Consumer medicine information

Fostair 100/6 and 200/6

Beclometasone dipropionate; Formoterol (eformoterol) fumarate dihydrate

BRAND INFORMATION

Brand name

Fostair

Active ingredient

Beclometasone dipropionate; Formoterol (eformoterol) fumarate dihydrate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Fostair 100/6 and 200/6.

What is in this leaflet

This leaflet answers some of the more common questions about FOSTAIR.

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 being given this medicine against the benefits this medicine is expected to have for you.

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 FOSTAIR is used for

FOSTAIR is a pressurised metered dose inhaler containing two active substances which are inhaled through your mouth and delivered directly into your lungs.

The two active substances are beclometasone dipropionate and formoterol (eformoterol) fumarate dihydrate.

Beclometasone dipropionate is a corticosteroid, a medicine used to treat swelling and irritation in your lungs.

Formoterol (eformoterol) fumarate dihydrate is a long-acting bronchodilator, a medicine which relaxes the muscles in your airways and helps you to breathe more easily.

Together these two active substances make breathing easier, by providing relief from symptoms such as shortness of breath, wheezing and cough in patients with asthma or Chronic Obstructive Pulmonary Diseases (COPD). They can also help to prevent the symptoms of asthma.

Asthma

FOSTAIR used for the treatment of asthma in adult patients in whom:

  • asthma is not adequately controlled by using inhaled corticosteroids and “as needed” short-acting bronchodilators or
  • asthma is responding well to treatment with both corticosteroids and long-acting bronchodilators.

COPD (FOSTAIR 100/6 only)

FOSTAIR 100/6 can also be used to treat the symptoms of severe COPD in adult patients. COPD is a long-term disease of the airways in the lungs which is primarily caused by cigarette smoking.

Ask your doctor if you have any questions about why FOSTAIR has been prescribed for you.

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

This medicine is not expected to affect your ability to drive a car or operate machinery.

Before you use FOSTAIR

When you must not use it

Do not take FOSTAIR if you have an allergy to:

  • any medicine containing beclometasone dipropionate or formoterol (eformoterol) fumarate dihydrate
  • any of the 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 children and adolescents under the age of 18 years.

Do not use 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 or have had any of the following medical conditions:

  • heart problems (heart pain, pain in the chest, recent heart attack, heart failure, narrowing of the arteries around your heart, valvular heart disease or any other known abnormalities or conditions of your heart)
  • narrowing of the arteries, have high blood pressure or an abnormal bulging of the blood vessel wall
  • heart rhythm disorders such as increased or irregular heart rate, fast pulse rate, palpitations or abnormal heart trace (ECG)
  • an overactive thyroid gland
  • low blood levels of potassium
  • disease of your liver or kidneys
  • diabetes or high blood sugars
  • a tumour of the adrenal gland
  • tuberculosis (TB)
  • viral or fungal chest infection.

FOSTAIR contains a small amount of alcohol. Talk to your doctor if you have been told to avoid alcohol for any reason.

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.

If you have not told your doctor about any of the above, speak with your doctor before you start using FOSTAIR.

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 FOSTAIR may interfere with each other. These include:

  • medicines for HIV such as ritonavir, cobicistat
  • medicines for high blood pressure, heart conditions and abnormal heart rhythms (such as quinidine, disopyramide, procainamide)
  • medicines to treat glaucoma
  • medicines to treat migraines
  • other medicines to treat COPD or asthma (such as theophylline, aminophylline or corticosteroids)
  • medicines used to treat allergic reactions such as antihistamines
  • medicines to treat depression or mental disorders such as monoamine oxidase inhibitors (phenelzine and isocarboxazid), tricyclic antidepressants (amitriptyline and imipramine) or phenothiazines
  • L-dopa, a medicine used to treat Parkinson’s Disease
  • L-thyroxine, a medicine used to treat an underactive thyroid gland
  • oxytocin, used to bring on (induce) labour
  • alcohol
  • fluid or water tablets
  • disulfiram, a medicine used to treat drinking problems
  • metronidazole, an antibiotic to treat infection in your body
  • anaesthetics used during surgery.

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

How to use FOSTAIR

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 this leaflet, ask your doctor or pharmacist for help.

How much to use

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

Asthma

FOSTAIR can be used in two different ways:

(a) use FOSTAIR 100/6 or FOSTAIR 200/6 every day to treat your asthma together with a separate “reliever” inhaler to treat sudden worsening of asthma symptoms, such as shortness of breath, wheezing and cough

(b) use FOSTAIR 100/6 every day to treat your asthma and also use FOSTAIR 100/6 to treat sudden worsening of your asthma symptoms, such as shortness of breath, wheezing and cough.

Your doctor will advise you on the dose and how to use FOSTAIR to control your asthma.

a) Using FOSTAIR together with a separate “reliever” to treat sudden worsening of asthma symptoms, such as shortness of breath, wheezing and cough

FOSTAIR 100/6
The recommended dose is one or two puffs twice daily. The maximum daily dose is 4 puffs.

FOSTAIR 200/6
The recommended dose is two puffs twice daily. The maximum daily dose is 4 puffs.

You will be told to stop using FOSTAIR 100/6 before starting on FOSTAIR 200/6.

Remember: You should always have your quick-acting “reliever” inhaler with you at all times to treat worsening symptoms of asthma or a sudden asthma attack.

If you are using more inhalations of your reliever than usual, tell your doctor as this may indicate worsening of your asthma.

b) Using FOSTAIR 100/6 every day to treat your asthma and also use FOSTAIR 100/6 to treat sudden worsening of your asthma symptoms, such as shortness of breath, wheezing and cough

FOSTAIR 100/6 only
The recommended dose is one puff twice daily.

You should also use FOSTAIR 100/6 as a “reliever” inhaler to treat sudden asthma symptoms.

If you get asthma symptoms, take one puff and wait a few minutes. If you do not feel better, take another puff. Do not take more than 6 reliever puffs on any single occasion.

The maximum daily dose of FOSTAIR 100/6 is 8 puffs.

If you feel you need more puffs each day to control your asthma symptoms, talk to your doctor. Your doctor may need to change your medicines.

COPD (FOSTAIR 100/6 only)
The recommended dose of FOSTAIR 100/6 is two puffs twice daily in the morning and two puffs in the evening.

How to use it

Testing your inhaler

Before using the inhaler for the first time or if you have not used the inhaler for 14 days or more, you should test your inhaler to make sure that it is working properly.

  1. Remove the protective cap from the mouthpiece
  2. Hold your inhaler upright with the mouthpiece at the bottom
  3. Direct the mouthpiece away from yourself and firmly depress the canister to release one puff
  4. Check the dose counter. If you are testing your inhaler for the first time, the counter/indicator should read:

120 - when using the containing providing 120 puffs.

180 - when using the containing providing 180 puffs.

How to use your inhaler

FOSTAIR is for inhalation use.

You should inhale the medicine through your mouth and this takes the medicine directly into your lungs.

Whenever possible, stand or sit in an upright position when inhaling.

Important: Do not perform steps 2 to 5 too quickly.

  1. Remove the protective cap from the mouthpiece and check that the mouthpiece is clean and free from dust and dirt or any other foreign objects.
  2. Breathe out as slowly and deeply as possible.
  3. Hold the canister vertically with its body upwards and put your lips around the mouthpiece. Do not bite the mouthpiece.
  4. Breathe in slowly and deeply through your mouth and, just after starting to breathe in press down firmly on the top of the inhaler to release one puff.
  5. Hold your breath for as long as possible and, finally, remove the inhaler from your mouth and breathe out slowly. Do not breath into the inhaler.

If you need to take another puff, keep the inhaler in the vertical position for about half a minute, then repeat steps 2 to 5.

If you see 'mist' coming from the top of the inhaler or the sides of your mouth, this means that FOSTAIR will not be getting into your lungs as it should. Take another puff, following the instruction starting again from step 2.

After use, close with the protective cap and check the dose counter.

To lower the risk of a fungal infection in the mouth and throat, rinse your mouth or gargle with water or brush your teeth each time you use your inhaler.

You should get a replacement when the counter shows the number 20. Stop using the inhaler when the counter shows 0 as any puffs left in the device may not be enough to give you a full dose.

If you have weak hands, it may be easier to hold the inhaler with both hands: hold the upper part of the inhaler with both index fingers and its lower part with both thumbs.

If you find it difficult to operate the inhaler while starting to breathe in, you may use a suitable spacer device. Ask your doctor or pharmacist about this device.

It is important that you read the package leaflet which is supplied with your spacer device and that you follow the instructions on how to use the spacer device and how to clean it, carefully.

Cleaning the FOSTAIR inhaler

You should clean your inhaler once a week.

  1. Do not remove the canister from the inhaler and do not use water or other liquids to clean your inhaler.
  2. Remove the protective cap from the mouthpiece by pulling it away from your inhaler.
  3. Wipe inside and outside of the mouthpiece and the inhaler with a clean, dry cloth or tissue.
  4. Replace the mouthpiece cover.

When to use it

You should use FOSTAIR every day, even when your asthma or COPD is not troubling you.

Your doctor may tell you to use a separate “reliever” inhaler or to use FOSTAIR 100/6 as a “reliever” to treat sudden worsening of your asthma symptoms.

If you feel that the medicine is not working or you are getting breathless or wheezy, talk to your doctor.

How long to use it

Continue taking your medicine for as long as your doctor tells you. Do not stop using FOSTAIR or lower the dose, even if you are feeling better or have no symptoms.

It is important to use FOSTAIR every day as directed.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

If you forget to use FOSTAIR

Use it as soon as you remember.

If it is almost time for your next dose, skip the dose you missed and use your next dose when you are meant to.

Do not take a double to make up for the dose you have missed. 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 take too much (overdose)

Immediately telephone your doctor or Poisons Information Centre (telephone 13 11 26) or go to Accident and Emergency at your nearest hospital, if you think that you or anyone else may have taken or been given too much FOSTAIR. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

If you use more FOSTAIR than you should, side effects may occur (see “Side Effects”).

While you are using FOSTAIR

Things you must do

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

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

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. It may affect other medicines used during surgery.

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

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

Stop taking FOSTAIR, use your quick-acting “reliever” inhaler and seek medical help immediately if your breathing gets worse, this may include short of breath or start wheezing (breathing with an audible whistling sound) straight after using FOSTAIR.

Things you must not do

Do not take FOSTAIR 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

If you take higher doses of inhaled corticosteroids over long periods, you may need a higher dose of corticosteroids in stressful situations such as being taken to hospital after an accident, having a serious injury or before an operation. Your doctor will decide whether you need to increase your dose of corticosteroids and may prescribe some steroid tablets or a steroid injection.

FOSTAIR contains alcohol

FOSTAIR contains 9 mg of alcohol (ethanol) in each actuation which is equivalent to 0.25 mg/kg per dose of two actuations. The amount in two actuations of this medicines is equivalent to less than 1 ml of wine or beer. The small amount of alcohol in this medicine will not have any noticeable effects.

Side effects

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

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Do not be alarmed by the list of possible side effects. You may not experience any of them.

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

Tell your doctor or pharmacist if you notice any of the following and they worry you:

  • sore, raised patches in the mouth, throat or oesophagus (food pipe) caused by a fungal infection (oral thrush). Rinsing your mouth out with water immediately after using the inhaler may prevent this side effect.
  • sore, dry or irritated throat
  • hoarseness of the voice
  • headache
  • flu-like symptoms
  • runny or stuffy nose and sneezing
  • feeling of tension or fullness in your sinuses
  • cough
  • inflammation of the ear
  • skin rash, hives, itchy skin
  • increased sweating, flushing of the skin
  • fungal infection of the vagina with itching, burning and white discharge (thrush)
  • diarrhoea, indigestion, upset stomach, nausea
  • abnormal or impaired sense of taste, burning of the lips, dry mouth, swallowing difficulties
  • muscle cramps or pain
  • swelling of the hands and feet
  • bleeding or bruising more easily than normal, bleeding into the tissues
  • trembling, restlessness
  • dizziness
  • painful, difficult or frequent urination (may be a sign of a kidney infection)
  • irregular heartbeat, sensation of fast or missed heart beats, palpitations.

The above list includes less serious side effects of your medicine.

Tell your doctor as soon as possible if you notice any of the following:

  • symptoms of a lung infection such as fever or chills, increased mucus production, change in mucus colour, or increased cough or increased breathing difficulties
  • severe chills, sore throat or mouth ulcers.

The above list includes serious side effects that may require medical attention.

If any of the following happen, tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

  • worsening shortness of breath and wheezing immediately after using FOSTAIR
  • sudden signs of allergy such as rash, itching or hives on the skin, swelling of the face, lips, tongue or other parts of the body
  • blurred vision
  • crushing chest pain often spreading to the arms or neck and sometimes to the shoulders and back (angina).

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation.

Tell your doctor or pharmacist if you notice anything else that is making you feel unwell. Other side effects not listed above may occur in some patients. Some of these side effects (for example, changes in blood pressure, changes in blood levels of sugars, electrolytes, hormones, blood cells, cells to help your blood clot, fatty acids, ketones, or proteins in the blood) can only be found when your doctor does tests from time to time to check your progress.

Using high-dose inhaled corticosteroids over a long time can cause other very rare side effects. FOSTAIR does not contain a high-dose of corticosteroids, however, your doctor will monitor you for other rare side effects such as:

  • problems with how your adrenal glands work
  • thinning of your bones
  • increased pressure in your eyes (glaucoma)
  • clouding of the lens of your eyes (cataracts)
  • changes in behaviour such sleeping problems, depression or feeling worried, restlessness, nervousness, over-excitement or irritability
  • growth retardation or behavioural changes in children and adolescents.

After using FOSTAIR

Storage

Keep it where children cannot reach it.

If the inhaler has been exposed to severe cold, warm it with your hands for a few minutes before using. Never warm it by artificial means.

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

After opening:

120 or 180 puff inhalers:
Store below 30°C for a maximum of 2 months. Your pharmacist will enter the dispensing date on a label affixed to the inhaler.

From a multipack:
Store the unused inhaler(s) in a refrigerator (2°C-8°C) until you are ready to use. Do Not Freeze.

Before use, take one inhaler out of the refrigerator for some minutes to allow for the solution to warm up. After first use, store the inhaler below 30°C for a maximum of 2 months. Enter the date of first use on the removable label and affix to the inhaler. Do not put the inhaler back into the refrigerator.

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

FOSTAIR is a pressurised solution.

FOSTAIR comes in an aluminium canister with a metering valve, fitted in a polypropylene plastic inhaler with a plastic protective cap and dose counter.

For FOSTAIR 100/6 the plastic inhaler is light purplish-red with a dark purplish-red cap.

For FOSTAIR 200/6 the plastic inhaler is light purplish-red with a dark green cap.

FOSTAIR 100/6
Pack of 1 container with either 120 or 180 puffs.

Multipack containing 240 puffs (2 containers of 120 puffs each)

FOSTAIR 200/6
Pack of 1 container with 120 puffs.

Multipack containing 240 puffs (2 containers of 120 puffs each).

Not all pack sizes may be marketed.

Ingredients

The active ingredients of FOSTAIR are beclometasone dipropionate and formoterol fumarate dihydrate.

FOSTAIR 100/6:
Each metered dose (the dose leaving the mouthpiece) contains 100 micrograms of beclometasone dipropionate, 6 micrograms of formoterol (eformoterol) fumarate dihydrate.

FOSTAIR 200/6:
Each metered dose (the dose leaving the mouthpiece) contains 200 micrograms of beclometasone dipropionate, 6 micrograms of formoterol (eformoterol) fumarate dihydrate.

The other ingredients are:

  • ethanol absolute (alcohol)
  • hydrochloric acid
  • norflurane as the propellant.

Supplier

FOSTAIR is supplied by:

Chiesi Australia Pty Ltd
Suite 3, 22 Gillman Street,
Hawthorn East, VIC. 3123
Email: [email protected]
W: www.chiesi.com.au

This leaflet was prepared in August 2022.

FOSTAIR 100/6: AUST R 310360

FOSTAIR 200/6: AUST R 373934

Published by MIMS September 2022

BRAND INFORMATION

Brand name

Fostair

Active ingredient

Beclometasone dipropionate; Formoterol (eformoterol) fumarate dihydrate

Schedule

S4

 

1 Name of Medicine

Beclometasone dipropionate and formoterol (eformoterol) fumarate dihydrate.

2 Qualitative and Quantitative Composition

Fostair is a pressurised metered dose inhaler (pMDI).

Fostair 100/6.

Each metered dose (the dose leaving the valve) contains: 100 micrograms of beclometasone dipropionate and 6 micrograms of formoterol fumarate dihydrate.
Each delivered dose (the dose leaving the mouthpiece) contains 84.6 micrograms of beclometasone dipropionate and 5.0 micrograms of formoterol fumarate dihydrate.

Fostair 200/6.

Each metered dose (the dose leaving the valve) contains 200 micrograms of beclometasone dipropionate and 6 micrograms of formoterol fumarate dihydrate.
Each delivered dose (the dose leaving the mouthpiece) contains 177.7 micrograms of beclometasone dipropionate and 5.1 micrograms of formoterol fumarate dihydrate.

Excipient with known effect.

Ethanol absolute.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Pressurised inhalation solution.
Colourless to yellowish solution.
The inhalation solution is contained in a pressurised aluminium container sealed with a metering valve. The canister is inserted into a polypropylene plastic actuator which incorporates a mouthpiece and is fitted with a plastic protective cap. The actuator is light purplish-red with a dark purplish-red cap (Fostair 100/6) or dark green cap (Fostair 200/6). The actuator has a dose counter.

4 Clinical Particulars

4.1 Therapeutic Indications

Asthma.

Fostair is indicated in adults (18 years and older) in the treatment of asthma where use of a combination product (inhaled corticosteroid and long-acting beta2-agonist) is appropriate:
patients not adequately controlled with inhaled corticosteroids (ICS) and 'as needed' inhaled rapid-acting beta2-agonist, or
patients already adequately controlled on both ICS and long-acting beta2-agonists (LABA). (See Section 4.2 Dose and Method of Administration for treatment approaches.)

COPD (Fostair 100/6 only).

Symptomatic treatment of adults with severe COPD (FEV1 < 50% predicted normal) and a history of repeated exacerbations, who have significant symptoms despite regular therapy with long-acting bronchodilators.

4.2 Dose and Method of Administration

Dosage.

Fostair is only for use in adults 18 years and above.

Asthma.

Fostair is not intended for the initial management of asthma. The dosage of the components of Fostair is individual and should be adjusted to the severity of the disease. This should be considered not only when treatment with combination products is initiated but also when the dose is adjusted. If an individual patient should require a combination of doses other than those available in the combination inhaler, appropriate doses of beta2-agonists and/or corticosteroids by individual inhalers should be prescribed.
There are two treatment approaches:
A. Maintenance therapy: Fostair 100/6 or Fostair 200/6 is taken as regular maintenance treatment with a separate as needed rapid-acting bronchodilator.
B. Maintenance and reliever therapy: Fostair 100/6 is taken as regular maintenance treatment and as needed in response to asthma symptoms.
A. Maintenance therapy. Patients should be advised to have their separate rapid-acting bronchodilator available for rescue use at all times.

Fostair 100/6.

One or two inhalations twice daily.
The maximum daily dose is 4 inhalations.
The starting dose is 1 inhalation taken twice daily for patients who are inadequately controlled with an ICS and SABA or adequately controlled with an ICS and LABA. The dose should be increased to 2 inhalations taken twice daily if the patient's asthma is poorly controlled. Fostair 100/6 should be discontinued if the patient is commenced on Fostair 200/6 for maintenance therapy.

Fostair 200/6.

Two inhalations twice daily. The maximum daily dose is 4 inhalations.
Fostair 200/6 should be used as maintenance therapy only.
Increasing use of short-acting bronchodilators can indicate worsening of the underlying condition and warrants the reassessment of the patient and therapy (see Section 4.4 Special Warnings and Precautions for Use).
B. Maintenance and reliever therapy for Fostair 100/6 only. Patients take their daily maintenance dose of Fostair 100/6 and in addition take Fostair 100/6 as needed in response to asthma symptoms. The as-needed inhalations provide both rapid relief of symptoms and improved overall asthma control. Patients should be advised to always have Fostair 100/6available for rescue use.
Fostair 100/6 maintenance and reliever therapy should especially be considered for patients with:
not fully controlled asthma and in need of reliever medication;
asthma exacerbations in the past requiring medical intervention.
Close monitoring for dose-related adverse effects is needed in patients who frequently take high numbers of Fostair as-needed inhalations.
The recommended maintenance dose is 1 inhalation twice daily (one inhalation in the morning and one inhalation in the evening).
Patients should take 1 additional inhalation as needed in response to symptoms. If symptoms persist after a few minutes, an additional inhalation should be taken. Patients should not take more than 6 inhalations on any single occasion. The maximum daily dose is 8 inhalations.
Patients who require 6 rescue inhalations per day for two consecutive days will be requested to contact their physician for asthma re-evaluation. Fostair 100/6 should be discontinued if the patient is commenced on Fostair 200/6 for maintenance therapy.
Patients should be regularly reassessed by a doctor, so that the dosage of Fostair 100/6 remains optimal and is only changed on medical advice. The dose should be titrated to the lowest dose at which effective control of symptoms is maintained. When control of symptoms is maintained with the lowest recommended dosage, then the next step could include a test of inhaled corticosteroid alone.
Patients should be advised to take Fostair 100/6 every day even when asymptomatic.

COPD for Fostair 100/6 only.

Two inhalations twice daily.
Special patient groups.

Elderly.

There is no need to adjust the dose in elderly patients. There are no data available for use of Fostair in patients with hepatic or renal impairment (see Section 5.2 Pharmacokinetic Properties).

Method of administration.

Fostair is for inhalation use. To ensure proper administration of the drug, the patient should be shown how to use the inhaler correctly by a physician or other health professional. Correct use of the pMDI is essential in order that treatment is successful. The patient should be advised to read the package leaflet carefully and follow the instructions for use as given in the leaflet.
Fostair inhaler is provided with a counter on the back of the actuator, which shows how many doses are left. For the 120 doses presentation each time the patient presses the canister, a puff of medicine is released, and the counter counts down by one. For the 180 doses presentation, each time the patient presses the canister the counter rotates by a small amount and the number of puffs remaining is displayed in intervals of 20. Patients should be advised not to drop the inhaler as this may cause the counter to count down.
Instructions for use.

Testing the inhaler.

Before using the inhaler for the first time or if the inhaler has not been used for 14 days or more, the patient should release one actuation into the air in order to ensure that the inhaler is working properly. After testing the inhaler for the first time, the counter should read 120 or 180.
Whenever possible patients should stand or sit in an upright position when inhaling from their inhaler.

Use of the inhaler.

1. Patients should remove the protective cap from the mouthpiece and check that the mouthpiece is clean and free from dust and dirt or any other foreign objects.
2. Patients should breathe out as slowly and deeply as possible.
3. Patients should hold the canister vertically with its body upwards and put the lips around the mouthpiece without biting the mouthpiece.
4. At the same time, patients should breathe in slowly and deeply through the mouth. After starting to breathe in, they should press down on the top of the inhaler to release one puff.
5. Patients should hold the breath for as long as possible and, finally, they should remove the inhaler from the mouth and breathe out slowly. Patients should not breathe out into the inhaler.
To inhale a further puff, patients should keep the inhaler in a vertical position for about half a minute and repeat steps 2 to 5.

Important.

Patients should not perform steps 2 to 5 too quickly.
After use, patients should close the inhaler with protective cap and check the dose counter.
Patients should be advised to get a new inhaler when the dose counter or indicator shows the number 20. They should stop using the inhaler when the counter shows 0 as any puffs left in the device may not be enough to release a full dose.
If mist appears following inhalation, either from the inhaler or from the sides of the mouth, the procedure should be repeated from step 2.
For patients with weak hands it may be easier to hold the inhaler with both hands. Therefore, the index fingers should be placed on the top of the inhaler canister and both thumbs on the base of the inhaler.
Patients should rinse their mouth or gargle with water or brush the teeth after inhaling (see Section 4.4 Special Warnings and Precautions for Use).

Cleaning.

Patients should be advised to read the package leaflet carefully for cleaning instructions. For the regular cleaning of the inhaler, patients should remove the cap from the mouthpiece and wipe the outside and inside of the mouthpiece with a dry cloth. They should not remove the canister from the actuator and should not use water or other liquids to clean the mouthpiece.
Patients who find it difficult to synchronise aerosol actuation with inspiration of breath, may use a suitable spacer device. They should be advised by their doctor, pharmacist or a nurse in the proper use and care of their inhaler and spacer and their technique checked to ensure optimum delivery of the inhaled drug to the lungs. This may be obtained by the patients using the spacer by one continuous slow and deep breath through the spacer, without any delay between actuation and inhalation.

4.3 Contraindications

Hypersensitivity to beclometasone dipropionate, formoterol fumarate dihydrate or any of the excipients (see Section 6.1 List of Excipients).

4.4 Special Warnings and Precautions for Use

Treatment of asthma or COPD should be in accordance with current national treatment guidelines.
Patients with asthma should have a personal asthma action plan designed in association with their general practitioner. This plan should incorporate a stepwise treatment regime which can be instituted if the patient's asthma improves or deteriorates.

Identified precautions.

Use of Fostair.

Use of ICS/LABA is not the recommended 'preventer' treatment for mild asthma, and should be considered only when patients have not responded to ICS alone.
For treatment of acute asthma attacks patients should be advised to have their rapid-acting bronchodilator available at all times, either Fostair 100/6 (for patients using Fostair 100/6 as maintenance and reliever therapy) or a separate rapid-acting bronchodilator (for patients using Fostair 200/6 as maintenance therapy only).

Patients with heart conditions.

Fostair should be used with caution (which may include monitoring) in patients with cardiac arrhythmias, especially third degree atrioventricular block and tachyarrhythmias (accelerated and/or irregular heart beat), idiopathic subvalvular aortic stenosis, hypertrophic obstructive cardiomyopathy, severe heart disease, particularly acute myocardial infarction, ischaemic heart disease, congestive heart failure, occlusive vascular diseases, particularly arteriosclerosis, arterial hypertension and aneurysm.

QTc interval.

Caution should also be observed when treating patients with known or suspected prolongation of the QTc interval, either congenital or drug induced (QTc > 0.44 seconds). Formoterol itself may induce prolongation of the QTc interval.

Use with anaesthesia.

If anaesthesia with halogenated anaesthetics is planned, it should be ensured that Fostair is not administered for at least 12 hours before the start of anaesthesia as there is a risk of cardiac arrhythmias.

Patients with pulmonary infections.

As with all inhaled medication containing corticosteroids, Fostair should be administered with caution in patients with active or quiescent pulmonary tuberculosis, fungal and viral infections in the airways.
It is recommended that treatment with Fostair should not be stopped abruptly.

Ineffective treatment.

If patients find the treatment ineffective medical attention must be sought. Increasing use of rescue bronchodilators indicates a worsening of the underlying condition and warrants a reassessment of the asthma therapy. Sudden and progressive deterioration in control of asthma or COPD is potentially life-threatening and the patient should undergo urgent medical assessment.
Consideration should be given to the need for increased treatment with corticosteroids, either inhaled or oral therapy, or antibiotic treatment if an infection is suspected.

Exacerbations.

Sudden and progressive worsening in the control of asthma or COPD is potentially life threatening. In such cases, patients should receive urgent medical assessment with consideration given to increased corticosteroid therapy (such as a course of oral corticosteroids) or antibiotic treatment in the presence of a bacterial infection.
Patients should not be initiated on Fostair during an exacerbation, or if they have significantly worsening or acutely deteriorating asthma. Serious asthma-related adverse events and exacerbations may occur during treatment with Fostair. Patients should be asked to continue treatment but to seek medical advice if asthma symptoms remain uncontrolled or worsen after initiation on Fostair.
As with other inhalation therapy paradoxical bronchospasm may occur with an immediate increase in wheezing and rapidness of breath after dosing. This should be treated immediately with a fast-acting inhaled bronchodilator. Fostair should be discontinued immediately, the patient assessed and alternative therapy instituted if necessary.

Reliever inhalations.

Patients should be reminded to take Fostair daily as prescribed even when asymptomatic. The reliever inhalations of Fostair 100/6 (for patients using Fostair 100/6 for maintenance and reliever therapy) should be taken in response to asthma symptoms but are not intended for regular prophylactic use, e.g. before exercise. For such use, a separate rapid-acting bronchodilator should be considered.
Once asthma symptoms are controlled, consideration may be given to gradually reducing the dose of beclometasone dipropionate and formoterol (eformoterol) fumarate dihydrate. Regular review of patients as treatment is stepped down is important. The lowest effective dose of inhaled steroid should be used (see Section 4.2 Dose and Method of Administration).

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 inhaled than with oral corticosteroids. Possible systemic effects include: Cushing's syndrome, Cushingoid features, adrenal suppression, decrease in bone mineral density, growth retardation in children and adolescents, 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).
Therefore, it is important that the patient is reviewed regularly, and the dose of inhaled corticosteroid is reduced to the lowest dose at which effective control of asthma is maintained.

Use with spacers.

Single dose pharmacokinetic data (see Section 5.2 Pharmacokinetic Properties) have demonstrated that the use of Fostair with a suitable spacer device in comparison to the use of standard actuator, does not increase the total systemic exposure to formoterol and reduces the systemic exposure to beclometasone 17-monopropionate, while there is an increase for unchanged beclometasone dipropionate that reaches systemic circulation from the lung. However, taking into account that unchanged beclometasone diproprionate is 30 times less potent compared to beclometasone 17-monopropionate in terms of glucocorticoid receptor activity, the observed increase in beclometasone diproprionate levels is not expected to have any clinically relevant impact on beclometasone diproprionate systemic effects.

Prolonged treatment.

Prolonged treatment of patients with high doses of inhaled corticosteroids may result in adrenal suppression. Acute adrenal crisis may occur if the ICS are ceased or reduced in dose or during an intercurrent illness. Situations which could potentially trigger acute adrenal crisis, include trauma, surgery, infection or any rapid reduction in dosage. Presenting symptoms are typically vague and may include anorexia, abdominal pain, weight loss, tiredness, headache, nausea, vomiting, hypotension, decreased level of consciousness, hypoglycaemia, and seizures. Additional systemic corticosteroid cover should be considered during periods of stress or elective surgery.

Pneumonia in patients with COPD.

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 patients with COPD include current smoking, older age, low body mass index (BMI) and severe COPD.
Patients should be advised that Fostair contains a small amount of ethanol (approximately 7 mg per actuation); however, at normal doses, the amount of ethanol is negligible and does not pose a risk to patients.
Patients should be advised to rinse the mouth or gargle with water or brush the teeth after inhaling the prescribed dose to minimise the risk of oropharyngeal candida infection.

Visual disturbance.

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.

Use in the elderly.

No data available.

Paediatric use.

The safety and efficacy of Fostair in children and adolescents under 18 years of age have not been established yet. No data are available with Fostair in children under 12 years of age. Only limited data are available in adolescents between 12 and 17 years of age. Therefore, Fostair is not recommended for children and adolescents under 18 years until further data become available.

Effects on laboratory tests.

Caution is also required when Fostair is used by patients with thyrotoxicosis, diabetes mellitus, phaeochromocytoma and untreated hypokalaemia.
Potentially serious hypokalaemia may result from beta2-agonist therapy. Particular caution is advised in severe asthma as this effect may be potentiated by hypoxia. Hypokalaemia may also be potentiated by concomitant treatment with other drugs which can induce hypokalaemia, such as xanthine derivatives, steroids and diuretics (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Caution is also recommended in unstable asthma when a number of "rescue" bronchodilators may be used. It is recommended that serum potassium levels are monitored in such situations.
The inhalation of formoterol may cause a rise in blood glucose levels. Therefore, blood glucose should be closely monitored in patients with diabetes.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Pharmacokinetic interactions.

Beclometasone dipropionate undergoes a very rapid metabolism via esterase enzymes. Beclometasone is less dependent on CYP3A metabolism than some other corticosteroids, and in general interactions are unlikely; however the possibility of systemic effects with concomitant use of strong CYP3A inhibitors (e.g. ritonavir, cobicistat) cannot be excluded, and therefore caution and appropriate monitoring is advised with the use of such agents.

Pharmacodynamic interactions.

Beta-blockers (including eye drops) should be avoided in asthmatic patients. If beta-blockers are administered for compelling reasons, the effect of formoterol will be reduced or abolished.
On the other hand, concomitant use of other beta-adrenergic drugs can have potentially additive effects, therefore caution is required when theophylline or other beta-adrenergic drugs are prescribed concomitantly with formoterol.
Concomitant treatment with quinidine, disopyramide, procainamide, phenothiazines, antihistamines, monoamine oxidase inhibitors 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 beta2-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 treatment with xanthine derivatives, steroids, or diuretics may potentiate a possible hypokalaemic effect of beta2-agonists (see Section 4.4 Special Warnings and Precautions for Use). Hypokalaemia may increase the disposition towards arrhythmias in patients who are treated with digitalis glycosides.
Fostair contains a small amount of ethanol. There is a theoretical potential for interaction in particularly sensitive patients taking disulfiram or metronidazole.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There are no relevant clinical data on the effect of Fostair on fertility.
Disruption of normal oestrus cycling was observed in female rats treated with beclometasone dipropionate and formoterol fumarate dihydrate in combination at an oral dose of 18.9/1.1 mg/kg/day, yielding almost 600 times the systemic exposure to beclometasone and 6 times the systemic exposure to formoterol in patients at the maximum recommended clinical dose (based on plasma AUC). Fertility was unaffected in male rats at this dose level, and female fertility was unaffected at a dose of 1.89/0.11 mg/kg/day, yielding approximately 120 times the systemic exposure to beclometasone and 0.2 times the exposure to formoterol in patients at the maximum recommended clinical dose. The effects on female fertility observed in animals are likely to be due to the beclometasone dipropionate (corticosteroid) component of Fostair. Given the magnitude of the exposure multiples, impairment of fertility is not expected in patients.
(Category B3)
There are no relevant clinical data on the use of Fostair in pregnant women. Because of the tocolytic actions of formoterol as a beta2-adrenergic agonist particular care should be exercised in the run up to delivery. Fostair should not be recommended for use during pregnancy and particularly at the end of pregnancy or during labour unless there is no other (safer) established alternative.
In pregnant rats, administration of beclometasone dipropionate and formoterol fumarate dihydrate in combination was not teratogenic with oral administration at up to 18.9/1.13 mg/kg/day, yielding almost 600 times the systemic exposure to beclometasone and 6 times the systemic exposure to formoterol in patients at the maximum recommended clinical dose (based on plasma AUC). Dystocia and litter loss, decreased fetal weight, increased fetal visceral variations, and impaired fetal ossification were observed in pregnant rats treated at ≥ 1.89/0.11 mg/kg/day (yielding approximately 120 times the systemic exposure to beclometasone and 0.2 times the systemic exposure to formoterol in patients at the maximum recommended clinical dose).
Fostair should only be used during pregnancy if the expected benefits outweigh the potential risks.
 There are no relevant clinical data on the use of Fostair in lactation in humans.
Although no data from animal experiments are available, it is reasonable to assume that beclometasone dipropionate is secreted in milk, like other corticosteroids. While it is not known whether formoterol passes into human breast milk, it has been detected in the milk of lactating animals.
Administration of Fostair to women who are breast-feeding should only be considered if the expected benefits outweigh the potential risks.

4.7 Effects on Ability to Drive and Use Machines

Fostair is unlikely to have any effect on the ability to drive and operate machinery.
However, adverse effects of Fostair include dizziness and visual disturbances such as blurred vision which could affect the ability to drive or use machines (see Section 4.8 Adverse Effects (Undesirable Effects)).

4.8 Adverse Effects (Undesirable Effects)

As Fostair contains beclometasone dipropionate and formoterol fumarate dihydrate, the type and severity of adverse reactions associated with each of the compounds may be expected. There is no incidence of additional adverse events following concurrent administration of the two compounds.
Undesirable effects which have been associated with beclometasone dipropionate and formoterol administered as a fixed combination (Fostair) and as single agents are given below, listed by system organ class. Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1,000 and < 1/100), rare (≥ 1/10,000, < 1/1,000) and very rare (≤ 1/10,000). Common and uncommon ADRs were derived from clinical trials in asthmatic and COPD patients. See Table 1.
As with other inhalation therapy, paradoxical bronchospasm may occur (see Section 4.4 Special Warnings and Precautions for Use).
Among the observed adverse reactions those typically associated with formoterol are:
hypokalaemia, headache, tremor, palpitations, cough, muscle spasms and prolongation of QTc interval.
Adverse reactions typically associated with the administration of beclometasone dipropionate are:
oral fungal infections, oral candidiasis, dysphonia, throat irritation.
Dysphonia and candidiasis may be relieved by gargling or rinsing the mouth with water or brushing the teeth after using the product. Symptomatic candidiasis can be treated with topical anti-fungal therapy whilst continuing the treatment with Fostair.
Systemic effects of inhaled corticosteroids (e.g. beclometasone dipropionate) may occur particularly when administered at high doses prescribed for prolonged periods, these may include adrenal suppression, decrease in bone mineral density, growth retardation in children and adolescents, cataract and glaucoma (also see Section 4.4 Special Warnings and Precautions for Use).
Hypersensitivity reactions including rash, urticaria pruritus, erythema and oedema of the eyes, face, lips and throat may also occur.

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

Inhaled doses of Fostair up to twelve cumulative actuations (total beclometasone dipropionate 1200 micrograms, formoterol 72 micrograms) have been studied in asthmatic patients. The cumulative treatments did not cause abnormal effect on vital signs and neither serious nor severe adverse events were observed.
Excessive doses of formoterol may lead to effects that are typical of beta2-adrenergic agonists: nausea, vomiting, headache, tremor, somnolence, palpitations, tachycardia, ventricular arrhythmias, prolongation of QTc interval, metabolic acidosis, hypokalaemia, hyperglycaemia.
In case of overdose of formoterol, supportive and symptomatic treatment is indicated. Serious cases should be hospitalised. Use of cardioselective beta-adrenergic blockers may be considered, but only subject to extreme caution since the use of beta-adrenergic blocker medication may provoke bronchospasm. Serum potassium should be monitored.
Acute inhalation of beclometasone dipropionate doses in excess of those recommended may lead to temporary suppression of adrenal function. This does not need emergency action as adrenal function recovers in a few days, as verified by plasma cortisol measurements. In these patients, treatment should be continued at a dose sufficient to control asthma.
Chronic overdose of inhaled beclometasone dipropionate: risk of adrenal suppression (see Section 4.4 Special Warnings and Precautions for Use). Monitoring of adrenal reserve may be necessary. Treatment should be continued at a dose sufficient to control asthma.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Drugs for obstructive airway diseases: Adrenergics, Inhalants ATC-code: R03 AK08.

Mechanism of action.

Fostair contains beclometasone dipropionate and formoterol. These two drugs have different modes of action. In common with other inhaled corticosteroids and beta2-adrenergic agonist combinations, additive effects are seen in respect of reduction in asthma exacerbations.

Beclometasone dipropionate (BDP).

Beclometasone dipropionate given by inhalation at recommended doses has a glucocorticoid anti-inflammatory action within the lungs, resulting in reduced symptoms and exacerbations of asthma with less adverse effects than when corticosteroids are administered systemically.

Formoterol.

Formoterol is a selective beta2-adrenergic agonist that produces relaxation of bronchial smooth muscle in patients with reversible airways obstruction. The bronchodilating effect sets in rapidly, within 1-3 minutes after inhalation, and has a duration of 12 hours after a single dose.

Clinical trials.

Asthma.

Maintenance therapy.

The efficacy of Fostair 100/6 as maintenance treatment for asthma was evaluated in randomized double blind, multicentre trials in patients with different degrees of asthma severity. The efficacy of Fostair 100/6 fixed combination was first evaluated in patients with mild to moderate asthma who were still symptomatic despite receiving low-dose ICS. Fostair 100/6 given at one inhalation twice daily proved to be more effective at improving lung function than a double equipotent dosage of BDP non-extrafine.
A second investigation was carried out in patients with more severe asthma. In this setting, Fostair 100/6 given as two inhalations twice daily was as effective as non-extrafine BDP and formoterol administered via separate inhalers, and superior to non-extrafine BDP alone in improving lung function. The study also showed that after 24-weeks of treatment with extrafine Fostair 100/6 delivered by an HFA pMDI, Fostair 100/6 was superior in improving asthma control to the combination of the same drugs formulated as larger non-extrafine agents at equipotent doses.
Two head-to-head clinical trials assessed the efficacy and tolerability of Fostair 100/6 vs budesonide/formoterol and fluticasone propionate/salmeterol. The two studies shared a similar study design. Subjects were allowed to enter the studies only if they had asthma symptoms and impaired lung function despite receiving ICS. In the first trial, patients given Fostair 100/6 as 2 inhalations twice daily showed improvement in lung function, measured by morning pre-dose Peak Expiratory Flow (PEF), which was comparable with an equipotent regimen of budesonide/formoterol administered as 2 inhalations twice daily. In the second trial, Fostair 100/6 was compared with fluticasone propionate/salmeterol, both administered as 2 inhalations twice daily. Fostair 100/6 demonstrated improvement in lung function comparable to that of fluticasone propionate/salmeterol.
The efficacy of Fostair 200/6, 2 puffs twice a day, was evaluated in a 12-week pivotal FORCE trial comparing the effect on lung function versus treatment with extrafine beclometasone dipriopionate monotherapy BDP 100 micrograms in asthmatic patients not adequately controlled with previous treatment (high dose ICS or medium dose ICS+LABA combinations). The study demonstrated the superiority of Fostair 200/6 micrograms compared to BDP 800 micrograms daily dose in terms of change from baseline in the average pre-dose morning PEF (adjusted mean difference 18.53 L).
In a 24-week pivotal trial the safety profile of Fostair 200/6, 2 puffs twice a day, was comparable to fixed dose combination fluticasone/salmeterol 500/50, 1 puff twice daily. No clinically relevant effect was observed with Fostair 200/6 on the HPA axis after 6 months of treatment. The study showed that both Fostair 200/6 micrograms and fluticasone/salmeterol were not superior to non extrafine beclometasone dipriopionate monotherapy (2000 micrograms/day) on the change in pre-dose morning FEV1 and percentage of complete days without asthma symptoms.

Maintenance and reliever therapy for Fostair 100/6 only.

In a 48-week parallel group study involving 1701 asthma patients, the efficacy of Fostair 100/6 administered as maintenance (1 inhalation BID) and reliever therapy (up to a total of 8 puffs per day) was compared to Fostair 100/6 administered as maintenance therapy (1 inhalation BID) plus as needed salbutamol, in adult patients with un-controlled moderate to severe asthma. The results demonstrated that Fostair 100/6 used as maintenance and reliever therapy significantly prolonged the time to first severe exacerbation (*) when compared with Fostair 100/6 used as maintenance plus as needed salbutamol (p < 0.001 for both ITT and PP population). The rate of severe asthma exacerbations per patients/year, was significantly reduced in the maintenance and reliever therapy group compared to salbutamol group: 0,1476 vs 0,2239 respectively (statistically significant reduction: p < 0.001). Patients in the Fostair 100/6 maintenance and reliever group achieved a clinically meaningful improvement in asthma control. The mean number of inhalations/day of reliever medication and the proportion of patients using reliever medication decreased similarly in both groups.
Note*: severe exacerbations were defined as deterioration in asthma resulting in hospitalisation or emergency room treatment or resulting in the need for systemic steroids for more than 3 days.
In another clinical study, a single dose of Fostair 100/6 provided a quick bronchodilation effect and a rapid relief from dyspnea symptoms similar to that of salbutamol 200 microgram/dose in asthmatic patients when metacholine challenge is used to induce bronchoconstriction.
COPD for Fostair 100/6 only. In two 48-weeks studies, the effects on lung function and the rate of exacerbation (defined as courses of oral steroids and/or course of antibiotics and/or hospitalisations) in patients with severe COPD (30% < FEV1% < 50%) was evaluated.
One pivotal trial in 1199 patients with severe COPD showed a significant improvement in lung function (primary endpoint change in pre-dose FEV1) compared to formoterol after 12 weeks of treatment (adjusted mean difference between Fostair 100/6 and formoterol: 69 mL) as well as at each clinic visit during the whole treatment period (48 weeks). The study demonstrated that the mean number of exacerbations per patient/year (exacerbation rate, co-primary endpoint) was statistically significantly reduced with Fostair 100/6 as compared with formoterol treatment (adjusted mean rate 0.80 compared with 1.12 in the formoterol group, adjusted ratio 0.72, p < 0.001). In addition, Fostair 100/6 statistically significantly prolonged the time to first exacerbation compared to formoterol. The superiority of Fostair 100/6 versus formoterol was also confirmed in terms of exacerbation rate in subgroups of patients taking (around 50% in each treatment arm) or not tiotropium bromide as concomitant medication.
The other pivotal study, which was a three arm, randomised, parallel group study in 718 patients, confirmed the superiority of Fostair 100/6 versus formoterol treatment in terms of change in pre-dose FEV1 at the end of treatment (48 weeks) and demonstrated the non-inferiority of Fostair 100/6 compared to budesonide/formoterol fixed dose combination on the same parameter.

5.2 Pharmacokinetic Properties

The systemic exposure to the active substances beclometasone dipropionate and formoterol in the fixed combination Fostair have been compared to the single components.
In a pharmacokinetic study conducted in healthy subjects treated with a single dose of Fostair 100/6 fixed combination (4 puffs of 100/6 micrograms) or a single dose of beclometasone dipropionate CFC (4 puffs of 250 micrograms) and formoterol HFA (4 puffs of 6 micrograms), the AUC of beclometasone dipropionate main active metabolite (beclometasone 17-monopropionate) and its maximal plasma concentration were, respectively, 35% and 19% lower with the fixed combination than with non-extrafine beclometasone dipropionate CFC formulation, in contrast, the rate of absorption was more rapid (0.5 vs 2h) with the fixed combination compared to non-extrafine beclometasone dipropionate CFC formulation alone.
For formoterol, maximal plasma concentration was similar after administration of the fixed or the separate combination and the systemic exposure was slightly higher after administration of Fostair 100/6 than with the separate combination.
There was no evidence of pharmacokinetic or pharmacodynamic (systemic) interactions between beclometasone dipropionate and formoterol.
In another pharmacokinetic study 12 healthy volunteers were treated with a single dose of Fostair 100/6 fixed combination (4 puffs of 100/6 micrograms) or a single dose of beclometasone dipropionate HFA, Qvar (4 puffs of 100 micrograms) and formoterol HFA, Atimos (2 puffs of 12 micrograms). The results showed similar formoterol PK parameters and a rapid systemic absorption and metabolisation of BDP to the active metabolite B17MP. Systemic exposure and peak concentration of BDP were lower after administration of the fixed combination than after administration of the separate combination. B17MP total systemic exposure was comparable and peak B17MP was slightly lower. Administration of formoterol and BDP as a free combination or as a fixed combination were both safe and well tolerated.
The use of Fostair 100/6 with Aerochamber Plus spacer increased the lung delivery of beclometasone dipropionate active metabolite beclometasone 17-monopropionate and formoterol by 41% and 45% respectively, in comparison to the use of standard actuator in a study conducted in healthy volunteers. The total systemic exposure was unchanged for formoterol, reduced by 10% for beclometasone 17-monopropionate and increased for unchanged beclometasone dipropionate.
A lung deposition study conducted in stable COPD patients, healthy volunteers and asthmatic patients, demonstrated that on average 33% of the nominal dose is deposited into the lung of COPD patients compared to 34% in healthy subjects and 31% in asthmatic patients. Beclometasone 17-monopropionate and formoterol plasma exposures were comparable across the three groups during the 24 hours following the inhalation. The total exposure of beclometasone dipropionate was higher in COPD patients compared to the exposure in asthmatic patients and healthy volunteers.
A pharmacokinetic study conducted in healthy volunteers with activated charcoal blockade demonstrated that the lung bioavailability of beclometasone-17-monopropionate in the Fostair 200/6 formulation is dose proportional with respect to that of the 100/6 strength for AUC only (mean ratio between systemic bioavailability in the 200/6 formulation and in the 100/6 strength equal to 91.63 (90 % Confidence Interval: 83.79; 100.20)). For formoterol fumarate the mean ratio between systemic bioavailability in the 200/6 formulation and in the 100/6 strength was equal to 86.15 (90% Confidence Interval: 75.94; 97.74).
In another pharmacokinetic study conducted in healthy volunteers without charcoal blockade, the systemic exposure of beclometasone-17-monopropionate in the Fostair 200/6 formulation was shown to be dose proportional with respect to that of the 100/6 strength (mean ratio between systemic bioavailability in the 200/6 formulation and in the 100/6 strength equal to 89.2 (90 % Confidence Interval: 79.8; 99.7)). The total systemic exposure of formoterol fumarate was unchanged (mean ratio between systemic bioavailability in the 200/6 formulation and in the 100/6 strength equal to 102.2 (90% Confidence Interval: 90.4; 115.5).
The use of Fostair 200/6 with a suitable spacer increased the lung delivery of beclometasone dipropionate active metabolite beclometasone 17-monopropionate and formoterol in healthy volunteers by 25 % and 32 % respectively, while the total systemic exposure was slightly reduced for beclometasone 17-monopropionate (by 17%) and formoterol (by 17%) and increased for unchanged beclometasone dipropionate (by 54%).

Beclometasone dipropionate.

Beclometasone dipropionate is a pro-drug with weak glucocorticoid receptor binding affinity that is hydrolysed via esterase enzymes to an active metabolite beclometasone 17-monopropionate which has a more potent topical anti-inflammatory activity compared with the pro-drug beclometasone dipropionate.
Absorption, distribution and metabolism. Inhaled beclometasone dipropionate is rapidly absorbed through the lungs; prior to absorption there is extensive conversion to its active metabolite beclometasone 17-monopropionate via esterase enzymes that are found in most tissues. The systemic availability of the active metabolite arises from lung (36%) and from gastrointestinal absorption of the swallowed dose. The bioavailability of swallowed beclometasone dipropionate is negligible however, pre-systemic conversion to beclometasone 17-monopropionate results in 41% of the dose being absorbed as the active metabolite.
There is an approximately linear increase in systemic exposure with increasing inhaled dose.
The absolute bioavailability following inhalation is approximately 2% and 62% of the nominal dose for unchanged beclometasone dipropionate and beclometasone 17-monopropionate respectively.
Following intravenous dosing, the disposition of beclometasone dipropionate and its active metabolite are characterised by high plasma clearance (150 and 120 L/h respectively), with a small volume of distribution at steady state for beclometasone dipropionate (20 L) and larger tissue distribution for its active metabolite (424 L).
Plasma protein binding is moderately high.
Excretion. Faecal excretion is the major route of beclometasone dipropionate elimination mainly as polar metabolites. The renal excretion of beclometasone dipropionate and its metabolites is negligible. The terminal elimination half-lives are 0.5 h and 2.7 h for beclometasone dipropionate and beclometasone 17-monopropionate respectively.

Special populations.

The pharmacokinetics of beclometasone dipropionate in patients with renal or hepatic impairment has not been studied; however, as beclometasone dipropionate undergoes a very rapid metabolism via esterase enzymes present in intestinal fluid, serum, lungs and liver, to originate the more polar products beclometasone 21-monopropionate, beclometasone 17-monopropionate and beclometasone, hepatic impairment is not expected to modify the pharmacokinetics and safety profile of beclometasone dipropionate.
As beclometasone dipropionate or its metabolites were not traced in the urine, an increase in systemic exposure is not envisaged in patients with renal impairment.

Formoterol.

Absorption and distribution. Following inhalation, formoterol is absorbed both from the lung and from the gastrointestinal tract. The fraction of an inhaled dose that is swallowed after administration with a metered dose inhaler (MDI) may range between 60% and 90%. At least 65% of the fraction that is swallowed is absorbed from the gastrointestinal tract. Peak plasma concentrations of unchanged drug occur within 0.5 to 1 hours after oral administration. Plasma protein binding of formoterol is 61-64% with 34% bound to albumin. There was no saturation of binding in the concentration range attained with therapeutic doses. The elimination half-life determined after oral administration is 2-3 hours. Absorption of formoterol is linear following inhalation of 12 to 96 micrograms of formoterol fumarate.
Metabolism. Formoterol is widely metabolised and the prominent pathway involves direct conjugation at the phenolic hydroxyl group. Glucuronide acid conjugate is inactive. The second major pathway involves O-demethylation followed by conjugation at the phenolic 2'-hydroxyl group. Cytochrome P450 isoenzymes CYP2D6, CYP2C19 and CYP2C9 are involved in the O-demethylation of formoterol. The liver appears to be the primary site of metabolism. Formoterol does not inhibit CYP450 enzymes at therapeutically relevant concentrations.
Excretion. The cumulative urinary excretion of formoterol after single inhalation from a dry powder inhaler increased linearly in the 12 - 96 micrograms dose range. On average, 8% and 25% of the dose was excreted as unchanged and total formoterol, respectively. Based on plasma concentrations measured following inhalation of a single 120 micrograms dose by 12 healthy subjects, the mean terminal elimination half-life was determined to be 10 hours. The (R,R)- and (S,S)-enantiomers represented about 40% and 60% of unchanged drug excreted in the urine, respectively. The relative proportion of the two enantiomers remained constant over the dose range studied and there was no evidence of relative accumulation of one enantiomer over the other after repeated dosing.
After oral administration (40 to 80 micrograms), 6% to 10% of the dose was recovered in urine as unchanged drug in healthy subjects; up to 8% of the dose was recovered as the glucuronide.
A total 67% of an oral dose of formoterol is excreted in urine (mainly as metabolites) and the remainder in the faeces. The renal clearance of formoterol is 150 mL/min.

Special populations.

The pharmacokinetics of formoterol has not been studied in patients with hepatic or renal impairment however, as formoterol is primarily eliminated via hepatic metabolism, an increased exposure can be expected in patients with severe liver cirrhosis.

5.3 Preclinical Safety Data

Genotoxicity.

Beclometasone dipropionate and formoterol fumarate dihydrate, tested in combination, were not mutagenic in bacterial reverse mutation assays, and not clastogenic in vitro in human lymphocytes or in vivo in the rat bone marrow micronucleus test.

Carcinogenicity.

No carcinogenicity studies have been performed with beclometasone dipropionate and formoterol fumarate dihydrate in combination. Data for the individual active components are described below.

Beclometasone dipropionate.

The potential carcinogenicity of beclometasone dipropionate has not been adequately investigated in animal studies. Other glucocorticoids (budesonide, prednisolone and triamcinolone acetate) have been shown to increase the incidence of hepatocellular tumours in rats by a non-genotoxic mechanism.

Formoterol fumarate.

In 2-year studies in mice and rats, treatment with formoterol fumarate, given via the diet or drinking water at very high doses, was associated with increases in several tumour types. In mice, these included hepatocellular adenoma and carcinomas (≥ 2 mg/kg/day), leiomyomas and leiomyosarcomas in the female reproductive tract (≥ 2 mg/kg/day) and adrenal subcapsular cell tumours (≥ 66 mg/kg/day). In rats, treatment was associated with benign granulosa/theca cell tumours in the ovaries (≥ 0.5 mg/kg/day), mesovarian leiomyomas (≥ 18 mg/kg/day), mammary adenocarcinomas (≥ 36 mg/kg/day) and thyroid C-cell neoplasms (46 mg/kg/day). A mesovarian leiomyoma was also observed in a female rat dosed by inhalation at 130 micrograms/kg/day for two years (approximately 30 times the maximum recommended human dose for Fostair, adjusted for body surface area).
Mammary adenocarcinomas, smooth muscle tumours in the female reproductive tract and effects on the ovary have been reported in rats and mice treated with other beta2-adrenergic agonists and are likely to be secondary to prolonged stimulation of beta2-adrenoceptors in these tissues.
Pre-clinical data on the CFC-free propellant HFA-134a reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction.

6 Pharmaceutical Particulars

6.1 List of Excipients

Norflurane, ethanol absolute, hydrochloric acid.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

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

Fostair 100/6.

120 actuations; 180 actuations.

Prior to dispensing: Store in a refrigerator (2-8°C) (for a maximum of 15 months). Do not freeze.
After dispensing: Store below 30°C (for a maximum of 2 months).

Multipack (120 actuations).

Prior and after dispensing: Store in a refrigerator (2-8°C) for a maximum of 15 months. Do not freeze.
After first use: Store below 30°C (for a maximum of 2 months).

Fostair 200/6.

120 actuations.

Prior to dispensing: Store in a refrigerator (2-8°C) for a maximum of 15 months. Do not freeze.
After dispensing: Store below 30°C (for a maximum of 2 months).

Multipack (120 actuations).

Prior and after dispensing: Store in a refrigerator (2-8°C) for a maximum of 15 months. Do not freeze.
After first use: Store below 30°C (for a maximum of 2 months).
The canister contains a pressurised liquid. Do not expose to temperatures higher than 50°C. Do not pierce the canister.

For pharmacists.

Single packs.

Enter the date of dispensing to the patient on the pack.

Multipacks.

Advise the patient to enter the date of first use on the removable first use label and affix to the actuator.
Ensure that there is a period of at least 2 months between the date of dispensing and the expiry date printed on the pack.

6.5 Nature and Contents of Container

The inhalation solution is contained in a pressurised aluminium container sealed with a metering valve. The canister is inserted into a polypropylene plastic actuator which incorporates a mouthpiece and is fitted with a plastic protective cap.
The actuator has a dose counter (120 doses pack) or a dose indicator (180 doses pack). The dose counter/indicator will show the number of actuations left in the canister through a window in the plastic actuator.

Fostair 100/6 pack sizes.

Pack of 1 container with either 120 or 180 actuations.
Multipack containing 240 actuations (2 containers of 120 actuations each).

Fostair 200/6 pack sizes.

Pack of 1 container with 120 actuations.
Multipack containing 240 actuations (2 containers of 120 actuations each).
Not all pack sizes may be marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.


CAS number.

Beclometasone dipropionate: 5534-09-8.
Formoterol fumarate dihydrate: 183814-30-4.

7 Medicine Schedule (Poisons Standard)

Schedule 4.

Summary Table of Changes