacokinetic data have demonstrated that the

systemic exposure to salmeterol and fluticasone propionate may change when different spacer

devices are used (see section 4.4).

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 medicinal product to the lungs.

Patients should continue to use the same make of spacer device as switching between spacer

devices can result in changes in the dose delivered to the lungs (see section 4.4).

Re-titration to the lowest effective dose should always follow the introduction or change of a

spacer device.

Special patient groups

There is no need to adjust the dose in elderly patients or in those with renal impairment. There are

no data available for use of salmeterol/fluticasone propionate in patients with hepatic impairment.

Instructions for use

Patients should be instructed in the proper use of their inhaler (see patient information leaflet).

During inhalation, the patient should preferably sit or stand. The inhaler has been designed for use

in a vertical position.

Testing the inhaler

Before using for the first time patients should remove the mouthpiece cover by gently squeezing

the sides of the cover, shake the inhaler well, hold the inhaler between the fingers and thumb with

their thumb on the base, below the mouthpiece and release four puffs into the air to make sure

that it works. The inhaler should be shaken immediately before releasing each puff. If the inhaler

has not been used for a week or more remove the mouthpiece cover, the patients should shake the

inhaler well and release two puffs into the air.

Use of the inhaler

Patients should remove the mouthpiece cover by gently squeezing the sides of the cover

Patients should check inside and outside of the inhaler including the mouthpiece for the

presence of loose objects.

Patients should shake the inhaler well to ensure that any loose objects are removed and that

the contents of the inhaler are evenly mixed

Patients should hold the inhaler upright between fingers and thumb with their thumb on the

base, below the mouthpiece.

Patients should breathe out as far as is comfortable and then place the mouthpiece in their

mouth between their teeth and close their lips around it. Patients should be instructed not to

bite the mouth piece.

Just after starting to breathe in through their mouth, patients should press firmly down on the

top of the inhaler to release Duohal, while still breathing in steadily and deeply.

While holding their breath, patients should take the inhaler from their mouth and take their

finger from the top of the inhaler. Patients should continue holding their breath for as long as

is comfortable.

To take a second inhalation, patients should keep the inhaler upright and wait about half a

minute before repeating steps 3 to 7.

Patients should immediately replace the mouthpiece cover in the correct orientation by

firmly pushing and snapping the cap into position. The cover does not require excessive

force and it will click into position.

IMPORTANT

Patients should not rush stages 5, 6 and 7. It is important that patients start to breathe in as slowly

as possible just before operating their inhaler. Patients should practice in front of a mirror for the

first few times. If they see "mist" coming from the top of their inhaler or the sides of their mouth

they should start again from stage 3.

Patients should rinse their mouth out with water and spit out, and/or brush their teeth after each

dose of medicine, in order to minimise the risk of oropharyngeal candidiasis and hoarseness.

Patients should consider getting a replacement when the indicator shows the number ‘40’ and the

colour on the dose indicator will change from green to red. Stop using the inhaler when the

indicator shows ‘0’ as any puffs left in the device may not be enough to give you a full dose.

Never try to alter the numbers on the indicator or detach the indicator from the actuator. The

indicator cannot be reset and is permanently attached to the actuator.

Cleaning

Your inhaler should be cleaned at least once a week.

Remove the mouth piece 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. This does not require excessive

force, the cover should click into position.

DO NOT PUT THE METAL CONTAINER IN WATER

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 patient response

should be monitored clinically and by lung function tests.

Salmeterol/fluticasone propionate 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

medicinal product to be used for relief in an acute asthma attack available at all times.

Patients should not be initiated on salmeterol/fluticasone propionate 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

salmeterol/fluticasone propionate Patients should be asked to continue treatment but to seek

medical advice if asthma symptoms remain uncontrolled or worsen after initiation on

salmeterol/fluticasone propionate.

Increased requirements for use of reliever medication (short-acting bronchodilators), or decreased

response to reliever medication indicate deterioration of asthma control and patients should be

reviewed by a physician.

Sudden and progressive deterioration in control of asthma is potentially 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 where the current dosage of salmeterol/fluticasone

propionate 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 salmeterol/fluticasone propionate. Regular review of patients as treatment is stepped down is

important. The lowest effective dose of salmeterol/fluticasone propionate should be used (see

section 4.2).

Treatment with salmeterol/fluticasone propionate should not be stopped abruptly due to risk of

exacerbation. Therapy should be down-titrated under physician supervision.

As with all inhaled medication containing corticosteroids, salmeterol/fluticasone propionate

should be administered with caution in patients with active or quiescent pulmonary tuberculosis

and fungal, viral or other infections of the airway. Appropriate treatment should be promptly

instituted, if indicated.

Rarely, salmeterol/fluticasone propionate may cause cardiac arrhythmias e.g. supraventricular

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

at high therapeutic doses. Salmeterol/fluticasone propionate should be used with caution in

patients with severe cardiovascular disorders or heart rhythm abnormalities and in patients with

diabetes mellitus, thyrotoxicosis, uncorrected hypokalaemia or patients predisposed to low levels

of serum potassium.

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

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

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

increase in wheezing and shortness of breath after dosing. Paradoxical bronchospasm responds to

a rapid-acting bronchodilator and should be treated straightaway. Salmeterol/fluticasone

propionate should be discontinued immediately, the patient assessed and alternative therapy

instituted if necessary.

Care should be taken when transferring patients to salmeterol/fluticasone propionate therapy,

particularly if there is any reason to suppose that adrenal function is impaired from previous

systemic steroid therapy.

The pharmacological side effects of β2 agonist treatment, such as tremor, palpitations and

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

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

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

Possible systemic effects include Cushing's syndrome, Cushingoid features, adrenal suppression,

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

psychological or behavioural effects including psychomotor hyperactivity, sleep disorders,

anxiety, depression or aggression (particularly in children) (see Paediatric population sub-heading

below for information on the systemic effects of inhaled corticosteroids in children and

adolescents). It is important, therefore, that the patient is reviewed regularly and the dose of

inhaled corticosteroid is reduced to the lowest dose at which effective control of asthma is

maintained.

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.

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

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

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

1000 micrograms. Situations, which could potentially trigger acute adrenal crisis, include trauma,

surgery, infection or any rapid reduction in dosage. Presenting symptoms are typically vague and

may include anorexia, abdominal pain, weight loss, tiredness, headache, nausea, vomiting,

hypotension, decreased level of consciousness, hypoglycaemia, and seizures. Additional systemic

corticosteroid cover should be considered during periods of stress or elective surgery.

Systemic absorption of salmeterol and fluticasone propionate is largely through the lungs. As the

use of a spacer device with a metered dose inhaler may increase drug delivery to the lungs it

should be noted that this could potentially lead to an increase in the risk of systemic adverse

effects. Single dose pharmacokinetic data have demonstrated that the systemic exposure to

salmeterol and fluticasone propionate may change when the different spacer devices are used.

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, including cobicistat-

containing products (see section 4.5).

There was an increased reporting of lower respiratory tract infections (particularly pneumonia and

bronchitis) in a 3-year study in patients with Chronic Obstructive Pulmonary Disease (COPD)

receiving salmeterol and fluticasone propionate as a fixed-dose combination administered via the

Diskus/Accuhaler compared with placebo (see section 4.8). In a 3-year COPD study, older

patients, patients with a lower body mass index (<25kg/m2) and patients with very severe disease

(FEV1<30% predicted) were at greatest risk of developing pneumonia regardless of treatment.

Physicians should remain vigilant for the possible development of pneumonia and other lower

respiratory tract infections in patients with COPD as the clinical features of such infections and

exacerbation frequently overlap

.

If a patient with severe COPD has experienced pneumonia the

treatment with salmeterol/fluticasone propionate should be re- evaluated. The safety and efficacy

of salmeterol/fluticasone propionate has not been established in patients with COPD and therefore

salmeterol/fluticasone propionate is not indicated for use in the treatment of patients with COPD.

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

Adolescents < 16 years taking high doses of fluticasone propionate (typically ≥ 1000

micrograms/day) may be at particular risk of systemic effects. Systemic effects may occur,

particularly at high doses prescribed for long periods. Possible systemic effects include Cushing's

syndrome, Cushingoid features

,

adrenal suppression, acute adrenal crisis and growth retardation

in 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 adolescent to a paediatric respiratory specialist.

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

corticosteroid is regularly monitored.

The dose of inhaled corticosteroid should be reduced to the lowest dose at which effective control

of asthma is maintained.

4.5

Interaction with other medicinal products and other forms of interaction

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

selective β blockers should be avoided in patients with asthma, unless there are compelling

reasons for their use. Potentially serious hypokalaemia may result from β

agonist therapy.

Particular caution is advised in acute severe asthma as this effect may be potentiated by

concomitant treatment with xanthine derivatives, steroids and diuretics.

Concomitant use of other β adrenergic containing medicinal products can have a potentially

additive effect.

Fluticasone propionate

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

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

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

mediated by fluticasone propionate are unlikely.

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

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

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

concentrations. Information about this interaction is lacking for inhaled fluticasone propionate,

but a marked increase in fluticasone propionate plasma levels is expected. Cases of Cushing's

syndrome and adrenal suppression have been reported. The combination should be avoided unless

the benefit outweighs the increased risk of systemic glucocorticoid side effects.

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

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

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

treatment with other potent CYP3A inhibitors, such as itraconazole and cobicistat-containing

products, and moderate CYP 3A inhibitors, such as erythromycin, is also expected to increase the

systemic fluticasone propionate exposure and 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.

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 CYP 3A4 inhibitors

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

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

statistically significant increase in salmeterol exposure (1.4-fold C

and 1.2-fold AUC). Co-

administration with erythromycin was not associated with any serious adverse effects.

4.6

Fertility, pregnancy and lactation

Fertility

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

fluticasone propionate on fertility.

Pregnancy

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

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

studies have shown reproductive toxicity after administration of β

adrenoreceptor agonists and

glucocorticosteroids (see section 5.3).

Administration of salmeterol/fluticasone propionate 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 salmeterol/fluticasone propionate therapy taking into

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

4.7

Effects on ability to drive and use machines

Salmeterol/fluticasone propionate has no or negligible influence on the ability to drive and use

machines.

4.8

Undesirable effects

As Duohal contains salmeterol and fluticasone propionate, the type and severity of adverse

reactions associated with each of the compounds may be expected. There is no incidence of

additional adverse events following concurrent administration of the two compounds.

Adverse events which have been associated with salmeterol/fluticasone propionate are given

below, listed by system organ class and frequency. Frequencies are defined as: very common

(≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (<1/10,000 to

<1/1000) and not known (cannot be estimated from the available data).

Frequencies were derived from clinical trial data. The incidence in placebo was not taken into

account.

System Organ Class

Adverse Event

Frequency

Infections and infestations

Candidiasis of the mouth and throat

Pneumonia

Bronchitis

Oesophageal candidiasis

Common

Common

Common

Rare

Immune system disorders

Hypersensitivity reactions with the

following manifestations:

Cutaneous hypersensitivity reactions

Uncommon

Dyspnoea

Angioedema (mainly facial and

oropharyngeal oedema)

Bronchospasm

Anaphylactic reactions including

anaphylactic shock

Uncommon

Rare

Rare

Rare

Endocrine disorders

Cushing's syndrome, Cushingoid

features, Adrenal suppression,

Growth retardation in children and

adolescents, Decreased bone mineral

density

Rare

Metabolism and 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 disorder

Cataract

Glaucoma

Vision, blurred (see section 4.4)

Uncommon

Rare

Not Known

Cardiac disorders

Palpitations

Tachycardia

Atrial fibrillation

Angina pectoris

Cardiac arrhythmias (including

supraventricular tachycardia and

extrasystoles).

Uncommon

Uncommon

Uncommon

Uncommon

Rare

Respiratory, thoracic and

mediastinal disorders

Nasopharyngitis

Throat irritation

Hoarseness/dysphonia

Sinusitis

Very

common

Common

Common

Common

Paradoxical bronchospasm

Rare

Skin and subcutaneous tissue

disorders

Contusions

Common

Musculoskeletal and

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

Description of selected adverse reactions

The pharmacological side effects of β

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. Salmeterol/fluticasone 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 medicinal product. Symptomatic mouth and throat candidiasis

can be treated with topical anti-fungal therapy whilst still continuing with the

salmeterol/fluticasone propionate.

Paediatric population

Possible systemic effects include Cushing's syndrome, Cushingoid features, adrenal suppression

and growth retardation in adolescents (see section 4.4). Adolescent 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

systems listed in Appendix V*.

4.9

Overdose

There are no data available from clinical trials on overdose with salmeterol/fluticasone

propionate, however data on overdose with both medicinal products are given below:

The signs and symptoms of salmeterol overdose are dizziness, increase in systolic blood pressure,

tremor, headache and tachycardia. The preferred antidotes are cardioselective β blocking agents,

which should be used with caution in patients with a history of bronchospasm. If

salmeterol/fluticasone propionate therapy has to be withdrawn due to overdose of the β agonist

component of the medicinal product, 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.

Monitoring of adrenal reserve may be necessary. In cases of both acute and chronic fluticasone

propionate overdose, salmeterol/fluticasone propionate therapy should be continued at a suitable

dosage for symptom control.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Adrenergics in combination with corticosteroids or other drugs, excl.

Anticholinergics.

ATC Code: R03AK06

Mechanism of action and pharmacodynamics effects

Duohal contains salmeterol and fluticasone propionate which have differing modes of action.

The respective mechanisms of action of both medicinal products are discussed below.

Salmeterol

Salmeterol is a selective long-acting (12 hour) β

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 β

agonists.

Fluticasone propionate

Fluticasone propionate given by inhalation at recommended doses has a glucocorticoid anti-

inflammatory action within the lungs, resulting in reduced symptoms and exacerbations of

asthma, with less adverse effects than when corticosteroids are administered systemically.

Clinical efficacy and safety

Salmeterol/fluticasone propionate asthma clinical trials

A twelve month study (Gaining Optimal Asthma ControL, GOAL), in 3416 adult and adolescent

patients with persistent asthma, compared the safety and efficacy of salmeterol/fluticasone

propionate versus inhaled corticosteroid (fluticasone propionate) alone to determine whether the

goals of asthma management were achievable. Treatment was stepped up every 12 weeks until

Total control

was achieved or the highest dose of study drug was reached. GOAL showed more

patients treated with salmeterol/fluticasone propionate achieved asthma control than patients

treated with ICS alone and this control was attained at a lower corticosteroid dose.

Well controlled

asthma was achieved more rapidly with salmeterol/fluticasone propionate than

with ICS alone. The time on treatment for 50% of subjects to achieve a first individual

well

controlled

week was 16 days for salmeterol/fluticasone propionate compared to 37 days for the

ICS group. In the subset of steroid naive asthmatics the time to an individual

well controlled

week was 16 days in the salmeterol/fluticasone propionate treatment compared to 23 days

following treatment with ICS.

The overall study results showed:

Percentage of Patients Attaining *Well Controlled (WC) and **Totally Controlled (TC)

Asthma over 12 months

Salmeterol/FP

Pre-Study Treatment

No ICS (SABA alone)

Low dose ICS (≤500 microgram BDP

or equivalent/day)

Medium dose ICS (>500-1000

microgram BDP or equivalent/day)

Pooled results across the 3 treatment

levels

*Well controlled asthma; less than or equal to 2 days with symptoms 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.

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

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

dose) of salmeterol/fluticasone propionate for two weeks. The study showed that doubling the

inhalations of each strength of salmeterol/fluticasone propionate for up to 14 days resulted in a

small increase in β agonist-related adverse events (tremor; 1 patient [1%] vs 0, palpitations; 6

[3%] vs 1 [<1%], muscle cramps; 6[3%] vs 1 [<1%]) and a similar incidence of inhaled

corticosteroid related adverse events (e.g. oral candidiasis; 6 [6%] vs 16 [8%], hoarseness; 2 [2%]

vs 4 [2%]) compared to one inhalation twice daily. The small increase in β agonist-related

adverse events should be taken into account if doubling the dose of salmeterol/fluticasone

propionate is considered by the physician in adult patients requiring additional short-term (up to

14 days) inhaled corticosteroid therapy.

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%)

27 (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)

Fluticasone propionate containing medications in asthma during pregnancy

An observational retrospective epidemiological cohort study utilising electronic health records

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

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

comparator was included in this study.

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

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

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

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

2.0) for women with considerable to severe asthma. No difference in the risk of MCMs was

identified following first trimester exposure to FP alone versus salmeterol-FP. Absolute risks of

MCM across the asthma severity strata ranged from 2.0 to 2.9 per 100 FP-exposed pregnancies

which is comparable to results from a study of 15,840 pregnancies unexposed to asthma therapies

in the General Practice Research Database (2.8 MCM events per 100 pregnancies).

5.2

Pharmacokinetic properties

When salmeterol and fluticasone propionate were administered in combination by the inhaled

route, the pharmacokinetics of each component were similar to those observed when the

medicinal products were administered separately. For pharmacokinetic purposes therefore each

component can be considered separately.

Salmeterol

Salmeterol acts locally in the lung therefore plasma levels are not an indication of therapeutic

effects. In addition there are only limited data available on the pharmacokinetics of salmeterol

because of the technical difficulty of assaying the drug in plasma due to the low plasma

concentrations at therapeutic doses (approximately 200 picogram/mL or less) achieved after

inhaled dosing.

Fluticasone propionate

The absolute bioavailability of a single dose of inhaled fluticasone propionate in healthy subjects

varies between approximately 5 to 11% of the nominal dose depending on the inhalation device

used. In patients with asthma a lesser degree of systemic exposure to inhaled fluticasone

propionate has been observed.

Systemic absorption occurs mainly through the lungs and is initially rapid then prolonged. The

remainder of the inhaled dose may be swallowed but contributes minimally to systemic exposure

due to the low aqueous solubility and pre-systemic metabolism, resulting in oral availability of

less than 1%. There is a linear increase in systemic exposure with increasing inhaled dose.

The disposition of fluticasone propionate is characterised by high plasma clearance (1150

mL/min), a large volume of distribution at steady-state (approximately 300 L) and a terminal half-

life of approximately 8 hours.

Plasma protein binding is 91%.

Fluticasone propionate is cleared very rapidly from the systemic circulation. The main pathway is

metabolism to an inactive carboxylic acid metabolite, by the cytochrome P450 enzyme CYP3A4.

Other unidentified metabolites are also found in the faeces.

The renal clearance of fluticasone propionate is negligible. Less than 5% of the dose is excreted

in urine, mainly as metabolites. The main part of the dose is excreted as faeces as metabolites and

unchanged drug.

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.

The non-CFC propellant, norflurane, has been shown to have no toxic effect at very high vapour

concentrations, far in excess of those likely to be experienced by patients, in a wide range of

animal species exposed daily for periods of two years.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Norflurane (HFA 134a).

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

2 years

6.4

Special precautions for storage

Replace the mouthpiece cover firmly and snap it into position.

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

not pierce the canister.

As with most inhaled medicinal products in pressurised containers, the therapeutic effect of this

medicinal product may decrease when the container is cold.

6.5

Nature and contents of container

Aluminium canister with a suitable metering valve and a polypropylene actuator with dust cap

having dose indicator in a sealed pouch containing desiccant.

Each container is filled to deliver 120 doses.

Pack sizes:

1, 2 (bundled package 2x1) or 3 (bundled package 3x1) canisters containing 120 doses.

10 (bundled package 10x1) canisters containing 120 doses -hospital/pharmacy use only

Not all pack sizes may be marketed.

6.6

Special precautions for disposal

No special requirements for disposal.

7.

MARKETING AUTHORISATION HOLDER

Cipla (EU) Ltd.,

Hillbrow House, Hillbrow road,

Esher Surrey, KT109NW,

United Kingdom.

8.

MARKETING AUTHORISATION NUMBER(S)

<[To be completed nationally]>

9.

DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION

<[To be completed nationally]>

10.

DATE OF REVISION OF THE TEXT

2019-07-25

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