Consumer medicine information

Atectura Breezhaler 125/62.5, 125/127.5, 125/260 Micrograms

Indacaterol; Mometasone furoate

BRAND INFORMATION

Brand name

Atectura Breezhaler

Active ingredient

Indacaterol; Mometasone furoate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Atectura Breezhaler 125/62.5, 125/127.5, 125/260 Micrograms.

What is in this leaflet

This leaflet answers some common questions about ATECTURA BREEZHALER.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking ATECTURA BREEZHALER against the benefits they expect it will have for you.

The information in this leaflet was last updated on the date listed on the final page. More recent information on the medicine may be available.

You should ensure that you speak to your pharmacist or doctor to obtain the most up to date information on the medicine.

You can also download the most up to date leaflet from www.novartis.com.au Those updates may contain important information about the medicine and its use of which you should be aware.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What ATECTURA Breezhaler is used for

Your doctor has prescribed this medicine to treat asthma in adults and adolescents 12 years of age and older.

Asthma is a serious, long-term lung disease where the muscles surrounding the smaller airways become tight (bronchoconstriction), swollen and irritated (inflammation). Symptoms come and go, and include shortness of breath, wheezing, chest tightness and cough.

Atectura capsules for inhalation contains two active substances called indacaterol and mometasone furoate.

Indacaterol belong to a group of medicines called bronchodilators. They relax the muscles of the small airways in the lungs. This helps to open the airways and makes it easier for air to get in and out of the lungs. When they are taken regularly, it helps the small airways to remain open.

Mometasone furoate belongs to a group of medicines called corticosteroids, often simply called steroids. Corticosteroids reduce inflammation. They reduce the swelling and irritation in the small airways in the lungs and so gradually ease breathing problems. Corticosteroids also help to prevent attacks of asthma.

The pack contains an inhaler (Breezhaler®) and capsules in blister cards that contain the medicine as inhalation powder. The inhaler enables you to inhale (breathe into the lungs) the medicine contained in a capsule. Only use the inhaler provided in the pack.

You should use ATECTURA BREEZHALER every day as directed by your doctor and not only when you have breathing problems or other symptoms of asthma. This will make sure that it works properly in controlling your asthma. It should not be used to relieve a sudden attack of breathlessness or wheezing.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

This medicine is not addictive.

This medicine is available only with a doctor's prescription.

Before you use ATECTURA Breezhaler

When you must not use it

Do not use ATECTURA BREEZHALER if you have an allergy (hypersensitive) to:

  • lactose or milk protein
  • indacaterol, mometasone furoate, or any other ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin

Do not give this medicine to a child under the age of 12 years. Safety and effectiveness in children younger than 12 years have not been established.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to use it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any of the following medical conditions:

  • heart problems, including an irregular or fast heart beat
  • thyroid gland problems
  • diabetes or high blood sugar
  • suffer from seizures or fits
  • low potassium in your blood
  • severe liver problems
  • tuberculosis (TB) of the lung, or any long standing or untreated infections

Tell your doctor if you are pregnant or plan to become pregnant or are breast-feeding. Your doctor can discuss with you the risks and benefits involved.

ATECTURA Breezhaler should only be used during pregnancy if the expected benefit to the patient justifies the potential risk to the fetus.

It is not known whether the active ingredients passes into breast milk. If you are breast-feeding, your doctor will help you decide whether you can use ATECTURA Breezhaler.

If you have not told your doctor about any of the above, tell him/ her before you start taking ATECTURA BREEZHALER.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and Atectura may interfere with each other. These include:

  • medicines to treat depression (e.g. tricyclic antidepressants, monoamine oxidase inhibitors)
  • medicines similar to ATECTURA Breezhaler (contain similar active substances); these medicines may increase the risk of experiencing possible side effects
  • medicines that decrease the level of potassium in your blood such as diuretics (also known as “water tablets” and used to treat high blood pressure, e.g. hydrochlorothiazide), other bronchodilators such as methylxanthines for breathing problems (e.g. theophylline) or steroids (e.g. prednisolone)
  • medicine to treat high blood pressure or other heart problems (e.g. propranolol) or to treat glaucoma (e.g. timolol)
  • medicine to treat fungal infections (e.g., ketoconazole or itraconazole)
  • medicine to treat HIV infection (e.g., ritonavir, nelfinavir or cobicistat)

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

How to inhale ATECTURA Breezhaler

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions in the user leaflet, ask your doctor or pharmacist for help.

How much to inhale

There are three dose strengths of ATECTURA Breezhaler, 125/62.5 micrograms, 125/127.5 micrograms and 125/260 micrograms. Your doctor will decide which dose strength is appropriate for you.

The usual dose is to inhale the content of one capsule each day. You only need to use this medicine once a day because its effect lasts for 24 hours. Do not use more than your doctor tells you to use.

You should inhale the content of one capsule of ATECTURA Breezhaler every day and continue to use it even when you are not experiencing asthma symptoms.

How to use the Breezhaler

Carefully read the full Instructions for use provided in the package leaflet before use.

Only use the capsules with the inhaler provided in the pack. The capsules should remain in the blister until you need to use them.

Peel the backing away from the blister to open it, do not push the capsule through the foil.

Do not swallow the capsules.

Ensure you rinse your mouth out with water after each use.

Make sure you understand how to use the Breezhaler properly. If you are not sure, ask your doctor or pharmacist.

When to use it

Inhale ATECTURA Breezhaler at the same time each day. This will help minimize your symptoms throughout the day and night. It will also help you remember to use your medicine.

How long to use it

Keep using ATECTURA Breezhaler for as long as your doctor tells you.

Don’t stop unless your doctor advises you to, even if you feel better, as your symptoms may get worse.

This medicine helps to control your condition, but does not cure it. Your asthma symptoms may come back if you stop using this medicine.

If you have questions about how long to continue your treatment with ATECTURA Breezhaler, talk to your doctor or your pharmacist.

If you forget to take it

If you forget to inhale a dose, inhale the dose as soon as possible. Then inhale the next dose at the usual time. However, do not inhale two doses on the same day. This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take use much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much Atectura. Do this even if there are no signs of discomfort or poisoning.

While you are using ATECTURA Breezhaler

Things you must do

Only use the inhaler contained in the pack.

Always use this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking ATECTURA Breezhaler.

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine.

If you become pregnant while taking this medicine, tell your doctor immediately.

Keep all of your doctor's appointments so that your progress can be checked.

Stop taking ATECTURA Breezhaler and seek medical help immediately if you experience any of the following:

  • tightness of the chest, coughing, wheezing or breathlessness immediately after inhalation of Atectura Breezhaler (signs of paradoxical bronchospasm).
  • difficulty breathing or swallowing, swelling of the tongue, lips or face, skin rash, itching and hives (signs of allergic reaction and angioedema).

Things you must not do

Do not use ATECTURA Breezhaler to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Do not stop taking your medicine or lower the dosage without checking with your doctor.

Things to be careful of

Be careful driving or operating machinery until you know how ATECTURA Breezhaler affects you.

Side effects

As with all medicines, patients using ATECTURA Breezhaler may experience side effects, although not everybody gets them.

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking ATECTURA Breezhaler.

This medicine helps most people with asthma, but it may have unwanted side effects in a few people. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Common side effects

  • voice alteration (hoarseness)
  • headache
  • pain in muscles, bones or joints (signs of musculoskeletal pain)
  • sore throat

The above list may affect up to 1 in every 10 people.

Uncommon side effects

  • fast heart beat
  • oral thrush (signs of candidiasis)
  • high level of sugar in the blood
  • muscle spasm
  • skin itching
  • rash

The above list may affect up to 1 in every 100 people.

If these side effects become severe, tell your doctor or pharmacist.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people.

After using ATECTURA Breezhaler

Cleaning and Storage

Follow the instructions in the user leaflet on how to properly clean and take care of your ATECTURA Breezhaler.

Keep your capsules in the original blister in order to protect from moisture and light, and do not remove until immediately before use.

Keep your capsules in a cool dry place where the temperature stays below 25°C.

Do not store ATECTURA BREEZHALER or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What it looks like

The pack contains a white plastic Breezhaler inhaler device together with capsules in blister cards.

ATECTURA BREEZHALER registered pack sizes include:

  • 125/62.5 micrograms
  • 125/127.5 micrograms
  • 125/260 micrograms

Single pack containing 10 x 1, 30 x 1 hard capsules, together with 1 inhaler.

Ingredients

ATECTURA BREEZHALER contains the active ingredients:
indacaterol acetate and mometasone furoate.

Each capsule delivers:

125 micrograms of indacaterol

62.5 or 127.5 or 260 micrograms of mometasone furoate, depending on which strength of ATECTURA you have been given.

Atectura capsules also contain:

  • lactose monohydrate
  • gelatin (capsule shell)

This medicine does not contain sucrose, gluten, tartrazine or any other azo dyes.

Sponsor

ATECTURA BREEZHALER is supplied in Australia by:

Novartis Pharmaceuticals Australia Pty Limited
ABN 18 004 244 160
54 Waterloo Road
Macquarie Park NSW 2113
Telephone: 1 800 671 203
Web site: www.novartis.com.au

® = Registered Trademark

This leaflet was prepared in June 2020.

Atectura Breezhaler 125/62.5
AUST R 319076

Atectura Breezhaler 125/127.5
AUST R 319075

Atectura Breezhaler 125/260
AUST R 319074

(ate160720c_V2 based on PI ate160720i)

Published by MIMS April 2021

BRAND INFORMATION

Brand name

Atectura Breezhaler

Active ingredient

Indacaterol; Mometasone furoate

Schedule

S4

 

1 Name of Medicine

Indacaterol/mometasone furoate.

2 Qualitative and Quantitative Composition

Atectura Breezhaler 125/62.5 micrograms, inhalation powder, hard capsules.

Atectura Breezhaler hard capsules are for oral inhalation only. They are also supplied with an Atectura Breezhaler inhalation device to permit oral inhalation of the contents of the capsule shell.
Each capsule contains 173 micrograms of indacaterol acetate equivalent to 150 micrograms of indacaterol and 80 micrograms of mometasone furoate.
The delivered dose (the dose that leaves the mouthpiece of the inhaler) is equivalent to 125 micrograms indacaterol, and 62.5 micrograms mometasone furoate.

Atectura Breezhaler 125/127.5 micrograms, inhalation powder, hard capsules.

Atectura Breezhaler hard capsules are for oral inhalation only. They are also supplied with an Atectura Breezhaler inhalation device to permit oral inhalation of the contents of the capsule shell.
Each capsule contains 173 micrograms of indacaterol acetate equivalent to 150 micrograms of indacaterol and 160 micrograms of mometasone furoate.
The delivered dose (the dose that leaves the mouthpiece of the inhaler) is equivalent to 125 micrograms indacaterol, and 127.5 micrograms mometasone furoate.

Atectura Breezhaler 125/260 micrograms, inhalation powder, hard capsules.

Atectura Breezhaler hard capsules are for oral inhalation only. They are also supplied with an Atectura Breezhaler inhalation device to permit oral inhalation of the contents of the capsule shell.
Each capsule contains 173 micrograms of indacaterol acetate equivalent to 150 micrograms of indacaterol and 320 micrograms of mometasone furoate.
The delivered dose (the dose that leaves the mouthpiece of the inhaler) is equivalent to 125 micrograms indacaterol, and 260 micrograms mometasone furoate.

Excipients with known effect.

Each capsule contains approximately 25 mg lactose (as monohydrate).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Inhalation powder, hard capsule.

Atectura Breezhaler 125/62.5 micrograms, inhalation powder, hard capsules.

Capsules with natural transparent cap and uncoloured transparent body containing a white to practically white powder, with the product code "IM150-80" printed in blue above one blue bar on the body and with a logo printed in blue and surrounded by two blue bars on the cap.

Atectura Breezhaler 125/127.5 micrograms, inhalation powder, hard capsules.

Capsules with natural transparent cap and uncoloured transparent body containing a white to practically white powder, with the product code "IM150-160" printed in grey on the body and with a logo printed in grey on the cap.

Atectura Breezhaler 125/260 micrograms, inhalation powder, hard capsules.

Capsules with natural transparent cap and uncoloured transparent body containing a white to practically white powder, with the product code "IM150-320" printed in black above two black bars on the body and with a logo printed in black and surrounded by two black bars on the cap.

4 Clinical Particulars

4.1 Therapeutic Indications

Atectura Breezhaler is indicated as a once-daily maintenance treatment of asthma in adults and adolescents 12 years of age and older where use of a combination of long-acting beta2-agonist and inhaled corticosteroid is appropriate:
patients not adequately controlled with inhaled corticosteroids and "as needed" inhaled short-acting beta2-agonists; or
patients not adequately controlled with long-acting beta2-agonists and low dose of inhaled corticosteroids and "as needed" inhaled short-acting beta2-agonists.

4.2 Dose and Method of Administration

Dosage.

Adults and adolescents 12 years of age and older.

Inhalation of the content of one capsule of Atectura Breezhaler 125/62.5 micrograms once daily is recommended in patients who require a combination of a long-acting beta2-agonist and a low dose of inhaled corticosteroid.
Inhalation of the content of one capsule of Atectura Breezhaler 125/127.5 micrograms or 125/260 micrograms once-daily is recommended in patients who require a combination of a long-acting beta2-agonist and a medium or high dose of inhaled corticosteroid.
Patients should be informed that regular daily use is necessary to maintain control of asthma symptoms and that use should be continued even when asymptomatic.
The maximum recommended dose is Atectura Breezhaler 125/260 micrograms once daily.

Hepatic impairment.

No dose adjustment is required in patients with mild or moderate hepatic impairment. No data are available for Atectura Breezhaler in subjects with severe hepatic impairment, therefore Atectura Breezhaler should be used in these patients only if the expected benefit outweighs the potential risk (see Section 5 Pharmacological Properties).

Renal impairment.

No dose adjustment is required in patients with renal impairment.

Elderly patients.

No dose adjustment is required in elderly patients 65 years of age or older (see Section 5 Pharmacological Properties).

Paediatric patients.

Atectura Breezhaler may be used in paediatric patients 12 years of age and older at the same posology as in adults. The safety and efficacy of Atectura Breezhaler in paediatric patients below 12 years of age have not been established.

Method of administration.

For inhalation use only. Atectura Breezhaler capsules must not be swallowed.
Patients should be instructed on how to administer the medicinal product correctly. Patients who do not experience improvement in breathing should be asked if they are swallowing the capsule rather than inhaling it.
The capsules must be administered only using the Atectura Breezhaler inhaler. The inhaler provided with each new prescription should be used.
Atectura Breezhaler should be administered at the same time of the day each day. It can be administered irrespective of the time of the day.
The capsules must always be stored in the blister to protect from moisture and light, and only removed immediately before use (see Section 6.4 Special Precautions for Storage).
After inhalation, patients should rinse their mouth with water without swallowing.
If a dose is missed, it should be taken as soon as possible. Patients should be instructed not to take more than one dose in a day.

4.3 Contraindications

Atectura Breezhaler is contraindicated in patients with hypersensitivity to any of the active substances or excipients.

4.4 Special Warnings and Precautions for Use

Deterioration of disease.

Atectura Breezhaler should not be used to treat acute asthma symptoms including acute episodes of bronchospasm, for which a short-acting bronchodilator is required. Increasing use of short-acting bronchodilators to relieve symptoms indicates deterioration of control and patients should be reviewed by a physician.
Patients should not stop Atectura Breezhaler treatment without physician supervision since symptoms may recur after discontinuation.
Asthma-related adverse events and exacerbations may occur during treatment with Atectura Breezhaler. Patients should be asked to continue treatment but to seek medical advice if asthma symptoms remain uncontrolled or worsen after initiation of treatment with Atectura Breezhaler.

Hypersensitivity.

Immediate hypersensitivity reactions have been observed after administration of Atectura Breezhaler. If signs suggesting allergic reactions occur, in particular angioedema (including difficulties in breathing or swallowing, swelling of the tongue, lips, and face), urticaria, or skin rash, Atectura Breezhaler should be discontinued immediately and alternative therapy instituted.

Paradoxical bronchospasm.

As with other inhalation therapy, administration of Atectura Breezhaler may result in paradoxical bronchospasm which can be life-threatening. If paradoxical bronchospasm occurs, Atectura Breezhaler should be discontinued immediately and alternative therapy instituted.

Cardiovascular effects of beta agonists.

Like other medicinal products containing beta2-adrenergic agonists, Atectura Breezhaler may produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, blood pressure, and/or symptoms. If such effects occur, treatment may need to be discontinued.
Atectura Breezhaler should be used with caution in patients with cardiovascular disorders (coronary artery disease, acute myocardial infarction, cardiac arrhythmias, hypertension), convulsive disorders or thyrotoxicosis, and in patients who are unusually responsive to beta2-adrenergic agonists. While beta2-adrenergic agonists have been reported to produce electrocardiographic (ECG) changes, such as flattening of the T wave, prolongation of QT interval, and ST segment depression, the clinical significance of these findings is unknown.
Therefore, long acting beta2-adrenergic agonists (LABA) or LABA containing combination products such as Atectura Breezhaler should be used with caution in patients with known or suspected prolongation of the QT interval or who are being treated with medicinal products affecting the QT interval.

Hypokalaemia with beta agonists.

Beta2-adrenergic agonists may produce significant hypokalaemia in some patients, which has the potential to produce adverse cardiovascular effects. The decrease in serum potassium is usually transient, not requiring supplementation. In patients with severe condition, hypokalaemia may be potentiated by hypoxia and concomitant treatment which may increase the susceptibility to cardiac arrhythmias (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Clinically relevant hypokalaemia has not been observed in clinical studies of Atectura Breezhaler at the recommended therapeutic dose.

Hyperglycaemia.

Inhalation of high doses of beta2-adrenergic agonists and corticosteroids may produce increases in plasma glucose. Upon initiation of treatment with Atectura Breezhaler, plasma glucose should be monitored more closely in diabetic patients.

Use in hepatic impairment.

Enerzair Breezhaler can be used at the recommended dose in patients with mild and moderate hepatic impairment. No data are available for subjects with severe hepatic impairment, therefore caution should be observed in these patients (see Section 5.2).

Systemic effects of corticosteroids.

Systemic effects may occur with inhaled corticosteroids, particularly at high doses prescribed for prolonged periods. These effects are much less likely to occur than with oral corticosteroids and may vary in individual patients and between different corticosteroid preparations.
Possible systemic effects may include Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataracts, 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 therefore important that the dose of inhaled corticosteroid is titrated to the lowest dose at which effective control of asthma is maintained.
Atectura Breezhaler should be administered with caution in patients with pulmonary tuberculosis or in patients with chronic or untreated infections.

Use in the elderly.

See Section 4.2 Dose and Method of Administration.

Paediatric use.

See Section 4.2 Dose and Method of Administration.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Interactions linked to Atectura Breezhaler.

No specific interaction studies were conducted with Atectura Breezhaler. Information on the potential for interactions is based on the potential for each of the monotherapy components.
Clinically significant pharmacokinetic drug interactions mediated by Atectura Breezhaler at clinical doses are considered unlikely due to the low plasma concentrations achieved after inhaled dosing.
Concomitant administration of orally inhaled indacaterol and mometasone furoate under steady-state conditions did not affect the pharmacokinetics of either active substances.

Medicinal products known to prolong the QTc interval.

Atectura Breezhaler, like other medicinal products containing beta2-adrenergic agonists, should be administered with caution to patients being treated with monoamine oxidase inhibitors, tricyclic antidepressants or medicinal products known to prolong the QT interval, as any effect of these on the QT interval may be potentiated. Medicinal products known to prolong the QT interval may increase the risk of ventricular arrhythmia (see Section 4.4 Special Warnings and Precautions for Use).

Hypokalaemic treatment.

Concomitant treatment with methylxanthine derivatives, steroids or non-potassium-sparing diuretics may potentiate the possible hypokalaemic effect of beta2-adrenergic agonists (see Section 4.4 Special Warnings and Precautions for Use).

Beta-adrenergic blockers.

Beta-adrenergic blockers may weaken or antagonise the effect of beta2-adrenergic agonists. Therefore, Atectura Breezhaler should not be given together with beta-adrenergic blockers unless there are compelling reasons for their use. Where required, cardioselective beta-adrenergic blockers should be preferred, although they should be administered with caution.

Interaction with CYP3A4 and P-glycoprotein inhibitors.

Inhibition of CYP3A4 and P-glycoprotein (P-gp) has no impact on the safety of therapeutic doses of Atectura Breezhaler.
Inhibition of the key contributors of indacaterol clearance (CYP3A4 and P-gp) or mometasone furoate clearance (CYP3A4) raises the systemic exposure of indacaterol or mometasone furoate up to two-fold.
The magnitude of exposure increases for indacaterol due to interactions does not raise any safety concerns given the safety experience of treatment with indacaterol in clinical studies of up to one year at doses of 600 micrograms.
Due to the very low plasma concentration achieved after inhaled dosing, clinically significant drug interactions with mometasone furoate are unlikely. However, there may be a potential for increased systemic exposure to mometasone furoate when strong CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, nelfinavir, ritonavir, cobicistat) are co-administered.

Other long acting beta2-adrenergic agonists.

The co-administration of Atectura Breezhaler with other medicinal products containing long-acting beta2-adrenergic agonists has not been studied and is not recommended as it may potentiate adverse reactions (see Section 4.8 Adverse Effects (Undesirable Effects); Section 4.9 Overdose).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No studies on the effect on fertility have been conducted with indacaterol and mometasone furoate in combination. No adverse effects on fertility were observed in male and female rats given indacaterol by subcutaneous injection at doses up to 2 mg/kg/day, yielding systemic exposure hundreds of times higher than in patients. As with other corticosteroids, at exposure levels associated with marked signs of systemic corticosteroid toxicity, mometasone furoate had progestogenic effects on the female reproductive tract and mammary glands. However, fertility was unimpaired in a reproductive toxicity study carried out in rats.
(Category B3)

Risk summary.

There are insufficient data on the use of Atectura Breezhaler or its individual components (indacaterol and mometasone furoate) in pregnant women to inform a drug-associated risk.
Indacaterol was not teratogenic in rats or rabbits following subcutaneous administration (see Animal data). In animal reproduction studies with pregnant mice, rats and rabbits, mometasone furoate caused increased foetal malformations and decreased foetal survival and growth.
Atectura Breezhaler should only be used during pregnancy if the expected benefit to the patient justifies the potential risk to the foetus.

Clinical considerations.

Disease-associated maternal and/or embryo/foetal risk.

In women with poorly or moderately controlled asthma, there is an increased risk of several perinatal adverse outcomes such as pre-eclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. Pregnant women with asthma should be closely monitored and medication adjusted as necessary to maintain optimal asthma control.

Labour and delivery.

Like other medicinal products containing beta2-adrenergic agonists, indacaterol may inhibit labour due to a relaxant effect on uterine smooth muscle.

Animal data.

The combination of indacaterol and mometasone furoate has not been studied in pregnant animals.

Indacaterol.

Indacaterol was not teratogenic at subcutaneous doses up to 1 mg/kg/day in rats and 3 mg/kg/day in rabbits (yielding more than 150-and 920-times, respectively, the AUC in humans at 150 microgram/day). An increase in the incidence of a rib skeletal variation and retarded ossification were observed in the rabbit at 3 mg/kg/day, possibly secondary to maternal toxicity; embryofoetal development was unaffected in the species at 1 mg/kg/day (relative exposure, 365). Impaired learning and decreased fertility were observed in the pups of rats given indacaterol at a subcutaneous dose of 1 mg/kg/day during pregnancy and lactation (relative exposure, approximately 140; unaffected at 0.3 mg/kg/day, associated with a relative exposure level of 55). The potential risk for humans is unknown.

Mometasone furoate.

Like other glucocorticoids, mometasone furoate is a teratogen in rodents and rabbits. Effects noted were umbilical hernia in rats, cleft palate in mice and gallbladder agenesis, umbilical hernia and flexed front paws in rabbits. There were also reductions in maternal body weight gains, effects on foetal growth (lower foetal body weight and/or delayed ossification) in rats, rabbits and mice, and reduced offspring survival in mice. In rats, subcutaneous mometasone furoate at 15 micrograms/kg prolonged gestation and difficult labour occurred with a reduction in offspring survival and body weight.
 There is no information available on the presence of indacaterol or mometasone furoate in human milk, on the effects on a breastfed child, or on the effects on milk production. Other inhaled corticosteroids, similar to mometasone furoate, are transferred into human milk. Indacaterol (including its metabolites) and mometasone furoate have been detected in the milk of lactating rats. Reduced body weight gain, impaired learning and decreased fertility were observed in pups of rats treated with indacaterol during pregnancy and lactation.
The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Atectura Breezhaler and any potential adverse effects on the breast-fed child from Atectura Breezhaler or from the underlying maternal condition.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

Summary of the safety profile.

The safety profile of Atectura Breezhaler was based on safety data from three phase 3 studies with a total of 2497 adult or adolescent patients with asthma treated with Atectura Breezhaler 125/62.5, 125/127.5 or 125/260 micrograms once daily for up to 52 weeks.
The most common adverse drug reaction related to Atectura Breezhaler was headache.

Tabulated summary of adverse drug reactions from clinical trials.

Adverse drug reactions are listed by MedDRA system organ class. The frequency of the ADRs are based on the 52-week clinical study PALLADIUM (Table 1). Similar adverse event profile was observed in a 12-week clinical study (QUARTZ) except that no events of angioedema, myalgia, rash or tachycardia were observed. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): 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).

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.9 Overdose

There is limited experience with overdose in clinical studies with Atectura Breezhaler. General supportive measures and symptomatic treatment should be initiated in cases of suspected overdose.
An overdose will likely produce signs, symptoms or adverse effects associated with the pharmacological actions of the individual components (e.g. tachycardia, tremor, palpitations, headache, nausea, vomiting, drowsiness, ventricular arrhythmias, metabolic acidosis, hypokalaemia, hyperglycaemia, suppression of hypothalamic pituitary adrenal axis function). Use of cardioselective beta blockers may be considered for treating beta2-adrenergic effects, but only under the supervision of a physician and with extreme caution since the use of beta-adrenergic blockers may provoke bronchospasm. In serious cases, patients should be hospitalised.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Atectura Breezhaler is a combination of indacaterol, a long-acting beta2-adrenergic agonist (LABA), and mometasone furoate, an inhaled synthetic corticosteroid (ICS). Following oral inhalation, indacaterol acts locally on airways to produce bronchodilation and mometasone furoate reduces pulmonary inflammation.

Indacaterol.

Indacaterol is a long-acting beta2-adrenergic agonist for once-daily administration. The pharmacological effects of beta2-adrenoceptor agonists, including indacaterol, are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyses the conversion of adenosine triphosphate (ATP) to cyclic-3', 5'-adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle. In vitro studies have shown that indacaterol is a weak partial agonist at beta1-receptors with a potency more than 24-fold greater at beta2-receptors compared to beta1-receptors and is a full agonist at beta3-receptors with a potency 20-fold greater at beta2-receptors compared to beta3-receptors.
When inhaled, indacaterol acts locally in the lung as a bronchodilator. Indacaterol is a nearly full agonist at the human beta2-adrenergic receptor with nanomolar potency. In isolated human bronchus, indacaterol has a rapid onset of action and a long duration of action.
Although beta2-adrenergic receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta1-receptors are the predominant receptors in the human heart, there are also beta2-adrenergic receptors in the human heart comprising 10% to 50% of the total adrenergic receptors. The precise function of beta2-adrenergic receptors in the heart is not known, but their presence raises the possibility that even highly selective beta2-adrenergic agonists may have cardiac effects.

Mometasone furoate.

Mometasone furoate is a synthetic corticosteroid with high affinity for glucocorticoid receptors and local anti-inflammatory properties. Studies in asthmatic patients have demonstrated that inhaled mometasone furoate provides a favourable ratio of pulmonary to systemic activity. It is likely that much of the mechanism for the effects of mometasone furoate lies in its ability to inhibit the release of mediators of the inflammatory cascade. In vitro, mometasone furoate inhibits the release of leukotrienes (LT) from leukocytes of allergic patients. In cell culture, mometasone furoate demonstrated high potency in inhibition of synthesis and release of IL-1, IL-5, IL-6 and TNF-alpha. It is also a potent inhibitor of LT production and an extremely potent inhibitor of the production of the Th2 cytokines, IL-4 and IL-5, from human CD4+ T-cells.

Pharmacodynamics.

The primary pharmacodynamics of Atectura Breezhaler in obstructive airway disease reflects the complementary mechanisms of action of the individual components of Atectura Breezhaler.
Clinical data confirmed the hypothesis that bronchodilation with indacaterol coupled with the anti-inflammatory action of mometasone furoate results in improved lung function and asthma control. The Atectura Breezhaler clinical program showed consistently superior lung function when Atectura Breezhaler 125/62.5, 125/127.5, 125/260 micrograms once daily were compared to mometasone furoate (MF) 200, 400 micrograms once daily and 400 micrograms twice daily, and placebo.
The pharmacodynamic response profile of Atectura Breezhaler is characterised by rapid onset of action within 5 minutes after dosing (see Section 5.1, Clinical trials) and sustained effect over the 24 h dosing interval as evidenced by improvements in trough forced expiratory volume in the first second (FEV1) versus comparators, 24 hours after dosing.
No tachyphylaxis to the lung function benefits of Atectura Breezhaler were observed over time.

Effects on the QTc interval.

The effect of Atectura Breezhaler on the QTc interval has not been evaluated in a thorough QT (TQT) study.
For mometasone furoate, no QTc prolonging properties are known.

Clinical trials.

Two phase III randomized, double-blind studies (PALLADIUM and QUARTZ) of different durations evaluated the safety and efficacy of Atectura Breezhaler in adults and adolescent patients with asthma.
Study PALLADIUM was a 52-week pivotal study evaluating Atectura Breezhaler 125/127.5 micrograms once daily (N=439) and 125/260 micrograms once-daily (N=445) via Breezhaler over mometasone furoate (MF) 400 micrograms once daily (N=444) and 800 micrograms per day given as 400 micrograms twice daily (N=442), respectively. A third active control arm included subjects treated with salmeterol xinafoate/fluticasone propionate (SAL/FP) 50/500 micrograms twice daily (N=446). All subjects were required to be asthma symptomatic and on asthma maintenance therapy using an inhaled corticosteroid (ICS) with or without LABA for at least 3 months prior to study entry. At screening, 30% of patients had a history of exacerbation in the previous year. At study entry, the most common asthma medications reported were medium and high dose of ICS (27%) or LABA and low dose of ICS (69%). The baseline % predicted FEV1, mean ACQ-7 score and proportion of patients with at least one exacerbations 12 months prior to start of the study was 67.3%, 2.3 and 30.6%, respectively. A total of 107 adolescents were randomized.
The primary objective of the study was to demonstrate superiority of either Atectura Breezhaler 125/127.5 micrograms once daily to MF 400 micrograms once daily or Atectura Breezhaler 125/260 micrograms once daily to MF 400 micrograms twice daily in terms of trough FEV1 at week 26.
Mometasone furoate (MF) 127.5 (medium dose) and 260 (high dose) micrograms in Atectura Breezhaler once daily are comparable to MF 400 micrograms once daily (medium dose) and 800 micrograms (given as 400 micrograms twice daily, high dose) using multi-dose dry powder inhaler, respectively.
Atectura Breezhaler 125/127.5 and 125/260 micrograms once daily both demonstrated statistically significant improvements in trough FEV1 at week 26 and Asthma Control Questionnaire (ACQ-7) score compared to MF 400 micrograms once or twice daily, respectively (see Table 2). Findings at week 52 were consistent with week 26.
Atectura Breezhaler 125/127.5 and 125/260 micrograms once daily both demonstrated a clinically meaningful reduction in the annual rate of moderate or severe exacerbations, compared to MF 400 micrograms once and twice daily (see Table 2).
Results for the most clinically relevant endpoints are described in Table 2.

Lung function, symptoms and exacerbations.

See Table 2.
MF 80 micrograms (low dose) in Atectura Breezhaler once daily is comparable to MF 200 micrograms once daily (low dose) using multi-dose dry powder inhaler.
Atectura Breezhaler 125/62.5 micrograms once daily demonstrated a statistically significant improvement in baseline trough FEV1 at week 12 and Asthma Control Questionnaire (ACQ-7) score compared to MF 200 micrograms once daily. For additional details, see Table 3.

5.2 Pharmacokinetic Properties

Absorption.

Following inhalation of Atectura Breezhaler, the median time to reach peak plasma concentrations of indacaterol and mometasone furoate was approximately 15 minutes and 1 hour, respectively.
Based on the in vitro performance data, the dose of each of the monotherapy components delivered to the lung is expected to be similar for Atectura Breezhaler and the monotherapy products. Steady-state plasma exposure to indacaterol and mometasone furoate after Atectura Breezhaler inhalation was similar to the systemic exposure after inhalation of indacaterol maleate or mometasone furoate as monotherapy products.
Following inhalation of Atectura Breezhaler, the absolute bioavailability was estimated to be about 45% for indacaterol and less than 10% for mometasone furoate.

Indacaterol.

Indacaterol concentrations increased with repeated once-daily administration. Steady state was achieved within 12 to 14 days. The mean accumulation ratio of indacaterol, i.e. AUC over the 24-hour dosing interval on Day 14 compared to Day 1, was in the range of 2.9 to 3.8 for once-daily inhaled doses between 60 and 480 micrograms (delivered dose). Systemic exposure results from a composite of pulmonary and gastrointestinal absorption; about 75% of systemic exposure was from pulmonary absorption and about 25% from gastrointestinal absorption.

Mometasone furoate.

Mometasone furoate concentrations increased with repeated once-daily administration via the Breezhaler device. Steady state was achieved after 12 days. The mean accumulation ratio of mometasone furoate, i.e. AUC0-24hr on Day 14 compared to AUC0-24hr on Day 1, was in the range of 1.61 to 1.71 for once-daily inhaled doses of between 62.5 and 260 micrograms (delivered dose) as part of Atectura Breezhaler.
Following oral administration of mometasone furoate, the absolute oral systemic bioavailability of mometasone furoate was estimated to be very low (< 2%).

Distribution.

Indacaterol.

After intravenous infusion the volume of distribution (Vz) of indacaterol was 2,361 to 2,557 L indicating an extensive distribution. The in vitro human serum and plasma protein binding were 94.1 to 95.3% and 95.1 to 96.2%, respectively.

Mometasone furoate.

After intravenous bolus administration, the Vd is 332 L. The in vitro protein binding for mometasone furoate is high, 98% to 99% in concentration range of 5 to 500 nanogram/mL.

Metabolism.

Indacaterol.

After oral administration of radiolabelled indacaterol in a human absorption, distribution, metabolism, excretion (ADME) study, unchanged indacaterol was the main component in serum, accounting for about one third of total drug-related AUC over 24 hours. A hydroxylated derivative was the most prominent metabolite in serum. Phenolic O-glucuronides of indacaterol and hydroxylated indacaterol were further prominent metabolites. A diastereomer of the hydroxylated derivative, an N-glucuronide of indacaterol, and C- and N-dealkylated products were further metabolites identified.
In vitro investigations indicated that UGT1A1 was the only UGT isoform that metabolised indacaterol to the phenolic O-glucuronide. The oxidative metabolites were found in incubations with recombinant CYP1A1, CYP2D6, and CYP3A4. CYP3A4 is concluded to be the predominant isoenzyme responsible for hydroxylation of indacaterol. In vitro investigations further indicated that indacaterol is a low affinity substrate for the efflux pump P-gp.
In vitro the UGT1A1 isoform is a major contributor to the metabolic clearance of indacaterol. However, as shown in a clinical study in populations with different UGT1A1 genotypes, systemic exposure to indacaterol is not significantly affected by the UGT1A1-genotype.

Mometasone furoate.

The portion of an inhaled mometasone furoate dose that is swallowed and absorbed in the gastrointestinal tract undergoes extensive metabolism to multiple metabolites. There are no major metabolites detectable in plasma. In human liver microsomes, mometasone furoate is metabolised by cytochrome P-450 3A4 (CYP3A4).

Excretion.

Indacaterol.

In clinical studies which included urine collection, the amount of indacaterol excreted unchanged via urine was generally lower than 2% of the dose. Renal clearance of indacaterol was, on average, between 0.46 and 1.20 L/h. When compared with the serum clearance of indacaterol of 18.8 to 23.3 L/h, it is evident that renal clearance plays a minor role (about 2 to 6% of systemic clearance) in the elimination of systemically available indacaterol.
In a human ADME study where indacaterol was given orally, the faecal route of excretion was dominant over the urinary route. Indacaterol was excreted into human faeces primarily as unchanged parent substance (54% of the dose) and, to a lesser extent, hydroxylated indacaterol metabolites (23% of the dose). Mass balance was complete with ≥ 90% of the dose recovered in the excreta.
Indacaterol serum concentrations declined in a multi-phasic manner with an average terminal half-life ranging from 45.5 to 126 hours. The effective half-life, calculated from the accumulation of indacaterol after repeated dosing ranged from 40 to 52 hours which is consistent with the observed time to steady state of approximately 12 to 14 days.

Mometasone furoate.

After intravenous bolus administration, mometasone furoate has a terminal elimination T1/2 of approximately 4.5 hours. A radiolabelled, orally inhaled dose is excreted mainly in the faeces (74%) and to a lesser extent in the urine (8%).

Linearity/non-linearity.

Systemic exposure of mometasone furoate increased in a dose proportional manner following single and multiple doses of Atectura Breezhaler 125/62.5 and 125/260 micrograms in healthy subjects. A less than proportional increase in steady state systemic exposure was noted in patients with asthma over the dose range of 125/62.5 and 125/260 micrograms. Dose proportionality assessments were not performed for indacaterol as only one dose was used across all dose strengths of Atectura Breezhaler.

Specific populations.

A population PK analysis in patients with asthma after inhalation of Atectura Breezhaler indicated no significant effect of age, gender, body weight, smoking status, baseline estimated glomerular filtration rate (eGFR) and FEV1 at baseline on the systemic exposure to indacaterol and mometasone furoate.

Renal impairment.

Due to the very low contribution of the urinary pathway to total body elimination of indacaterol and mometasone furoate, the effects of renal impairment on their systemic exposure have not been investigated.

Hepatic impairment.

The effect of indacaterol/mometasone furoate has not been evaluated in subjects with hepatic impairment. However, studies have been conducted with the mono components.

Indacaterol.

Patients with mild or moderate hepatic impairment showed no relevant changes in Cmax or AUC of indacaterol, nor did protein binding differ between mild and moderate hepatic impaired subjects and their healthy controls. No data are available for subjects with severe hepatic impairment.

Mometasone furoate.

A study evaluating the administration of a single inhaled dose of 400 micrograms mometasone furoate by dry powder inhaler to subjects with mild (n=4), moderate (n=4), and severe (n=4) hepatic impairment resulted in only 1 or 2 subjects in each group having detectable peak plasma concentrations of mometasone furoate (ranging from 50 to 105 picogram/mL). The observed peak plasma concentrations appear to increase with severity of hepatic impairment; however, the numbers of detectable levels (assay Lower Limit of Quantification was 50 picogram/mL) were few.

Race/ethnicity.

There were no major differences in total systemic exposure (AUC) for both compounds between Japanese and Caucasian subjects. Insufficient pharmacokinetic data is available for other ethnicities or races.

5.3 Preclinical Safety Data

Genotoxicity.

Indacaterol.

Indacaterol was not mutagenic or clastogenic in a battery of in vitro and in vivo assays including bacterial reverse mutation, chromosomal aberrations in Chinese hamster V79 cells and the rat bone marrow micronucleus test.

Mometasone furoate.

Mometasone furoate is not considered to be genotoxic. There was no evidence of mutagenicity in in vitro tests which included tests for reverse mutation in Salmonella typhimurium and Escherichia coli and forward gene mutation in a mouse lymphoma cell line. Limited evidence of clastogenicity was obtained in Chinese Hamster ovary cells, although this finding was not confirmed in a second assay in Chinese Hamster lung cells in vitro, nor in vivo assays including a chromosomal aberration assay in mouse spermatogonia, a mouse micronucleus assay or in a rat bone marrow clastogenicity assay. Mometasone furoate did not cause DNA damage in rat liver cells.

Carcinogenicity.

No carcinogenicity studies have been conducted with indacaterol and mometasone furoate in combination.

Indacaterol.

The carcinogenic potential of indacaterol has been evaluated in a 26-week oral gavage study in transgenic mice (CB6F1/TgrasH2) and a 2-year inhalation study in rats. No carcinogenicity was observed in mice at doses up to 600 mg/kg/day (approximately 180-times in males and almost 400-times in females the AUC in humans at the maximum recommended clinical dose of 150 microgram/day). Lifetime treatment of rats at 2.1 mg/kg/day (relative exposure, 53) resulted in increased incidences of benign ovarian leiomyoma and focal hyperplasia of ovarian smooth muscle in females. Increases in leiomyomas of the rat female genital tract have been similarly demonstrated with other β2-adrenergic agonist drugs. Their development is consistent with proliferation in response to prolonged relaxation of the smooth muscle (pharmacologically mediated), and the finding is not considered to indicate a carcinogenic hazard to patients. Squamous metaplasia was observed in the upper respiratory tract tissues of mice, rats and dogs following inhalation administration of indacaterol. This finding is consistent with an adaptive response to irritation and occurred at large multiples of the human dose. It is not considered to indicate a carcinogenic hazard to humans with the therapeutic use of indacaterol. No data are available to determine whether exposure to tobacco smoke enhances the respiratory tract toxicity of indacaterol.

Mometasone furoate.

Mometasone furoate demonstrated no statistically significant increase in the incidence of tumours with inhalational administration at doses up to 160 microgram/kg/day in a 19-month study in mice and at up to 67 microgram/kg/day in a 2-year study in rats. These doses are approximately 2 times that in patients at the maximum recommended clinical dose of 320 microgram/day, adjusted for body surface area.

6 Pharmaceutical Particulars

6.1 List of Excipients

Capsule fill.

Lactose monohydrate.

Capsule shell components.

Gelatin.

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Do not store above 25°C.
Protect from moisture and light.
The capsules must always be stored in the blister to protect from moisture and light, and only removed immediately before use.

6.5 Nature and Contents of Container

Inhaler body and cap are made from acrylonitrile butadiene styrene, push buttons are made from methyl metacrylate acrylonitrile butadiene styrene. Needles and springs are made from stainless steel.
PA/Alu/PVC - Alu perforated unit-dose blister. Each blister contains 10 hard capsules.

Pack sizes.

Carton containing 10 Atectura capsules, together with 1 Breezhaler inhaler.
Carton containing 30 Atectura capsules, together with 1 Breezhaler inhaler.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.


CAS number.

Indacaterol acetate.

1000160-96-2.

Mometasone furoate.

83919-23-7.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription medicine.

Summary Table of Changes