Salmeterol/Fluticasone Hexal 50 mikrogram/500 mikrogram/dos Inhalationspulver, avdelad dos

Sverige - svenska - Läkemedelsverket (Medical Products Agency)

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Bipacksedel Bipacksedel (PIL)

22-04-2018

Produktens egenskaper Produktens egenskaper (SPC)

28-04-2018

Aktiva substanser:
flutikasonpropionat; salmeterolxinafoat
Tillgänglig från:
Hexal AG
ATC-kod:
R03AK06
INN (International namn):
fluticasone propionate; salmeterol
Dos:
50 mikrogram/500 mikrogram/dos
Läkemedelsform:
Inhalationspulver, avdelad dos
Sammansättning:
flutikasonpropionat 500 mikrog Aktiv substans; salmeterolxinafoat 73 mikrog Aktiv substans; laktosmonohydrat Hjälpämne
Klass:
Apotek
Receptbelagda typ:
Receptbelagt
Terapiområde:
Salmeterol och flutikason
Produktsammanfattning:
Förpacknings: Inhalator, 1 x 60 doser; Inhalator, 2 x 60 doser; Inhalator, 3 x 60 doser; Inhalator, 4 x 60 doser; Inhalator, 5 x 60 doser; Inhalator, 6 x 60 doser; Inhalator, 10 x 60 doser
Bemyndigande status:
Avregistrerad
Godkännandenummer:
49084
Tillstånd datum:
2014-02-13

Dokument på andra språk

Bipacksedel Bipacksedel - engelska

23-02-2018

Produktens egenskaper Produktens egenskaper - engelska

23-02-2018

Offentlig bedömningsrapport Offentlig bedömningsrapport - engelska

13-02-2014

Läs hela dokumentet

Package leaflet: Information for the user

Salmeterol/Fluticasone Hexal, 50 microgram/500 microgram/dose, inhalation powder, predispensed

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 or pharmacist.

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

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

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

effects not listed in this leaflet. See section 4.

What is in this leaflet

1. What Salmeterol/Fluticasone Hexal is and what it is used for

2. What you need to know before you use Salmeterol/Fluticasone Hexal

3. How to use Salmeterol/Fluticasone Hexal

4. Possible side effects

5. How to store Salmeterol/Fluticasone Hexal

6. Contents of the pack and other information

1.

What Salmeterol/Fluticasone Hexal is and what it is used for

Salmeterol/Fluticasone Hexal is used to treat:

asthma

chronic obstructive pulmonary disease (COPD)

This disease is characterized by continuous breathing difficulties caused by narrowed airways,

often accompanied with coughing and phlegm. This medicine reduces the number of flare ups of

COPD symptoms.

This medicine contains two active substances.

Salmeterol: a long-acting substance that widens the airways

Fluticasone: a corticosteroid which reduces swelling and inflammation in the lungs

2.

What you need to know before you use Salmeterol/Fluticasone Hexal

Do not use Salmeterol/Fluticasone Hexal

if you are

allergic

to salmeterol, fluticasone or to the other ingredient of this medicine (listed in

section 6).

Warnings and precautions

Talk to your doctor or pharmacist before using Salmeterol/Fluticasone Hexal if you have:

heart disease, including an irregular or fast heartbeat

overactive thyroid gland

high blood pressure

diabetes mellitus

low potassium in your blood

tuberculosis now or in the past, or other lung infections

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

Salmeterol/Fluticasone Hexal prevents the onset of breathlessness and wheezing. Please note that it

does not work when you are already breathless or wheezy.

If such a

breathlessness attack

occurs, you need to use a medicine which quickly widens the

airways, such as salbutamol.

Inform your doctor immediately if your asthma or breathing gets worse. You may find that:

you feel more wheezy

your chest feels tight more often

you need to use more of your fast acting airway widening inhaler

Continue to use Salmeterol/Fluticasone Hexal if any of these happen, but do not increase the number

of inhalations. Your chest condition may be getting worse and you could become seriously ill. Talk to

your doctor as you may need additional treatment.

Children and adolescents

Salmeterol/Fluticasone Hexal is not recommended for children under the age of 12 years.

Other medicines and Salmeterol/Fluticasone Hexal

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

medicines, including medicines obtained without a prescription.

The following medicines can influence or be influenced by Salmeterol/Fluticasone Hexal:

medicines to treat high blood pressure, heart or other illnesses, with active substance names ending

with “olol” (beta-blockers), such as atenolol, propranolol and sotalol

medicines to treat viruses including some medicines for HIV, such as ritonavir or cobicistat; Your

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

medicines to treat infections, such as ketoconazole, itraconazole and erythromycin

corticosteroid taken by the mouth or injected: medicines to treat inflammation or prevent organ

transplant rejection

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

other bronchodilators (such as salbutamol)

xanthine medicines. These are often used to treat asthma.

Pregnancy, breast-feeding and fertility

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

your doctor or pharmacist for advice before taking this medicine. Your doctor will assess whether you

can take Salmeterol/Fluticasone Hexal during this time.

Driving and using machines

Salmeterol/Fluticasone Hexal is unlikely to impair your ability to drive or operate machinery.

Salmeterol/Fluticasone Hexal contains lactose

If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor

before taking this medicine.

The amount of lactose in this medicine does not normally cause problems in people who are lactose

intolerant.

3.

How to use Salmeterol/Fluticasone Hexal

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

or pharmacist if you are not sure.

Asthma

The recommended dose

for adults and children from 12 years

One inhalation twice daily

Your doctor will want to regularly check your asthma symptoms.

Chronic obstructive pulmonary disease

The recommended dose

for adults

One inhalation twice daily

If your symptoms become controlled using Salmeterol/Fluticasone Hexal twice daily, your doctor may

reduce your dose to once daily:

once at night if you have night-time

symptoms

once in the morning if you have daytime

symptoms

Method of use

Use Salmeterol/Fluticasone Hexal every day as prescribed by your doctor, preferably

right before

mealtime

in the morning and/or in the evening.

After use, rinse your mouth with water.

Not using Salmeterol/Fluticasone Hexal properly or as prescribed may worsen your breathing

difficulties. For optimal therapy, you must use Salmeterol/Fluticasone Hexal daily, even if you don’t

have any symptoms.

Instructions for use

Your doctor, nurse or pharmacist should demonstrate how to use the inhaler and should check your

use regularly.

The inhaler contains 60 doses of powder medication in a coiled strip of foil. It has a dose counter

which shows you how many doses you have remaining counting down from 60 to 0. When you have

reached the last 10 doses the numbers will be on a red background.

The inhaler is not refillable – please dispose of the inhaler when it is empty and replace it with a new

one.

Before using the inhaler

Open the transparent side chamber door.

Remove the foil strip from the side chamber by carefully tearing away the full length of strip

against the ‘teeth’ of the side chamber as shown below.

Do not pull or tug

on the strip.

Close the side chamber door and dispose of the used strip.

Important:

As you use the inhaler the side chamber will gradually fill up with used strip. The foil strips

with

black bars don’t contain medication

. Eventually the numbered sections of the strip

will appear in the side chamber.

Do not let more than 2 sections of foil strip build up

in the side chamber as they may cause

the inhaler to jam. Tear the strip away carefully as shown above, and dispose of it safely.

Using the inhaler

Hold the inhaler in your hands as seen in the pictures.

1.

Open

Open

the protective

cap downwards

to reveal the mouthpiece.

Check the dose counter to see how many doses are left.

2.

Prepare the dose

Lift up

the edge of the

white lever

. Make sure the side chamber is closed.

Remember

: Only operate the white lever when you are ready to inhale a dose of your

medication. If you play with the white lever, you will waste doses.

Open: Move

white lever fully over

as far as it will go and

until it clicks

. This action

moves a new dose into position with the number at the top.

Close:

Afterwards

close

white lever fully

so that it

clicks

back into its original position.

The inhaler is now ready for immediate use.

3.

Inhale

Away from the inhaler mouthpiece, breathe out as much as is comfortable

. Never breathe

directly into

the inhaler as this could affect the dose.

Hold the inhaler level with the

protective cap pointing downwards

Close your lips firmly around the mouthpiece.

Breathe

in steadily and

deeply

through the inhaler, not through your nose.

Remove the inhaler from your mouth and

hold your breath for 5-10 seconds

or as long as

you can without causing

discomfort.

Afterwards, breathe out slowly,

but not into the inhaler

Close the protective cap over the mouthpiece.

Rinse your mouth with water and spit it out. This may help to prevent you from getting fungal

infection in the mouth and becoming hoarse.

Cleaning

Wipe the outside of the mouthpiece with a clean, dry tissue if necessary.

Do not attempt to take the inhaler apart to clean it or for any other purpose!

Do not use water or wet wipes to clean the inhaler parts as dampness can affect the dose!

Never insert a pin or other sharp objects into the mouthpiece, or any other part, as this could

damage the inhaler!

If you use more Salmeterol/Fluticasone Hexal than you should

Contact your doctor or pharmacist.

Overdose symptoms are:

dizziness

headache

rapid heart beat

muscle weakness

aching joints

feeling shaky

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

for advice. This is because larger doses of Salmeterol/Fluticasone Hexal may reduce the ammount of

steroid hormones produced by the adrenal gland.

If you forget to use Salmeterol/Fluticasone Hexal

Do not take a double dose to make up for a forgotten dose. Use your next dose when it is due.

If you stop using Salmeterol/Fluticasone Hexal

Do not stop or suddenly reduce your dose of Salmeterol/Fluticasone Hexal without your doctor’s

permission as this could cause your breathing problems to worsen and very rarely side effects could

occur. These include:

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

Very rarely, if you get an infection or at times of extreme stress (such as after a serious accident or if

you have surgery), you may get similar side effects. To prevent these symptoms ocuring, your doctor

may prescribe extra corticosteroids (like 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.

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

Salmeterol/Fluticasone Hexal

. You may be very wheezy and cough. You may also notice itching, a

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

heart 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

Salmeterol/Fluticasone Hexal, tell your doctor straight away.

Allergic reactions to

Salmeterol/Fluticasone Hexal are uncommon (they may affect up to 1 in 100 people).

Other side effects can occur with the following frequencies:

Very Common,

may affect more than 1 in 10 people

headache

This usually gets better as treatment continues.

increased number of colds 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

each inhalation may help. Your doctor may prescribe an anti-fungal medication to treat the thrush.

aching, swollen joints and muscle pain

muscle cramps

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

Disease (COPD)

Pneumonia (infection of the lung)Tell your doctor if you have any of the following while taking

Salmeterol/Fluticasone Hexal, they could be symptoms of a lung infection:

increase in mucous production

change in mucous colour

fever

chills

increased cough

increased breathing difficulties

bruising and fractures throughout the body

inflammation of the sinuses

low potassium level in the blood (you may get an uneven heartbeat, muscle weakness and/or cramp)

Uncommon,

may affect up to 1 in 100 people

very fast heartbeat (tachycardia)

feeling shaky and a fast or uneven heartbeat (palpitation)

This is usually harmless and decreases during therapy.

feeling worried

This effect mainly occurs in children.

increased blood sugar level

If you have diabetes, more frequent blood sugar monitoring and possible adjustment of your

diabetic medicines may be required.

disturbed sleep

allergic skin rash

chest pain

clouding of the eye lens (cataract)

Rare,

may affect up to 1 in 1,000 people

breathing difficulties

wheezing

that

gets worse

straight after using Salmeterol/Fluticasone

Hexal.

Stop using

your Salmeterol/Fluticasone Hexal and use your fast-acting

airway widening inhaler

to help your breathing

. Tell your doctor

straight away.

abnormal production of certain hormones, particularly when using this medicine in high doses

over a long time

Signs are:

slowing of growth in children and adolescents

thinning of the bones

increased eye pressure (glaucoma)

weight gain

rounded, moon shaped face (Cushing’s Syndrome).

Your doctor will check you regularly for any of these side effects, ensuring you are on the lowest

dose possible.

behavioural changes, such as being unusually active and irritable

These effects mainly occur in children.

irregular heartbeat or heart gives an extra beat

Tell your doctor, but do not stop using Salmeterol/Fluticasone Hexal unless told to do so.

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

Frequency not known

, but may also occur

depression or aggression. These effects mainly occur in children.

blurred vision.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any side effects not listed

in this leaflet. You can also report side effects directly via the national reporting system listed in

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

medicine.

5.

How to store Salmeterol/Fluticasone Hexal

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

Do not store above 25 °C.

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

expiry date refers to the last day of that month.

Do not 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 Salmeterol/Fluticasone Hexal contains

Salmeterol/Fluticasone Hexal 50/500 microgram inhalation powder, predispensed:

The active substances are salmeterol and fluticasone. Each metered dose of

Salmeterol/Fluticasone Hexal provides 50 micrograms of salmeterol (as salmeterol xinafoate) and

500 micrograms of fluticasone propionate. Corresponding with a delivered dose of:

45 micrograms of Salmeterol (as salmeterol xinafoate) and 465 micrograms of fluticasone

propionate

The other ingredient is lactose monohydrate.

What Salmeterol/Fluticasone Hexal looks like and contents of the pack

In the purple plasticdry-powder inhalation device, 60 doses of powder blend are contained in an

aluminium blister.

Each dose is pre-dispensed.

Pack sizes:

1, 2, 3, 4, 5, 6 or 10 inhalation devices containing 60 doses.

Not all pack sizes may be marketed

Marketing Authorisation Holder and Manufacturer

[To be completed nationally]

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

names:

Germany:

Airflusal® Forspiro® 50 Mikrogramm/500 Mikrogramm/Dosis einzeldosiertes Pulver

zur Inhalation

Sweden:

Salmeterol/Fluticasone Hexal, 50 mikrogram/500 mikrogram/dos inhalationspulver,

avdelad dos

This leaflet was last revised in 23 February 2018.

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Produktinformationen för Salmeterol/Fluticasone Hexal 50 mikrogram/500 mikrogram/dos,

inhalationspulver, avdelad dos MTnr 49084, gäller vid det tillfälle då läkemedlet godkändes.

Informationen kommer inte att uppdateras eftersom läkemedlet inte marknadsförs i Sverige.

Av samma anledning finns inte någon svensk produktinformation.

Den engelska produktinformationen kommer dock att uppdateras för de produkter där Sverige

är referensland.

Om läkemedelsnamnet i följande produktinformation inte stämmer med namnet på

dokumentet, beror det på att läkemedlet i Sverige är godkänt under ett annat namn.

Summary of Product Characteristics

1.

NAME OF THE MEDICINAL PRODUCT

Salmeterol/Fluticasone Hexal,50 microgram/500 microgram/dose, inhalation powder, predispensed

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each metered dose of {Salmeterol/Fluticasone Hexal}provides:

For 50 microgram/500 microgram/dose, inhalation powder, predispensed:

50 micrograms of salmeterol (as salmeterol xinafoate) and 500 micrograms of fluticasone propionate.

Corresponding with a delivered dose of:

45 micrograms of Salmeterol (as salmeterol xinafoate) and 465 micrograms of fluticasone propionate

Excipient with known effect: lactose monohydrate : 11.95 mg per metered dose.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Inhalation powder, pre-dispensed.

White, homogenous powder.

The pre-dispensed powder, contained in blister, is delivered by a purple plastic dry-powder inhalation

device.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Asthma

Salmeterol/Fluticasone Hexalis indicated in the regular treatment of asthma where use of a

combination product (long-acting beta-2-agonist and inhaled corticosteroid) is appropriate:

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

beta-2-agonist

patients already adequately controlled on both inhaled corticosteroid and long-acting beta-2-

agonist.

Chronic Obstructive Pulmonary Disease (COPD)

Salmeterol/Fluticasone Hexalis indicated for the symptomatic treatment of patients with COPD, with

a FEV

<60% predicted normal (pre-bronchodilator) and a history of repeated exacerbations, who

have significant symptoms despite regular bronchodilator therapy.

4.2

Posology and method of administration

Method of administration:

{Salmeterol/Fluticasone Hexal} is for inhalation use only.

Patients should be made aware that {Salmeterol/Fluticasone Hexal} must be used daily for optimum

benefit, even when asymptomatic.

Patients should be regularly reassessed by a doctor, so that the strength of {Salmeterol/Fluticasone

Hexal} they are receiving remains optimal and is only changed on medical advice.

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

maintained. Where the control of symptoms is maintained with the lowest strength of the

combination given twice daily then the next step could include a test of inhaled corticosteroid

alone.

As an alternative, patients requiring a long acting beta-2-agonist could be titrated to

{Salmeterol/Fluticasone Hexal}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

day-time symptoms the dose should be given in the morning.

Patients should be given the strength of {Salmeterol/Fluticasone Hexal}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. For example, 100 micrograms of fluticasone propionate is

approximately equivalent to 200 micrograms of beclomethasone dipropionate (CFC containing) or

budesonide. If an individual patient should require dosages outside the recommended regimen,

appropriate doses of beta-agonist and/or corticosteroid should be prescribed.

Posology:

Asthma

Adults and adolescents 12 years and older:

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

A short term trial of {Salmeterol/Fluticasone Hexal}may be considered as initial maintenance therapy

in adults or adolescents with moderate persistent asthma (defined as patients with daily symptoms,

daily rescue use and moderate to severe airflow limitation) for whom rapid control of asthma is

essential. In these cases, the recommended initial dose is inhalation of 100 micrograms fluticasone

propionate and 50 micrograms salmeterol (given singly or as fixed combination) twice daily.

Once control of asthma is attained treatment should be reviewed and consideration given as to

whether patients should be stepped down to an inhaled corticosteroid alone. Regular review of

patients as treatment is stepped down is important.

A clear benefit has not been shown as compared to inhaled fluticasone propionate alone used as initial

maintenance therapy when one or two of the criteria of severity are missing. In general inhaled

corticosteroids remain the first line treatment for most patients. {Salmeterol/Fluticasone Hexal}is not

intended for the initial management of mild asthma.

Salmeterol/fluticasone propionate 50 microgram/100 micrograms strength is not appropriate in adults

with severe asthma; it is recommended to establish the appropriate dosage of inhaled corticosteroid

before any fixed combination can be used in patients with severe asthma.

For dosages, which cannot be achieved with {Salmeterol/Fluticasone Hexal}.other strengths of

salmeterol/fluticasone medicinal products are available.

COPD

Adults:

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

Special patient groups:

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

data available for use of {Salmeterol/Fluticasone Hexal}in patients with hepatic impairment.

Paediatric population:

{Salmeterol/Fluticasone Hexal}should not be used in children.

For instructions for use, see section 6.6.

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 program.

{Salmeterol/Fluticasone Hexal}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 Hexal}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 Hexal}. Patients should be asked to continue treatment but to seek medical

advice if asthma symptoms remain uncontrolled or worsen after initiation on {Salmeterol/Fluticasone

Hexal}.

Increasing use of short-acting bronchodilators to relieve symptoms indicates deterioration of control

and patients should be reviewed by a physician.

Sudden and progressive deterioration in control of asthma is potentially life threatening and the

patient should undergo urgent medical assessment. Consideration should be given to increasing

corticosteroid therapy.

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

{Salmeterol/Fluticasone Hexal}.Regular review of patients as treatment is stepped down is important.

The lowest effective dose of Salmeterol/Fluticasone should be used (see section 4.2).

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

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

deteriorate with {Salmeterol/Fluticasone Hexal}.

Treatment with {Salmeterol/Fluticasone Hexal}should not be stopped abruptly in patients with

asthma due to risk of exacerbation. Therapy should be down-titrated under physician supervision. For

patients with COPD cessation of therapy may also be associated with symptomatic decompensation

and should be supervised by a physician.

As with all inhaled medication containing corticosteroids, {Salmeterol/Fluticasone Hexal}should be

administered with caution in patients with pulmonary tuberculosis.

Rarely, {Salmeterol/Fluticasone Hexal}may cause cardiac arrhythmias e.g. supraventricular

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

high therapeutic doses. Therefore {Salmeterol/Fluticasone Hexal}should be used with caution in

patients with severe cardiovascular disorders, heart rhythm abnormalities, 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 after dosing. {Salmeterol/Fluticasone Hexal}should be discontinued immediately, the

patient assessed and alternative therapy instituted if necessary.

{Salmeterol/Fluticasone Hexal}contains lactose up to 12.2 mg/dose. This amount does not normally

cause problems in lactose intolerant people.

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

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

systemic effects include

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

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

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

(particularly in children).

It is important, therefore, that the patient is reviewed regularly and the

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

is maintained.

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

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

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

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

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

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

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

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

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

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

considerable time. Patients who have required high dose emergency corticosteroid therapy in the past

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

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

must be considered. The extent of the adrenal impairment may require specialist advice before

elective procedures.

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

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

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

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

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

bronchitis) in the TORCH study in patients with COPD receiving Salmeterol/Fluticasone propionate

50/500 micrograms bd compared with placebo as well as in studies SCO40043 and SCO1000250

comparing the lower non-approved COPD dose of Salmeterol/Fluticasone propionate,

50/250 micrograms bd, to salmeterol 50 micrograms bd only (see section 4.8 and 5.1). A similar

incidence of pneumonia in the Salmeterol/Fluticasone propionate group was seen across all studies. In

TORCH, older patients, patients with a lower body mass index (<25kg/m

) and patients with very

severe disease (FEV

<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 Hexal}should be re-evaluated.

Data from a large clinical trial (the Salmeterol Multi-Center Asthma Research Trial, SMART)

suggested African-American patients were at increased risk of serious respiratory-related events or

deaths when using salmeterol compared with placebo (see section 5.1). It is not known if this was due

to pharmacogenetic or other factors. Patients of black African or Afro-Caribbean ancestry should

therefore be asked to continue treatment but to seek medical advice if asthma symptoms remained

uncontrolled or worsen whilst using {Salmeterol/Fluticasone Hexal}.

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

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

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

inhibitors should therefore be avoided unless the benefits outweigh the potentially increased risk of

systemic side effects of salmeterol treatment (see section 4.5).

Paediatric Population

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

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

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

features

,

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

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

sleep disorders, anxiety, depression or aggression.

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

corticosteroid is regularly monitored.

The dose of inhaled corticosteroid should be reduced to the

lowest dose at which effective control of asthma is maintained.

4.5

Interaction with other medicinal products and other forms of interaction

Both non-selective and selective beta-blockers should be avoided unless there are compelling reasons

for their use.

Concomitant use of other beta-adrenergic containing drugs can have a potentially additive effect.

Fluticasone Propionate

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

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

cytochrome P450 3A4 in the gut and liver. Hence, clinically significant drug interactions mediated by

fluticasone propionate are unlikely.

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

potent cytochrome P450 3A4 inhibitor) 100 mg b.i.d. increased the fluticasone propionate plasma

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

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

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

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

increased risk of systemic glucocorticoid side-effects.

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

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

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

other potent CYP3A inhibitors, such as itraconazole, is also expected to increase the systemic

fluticasone propionate exposure and the risk of systemic side-effects. Caution is recommended and

long-term treatment with such drugs should if possible be avoided.

Salmeterol

Potent CYP3A4 inhibitors

Co-administration of ketoconazole (400 mg orally once daily) and salmeterol (50 mcg inhaled twice

daily) in 15 healthy subjects for 7 days resulted in a significant increase in plasma salmeterol

exposure (1.4-fold Cmax and 15-fold AUC). This may lead to an increase in the incidence of other

systemic effects of salmeterol treatment (e.g. prolongation of QTc interval and palpitations) compared

with salmeterol or ketoconazole treatment alone (see Section 4.4).

Clinically significant effects were not seen on blood pressure, heart rate, blood glucose and blood

potassium levels. Co-administration with ketoconazole did not increase the elimination half-life of

salmeterol or increase salmeterol accumulation with repeat dosing.

The concomitant administration of ketoconazole should be avoided, unless the benefits outweigh the

potentially increased risk of systemic side effects of salmeterol treatment. There is likely to be a

similar risk of interaction with other potent CYP3A4 inhibitors (e.g. itraconazole, telithromycin,

ritonavir).

Moderate CYP 3A4 inhibitors

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

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

increase in salmeterol exposure (1.4-fold Cmax and 1.2-fold AUC). Co-administration with

erythromycin was not associated with any serious adverse effects.

4.6

Fertility, pregnancy and lactation

Pregnancy

A moderate amount of data on pregnant women (between 300-1000 pregnancy outcomes) indicate no

malformative or feto/neonatal toxicity of salmeterol and fluticasone propionate. Animal studies have

shown reproductive toxicity after administration of beta-2-adrenoreceptor agonists and

glucocorticosteroids (see section 5.3).

Administration of {Salmeterol/Fluticasone Hexal}to pregnant women should only be considered if

the expected benefit to the mother is greater than any possible risk to the foetus.

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 breast-feeding or to discontinue {Salmeterol/Fluticasone Hexal}therapy taking into

account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

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

propionate on fertility.

4.7

Effects on ability to drive and use machines

No studies of the effect on the ability to drive and use machines have been performed.

4.8

Undesirable effects

As {Salmeterol/Fluticasone Hexal}contains salmeterol and fluticasone propionate, the type and

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

incidence of additional adverse events following concurrent administration of the two compounds.

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

listed by system organ class and frequency. Frequencies are defined as: very common (≥1/10);

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

(<1/10,000); not known (cannot be estimated form the available data).

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

account.

System Organ Class

Adverse Event

Frequency

Infections & Infestations

Candidiasis of the mouth and throat

Common

Pneumonia

Bronchitis

Common

1,3,5

Common

Immune System

Disorders

Hypersensitivity reactions with the following

manifestations:

Cutaneous hypersensitivity reactions

Angioedema (mainly facial and oropharyngeal

oedema)

Respiratory symptoms (dyspnoea)

Respiratory symptoms (bronchospasm)

Anaphylactic reactions including anaphylactic

shock

Uncommon

Rare

Uncommon

Rare

Rare

Endocrine Disorders

Cushing’s syndrome, Cushingoid features,

adrenal suppression, growth retardation in

children and adolescents, decreased bone

mineral density

Rare

Metabolism & Nutrition

Disorders

Hypokalaemia

Hyperglycaemia

Common

Uncommon

Psychiatric Disorders

Anxiety

Sleep disorders

behavioural changes, including psychomotor

hyperactivity and irritability (predominantly in

children)

Depression, aggression (predominantly in

children)

Uncommon

Uncommon

Rare

Rare

Nervous System

Disorders

Headache

Tremor

Very Common

Uncommon

Eye Disorders

Cataract

Uncommon

Glaucoma

Rare

Cardiac Disorders

Palpitations

Tachycardia

Cardiac arrhythmias (including

supraventricular tachycardia and extrasystoles).

Atrial fibrillation

Angina pectoris

Uncommon

Uncommon

Rare

Uncommon

Uncommon

Respiratory, Thoracic &

Mediastinal Disorders

Nasopharyngitis

Throat irritation

Hoarseness/dysphonia

Sinusitis

Paradoxical bronchospasm

Very Common

Common

Common

Common

Rare

Skin and subcutaneous

tissue disorders

Contusions

Common

Musculoskeletal &

Connective Tissue

Disorders

Muscle cramps

Traumatic fractures

Arthralgia

Myalgia

Common

Common

Common

Common

1 Reported commonly in placebo

2 Reported very commonly in placebo

3 Reported over 3 years in a COPD study

4 See section 4.4

5 See section 5.1.

Description of selected adverse reactions

The pharmacological side effects of beta-2-agonist treatment, such as tremor, palpitations and

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

Due to the fluticasone propionate component, hoarseness and candidiasis (thrush) of the mouth and

throat can occur in some patients. Both hoarseness and incidence of candidiasis may be relieved by

gargling with water after using the product. Symptomatic candidiasis can be treated with topical anti-

fungal therapy whilst still continuing with Salmeterol/Fluticasone.

Paediatric population

Possible systemic effects include Cushing's syndrome, Cushingoid features

,

adrenal suppression and

growth retardation in children and adolescents (see section 4.4). Children may also experience

anxiety, sleep disorders and behavioural changes, including hyperactivity and irritability.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is

important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

Healthcare professionals are asked to report any suspected adverse reactions via the national

reporting system listed in [To be completed nationally].

4.9

Overdose

There are no data available from clinical trials on overdose with {Salmeterol/Fluticasone

Hexal}:however data on overdose with both drugs are given below:

The signs and symptoms of salmeterol overdose are tremor, headache and tachycardia. The preferred

antidotes are cardioselective beta-blocking agents, which should be used with caution in patients with

a history of bronchospasm. If {Salmeterol/Fluticasone Hexal}therapy has to be withdrawn due to

overdose of the beta agonist component of the drug, provision of appropriate replacement steroid

therapy should be considered. Additionally, hypokalaemia can occur and 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: Refer to section 4.4: risk of adrenal

suppression:

Monitoring of adrenal reserve may be necessary. In cases of fluticasone propionate

overdose {Salmeterol/Fluticasone Hexal}therapy may still be continued at a suitable dosage for

symptom control.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Adrenergics and other drugs for obstructive airway diseases, salmeterol

and other drugs for obstructive airway diseases ATC code: R03AK06

Mechanism of action:

{Salmeterol/Fluticasone Hexal}contains salmeterol and fluticasone propionate which have differing

modes of action. The respective mechanisms of action of both drugs are discussed below:

Salmeterol:

Salmeterol is a selective long-acting (12 hour) beta-2-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 beta-2-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,

without the adverse effects observed when corticosteroids are administered systemically.

Clinical efficacy and safety:

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

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

were achievable. Treatment was stepped up every 12 weeks until **Total control was achieved or the

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

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

corticosteroid dose.

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

on treatment for 50% of subjects to achieve a first individual Well Controlled week was 16 days for

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

time to an individual Well Controlled week was 16 days in the salmeterol/FP treatment compared to

23 days following treatment with ICS.

The overall study results showed:

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

Asthma over 12 months

Salmeterol/FP

FP

Pre-Study

Treatment

WC

TC

WC

TC

No ICS

(SABA

alone)

Low dose ICS

(≤500mcg BDP or

equivalent/day)

Medium dose ICS

(>500-1000mcg

BDP or

equivalent/day)

Pooled results

across the 3

treatment levels

*Well controlled asthma; occasional symptoms or SABA use or less than 80% predicted lung

function plus no night-time awakenings, no exacerbations and no side effects enforcing a change in

therapy

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

function, no night-time awakenings, no exacerbations and no side effects enforcing a change in

therapy

The results of this study suggest that salmeterol/fluticasone 50/100 microgram bd may be considered

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

asthma is deemed essential (see section 4.2).

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

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

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

salmeterol/FP for up to 14 days resulted in a small increase in beta-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

beta-agonist-related adverse events should be taken into account if doubling the dose of

{Salmeterol/Fluticasone Hexal}is considered by the physician in adult patients requiring additional

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

COPD clinical trials

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

salmeterol 50mcg bd, FP 500mcg bd or placebo on all-cause mortality in patients with COPD. COPD

patients with a baseline (pre-bronchodilator) FEV

<60% of predicted normal were randomised to

double-blind medication. During the study, patients were permitted usual COPD therapy with the

exception of other inhaled corticosteroids, long-acting bronchodilators and long-term systemic

corticosteroids. Survival status at 3 years was determined for all patients regardless of withdrawal

from study medication. The primary endpoint was reduction in all cause mortality at 3 years for

salmeterol/FP vs Placebo.

Placebo

N = 1524

Salmeterol 50

N = 1521

FP 500

N = 1534

Salmeterol/FP 50/500

N = 1533

All cause mortality at 3 years

Number of deaths (%)

(15.2%)

(13.5%)

(16.0%)

(12.6%)

Hazard Ratio vs

Placebo (CIs)

p value

0.879

(0.73, 1.06)

0.180

1.060

(0.89, 1.27)

0.525

0.825

(0.68, 1.00 )

0.052

Hazard Ratio

salmeterol/FP 50/500

vs components (CIs)

p value

0.932

(0.77, 1.13)

0.481

0.774

(0.64, 0.93)

0.007

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

from a log-rank analysis stratified by smoking status

There was a trend towards improved survival in subjects treated with salmeterol/FP compared with

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

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

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

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

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

salmeterol/FP group 0.85 compared with 0.97 in the salmeterol group, 0.93 in the FP group and 1.13

in the placebo). This translates to a reduction in the rate of moderate to severe exacerbations of 25%

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

5% to 19%, p=0.002) and 9% compared with FP (95% CI: 1% to 16%, p=0.024). Salmeterol and FP

significantly reduced exacerbation rates compared with placebo by 15% (95% CI: 7% to 22%;

p<0.001) and 18% (95% CI: 11% to 24%; p<0.001) respectively.

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

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

three years for salmeterol/fluticasone compared with placebo was -3.1 units (95% CI: -4.1 to -2.1;

p<0.001), compared with salmeterol was -2.2 units (p<0.001) and compared with FP was -1.2 units

(p=0.017). A 4-unit decrease is considered clinically relevant.

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

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

salmeterol/FP vs placebo: 1.64, 95% CI: 1.33 to 2.01, p<0.001). There was no increase in pneumonia

related deaths; deaths while on treatment that were adjudicated as primarily due to pneumonia were 7

for placebo, 9 for salmeterol, 13 for FP and 8 for salmeterol/FP. There was no significant difference

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

Hazard ratio for salmeterol/FP vs placebo: 1.22, 95% CI: 0.87 to 1.72, p=0.248.

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

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

medication.

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

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

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

exacerbations in subjects with COPD with FEV1 less than 50% predicted and a history of

exacerbations. Moderate/ severe exacerbations were defined as worsening symptoms that required

treatment with oral corticosteroids and/or antibiotics or in-patient hospitalisation.

The trials had a 4 week run-in period during which all subjects received open-label salmeterol/ FP

50/250 to standardize COPD pharmacotherapy and stabilise disease prior to randomisation to blinded

study medication for 52 weeks. Subjects were randomised 1:1 to salmeterol/ FP 50/250 (total ITT

n=776) or salmeterol (total ITT n=778). Prior to run-in, subjects discontinued use of previous COPD

medications except short-acting bronchodilators. The use of concurrent inhaled long-acting

bronchodilators (beta2-agonist and anticholinergic), ipratropium/salbutamol combination products,

oral beta2-agonists, and theophylline preparations were not allowed during the treatment period. Oral

corticosteroids and antibiotics were allowed for the acute treatment of COPD exacerbations with

specific guidelines for use. Subjects used salbutamol on an as-needed basis throughout the studies.

The results of both studies showed that treatment with salmeterol/FP 50/250 resulted in a significantly

lower annual rate of moderate/severe COPD exacerbations compared with salmeterol (SCO40043:

1.06 and 1.53 per subject per year, respectively, rate ratio of 0.70, 95% CI: 0.58 to 0.83, p<0.001;

SCO100250: 1.10 and 1.59 per subject per year, respectively, rate ratio of 0.70, 95% CI: 0.58 to 0.83,

p<0.001). Findings for the secondary efficacy measures (time to first moderate/severe exacerbation,

the annual rate of exacerbations requiring oral corticosteroids, and pre-dose morning (AM) FEV1)

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

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

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

salmeterol. Pneumonia-related events were reported for 55 (7%) subjects in the salmeterol/FP 50/250

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

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

incidence reported following treatment with salmeterol/FP 50/500 micrograms bd in TORCH.

The Salmeterol Multi-center Asthma Research Trial (SMART)

SMART was a multi-centre, randomised, double-blind, placebo-controlled, parallel group 28-week

study in the US which randomised 13,176 patients to salmeterol (50μg twice daily) and 13,179

patients to placebo in addition to the patients' usual asthma therapy. Patients were enrolled if ≥12

years of age, with asthma and if currently using asthma medication (but not a LABA). Baseline ICS

use at study entry was recorded, but not required in the study. The primary endpoint in SMART was

the combined number of respiratory-related deaths and respiratory-related life-threatening

experiences.

Key findings from SMART: primary endpoint

Number of primary

endpoint events

/number of patients

Patient group

salmeterol

placebo

Relative Risk

(95% confidence intervals)

All patients

50/13,176

36/13,179

1.40 (0.91, 2.14)

Patients using

inhaled steroids

23/6,127

19/6,138

1.21 (0.66, 2.23)

Patients not

using inhaled

steroids

27/7,049

17/7,041

1.60 (0.87, 2.93)

African-

American

patients

20/2,366

5/2,319

4.10 (1.54, 10.90)

(Risk in bold is statistically significant at the 95% level.)

Key findings from SMART by inhaled steroid use at baseline: secondary endpoints

Number of secondary

endpoint events

/number of patients

salmeterol

placebo

Relative Risk

(95% confidence intervals)

Respiratory -related death

Patients using

inhaled steroids

10/6127

5/6138

2.01 (0.69, 5.86)

Patients not using

inhaled steroids

14/7049

6/7041

2.28 (0.88, 5.94)

Combined asthma-related death or life-threatening experience

Patients using

inhaled steroids

16/6127

13/6138

1.24 (0.60, 2.58)

Patients not using

inhaled steroids

21/7049

9/7041

2.39 (1.10, 5.22)

Asthma-related death

Patients using

inhaled steroids

4/6127

3/6138

1.35 (0.30, 6.04)

Patients not using

inhaled steroids

9/7049

0/7041

(*=could not be calculated because of no events in placebo group. Risk in bold figures is statistically

significant at the 95% level. The secondary endpoints in the table above reached statistical

significance in the whole population.) The secondary endpoints of combined all-cause death or life-

threatening experience, all cause death, or all cause hospitalisation did not reach statistical

significance in the whole population.

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 drugs 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 picograms/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 5-11% of the nominal dose depending on the inhalation device used. In

patients with asthma or COPD a lesser degree of systemic exposure to inhaled fluticasone propionate

has been observed.

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

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

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

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

The disposition of fluticasone propionate is characterised by high plasma clearance (1150ml/min), a

large volume of distribution at steady-state (approximately 300l) and a terminal half-life of

approximately 8 hours.

Plasma protein binding is 91%

.

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

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

Other unidentified metabolites are also found in the faeces.

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

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

unchanged drug.

5.3

Preclinical safety data

The only safety concerns for human use derived from animal studies of salmeterol xinafoate 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 xinafoate have shown

embryofoetal toxicity only at high exposure levels. Following co-administration, increased incidences

of transposed umbilical artery and incomplete ossification of occipital bone were found in rats at

doses associated with known glucocorticoid-induced abnormalities.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Lactose monohydrate

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

24 months

6.4

Special precautions for storage

Do not store above 25 °C.

6.5

Nature and contents of container

Plastic inhalation device containing an OPA/Al/PVC-Al blister with 60 pre-metered doses of powder

blend.

Pack sizes:

1, 2, 3, 4, 5, 6 or 10 devices containing 60 doses.

Not all pack sizes may be marketed.

6.6

Special precautions for disposal and other handling

Instructions for use:

Patients should be demonstrated how to use the Forspiro inhaler and correct use should be checked

regularly.

The inhaler contains 60 doses of powder medication in a coiled strip of foil. It has a dose counter

which indicates how many doses are left counting down from 60 to 0. When the last 10 doses have

been reached the numbers will be on a red background.

The inhaler is not refillable – it should be disposed of when it is empty and be replaced with a new

one.

Before using the inhaler

The transparent side chamber door should be opened.

The foil strip should be removed from the side chamber by carefully tearing away the full

length of strip against the ‘teeth’ of the side chamber as shown below.

The strip should

not be

pulled or tugged

The side chamber door should be closed and the used strip should be disposed of.

Note:

As the inhaler is used the side chamber will gradually fill up with used strip. The foil

strips with

black bars don’t contain medication

. Eventually the numbered sections of the

strip will appear in the side chamber.

There should never be more than 3 sections of foil

strip

in the side chamber as they may cause the inhaler to jam. The strip should be torn away

carefully as shown above, and disposed of safely.

Using the inhaler

The inhaler should be held in hands, as seen in the pictures.

1.

Open

The protective

cap should be opened downwards

to reveal the mouthpiece.

The dose counter should be checked to see how many doses are left.

2.

Preparation of the dose

The edge of the

white lever should be lifted up

. The side chamber should be closed.

Note

: The white lever should only be operated when the patient is ready to inhale a dose of

the medication. If the patient plays with the white lever he/she will waste doses.

Open:

white lever should be moved over fully

as far as it will go and

until it clicks

This action moves a new dose into position with the number at the top.

Close:

Afterwards the

white lever should be closed fully

so that it

clicks

back into its

original position. The inhaler is now ready for immediate use.

3.

Inhalation of the dose

Away from the inhaler mouthpiece, the patient should breathe out as much as is comfortable

.

It should

never be breathed directly into

the inhaler as this could affect the dose.

The inhaler should be hold level with the

protective cap pointing downwards

The lips should be closed firmly around the mouthpiece.

The patient should breathe in steadily and deeply through the inhaler, not through the nose.

The inhaler should be removed from the mouth and the

breath should be held for 5-

10 seconds

or as long as is possible without causing discomfort.

Afterwards, the patient should breathe out slowly,

but not into the inhaler

The protective cap should be closed over the mouthpiece.

The mouth should be rinsed with water, which should be spat out afterwards. This may help

to prevent getting fungal infection in the mouth and becoming hoarse.

Cleaning

The outside of the mouthpiece should be wiped with a clean, dry tissue if necessary.

The inhaler should not be taken apart to clean it or for any other purpose!

The inhaler parts must not be cleaned with water or wet wipes as dampness can affect the

dose!

Pins or other sharp objects must never be inserted into the mouthpiece, or any other part, as

this may damage the inhaler!

Any unused medicinal product or waste material should be disposed of in accordance with local

requirements

7.

MARKETING AUTHORISATION HOLDER

[To be completed nationally]

8.

MARKETING AUTHORISATION NUMBER(S)

[To be completed nationally]

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

2013-12-05

10.

DATE OF REVISION OF THE TEXT

2013-12-05

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