Gardette 160 mikrogram/4,5 mikrogram/inhalation Inhalationsspray, suspension

Sverige - svenska - Läkemedelsverket (Medical Products Agency)

Bipacksedel Bipacksedel (PIL)

24-05-2018

Produktens egenskaper Produktens egenskaper (SPC)

21-04-2018

Aktiva substanser:
budesonid; formoterolfumaratdihydrat
Tillgänglig från:
AstraZeneca AB
ATC-kod:
R03AK07
INN (International namn):
budesonide; formoterol
Dos:
160 mikrogram/4,5 mikrogram/inhalation
Läkemedelsform:
Inhalationsspray, suspension
Sammansättning:
budesonid 160 mikrog Aktiv substans; formoterolfumaratdihydrat 4,5 mikrog Aktiv substans
Receptbelagda typ:
Receptbelagt
Produktsammanfattning:
Förpacknings: Inhalator, 120 doser
Bemyndigande status:
Godkänd
Godkännandenummer:
51935
Tillstånd datum:
2016-02-18

Dokument på andra språk

Bipacksedel Bipacksedel - engelska

24-05-2018

Produktens egenskaper Produktens egenskaper - engelska

22-02-2021

Offentlig bedömningsrapport Offentlig bedömningsrapport - engelska

18-02-2016

Läs hela dokumentet

PACKAGE LEAFLET

Package leaflet: Information for the user

Gardette 160 micrograms /4.5 micrograms/actuation pressurised inhalation, suspension

Budesonide/Formoterol fumarate dihydrate

Read all of this leaflet carefully before you start using this medicine because it contains important

information for you.

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

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

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

their signs of illness are the same as yours.

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

listed in this leaflet. See section 4.

What is in this leaflet:

What Gardette is and what it is used for

What you need to know before you use Gardette

How to use Gardette

Possible side effects

How to store Gardette

Contents of the pack and other information

1.

What Gardette is and what it is used for

Gardette is an inhaler that is used to treat the symptoms of Chronic Obstructive Pulmonary Disease (COPD)

in adults aged 18 and older. COPD is a long-term disease of the airways in the lungs, which is often caused

by cigarette smoking. Gardette contains two different medicines: budesonide and formoterol fumarate

dihydrate.

Budesonide belongs to a group of medicines called ‘corticosteroids’. It works by reducing and

preventing swelling and inflammation in your lungs.

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

adrenoceptor

agonists’ or ‘bronchodilators’. It works by relaxing the muscles in your airways. This helps you to

breathe more easily.

Do not use this medicine as a “reliever” inhaler.

2.

What you need to know before you use Gardette

Do not use Gardette:

if you are allergic to budesonide, formoterol or any of the other ingredients of this medicine (listed in

section 6).

Warnings and precautions

Talk to your doctor or pharmacist before using Gardette if:

You are diabetic.

You have a lung infection.

You have high blood pressure or you have ever had a heart problem (including an uneven heart beat, a

very fast pulse, narrowing of the arteries or heart failure).

You have problems with your thyroid or adrenal glands.

You have low levels of potassium in your blood.

You have severe liver problems.

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

Children and adolescents

Gardette is not recommended for children and adolescents under 18 years.

Other medicines and Gardette

Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines.

In particular, tell your doctor or pharmacist if you are using any of the following medicines:

Beta-blocker medicines (such as atenolol or propranolol for high blood pressure), including eyedrops

(such as timolol for glaucoma).

Medicines for a fast or uneven heart beat (such as quinidine).

Medicines like digoxin, often used to treat heart failure.

Diuretics, also known as ‘water tablets’ (such as furosemide). These are used to treat high blood

pressure.

Steroid medicines that you take by mouth (such as prednisolone).

Xanthine medicines (such as theophylline or aminophylline). These are often used to treat COPD or

asthma.

Other bronchodilators (such as salbutamol).

Tricyclic anti-depressants (such as amitriptyline) and the anti-depressant nefazodone.

Phenothiazine medicines (such as chlorpromazine and prochlorperazine).

Medicines called ‘HIV-protease inhibitors’ (such as ritonavir) to treat HIV infection.

Medicines to treat infections (such as ketoconazole, itraconazole, voriconazole, posaconazole,

clarithromycin and telithromycin).

Medicines for Parkinson’s disease (such as leva-dopa).

Medicines for thyroid problems (such as levo-thyroxine).

If any of the above applies to you, or if you are not sure, talk to your doctor or pharmacist before using

Gardette.

Also tell your doctor or pharmacist if you are going to have a general anaesthetic for an operation or for

dental work.

Pregnancy, breast-feeding and fertility

If you are pregnant, or planning to get pregnant, talk to your doctor before using Gardette - do not use

Gardette unless your doctor tells you to.

If you get pregnant while using Gardette, do not stop using Gardette but talk to your doctor immediately.

If you are breast-feeding, talk to your doctor before using Gardette.

Driving and using machines

Gardette has no or negligible effect on your ability to drive or to use tools or machines.

3.

How to use Gardette

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

you are not sure.

It is important to use Gardette every day, even if you have no COPD symptoms at the time.

The usual dose is 2 inhalations twice a day. Gardette is not recommended for children or adolescents under

18 years of age.

If you have been taking steroid tablets for your COPD, your doctor may reduce the number of tablets that

you take, once you start to use Gardette. If you have been taking oral steroid tablets for a long time, your

doctor may want you to have blood tests from time to time. When reducing oral steroid tablets, you may feel

generally unwell even though your chest symptoms may be improving. You might experience symptoms

such as a stuffy or runny nose, weakness or joint or muscle pain and rash (eczema). If any of these symptoms

bother you, or if symptoms such as headache, tiredness, nausea (feeling sick) or vomiting (being sick) occur,

please contact your doctor immediately. You may need to take other medication if you develop allergic or

arthritic symptoms. You should speak to your doctor if you are concerned as to whether you should continue

to use Gardette.

Your doctor may consider adding steroid tablets to your usual treatment during periods of stress (for

example, when you have a chest infection or before an operation).

Important information about your COPD symptoms

If you feel you are getting breathless or wheezy while using Gardette, you should continue to use Gardette

but go to see your doctor as soon as possible, as you may need additional treatment.

Contact your doctor immediately if:

Your breathing is getting worse or you often wake up at night feeling breathless.

Your chest starts to feel tight in the morning or your chest tightness lasts longer than usual.

These signs could mean that your COPD is not being properly controlled and you may need different

or additional treatment immediately.

Your doctor may also prescribe other bronchodilator drugs, for example anticholinergics (such as tiotropium

or ipratropium bromide) for your COPD disease.

Information about your Gardette

Before starting to use your Gardette, remove it from the foil wrapper. Throw away the wrapper as well as

the drying agent which is inside the wrapper. If the drying agent has leaked out of its packet, do not use

the inhaler.

After you have taken the inhaler out of its foil wrapper, you should use it within 3 months. Write the use

by date (3 months from opening the wrapper) on the inhaler label to remind you when to stop using the

inhaler.

The parts of your inhaler are shown in the picture. The inhaler will already be assembled when you first

receive it. Do not take it apart. If the canister becomes loose, put it back in the inhaler and keep using the

inhaler.

Preparing your Gardette

You need to prepare your inhaler for use in the following situations:

If you are using your new Gardette for the first time.

If you have not used it for more than 7 days.

If it has been dropped.

To prepare your inhaler for use, follow the instructions below:

Shake the inhaler well for at least 5 seconds to mix the contents of the aerosol canister.

Remove the mouthpiece cover by pressing lightly on the bumps on the side. The strap on the mouthpiece

cover will stay attached to the inhaler.

Hold the inhaler upright. Then press the counter (on the top of the inhaler) to release a puff into the air.

You can use one or both hands, as shown in the pictures.

Release your finger(s) from the counter.

Wait for 10 seconds, shake well and then repeat steps 3 and 4.

Your inhaler is now ready for use.

How to take an inhalation

Each time you need to take an inhalation, follow the instructions below:

Shake the inhaler well for at least 5 seconds to mix the contents of the aerosol canister.

Remove the mouthpiece cover by pressing lightly on the bumps on the side. Check that the mouthpiece

is not blocked.

Hold your inhaler upright (using one or both hands). Breathe out gently.

Place the mouthpiece gently between your teeth. Close your lips.

Start to breathe in slowly and deeply through your mouth. Press the counter (on

the top of the inhaler) firmly to release a puff. Keep breathing in for a short

while after pressing the counter. Breathing in at the same time as pressing the

counter ensures that the medicine reaches your lungs.

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

Before you breathe out, release your finger from the counter and remove the inhaler from your mouth.

Keep the inhaler upright.

Then

breathe out slowly. To take another inhalation, shake the inhaler well for at least 5 seconds and

repeat steps 3 to 7.

Replace the mouthpiece cover.

Rinse your mouth with water after your daily morning and evening doses and spit it out.

Using a spacer device

Your doctor, nurse or pharmacist may suggest that you use a spacer device (e.g.

AeroChamber Plus Flow

Vu

AeroChamber Plus

). Follow the instructions in the leaflet that is packed with the spacer device.

Cleaning your Gardette

Wipe the inside and outside of the mouthpiece at least once a week with a dry tissue.

Do not use water or liquids and do not remove the canister from the inhaler.

How will I know when to replace my Gardette?

The counter on the top of your inhaler tells you how many puffs (actuations) are left in your Gardette. It

starts with 120 puffs when it is full.

Each time you take an inhalation, or release a puff into the air, the arrow counts down towards zero (‘0’).

When the arrow first enters the yellow area, this means that there are about 20 puffs left.

When the arrow reaches ‘0’, you must stop using your new Gardette. Your inhaler may not feel empty

and it may seem as though it still works. However, you will not get the right amount of medicine if you

keep using it.

If you use more Gardette than you should

If you use more Gardette than you should, contact your doctor or pharmacist for advice. The following

effects may happen: trembling, headache or a rapid heartbeat.

If you forget to use Gardette

If you forget to take a dose, take it as soon as you remember. However, if it is nearly time for your next

dose, skip the missed dose.

not

take a double dose to make up for a forgotten dose.

If you stop using Gardette

Before you stop using Gardette, you should talk to your doctor or your pharmacist. If you stop using

Gardette the signs and symptoms of COPD may worsen.

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.

If either of the following happens to you, stop using Gardette straightaway and talk to your doctor

immediately:

Swelling of your face, particularly around your mouth (tongue and/or throat and/or difficulty to swallow)

rash or hives together with difficulties to breathe (angioedema) and/or sudden feeling of faintness.

This may mean that you are having an allergic reaction. This happens rarely, affecting less than 1 in

1,000 people.

Sudden acute wheezing or shortness of breath immediately after using your inhaler. If either of these

symptoms occurs, stop using your Gardette straightaway and use your ‘reliever’ inhaler. Contact your

doctor immediately as you may need to have your treatment changed. This happens very rarely,

affecting less than 1 in 10,000 people.

Other possible side effects:

Common (may affect up to 1 in 10 people)

Palpitations (awareness of your heart beating), trembling or shaking. If these effects occur, they are

usually mild and usually disappear as you continue to use Gardette.

Thrush (a fungal infection) in the mouth. This is less likely if you rinse your mouth out with water after

using your Gardette.

Mild sore throat, coughing and a hoarse voice.

Headache.

Pneumonia (infection of the lung) in COPD patients.

Tell your doctor if you have any of the following while taking Gardette, they could be symptoms of a lung

infection:

Fever or chills.

Increased mucus production, change in mucus colour.

Increased cough or increased breathing difficulties.

Uncommon (may affect up to 1 in 100 people)

Feeling restless, nervous or agitated.

Disturbed sleep.

Feeling dizzy.

Nausea (feeling sick).

Fast heart beat.

Bruising of the skin.

Muscle cramps.

Blurred vision.

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

Rash, itching.

Bronchospasm (tightening of the muscles in the airways which causes wheezing). If the wheezing comes

on suddenly after using Gardette stop using Gardette and talk to your doctor immediately.

Low levels of potassium in your blood.

Uneven heart beat.

Very rare (may affect up to 1 in 10,000 people)

Depression.

Changes in behaviour, especially in children.

Chest pain or tightness in the chest (angina pectoris).

An increase in the amount of sugar (glucose) in your blood.

Taste changes, such as an unpleasant taste in the mouth.

Changes in your blood pressure.

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

use high doses for a long time. The effects include:

changes in bone mineral density (thinning of the bones)

cataract (clouding of the lens in the eye)

glaucoma (increased pressure in the eye)

a slowing of the rate of growth of children and adolescents.

an effect on the adrenal gland (a small gland next to the kidney).

These effects are much less likely to happen with inhaled corticosteroids than with corticosteroid tablets.

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 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 Gardette

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

Do not use this medicine after the expiry date which is stated on the label, carton and foil wrapper after

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

As with most inhaled medicines in pressurised canisters, the effect of this medicine may decrease when

the canister is cold. For best results, this medicine should be at room temperature before use. Do not

refrigerate or freeze. Protect from frost and direct sunlight.

After you have taken the inhaler out of its foil wrapper, you should use it within 3 months. Write the use

by date (3 months from opening the wrapper) on the inhaler label to remind you when to stop using the

inhaler.

Always replace the mouthpiece cover firmly and snap into position after using your inhaler.

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.

Warning:

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

not pierce the canister. The canister should not be broken, punctured or burnt, even when it seems empty.

6.

Contents of the pack and other information

What Gardette contains

The active substances are budesonide and formoterol fumarate dihydrate. Each puff (actuation) contains 160

micrograms of budesonide and 4.5 micrograms of formoterol fumarate dihydrate.

The other ingredients are apaflurane (HFA 227), povidone and macrogol. This is a CFC-free inhaler.

What Gardette looks like and contents of the pack

Gardette is an inhaler containing your medicine. The pressurised canister, with attached dose indicator,

contains a white suspension for inhalation. The canister is fitted into a red plastic actuator with a white

plastic mouthpiece and an integrated grey plastic dust cap. Each inhaler contains 120 puffs (actuations) after

it has been prepared for use. Each inhaler is individually packed in a foil wrapper containing a drying agent.

Gardette, 160 micrograms/4.5 micrograms/actuation pressurised inhalation, suspension

(Budesonide/Formoterol fumarate dihydrate) is available in packs of one inhaler.

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:

Country

Trade name and strength

Spain

Rilast 160 microgramos /4,5 microgramos/inhalación suspensión para

inhalación en envase a presión

Sweden

Gardette 160 mikrogram /4.5 mikrogram/inhalation

This leaflet was last revised in 2018-05-24

[To be completed nationally]

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ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT

Gardette, 160 micrograms/4.5 micrograms/actuation pressurised inhalation, suspension

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each delivered dose (ex-actuator) contains: budesonide 160 micrograms/actuation and formoterol fumarate

dihydrate 4.5 micrograms/actuation.

This is equivalent to a metered dose containing budesonide 200 micrograms/actuation and formoterol

fumarate dihydrate 6 micrograms/actuation.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Pressurised inhalation, suspension.

White suspension in an aluminium canister fitted into a red actuator with a grey dust cap.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Chronic Obstructive Pulmonary Disease (COPD)

Gardette is indicated in adults, aged 18 and older, for the symptomatic treatment of patients with COPD with

forced expiratory volume in 1 second (FEV

<70% predicted normal (post-bronchodilator) and an

exacerbation history despite regular bronchodilator therapy (see also section 4.4).

4.2

Posology and method of administration

Route of administration: Inhalation use.

COPD

Recommended dose:

Adults:

2 actuations twice daily.

General information

Special patient groups:

There are no special dosing requirements for elderly patients. There are no data available for use of Gardette

in patients with hepatic or renal impairment. As budesonide and formoterol are primarily eliminated via

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

Paediatric Population:

There is no relevant use of Gardette 160 micrograms /4.5 micrograms in children 11 years of age and under

or in adolescents 12 to 17 years of age in the symptomatic treatment of COPD.

Instructions for the correct use of Gardette

On actuation of Gardette, a volume of the suspension is expelled from the canister at high velocity. When the

patient inhales through the mouthpiece at the same time as actuating the inhaler, the substance will follow

the inspired air into the airways.

Use of a spacer device (e.g.

AeroChamber Plus Flow Vu or AeroChamber Plus

) with Gardette (pressurised

inhalation, suspension) is usually recommended, specially in patients who have, or are likely to have,

difficulties to coordinate actuation with inhalation (see section 5.2).

Note:

Patients should be instructed on the correct use and care of their inhaler and spacer, and their

inhalation technique checked to ensure optimum delivery of inhaled drugs to the lungs. It is important to

instruct the patient to:

Carefully read the instructions for use in the patient information leaflet which is packed together

with each inhaler.

If a spacer is to be used, carefully read the instructions for use in the instruction leaflet, which is

packed with each spacer device.

If the drying agent, which is inside the wrapper, has leaked out of its packet, do not use the inhaler.

Shake the inhaler well for at least 5 seconds prior to each use to mix its contents properly.

Prime the inhaler by actuating it twice into the air when the inhaler is new, has not been used for

more than one week or if it has been dropped.

Remove the mouthpiece cover.

Hold the inhaler upright.

Place the mouthpiece in the mouth. While breathing in slowly and deeply, press the device firmly to

release the medication. Continue to breathe in and hold the breath for approximately 10 seconds or

as long as is comfortable. Inhaling at the same time as actuating the inhaler ensures that active

substances reach the lungs.

Shake the inhaler again and repeat.

Replace the mouthpiece cover after use.

Rinse the mouth with water after inhaling the prescribed dose to minimise the risk of oropharyngeal

thrush.

Clean the mouthpiece of the inhaler regularly, at least once a week with a clean dry cloth.

Do not put the inhaler into 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

Dosing advice

Patients should be advised to have their rescue inhaler available at all times.

Patients should be reminded to take their Gardette maintenance dose as prescribed, even when

asymptomatic.

To minimise the risk of oropharyngeal candida infection (see section 4.8), the patient should be instructed to

rinse their mouth out with water after inhaling the dose.

It is recommended that treatment with Gardette is not stopped without supervision by a physician.

Deterioration of disease

If patients find the treatment ineffective, medical attention must be sought. Sudden and progressive

deterioration in control of COPD is potentially life threatening and the patient should undergo urgent medical

assessment. In this situation consideration should be given to the need for increased therapy with

corticosteroids, e.g. a course of oral corticosteroids, or antibiotic treatment if an infection is present.

Transfer from oral therapy

If there is any reason to suppose that adrenal function is impaired from previous systemic steroid therapy,

care should be taken when transferring patients to Gardette

therapy.

The benefits of inhaled budesonide therapy would normally minimise the need for oral steroids, but patients

transferring from oral steroids may remain at risk of impaired adrenal reserve for a considerable time.

Recovery may take a considerable amount of time after cessation of oral steroid therapy and hence oral

steroid-dependent patients transferred to inhaled budesonide may remain at risk from impaired adrenal

function for some considerable time. In such circumstances, HPA axis function should be monitored

regularly.

During transfer from oral therapy to Gardette, a generally lower systemic steroid action will be experienced

which may result in the appearance of allergic or arthritic symptoms such as rhinitis, eczema and muscle and

joint pain. Specific treatment should be initiated for these conditions. A general insufficient

glucocorticosteroid effect should be suspected if, in rare cases, symptoms such as tiredness, headache,

nausea and vomiting should occur. In these cases, a temporary increase in the dose of oral

glucocorticosteroids is sometimes necessary.

Interactions with other medicinal products

Concomitant treatment with itraconazole, ritonavir or other potent CYP3A4 inhibitors should be avoided

(see section 4.5). If this is not possible the time interval between administration of the interacting drugs

should be as long as possible.

Caution with special diseases

Gardette should be administered with caution in patients with thyrotoxicosis, phaeochromocytoma, diabetes

mellitus, untreated hypokalaemia, hypertrophic obstructive cardiomyopathy, idiopathic subvalvular aortic

stenosis, severe hypertension, aneurysm or other severe cardiovascular disorders, such as ischaemic heart

disease, tachyarrhythmias or severe heart failure.

Caution should be observed when treating patients with prolongation of the QTc-interval. Formoterol itself

may induce prolongation of the QTc-interval.

Potentially serious hypokalaemia may result from high doses of beta

adrenoceptor agonists. Concomitant

treatment of β

adrenoceptor agonists with drugs which can induce hypokalaemia or potentiate a

hypokalaemic effect, e.g. xanthine derivatives, steroids and diuretics, may add to a possible hypokalaemic

effect of the β

adrenoceptor agonist. It is recommended that serum potassium levels are monitored during

these circumstances.

As for all β

adrenoceptor agonists, additional blood glucose controls should be considered in diabetic

patients.

The need for inhaled corticosteroids should be re-evaluated in patients with active or quiescent pulmonary

tuberculosis, fungal and viral infections in the airways.

Systemic effects

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

periods. These effects are much less likely to occur with inhalation treatment than with oral corticosteroids.

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

retardation in children and adolescents, decrease in bone mineral density, cataract 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 section 4.8).

Potential effects on bone density should be considered particularly in patients on high doses for prolonged

periods that have coexisting risk factors for osteoporosis. Long-term studies with inhaled budesonide in

children at mean daily doses of 400 micrograms (metered dose) or in adults at daily doses of 800 micrograms

(metered dose) have not shown any significant effects on bone mineral density. No information regarding the

effect of Gardette

at higher doses is available.

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.

Adrenal function

Treatment with supplementary systemic steroids should not be stopped abruptly.

The prolonged treatment with high doses of inhaled corticosteroids, particularly higher than recommended

doses, may also result in clinically significant adrenal suppression. Therefore, additional systemic

corticosteroid cover should be considered during periods of stress such as severe infections or elective

surgery. Rapid reduction in the dose of steroids can induce acute adrenal crisis. Symptoms and signs which

might be seen in acute adrenal crisis may be somewhat vague but may include anorexia, abdominal pain,

weight loss, tiredness, headache, nausea, vomiting, decreased level of consciousness, seizures, hypotension

and hypoglycaemia.

Paradoxical bronchospasm

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

wheezing and shortness of breath, after dosing. If the patient experiences paradoxical bronchospasm Gardette

should be discontinued immediately, the patient should be assessed and an alternative therapy instituted, if

necessary. Paradoxical bronchospasm responds to a rapid-acting inhaled bronchodilator and should be

treated straightaway (see section 4.8).

COPD population

There are no clinical study data on Gardette available in COPD patients with a pre-bronchodilator

>50% predicted normal and with a post-bronchodilator FEV

<70% predicted normal (see section 5.1).

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

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

risk of pneumonia with increasing steroid dose but this has not been demonstrated conclusively across all

studies.

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

among inhaled corticosteroid products.

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

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

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

(BMI) and severe COPD.

4.5

Interaction with other medicinal products and other forms of interaction

Pharmacokinetic interactions

Potent inhibitors of CYP3A4 (e.g. ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin,

telithromycin, nefazodone and HIV protease inhibitors) are likely to markedly increase plasma levels of

budesonide and concomitant use should be avoided. If this is not possible the time interval between

administration of the inhibitor and budesonide should be as long as possible (see section 4.4).

The potent CYP3A4 inhibitor ketoconazole, 200 mg once daily, increased plasma levels of concomitantly

orally administered budesonide (single dose of 3 mg) on average six-fold. When ketoconazole was

administered 12 hours after budesonide the concentration was on average increased only three-fold showing

that separation of the administration times can reduce the increase in plasma levels. Limited data about this

interaction for high-dose inhaled budesonide indicates that marked increase in plasma levels (on average

four-fold) may occur if itraconazole, 200 mg once daily, is administered concomitantly with inhaled

budesonide (single dose of 1000 μg).

Pharmacodynamic interactions

Beta-adrenergic blockers can weaken or inhibit the effect of formoterol. Gardette should therefore not be

given together with beta-adrenergic blockers (including eye drops) unless there are compelling reasons.

Concomitant treatment with quinidine, disopyramide, procainamide, phenothiazines and tricyclic

antidepressants can prolong the QTc-interval and increase the risk of ventricular arrhythmias.

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

sympathomimetics.

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

furazolidone and procarbazine may precipitate hypertensive reactions.

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

hydrocarbons.

Concomitant use of other beta-adrenergic drugs or anticholinergic drugs can have a potentially additive

bronchodilating effect.

Hypokalaemia may increase the disposition towards arrhythmias in patients who are treated with digitalis

glycosides.

4.6

Fertility, pregnancy and lactation

Pregnancy

For Gardette

or the concomitant treatment with formoterol and budesonide, no clinical data on exposed

pregnancies are available. Data from an embryo-foetal development study in the rat showed no evidence of

any additional effect from the combination.

There are no adequate data from use of formoterol in pregnant women. In animal studies, formoterol has

caused adverse effects in reproduction studies at very high systemic exposure levels (see section 5.3).

Data on approximately 2000 exposed pregnancies indicate no increased teratogenic risk associated with the

use of inhaled budesonide. In animal studies, glucocorticosteroids have been shown to induce malformations

(see section 5.3). This is not likely to be relevant for humans given recommended doses.

Animal studies have also identified an involvement of excess prenatal glucocorticoids in increased risks for

intrauterine growth retardation, adult cardiovascular disease and permanent changes in glucocorticoid

receptor density, neurotransmitter turnover and behaviour at exposures below the teratogenic dose range.

During pregnancy, Gardette

should only be used when the benefits outweigh the potential risks.

Breastfeeding

Budesonide is excreted in breast milk. However, at therapeutic doses no effects on the suckling child are

anticipated. It is not known whether formoterol passes into human breast milk. In rats, small amounts of

formoterol have been detected in maternal milk. Administration of Gardette

to women who are breastfeeding

should only be considered if the expected benefit to the mother is greater than any possible risk to the child.

Fertility

There is no data available on the potential effect of budesonide on fertility. Animal reproduction studies with

formoterol have shown a somewhat reduced fertility in male rats at high systemic exposure (see section 5.3).

4.7

Effects on ability to drive and use machines

Gardette

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

4.8

Undesirable effects

Since Gardette

contains both budesonide and formoterol, the same pattern of undesirable effects as reported

for these substances may occur. No increased incidence of adverse reactions has been seen following

concurrent administration of the two compounds. The most common drug related adverse reactions are

pharmacologically predictable side-effects of β

adrenoceptor agonist therapy, such as tremor and

palpitations. These tend to be mild and usually disappear within a few days of treatment.

Adverse reactions, which have been associated with budesonide or formoterol, 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 <1/1000) and very rare (<1/10 000).

Table 1

SOC

Frequency

Adverse Drug Reaction

Infections and infestations

Common

Candida infections in the oropharynx

Pneumonia (in COPD patients)

Immune system disorders

Rare

Immediate and delayed hypersensitivity reactions,

e.g. exanthema, urticaria, pruritus, dermatitis,

angioedema and anaphylactic reaction

Endocrine disorders

Very rare

Cushing’s syndrome, adrenal suppression, growth

retardation, decrease in bone mineral density

Rare

Hypokalaemia

Metabolism and nutrition

disorders

Very rare

Hyperglycaemia

Uncommon

Aggression, psychomotor hyperactivity, anxiety,

sleep disorders

Psychiatric disorders

Very rare

Depression, behavioural changes (predominantly

in children)

Common

Headache, tremor

Uncommon

Dizziness

Nervous system disorders

Very rare

Taste disturbances

Uncommon

Vision blurred (see also section 4.4)

Eye disorders

Very rare

Cataract and glaucoma

Common

Palpitations

Uncommon

Tachycardia

Rare

Cardiac arrhythmias, e.g. atrial fibrillation,

supraventricular tachycardia, extrasystoles

Cardiac disorders

Very rare

Angina pectoris, prolongation of QTc-interval

Vascular disorders

Very rare

Variations in blood pressure

Common

Mild irritation in the throat, coughing, dysphonia

including hoarseness

Respiratory, thoracic and

mediastinal disorders

Rare

Bronchospasm

Gastrointestinal disorders

Uncommon

Nausea

Skin and subcutaneous

tissue disorders

Uncommon

Bruises

Musculoskeletal and

connective tissue disorders

Uncommon

Muscle cramps

Candida infection in the oropharynx is due to drug deposition. Advising the patient to rinse the mouth out

with water after each dose will minimise the risk. Oropharyngeal Candida infection usually responds to

topical anti-fungal treatment without the need to discontinue the inhaled corticosteroid.

As with other inhalation therapy, paradoxical bronchospasm may occur very rarely, affecting less than 1 in

10,000 people, with an immediate increase in wheezing and shortness of breath after dosing. Paradoxical

bronchospasm responds to a rapid-acting inhaled bronchodilator and should be treated straightaway. Gardette

should be discontinued immediately, the patient should be assessed and an alternative therapy instituted if

necessary (see section 4.4).

Systemic effects of inhaled corticosteroids may occur, particularly at high doses prescribed for prolonged

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

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

adolescents, decrease in bone mineral density, cataract and glaucoma. Increased susceptibility to infections

and impairment of the ability to adapt to stress may also occur. Effects are probably dependent on dose,

exposure time, concomitant and previous steroid exposure and individual sensitivity.

Treatment with β

adrenoceptor agonists may result in an increase in blood levels of insulin, free fatty acids,

glycerol and ketone bodies.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows

continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked

to report any suspected adverse reactions via the national reporting system listed in Appendix V.

4.9

Overdose

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

adrenoceptor agonists: tremor,

headache, palpitations. Symptoms reported from isolated cases are tachycardia, hyperglycaemia,

hypokalaemia, prolonged QTc-interval, arrhythmia, nausea and vomiting. Supportive and symptomatic

treatment may be indicated. A dose of 90 micrograms of formoterol administered during three hours in

patients with acute bronchial obstruction raised no safety concerns.

Acute overdosage with budesonide, even in excessive doses, is not expected to be a clinical problem. When

used chronically in excessive doses, systemic glucocorticosteroid effects, such as hypercorticism and adrenal

suppression, may appear.

If Gardette

therapy has to be withdrawn due to overdose of the formoterol component of the drug, provision

of appropriate inhaled corticosteroid therapy must be considered.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Drugs for obstructive airway diseases: Adrenergics, Inhalants.

ATC-code: R03AK07

Mechanisms of action and Pharmacodynamic effects

Gardette contains formoterol and budesonide, which have different modes of action and show additive

effects in terms of reduction of COPD exacerbations.

Budesonide

Budesonide is a glucocorticosteroid which when inhaled has a dose-dependent anti-inflammatory action in

the airways, resulting in reduced symptoms and fewer COPD exacerbations. Inhaled budesonide has less

severe adverse effects than systemic corticosteroids. The exact mechanism responsible for the anti-

inflammatory effect of glucocorticosteroids is unknown.

Formoterol

Formoterol is a selective β

-adrenoceptor agonist which when inhaled results in rapid and long-acting

relaxation of bronchial smooth muscle in patients with airway obstruction. The bronchodilating effect is dose

dependant, with an onset of effect within 1-3 minutes. The duration of effect is at least 12 hours after a single

dose.

Clinical efficacy and safety

The efficacy and safety of Gardette 160 micrograms /4.5 micrograms in the symptomatic treatment of

patients with COPD has been evaluated in two 12-month studies (Studies 001 and 003) and one 6-month

study (Study 002). Gardette 160 micrograms /4.5 micrograms, 2 inhalations twice daily, was compared with

the corresponding dose of formoterol fumarate dihydrate (4.5 µg, 2 inhalations twice daily) in Studies 001,

002 and 003 and the corresponding dose of budesonide (160 µg, 2 inhalations twice daily) in Study 002.

The primary endpoints were pre-dose FEV

and 1-hour post dose FEV

(Study 001 and 002) and COPD

exacerbations (Study 003). A total of 4887 patients with moderate to severe COPD were randomised into the

3 trials of which 1178 were on Gardette 160 micrograms /4.5 micrograms. The inclusion criteria for all three

studies was pre-bronchodilator FEV

<50% predicted normal. Median post-bronchodilator FEV

at screening

in the trials was 39% predicted normal.

In Studies 001 and 002, Gardette 160 micrograms /4.5 micrograms was superior to placebo for post-dose

(180 mL and 170 mL mean increase, respectively) and pre-dose (through) FEV

(90 mL and 80 mL

mean increase, respectively).

In Studies 001 and 002, Gardette 160 micrograms /4.5 micrograms was also superior to formoterol for post-

dose FEV

(30 mL and 40 mL mean increase, respectively) and pre-dose (through) FEV

(40 mL and 40 mL

mean increase, respectively).

In the 12-month study (001), Gardette 160 micrograms /4.5 micrograms resulted in statistically significant

and clinically meaningful reductions in severe exacerbations (defined as a worsening of COPD requiring oral

steroid use and/or hospitalisation), with a 37% reduction in exacerbation rate (p<0.001) compared with

placebo and a 25% reduction in exacerbation rate (p=0.004) compared with formoterol. Gardette

significantly reduced the risk of first severe exacerbation by 34% compared to placebo (p<0.001) and by

23% compared to formoterol (p=0.015).

Gardette 160 micrograms /4.5 micrograms also significantly reduced breathlessness, daily rescue medication

use, night-time awakenings and improved health-related quality of life (as measured by St. George’s

Respiratory Questionnaire total score) compared with placebo in both studies.

Serial FEV

measures over 12 hours were obtained in subsets of patients in both Studies 001 and 002. The

median time to onset of bronchodilation (>15% improvement in FEV

) was seen at 5 minutes in patients

receiving Gardette 160 micrograms /4.5 micrograms. Maximal improvement in FEV

occurred at

approximately 2 hours post-dose and post-dose bronchodilator effect was generally maintained over 12

hours.

In a second 12-month study (003), Gardette 160 micrograms /4.5 micrograms resulted in statistically

significant reductions in the severe exacerbations compared with formoterol, with a 35% reduction in

number of exacerbations (P<0.001) and a 21% reduction in the risk of first exacerbation (p=0.026).

The treatment was well tolerated. Evaluation of safety in the 3 trials revealed a safety profile for Gardette

that was consistent with the established profiles for Gardette Turbuhaler and the inhaled budesonide and

formoterol monoproducts.

Paediatric population

There is no relevant use of Gardette 160 micrograms /4.5 micrograms in children or adolescents in the

symptomatic treatment of COPD.

5.2

Pharmacokinetic properties

Absorption

Following administration of Gardette (pressurised inhalation, suspension) 160 micrograms /4.5 micrograms

(two or four inhalations twice daily) for 5 days in healthy subjects, plasma concentration of budesonide

generally increased in proportion to dose. The accumulation index for the group that received two inhalations

twice daily was 1.32 for budesonide and 1.77 for formoterol.

In a single-dose study, 12 inhalations of Gardette (pressurised inhalation, suspension) 80 micrograms /4.5

micrograms (total dose 960/54 µg) were administered to patients with COPD. Mean budesonide peak plasma

concentration of 3.3 nmol/L occurred at 30 minutes following dosing whilst mean peak formoterol plasma

concentration of 167 pmol/L was rapidly achieved at 15 minutes after dosing.

In a single-dose study, 8 inhalations of Gardette (pressurised inhalation, suspension) 160 micrograms /4.5

micrograms (total dose 1280/36 µg) and Gardette Turbuhaler 160 micrograms /4.5 micrograms (total dose

1280/36 µg) were administered to healthy volunteers. Gardette (pressurised inhalation, suspension) delivered

a comparable amount of active drug to the systemic circulation as Gardette Turbuhaler. The AUC for the

budesonide component in Gardette (pressurised inhalation, suspension) was 90% of the Turbuhaler

comparator. The AUC for the formoterol component in Gardette (pressurised inhalation, suspension) was

116% of the Turbuhaler comparator.

The systemic exposure to budesonide and formoterol from Gardette (pressurised inhalation, suspension)

160 micrograms /4.5 micrograms with and without the

AeroChamber Plus Flow Vu

spacer device was

evaluated in a study conducted in healthy volunteers.

The total systemic exposure of Gardette (pressurised inhalation, suspension) administered through the

AeroChamber Plus Flow Vu

spacer was increased compared to no spacer, with mean AUC being 68% and

77% higher for budesonide and formoterol, respectively. However, the highest increases in exposure with

spacer were observed in subjects showing low exposure without spacer (most probably due to poor

inhalation technique).

There is no evidence of pharmacokinetic interactions between budesonide and formoterol.

Distribution and biotransformation

Plasma protein binding is approximately 50% for formoterol and 90% for budesonide. Volume of

distribution is about 4 l/kg for formoterol and 3 l/kg for budesonide. Formoterol is inactivated via

conjugation reactions (active O-demethylated and deformylated metabolites are formed, but they are seen

mainly as inactivated conjugates). Budesonide undergoes an extensive degree (approximately 90%) of

biotransformation on first passage through the liver to metabolites of low glucocorticosteroid activity. The

glucocorticosteroid activity of the major metabolites, 6-beta-hydroxy-budesonide and

16-alfa-hydroxy-prednisolone, is less than 1% of that of budesonide. There are no indications of any

metabolic interactions or any displacement reactions between formoterol and budesonide.

Elimination

The major part of a dose of formoterol is transformed by liver metabolism followed by renal elimination.

After inhalation, 8% to 13% of the delivered dose of formoterol is excreted unmetabolised in the urine.

Formoterol has a high systemic clearance (approximately 1.4 l/min) and the terminal elimination half-life

averages 17 hours.

Budesonide is eliminated via metabolism mainly catalysed by the enzyme CYP3A4. The metabolites of

budesonide are eliminated in urine as such or in conjugated form. Only negligible amounts of unchanged

budesonide have been detected in the urine. Budesonide has a high systemic clearance (approximately

1.2 l/min) and the plasma elimination half-life after i.v. dosing averages 4 hours.

The pharmacokinetics of budesonide or formoterol in patients with renal failure is unknown. The exposure of

budesonide and formoterol may be increased in patients with liver disease.

Linearity/non-linearity

Systemic exposure for both budesonide and formoterol correlates in a linear fashion to administered dose.

5.3

Preclinical safety data

The toxicity observed in animal studies with budesonide and formoterol, given in combination or separately,

were effects associated with exaggerated pharmacological activity.

In animal reproduction studies, corticosteroids such as budesonide have been shown to induce malformations

(cleft palate, skeletal malformations). However, these animal experimental results do not seem to be relevant

in humans at the recommended doses. Animal reproduction studies with formoterol have shown a somewhat

reduced fertility in male rats at high systemic exposure and implantation losses as well as decreased early

postnatal survival and birth weight at considerably higher systemic exposures than those reached during

clinical use. However, these animal experimental results do not seem to be relevant in humans.

Pre-clinical data on the CFC-free propellant HFA 227 reveal no special hazard for humans based on

conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and

toxicity to reproduction and development.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Apaflurane (HFA 227)

Povidone

Macrogol 1000

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

The shelf life for Gardette

as packaged for sale is 2 years. The shelf life after first opening is 3 months.

6.4

Special precautions for storage

For best results, this medicine should be at room temperature before use. Do not refrigerate or freeze. Protect

from frost and direct sunlight.

Replace the mouthpiece cover firmly and snap into position after use.

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

product decreases when the container is cold. This medicine should be at room temperature before use. The

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

canister. The canister should not be broken, punctured or burnt, even when it seems empty.

6.5

Nature and contents of container

A pressurised container comprising an internally coated aluminium can, sealed with a metering valve and

attached to a dose indicator. The can is fitted into a red plastic actuator incorporating a white plastic

mouthpiece and integrated grey plastic dust cap. Each inhaler delivers 120 actuations of

budesonide/formoterol fumarate dihydrate 160/4.5 micrograms after initial priming. Each inhaler is

individually wrapped in a foil laminate pouch containing a desiccant.

6.6

Special precautions for disposal

No special requirements.

7.

MARKETING AUTHORISATION HOLDER

[To be completed nationally]

For Sweden (RMS):

AstraZeneca AB

151 85 Södertälje

Sweden

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

2021-02-19

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