Consumer medicine information

Bufomix Easyhaler

Budesonide; Formoterol (eformoterol) fumarate dihydrate

BRAND INFORMATION

Brand name

Bufomix Easyhaler

Active ingredient

Budesonide; Formoterol (eformoterol) fumarate dihydrate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Bufomix Easyhaler.

SUMMARY CMI

Bufomix Easyhaler®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using Bufomix Easyhaler?

Bufomix Easyhaler contains the active ingredients budesonide and formoterol fumarate dihydrate. Bufomix Easyhaler is used to help prevent breathing problems such as Asthma and Chronic Obstructive Pulmonary Disease (COPD).

For more information, see Section 1. Why am I using Bufomix Easyhaler? in the full CMI.

2. What should I know before I use Bufomix Easyhaler?

Do not use if you have ever had an allergic reaction to Bufomix Easyhaler or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use Bufomix Easyhaler? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Bufomix Easyhaler and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use Bufomix Easyhaler?

  • Use Bufomix Easyhaler every day as directed by your doctor. This will make sure that it works properly in controlling your asthma or COPD.

More instructions can be found in Section 4. How do I use Bufomix Easyhaler? in the full CMI.

5. What should I know while using Bufomix Easyhaler?

Things you should do
  • Remind any doctor, dentist, surgeon, anaesthetist or pharmacist you visit that you are using Bufomix Easyhaler.
  • Rinse your mouth after using Bufomix Easyhaler
Things you should not do
  • Do not stop using this medicine suddenly.
Driving or using machines
  • Bufomix Easyhaler is unlikely to affect your ability to drive or use machinery but you should be careful until you know how Bufomix Easyhaler affects you.
Looking after your medicine
  • Store Bufomix Easyhaler below 25°C and protect from moisture.
  • Keep the inhaler in the foil bag until you are ready to start using it
  • Place the inhaler in the protective cover provided after you take it out of the foil bag.

For more information, see Section 5. What should I know while using Bufomix Easyhaler? in the full CMI.

6. Are there any side effects?

Common side effects include sore, yellowish, raised patches in the mouth (thrush); shakiness; headache and rapid heartbeat.

Tell your doctor if you notice you feel more wheezy, your chest may feel tight more often or you have increased coughing or breathing problems.

Some side effects can only be found when your doctor does tests from time to time to check your progress.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

Bufomix Easyhaler®

Active ingredients: Budesonide and Formoterol fumarate dihydrate

Consumer Medicine Information (CMI)

This leaflet provides important information about using Bufomix Easyhaler. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Bufomix Easyhaler.

Where to find information in this leaflet:

1. Why am I using Bufomix Easyhaler?
2. What should I know before I use Bufomix Easyhaler?
3. What if I am taking other medicines?
4. How do I use Bufomix Easyhaler?
5. What should I know while using Bufomix Easyhaler?
6. Are there any side effects?
7. Product details

1. Why am I using Bufomix Easyhaler?

Bufomix Easyhaler contains two active ingredients, budesonide and formoterol (as formoterol fumarate dihydrate).

  • Budesonide is a corticosteroid which reduces swelling and irritation in the lungs.
  • Formoterol belongs to a group of medicines called ‘long acting beta-2 agonists’ or ‘bronchodilators’. Bronchodilators help the airways in the lungs to stay open. This makes it easier for air to get in and out to help you breathe more easily. The effects last for up to 12 hours

Bufomix Easyhaler is used to help prevent breathing problems such as:

  • Asthma
  • Chronic Obstructive Pulmonary Disease (COPD)

Bufomix Easyhaler can be used by some people with asthma to treat the symptoms when their asthma gets worse and to prevent asthma attacks or symptoms from happening.

Bufomix Easyhaler also helps to prevent breathlessness and wheeziness in people who need regular treatment.

2. What should I know before I use Bufomix Easyhaler?

Warnings

Do not use Bufomix Easyhaler if:

  • you are allergic to budesonide, formoterol fumarate dihydrate, or any of the ingredients listed at the end of this leaflet.
  • Always check the ingredients to make sure you can use this medicine.

If you have breathing difficulties or wheezing that get worse straight after using Bufomix Easyhaler stop using your Bufomix Easyhaler inhaler. Use your fast-acting ‘reliever’ inhaler to help your breathing and tell your doctor straight away.

Check with your doctor if you:

  • have or have had any other medical conditions especially the following:
    - thrush in your mouth
    - tuberculosis
    - diabetes
    - a thyroid condition
    - high blood pressure
    - heart problems including an irregular or fast heartbeat
    - liver problems
    - low levels of potassium in your blood
  • take any medicines for any other condition

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

3. What if I am taking other medicines?

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

Some medicines may interfere with Bufomix Easyhaler and affect how it works.

Tell your doctor about any other medicines you are taking especially the following:

  • Beta-blockers (such as atenolol, metoprolol, propranolol) used to treat high blood pressure and other heart conditions
  • Ketoconazole, a medicine used to treat fungal infections.
  • Medicines used to treat irregular heartbeats such as disopyramide, procainamide and quinidine
  • Medicines used to treat depression or other mood/mental disorders such as tricyclic antidepressants, monoamine oxidase inhibitors and phenothiazines
  • Medicines used to treat hayfever, coughs, colds and runny nose such as antihistamines
  • Diuretics (sometimes called fluid tablets) that are used to treat high blood pressure and heart problems
  • Xanthine derivatives (such as theophylline) which are a class of medicines used to treat asthma and COPD
  • Any other steroid medicines (taken by mouth or as an injection) used to treat swelling, inflammation or breathing problems.

These medicines may be affected by Bufomix Easyhaler or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect Bufomix Easyhaler.

4. How do I use Bufomix Easyhaler?

How much to use

Follow the instructions provided by your doctor about how to use Bufomix Easyhaler.

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

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

For Asthma

Your doctor will prescribe Bufomix Easyhaler for you to use as either:

  • an anti-inflammatory reliever medicine only,
  • both an anti-inflammatory reliever and a daily maintenance preventer medicine; or,
  • as a daily maintenance preventer only, where another medicine is used as a reliever.

Anti-inflammatory reliever medicine (Bufomix Easyhaler 200/6)

Adults and children over 12 years

  • When you get asthma symptoms, take 1 inhalation and wait a few minutes. If you do not feel better, take another inhalation.
  • If you use Bufomix Easyhaler to help stop asthma symptoms from happening (for example, just before exercise or before you get exposed to other things that cause symptoms), your doctor will tell you how many inhalations to take.
  • Do not use more than 6 inhalations on a single occasion or more than 12 inhalations in any day.
  • If your symptoms continue to get worse over 3 days, despite using your inhaler, tell your doctor.
  • Always keep your Bufomix Easyhaler reliever with you.

Anti-inflammatory reliever and a daily maintenance preventer medicine (Bufomix Easyhaler 200/6)

Adults and children over 12 years

  • Your doctor may tell you to use Bufomix Easyhaler every day to help prevent asthma symptoms. This is called a ‘maintenance dose’.
  • The usual maintenance dose is 2 inhalations per day of Bufomix Easyhaler 200/6. This is taken as either 1 inhalation in the morning and evening or as 2 inhalations in the morning or evening. Depending on your Asthma doctor may tell you to use 2 inhalations twice a day of Bufomix Easyhaler 200/6.
  • When you get asthma symptoms, take 1 inhalation of Bufomix Easyhaler 200/6 and wait a few minutes. If you do not feel better, take another inhalation.
  • If you also use Bufomix Easyhaler to help stop asthma symptoms from happening, just before exercise or before you get exposed to other things that cause symptoms, your doctor will tell you how many inhalations to take.
  • Do not use more than 6 inhalations on a single occasion or more than 12 inhalations in any day.
  • If your symptoms continue to get worse over 3 days, despite using your inhaler, tell your doctor.
  • Always keep your Bufomix Easyhaler reliever with you.

Daily fixed dose maintenance therapy (Bufomix Easyhaler 200/6 and 400/12)

  • For adults and children over 12 years, the usual maintenance dose is 1 or 2 inhalations per day of Bufomix Easyhaler 200/6 taken twice a day.
  • Patients over 18 years who need a higher dose can take up to 2 inhalations of Bufomix Easyhaler 400/12 twice a day.
  • Use Bufomix Easyhaler every day as directed by your doctor. This will make sure that it works properly in controlling your asthma or COPD.
  • Do not take more than 2 inhalations twice a day of 200/6 or 400/12.
  • Your doctor will tell you what dose to take. You should use Bufomix Easyhaler every day to help control your asthma.
  • Always keep your separate reliever medicine with you.

For Chronic Obstructive Pulm onary Disease (COPD)

Adults

  • 2 inhalations of Bufomix Easyhaler 200/6 twice daily
    or
  • 1 inhalation of Bufomix Easyhaler 400/12 twice daily.
  • Use Bufomix Easyhaler every day as directed by your doctor. This will make sure that it works properly in controlling your COPD.

When to use Bufomix Easyhaler

  • Your doctor will tell you how to use Bufomix Easyhaler depending on you condition and the best way to control your asthma or COPD.

If your asthma or breathing gets worse tell your doctor straight away. You may feel more wheezy, your chest may feel tight more often or you may need to use more of your fast acting ‘reliever’ medicine. This may mean your chest condition is getting worse and you could become seriously ill. If any of these happen, you should continue to take Bufomix Easyhaler and see your doctor as you may need additional treatment.

How to use Bufomix Easyhaler

Bufomix Easyhaler is for inhalation through the mouth only.

Bufomix Easyhaler is easy to use. Read through these instructions first: they tell you what you should do and what to look out for.

Unpack the inhaler

Take the inhaler out of its packaging. It comes in a laminate pouch to keep the powder dry. Only take it out of the pouch when you are ready to start using it.

The inhaler should come with a dust cap on the mouthpiece (Figure 1). The carton will also include a protective cover.

Figure 1

After removal from the laminate pouch, you must fit the inhaler into its protective cover which helps improve the durability of the product.

To fit the inhaler into the protective cover, open up the protective cover (Figure 2a). Ensure the dustcap (dark purple/blue cap) covers the mouthpiece of inhaler (this stops the inhaler going off by accident) before inserting the inhaler into the protective cover. Close the protective cover until you hear a click to ensure tight seal.

Figure 2a

The inhaler should remain inside the protective cover at all times until dosing. (Figure 2b)

Figure 2b

Discard the inhaler after 1 month after removal from the laminate pouch. The inhaler label includes a space for you to write the date when you should discard the inhaler.

How to take a dose from Bufomix Easyhaler

  1. Shake
  • Remove the dust cap.
  • Hold the inhaler upright, gripping it between your finger and thumb
  • Shake the device vigorously up and down three to five times. This is to make sure the powder flows properly and gives the correct dose (Figure 3).

Figure 3

  • Make sure you shake it up and down and you do not click it while you shake it.
  1. Click
  • Make sure the dust cap is not on the inhaler, it will stop you clicking it.
  • Still holding the inhaler upright, squeeze until you hear a click, and let it click back again. This delivers powder into the inhalation channel inside the mouthpiece (Figure 4).

Figure 4

  1. Inhale

In the sitting or standing position

  • Breathe out normally
  • Place the mouthpiece in your mouth between your teeth and close your lips tightly around the mouthpiece to make a good seal (Figure 5).

Figure 5

  • Make sure the whole mouthpiece is well inside your mouth, so the powder does not go on your teeth
  • Take a strong and deep breath in
  • Take the inhaler out of your mouth and, then breathe out gently away from the inhaler.
  • Do not breathe out into the inhaler. This is important: it could clog up the inhaler. If you breathed out into the inhaler, see section “If you have problems using the inhaler”

If you have problems using the inhaler

  • Do not rush things. It is important to breathe normally. Practice a few times, in front of the mirror if this helps.
  • If you click the inhaler by accident, or if you might have clicked it more than once, or if you breathe out into it, tap the mouthpiece to empty the powder onto a table top, or the palm of your hand (Figure 6). This ensures proper dosing. Then start again with steps 1, 2 and 3.

Figure 6

If you are to take a second inhalation

  • Start again with steps 1, 2 and 3 (Note that you need to shake the device again as instructed in step 1).

After you have used the inhaler

  • Put the dust cap back on the mouthpiece and close the protective cover.
  • Rinse your mouth with water and spit it out after you use Bufomix Easyhaler.

Cleaning the Easyhaler

  • Clean the Easyhaler's mouthpiece at least once a week with a dry cloth. Do not use water: the powder in the Easyhaler is sensitive to moisture. You can take the Easyhaler out of the protective cover to wipe it. When you are putting it back into its protective cover, put the dust cap on the mouthpiece to stop it going off accidentally.

Getting a new Easyhaler

  • The inhaler has a dose counter which shows how many doses are left. The counter turns after every fifth actuation (Figure 7). When the numbers go red, there are 20 doses left. If you do not already have a new Easyhaler, contact your doctor for a new prescription. When the counter reaches 0, you need to replace the Easyhaler.

Figure 7

For more information on how to use Bufomix Easyhaler please visit www.orionpharma.com.au/patient.

If you forget to use Bufomix Easyhaler

Bufomix Easyhaler should be used regularly at the same time each day.

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

Do not take a double dose to make up for the dose you missed.

  • If you become wheezy or feel tight in the chest before the next dose is due, use a 'reliever inhaler' in the usual way. You should get relief from your 'reliever inhaler' within a few minutes.

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

If you use too much Bufomix Easyhaler

If you think that you have used too much Bufomix Easyhaler, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

The most common symptoms that may occur if you too much Bufomix Easyhaler are trembling, headache, breathing faster than usual a rapid heartbeat or increased levels of blood sugar.

5. What should I know while using Bufomix Easyhaler?

Things you should do

Remind any doctor, dentist or pharmacist you visit that you are using Bufomix Easyhaler.

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

  • It may affect other medicines used during surgery.
  • It is important that all doctors treating you are aware that you are on inhaled steroids. If your body is stressed by, for example, severe infection, surgical operation, an accident etc, you may need steroid tablets or injections for a time.

Rinse your mouth after using Bufomix Easyhaler

  • Some people find that their mouth, throat or tongue becomes sore or that their voice becomes hoarse after inhaling this medicine. It may be helpful to rinse your mouth with water and spit it out after using your Bufomix Easyhaler. Tell your doctor but do not stop treatment unless told to do so.

Call your doctor straight away if you:

  • experience a change in your vision

Things you should not do

  • Do not stop using this medicine suddenly. If you stop using it suddenly, your condition may worsen, or you may have unwanted side effects. Check with your doctor before you stop using this medicine. If possible, your doctor will gradually reduce the amount you take each day before stopping the medicine completely.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how Bufomix Easyhaler affects you.

Looking after your medicine

  • Store Bufomix Easyhaler below 25°C and protect from moisture.
  • Keep the inhaler in the foil bag until you are ready to start using it.
  • Place the inhaler in the protective cover when you take it out of the foil bag.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

When to discard your medicine

Replace your Bufomix Easyhaler inhaler 1 month after first opening the foil bag.

If your Bufomix Easyhaler gets damp, you need to replace it with a new one.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Allergic reactions:

You may notice your breathing suddenly gets worse after using Bufomix Easyhaler. You may be very wheezy and cough. You may also notice itching and swelling (usually of the face, lips, tongue, or throat). If you get these effects or if they happen suddenly after using Bufomix Easyhaler, tell your doctor straight away or go to Accident and Emergency at your nearest hospital.

Common Side Effects

  • sore, yellowish, raised patches in the mouth (thrush)
  • soreness in the mouth, throat, or tongue
  • hoarseness
  • headache
  • shakiness
  • pains in joints
  • increase in heart rate

Pneumonia (lung infection) has been reported commonly in patients with COPD. Tell your doctor if you notice any of the following symptoms:

  • increase in sputum production
  • change in sputum colour
  • fever, chills
  • increased cough and increased breathing problems.

Uncommon Side Effects

  • skin rash
  • shortness of breath
  • sweating, trembling, feeling
  • nervous or anxious
  • weight gain
  • changes in vision
  • sleep disturbances
  • muscle cramps
  • dizziness

Rare Side Effects

  • behavioural changes, including unusual activity and irritability
  • rounded face
  • bruising
  • slowing of growth in children and adolescents
  • irregular heartbeat
  • chest pain

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

Some side effects can only be found when your doctor does tests from time to time to check your progress, for example:

  • increases in blood sugar (glucose) levels
  • changes in blood pressure
  • loss of bone density
  • reduced potassium levels in the blood
  • changes in the function of the adrenal glands, which make the body's own steroids

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

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

What Bufomix Easyhaler contains

Active ingredients
(main ingredients)		Metered doseDelivered dose
200 or 400 micrograms budesonide
and
6 or 12 micrograms formoterol fumarate dihydrate*		160 or 320 micrograms budesonide
and
4.5 or 9 micrograms formoterol fumarate dihydrate*
Other ingredients
(inactive ingredients)		Lactose monohydrate
Potential allergensLactose monohydrate
Milk proteins

*abbreviated to formoterol for ease of reference

Do not take this medicine if you are allergic to any of these ingredients.

What Bufomix Easyhaler looks like

Bufomix Easyhaler is a dry powder inhaler device that contains a white to yellowish powder. Each Easyhaler multiple dose powder inhaler is individually sealed in a foil bag and is provided in a carton together with a protective cover.

Bufomix Easyhaler 200/6 (AUST R 338159): 1 inhaler per carton, each inhaler contains 60 inhalations.

Bufomix Easyhaler 400/12 (AUST R 338160): 1 inhaler per carton, each inhaler contains 60 inhalations.

Who distributes Bufomix Easyhaler

Orion Pharma (Aus) Pty Limited
Level 24, Tower 3
300 Barangaroo Avenue, Sydney, NSW 2000, Australia
Telephone: 1800 861 913

This leaflet was prepared in February 2024.

Published by MIMS April 2024

BRAND INFORMATION

Brand name

Bufomix Easyhaler

Active ingredient

Budesonide; Formoterol (eformoterol) fumarate dihydrate

Schedule

S4

 

1 Name of Medicine

Budesonide.
Formoterol fumarate dihydrate.

2 Qualitative and Quantitative Composition

Bufomix Easyhaler is available as a multidose inspiratory flow driven, metered dose dry powder inhaler. For ease of reference, formoterol, formoterol fumarate or formoterol fumarate dihydrate have been used throughout the rest of this document.
The following strengths are registered:

Bufomix Easyhaler 200/6.

Each delivered dose (the dose that leaves the mouthpiece) contains as active constituents: budesonide 160 microgram/inhalation and formoterol 4.5 microgram/inhalation.

Bufomix Easyhaler 400/12.

Each delivered dose (the dose that leaves the mouthpiece) contains as active constituents: budesonide 320 microgram/inhalation and formoterol 9 microgram/inhalation.
To avoid confusion, Bufomix Easyhaler is labelled as the metered dose of the monotherapy products budesonide and formoterol dry powders for inhalation. The monotherapy products are also labelled as metered doses. Table 1 gives the corresponding dose delivered to the patient.

List of excipients with known effect.

Lactose monohydrate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Powder for inhalation in a multiple dose dry powder inhaler.

4 Clinical Particulars

4.1 Therapeutic Indications

Asthma.

Bufomix Easyhaler is indicated in adults and adolescents (12 years and older), for the treatment of asthma, to achieve overall asthma control, including the relief of symptoms and the reduction of the risk of exacerbations (see Section 4.2 Dose and Method of Administration).

Chronic obstructive pulmonary disease (COPD).

Bufomix Easyhaler is indicated for the symptomatic treatment of moderate to severe COPD (FEV1 ≤ 50% predicted normal) in adults with frequent symptoms despite long-acting bronchodilator use, and/or a history of recurrent exacerbations. Bufomix Easyhaler is not indicated for the initiation of bronchodilator therapy in COPD.

4.2 Dose and Method of Administration

Budesonide 80 microgram/formoterol 4.5 microgram per inhalation strength (100/6 metered dose) is available in another brand.

Asthma.

Bufomix Easyhaler can be used according to different treatment approaches:
A. Bufomix Easyhaler anti-inflammatory reliever therapy (patients with mild disease).
B. Bufomix Easyhaler anti-inflammatory reliever plus maintenance therapy.
C. Bufomix Easyhaler maintenance therapy (fixed dose).
Bufomix Easyhaler anti-inflammatory reliever therapy (patients with mild disease). Bufomix Easyhaler 200/6 is taken as needed for the relief of asthma symptoms when they occur, and as a preventative treatment of symptoms in those circumstances recognised by the patient to precipitate an asthma attack. Patients should be advised to always have Bufomix Easyhaler 200/6 available for relief of symptoms.
Preventative use of Bufomix Easyhaler 200/6 for allergen- or exercise-induced bronchoconstriction (AIB/EIB) should be discussed between physician and patient; the recommended dose frequency should take into consideration both allergen exposure and exercise patterns.

Adults and adolescents (12 years and older).

Patients should take 1 inhalation of Bufomix Easyhaler 200/6 as needed in response to symptoms. If symptoms persist after a few minutes, an additional inhalation should be taken. No more than 6 inhalations should be taken on any single occasion.
A total daily dose of more than 8 inhalations is normally not needed, however a total daily dose of up to 12 inhalations can be used temporarily. If the patient experiences a three-day period of deteriorating symptoms after taking additional as needed inhalations, the patient should be reassessed for alternative explanations of persisting symptoms.
Bufomix Easyhaler anti-inflammatory reliever plus maintenance therapy. When maintenance treatment with a combination of inhaled corticosteroid (ICS) and long-acting β2-agonist (LABA) is required, patients take Bufomix Easyhaler anti-inflammatory reliever therapy and in addition take a daily maintenance dose of Bufomix Easyhaler. The as needed inhalations provide both rapid relief of symptoms and improved overall asthma control. Patients should be advised to have Bufomix Easyhaler available for relief of symptoms at all times.
Preventative use of Bufomix Easyhaler 200/6 for AIB/EIB should be discussed between physician and patient; the recommended dose frequency should take into consideration both allergen exposure and exercise patterns.
The Bufomix Easyhaler 400/12 strength should not be used for the anti-inflammatory reliever plus maintenance therapy regimen.

Adults and adolescents (12 years and older).

Patients should take 1 inhalation Bufomix Easyhaler 200/6 as needed in response to symptoms to control asthma. If symptoms persist after a few minutes, another inhalation should be taken. No more than 6 inhalations should be taken on any single occasion.
Patients also take the recommended maintenance dose of Bufomix Easyhaler 200/6, which is two inhalations per day, given as either one inhalation in the morning and evening or as two inhalations in either the morning or evening. For some patients, a maintenance dose of Bufomix Easyhaler 200/6 two inhalations twice daily may be appropriate. The maintenance dose should be titrated to the lowest dose at which effective control of asthma is maintained.
A total daily dose of more than 8 inhalations is normally not needed, however a total daily dose of up to 12 inhalations can be used temporarily. If the patient experiences a three-day period of deteriorating symptoms after taking the appropriate maintenance therapy and additional as needed inhalations, the patient should be reassessed for alternative explanations of persisting symptoms.
Bufomix Easyhaler maintenance therapy (fixed dose). When maintenance treatment with a combination of ICS and LABA is required, Bufomix Easyhaler is taken as a fixed daily dose treatment, with a separate short-acting bronchodilator for relief of symptoms. Patients should be advised to have their separate short-acting bronchodilator available for relief of symptoms at all times.
Increasing use of short-acting bronchodilators indicates a worsening of the underlying condition and warrants reassessment of the asthma therapy. The dosage of Bufomix Easyhaler should be individualised according to disease severity. When control of asthma has been achieved, the maintenance dose should be titrated to the lowest dose at which effective asthma control is maintained.

Adults and adolescents (12 years and older).

Bufomix Easyhaler 200/6.

1-2 inhalations of Bufomix Easyhaler 200/6 twice daily. The maximum recommended daily maintenance dose is 4 inhalations (2 inhalations twice daily corresponding to 800 microgram budesonide/24 microgram formoterol).

Adults (18 years and over) who require a higher daily maintenance dose (1600/48).

Bufomix Easyhaler 400/12.

2 inhalations of Bufomix Easyhaler 400/12 twice daily. The maximum recommended daily maintenance dose is 4 inhalations (corresponding to 1600 microgram budesonide/48 microgram formoterol). When control of asthma has been achieved, the dose can be decreased to 1 inhalation twice daily.

COPD.

Adults.

Bufomix Easyhaler 200/6.

2 inhalations of Bufomix Easyhaler 200/6 twice daily. The maximum recommended daily dose is 4 inhalations (corresponding to 800 microgram budesonide/24 microgram formoterol).

Bufomix Easyhaler 400/12.

1 inhalation of Bufomix Easyhaler 400/12 twice daily. The maximum recommended daily dose is 2 inhalations (corresponding to 800 microgram budesonide/24 microgram formoterol).

General information.

If patients take Bufomix Easyhaler as an anti-inflammatory reliever (either alone or in combination with maintenance therapy) physicians should discuss allergen exposure and exercise patterns with the patients and take these into consideration when recommending the dose frequency for asthma treatment.
If patients take Bufomix Easyhaler as a maintenance therapy, they should be instructed that Bufomix Easyhaler must be used even when asymptomatic for optimal benefit.

Special patient populations.

Renal impairment.

There are no data available for use of Bufomix Easyhaler in patients with renal impairment.

Hepatic impairment.

There are no data available for use of Bufomix Easyhaler in patients with hepatic impairment. As budesonide and formoterol are primarily eliminated via hepatic metabolism an increased systemic availability can be expected in patients with severe liver disease.

Use in the elderly.

There are no special dosing requirements for elderly patients.

Use in paediatric patients.

Bufomix Easyhaler is not recommended for children below 12 years of age.

Method of administration.

Bufomix Easyhaler is for inhalation only. The inhaler is inspiratory flow-driven, which means that when the patient inhales through the mouthpiece, the substance will follow the inspired air into the airways. A dose counter on the Easyhaler indicates the number of doses left.
Instructions to the patient for the correct use of Bufomix Easyhaler.

Note.

It is important to instruct the patient:
To carefully read the instructions for use in the patient instruction leaflet which is packed together with each inhaler.
To hold the inhaler upright, gripping it between finger and thumb.
To vigorously shake the inhaler up and down 3 to 5 times before actuation.
To actuate (click) the inhaler before inhalation.
To breathe in forcefully and deeply through the mouthpiece to ensure that an optimal dose is delivered to the lungs.
Never to breathe out through the mouthpiece as this will result in a reduction in the delivered dose. Should this happen the patient is instructed to tap the mouthpiece onto a tabletop or the palm of a hand to empty the powder, and then to repeat the dosing procedure.
Never to actuate the device more than once without inhalation of the powder. Should this happen the patient is instructed to tap the mouthpiece onto a tabletop or the palm of a hand to empty the powder, and then to repeat the dosing procedure.
To always replace the dust cap on to the mouthpiece of the inhaler after use to prevent accidental actuation of the device, which could result in either overdosing or under dosing the patient when subsequently used.
To ensure that the inhaler closed with the dust-cap is always enclosed inside the protective cover unless it is needed for dosing. This helps improve the durability of the product.
To rinse the mouth out with water and/or brush teeth after inhaling the maintenance dose to minimise the risk of oropharyngeal thrush.
Water should never be used for cleaning the inhaler because the powder is sensitive to moisture.
To replace Bufomix Easyhaler when the counter reaches zero even though powder could still be observed within the inhaler.
For more detailed instructions for use refer to the patient instruction leaflet.

4.3 Contraindications

Hypersensitivity to budesonide, formoterol or lactose.

4.4 Special Warnings and Precautions for Use

Treatment of asthma or COPD should be in accordance with physician recommendations or current national treatment guidelines.
Patients with asthma should have a personal asthma action plan designed in association with their healthcare professional. This plan should incorporate a stepwise treatment regime which can be instituted if the patient's asthma improves or deteriorates.
Patients should be advised to have their reliever available at all times, either Bufomix Easyhaler (for asthma patients on Bufomix Easyhaler anti-inflammatory reliever therapy and Bufomix Easyhaler anti-inflammatory reliever plus maintenance therapy) or a separate short-acting bronchodilator (for other asthma patients using Bufomix Easyhaler as fixed dose maintenance therapy only and for COPD patients).
Sudden and progressive deterioration in control of asthma or COPD is potentially life threatening and the patient should undergo urgent medical assessment. In this situation, consideration should be given to the need for increased therapy with corticosteroids (e.g. a course of oral corticosteroids), or antibiotic treatment if a bacterial infection is present. For treatment of severe exacerbations, a combination product of ICS and LABA alone is not sufficient. Patients should be advised to seek medical attention if they find the treatment ineffective or they have exceeded the prescribed dose of Bufomix Easyhaler.
It is recommended that the maintenance dose is tapered when long-term treatment is discontinued, and the dosing should not be stopped abruptly. Complete withdrawal of ICS should not be considered unless it is temporarily required to confirm the diagnosis of asthma.

Oral corticosteroid usage.

Bufomix Easyhaler should not be used to initiate treatment with inhaled steroids in patients being transferred from oral steroids. Care should be taken when commencing Bufomix Easyhaler treatment, particularly if there is any reason to suspect that adrenal function is impaired from previous systemic steroid therapy.

Potential systemic effects of ICS.

ICS are designed to direct glucocorticoid delivery to the lungs in order to reduce overall systemic glucocorticoid exposure and side effects. However, in higher than recommended doses, ICS may have adverse effects; possible systemic effects of ICS include depression of the HPA axis, reduction of bone density, cataract and glaucoma, and retardation of growth rate in children and adolescents. In steroid-dependent patients, prior systemic steroid usage may be a contributing factor, but such effects may occur amongst patients who use only ICS regularly.

HPA axis suppression and adrenal insufficiency.

Dose-dependent HPA axis suppression (as indicated by 24 hour urinary and/or plasma cortisol AUC) has been observed with inhaled budesonide, although the physiological circadian rhythms of plasma cortisol were preserved. This indicates that the HPA axis suppression represents a physiological adaption in response to inhaled budesonide, not necessarily adrenal insufficiency. The lowest dose that results in clinically relevant adrenal insufficiency has not been established. Very rare cases of clinically relevant adrenal dysfunction have been reported in patients using inhaled budesonide at recommended doses.
Clinically important disturbances of the HPA axis and/or adrenal insufficiency induced by severe stress (e.g. trauma, surgery, infection in particular gastroenteritis or other conditions associated with severe electrolyte loss) may be related to inhaled budesonide in specific patient populations. These are patients with prolonged treatment at the highest recommended dose of Bufomix Easyhaler and patients administered concomitant CYP3A4 inhibitors (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Monitoring for signs of adrenal dysfunction is advisable in these patient groups. For these patients additional systemic glucocorticosteroid treatment should be considered during periods of stress, a severe asthma attack or elective surgery.

Bone density.

Whilst corticosteroids may have an effect on bone mass at high doses, long term follow up (3-6 years) studies of budesonide treatment in adults at recommended doses, have not demonstrated a negative effect on bone mass compared to placebo, including one study conducted in patients with a high risk of osteoporosis. The lowest dose that does effect bone mass has not been established.
Bone mineral density measurements in children should be interpreted with caution as an increase in bone area in growing children may reflect an increase in bone volume. In three large, medium to long term (12 months-6 years) studies in children (5-16 years), no effects on bone mineral density were observed after treatment with budesonide (189-1322 microgram/day) compared to nedocromil, placebo or age matched controls. However, in a randomised 18-month paediatric study (n = 176; 5-10 years), bone mineral density was significantly decreased by 0.11 g/cm2 (p = 0.023) in the group treated with inhaled budesonide compared with the group treated with inhaled disodium cromoglycate. The dose of budesonide was 400 microgram twice daily for 1 month, 200 microgram twice daily for 5 months and 100 microgram twice daily for 12 months and the dose of disodium cromoglycate 10 mg three times daily. The clinical significance of this result remains uncertain.

Growth.

Limited data from long-term studies suggest that most children and adolescents treated with inhaled budesonide will ultimately achieve their adult target height. However, an initial small but transient reduction in growth (approximately 1 cm) has been observed. This generally occurs within the first year of treatment.
Rare individuals may be exceptionally sensitive to ICS. Height measurements should be performed to identify patients with increased sensitivity. The potential growth effects of prolonged treatment should be weighed against the clinical benefit. To minimise the systemic effects of ICS, each patient should be titrated to his/her lowest dose at which effective control of symptoms is maintained (see Section 4.2 Dose and Method of Administration).

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.

Infections/tuberculosis.

Signs of existing infection may be masked by the use of high doses of glucocorticosteroids and new infections may appear during their use. Special care is needed in patients with active or quiescent pulmonary tuberculosis or fungal, bacterial or viral infections of the respiratory system.

Sensitivity to sympathomimetic amines.

In patients with increased susceptibility to sympathomimetic amines (e.g. inadequately controlled hyperthyroidism), formoterol should be used with caution.

Cardiovascular disorders.

β2-agonists have an arrhythmogenic potential that must be considered before commencing treatment for bronchospasm.
The effects of formoterol in acute as well as chronic toxicity studies were seen mainly on the cardiovascular system and consisted of hyperaemia, tachycardia, arrhythmias and myocardial lesions. These are known pharmacological manifestations seen after administration of high doses of β2-adrenoceptor agonists.
Patients with pre-existing cardiovascular conditions may be at greater risk of developing adverse cardiovascular effects following administration of β2-adrenoreceptor agonists. Caution is advised when formoterol is administered to patients with severe cardiovascular disorders such as ischaemic heart disease, tachyarrhythmias or severe heart failure.

Hypokalaemia.

High doses of β2-agonists can lower serum potassium by inducing a redistribution of potassium from the extracellular to the intracellular compartment, via stimulation of Na+/K+-ATPase in muscle cells.
Potentially serious hypokalaemia may result. Particular caution is advised in acute exacerbation as the associated risk may be augmented by hypoxia. The hypokalaemic effect may be potentiated by concomitant treatments (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Patients receiving digoxin are particularly sensitive to hypokalaemia. Serum potassium levels should therefore be monitored in such situations.

Diabetes.

Due to the blood-glucose increasing effects of β2-stimulants extra blood glucose controls are initially recommended when diabetic patients are commenced on formoterol.

Pneumonia.

Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of pneumonia and exacerbations frequently overlap. Pneumonia has been reported following the administration of inhaled corticosteroids. See Section 4.8 Adverse Effects (Undesirable Effects).

Lactose.

Bufomix Easyhaler contains lactose which may contain milk protein residue. Each inhalation of Bufomix Easyhaler 200/6 contains approximately 4 mg of lactose. Each inhalation of Bufomix Easyhaler 400/12 contains approximately 8 mg of lactose. This amount does not normally cause problems in lactose intolerant people.

Use in hepatic impairment.

The effect of decreased liver function on the pharmacokinetics of formoterol and budesonide are not known. As budesonide and formoterol are primarily eliminated via hepatic metabolism an increased exposure can be expected in patients with severe liver disease.

Use in renal impairment.

The effect of decreased kidney function on the pharmacokinetics of formoterol and budesonide are not known.

Use in the elderly.

See Section 5.1 Pharmacodynamic Properties, Clinical trials.

Paediatric use.

Bufomix Easyhaler is not recommended for children below 12 years of age.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Pharmacokinetic interactions.

The metabolism of budesonide is primarily mediated by the enzyme CYP3A4. Potent CYP3A4 inhibitors may therefore increase systemic exposure to budesonide. This is of limited clinical importance for short-term (1-2 weeks) treatment with potent CYP3A4 inhibitors but should be taken into consideration during long-term treatment.
If a patient requires long-term concomitant treatment with Bufomix Easyhaler and a potent CYP3A4 inhibitor, the benefit should be weighed against the increased risk of systemic corticosteroid side effects, patients should be monitored for corticosteroid side effects and/or a reduction of the ICS dose could be considered.

Pharmacodynamic interactions.

Neither budesonide nor formoterol have been observed to interact with any other drug used in the treatment of asthma or COPD.

β-receptor blocking agents.

β-receptor blocking agents, especially those that are non-selective, may partially or totally inhibit the effect of β2-agonists. These drugs may also increase airway resistance, therefore the use of these drugs in asthma patients is not recommended.

Other sympathomimetic agents.

Other β-adrenergic stimulants or sympathomimetic amines such as ephedrine should not be given concomitantly with formoterol, since the effects will be cumulative. Patients who have already received large doses of sympathomimetic amines should not be given formoterol.

Xanthine derivatives, mineralocorticosteroids and diuretics.

Hypokalaemia may result from β2-agonist therapy and may be potentiated by concomitant treatment with xanthine derivatives, mineralocorticosteroids, and diuretics (see Section 4.4 Special Warnings and Precautions for Use, Hypokalaemia).

Monoamine oxidase inhibitors, tricyclic antidepressants, quinidine, disopyramide, procainamide, phenothiazines and antihistamines.

The adverse cardiovascular effects of formoterol may be exacerbated by concurrent administration of drugs associated with QT interval prolongation and increased risk of ventricular arrhythmia. For this reason, caution is advised when formoterol is administered to patients already taking monoamine oxidase inhibitors, tricyclic antidepressants, quinidine, disopyramide, procainamide, phenothiazines or antihistamines associated with QT interval prolongation (e.g. terfenadine, astemizole).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There are no animal studies on the effect of the budesonide/formoterol combination on fertility.
Long-term treatment of female mice and rats with formoterol fumarate causes ovarian stimulation, the development of ovarian cysts and hyperplasia of granulosa/theca cells as a result of the β-agonist properties of the compound. A study showed no effect on fertility of female rats dosed orally with formoterol fumarate at 60 mg/kg/day for two weeks. This finding was repeated in another study where no effect was seen on the fertility of female rats dosed orally with formoterol fumarate at 15 mg/kg/day for two weeks.
Testicular atrophy was observed in mice given formoterol fumarate in the diet at 0.2 to 50 mg/kg/day for two years, but no effect on male fertility was observed in rats dosed orally at 60 mg/kg/day for nine weeks.
(Category B3)
For Bufomix Easyhaler or the concomitant treatment with budesonide and formoterol, no clinical data on exposed pregnancies are available. Animal studies with respect to the reproductive toxicity of the combination have not been performed.
Bufomix Easyhaler should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Only after special consideration should Bufomix Easyhaler be used during the first 3 months and shortly before delivery.
Because β-agonists, including formoterol, may potentially interfere with uterine contractility, due to a relaxant effect on uterine smooth muscle, Bufomix Easyhaler should be used during labour only if the potential benefit justifies the potential risk.

Budesonide.

Results from a large prospective epidemiological study and from worldwide postmarketing experience indicate no adverse effects of inhaled budesonide during pregnancy on the health of the fetus or newborn child.
If treatment with glucocorticosteroids during pregnancy is unavoidable, ICS such as budesonide should be considered due to their lower systemic effect. The lowest effective dose of budesonide to maintain asthma control should be used.

Formoterol.

No teratogenic effects were observed in rats receiving formoterol fumarate at doses up to 60 mg/kg/day orally or 1.2 mg/kg/day by inhalation. Fetal cardiovascular malformations were observed in one study in which pregnant rabbits were dosed orally at 125 or 500 mg/kg/day during the period of organogenesis, but similar results were not obtained in another study at the same dose range. In a third study, an increased incidence of subcapsular hepatic cysts was observed in fetuses from rabbits dosed orally at 60 mg/kg/day. Decreased birth weight and increased perinatal/postnatal mortality were observed when formoterol fumarate was given to rats at oral doses of 0.2 mg/kg/day or greater during late gestation.
 Budesonide is excreted in breast milk. However, due to the relatively low doses used via the inhalational route the amount of drug present in the breast milk, if any, is likely to be low.
It is not known whether formoterol is excreted in human milk. In reproductive studies in rats, formoterol was excreted into breast milk. There are no well-controlled human studies of the use of budesonide/formoterol in nursing mothers. Administration of Bufomix Easyhaler to women who are breastfeeding should only be considered if the expected benefit to the mother is greater than any possible risk to the child.

4.7 Effects on Ability to Drive and Use Machines

Driving or using machinery should be undertaken with caution until the effect of Bufomix Easyhaler on the individual is established. Bufomix Easyhaler does not generally affect the ability to drive or use machinery.

4.8 Adverse Effects (Undesirable Effects)

Since Bufomix Easyhaler contains both budesonide and formoterol, the same adverse effects as reported for these substances may be expected. No increased incidence of adverse reactions has been seen following concurrent administration of the two compounds. The most common drug related adverse reactions are pharmacologically predictable side effects of β2-agonist therapy, such as tremor and palpitations. These tend to be mild and usually disappear within a few days of commencing treatment.
If oropharyngeal candidiasis develops, it may be treated with appropriate anti-fungal therapy whilst still continuing with Bufomix Easyhaler therapy. The incidence of candidiasis can generally be held to a minimum by having patients rinse their mouth out with water after inhaling their maintenance dose.
Adverse reactions, which have been associated with budesonide, formoterol and their combined use, are given in Table 2.
As with other inhalation therapy, paradoxical bronchospasm may occur in very rare cases.
Treatment with β-sympathomimetics may result in an increase in blood levels of insulin, free fatty acids, glycerol and ketone bodies.

Pneumonia.

Table 3 provides the incidence of pneumonia observed in the four pivotal phase III COPD studies (see Section 5.1 Pharmacodynamic Properties, Clinical trials, COPD) for budesonide/formoterol (200/6) and comparative placebo arms.
In these placebo-controlled studies, the incidence of pneumonia was low.

Budesonide/formoterol anti-inflammatory reliever therapy.

Overall, budesonide/formoterol as anti-inflammatory reliever therapy is generally well tolerated, based on the frequency and nature of adverse effects. No new safety concerns were identified for the use of the budesonide/formoterol 200/6 fixed dose combination as needed in a mild asthma population.

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

An overdose of formoterol may lead to effects that are typical for β2-adrenergic agonists: tremor, headache, palpitations, and tachycardia. Monitoring of serum potassium concentrations may be warranted. Hypotension, metabolic acidosis, hypokalaemia and hyperglycaemia may also occur. Supportive and symptomatic treatment may be indicated. β-blockers should be used with care because of the possibility of inducing bronchospasm in sensitive individuals. A metered dose of 120 microgram administered during three hours in patients with acute bronchial obstruction raised no safety concerns.
Acute overdosage with budesonide, even in excessive doses, is not expected to be a clinical problem. However, the plasma cortisol level will decrease, and number and percentage of circulating neutrophils will increase. The number and percentage of lymphocytes and eosinophils will decrease concurrently. When used chronically in excessive doses, systemic glucocorticosteroid effects, such as hypercorticism and adrenal suppression, may appear.
Withdrawing Bufomix Easyhaler or decreasing the dose of budesonide will abolish these effects, although the normalisation of the HPA-axis may be a slow process.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Bufomix Easyhaler contains budesonide and formoterol, which have different modes of action and show additive effects in terms of reduction of asthma and COPD exacerbations. The specific properties of budesonide and formoterol allow the combination to be used either as an anti-inflammatory reliever or as maintenance treatment for asthma, and for symptomatic treatment of patients with moderate to severe COPD.

Budesonide.

Budesonide is a non-halogenated glucocorticosteroid structurally related to 16α hydroxyprednisolone with a high local anti-inflammatory effect. Budesonide has shown anti-anaphylactic and anti-inflammatory effects in provocation studies in animals and humans, manifested as decreased bronchial obstruction in the immediate as well as the late phase of an allergic reaction. Budesonide has also been shown to decrease airway reactivity to both direct (histamine, methacholine) and indirect (exercise) challenge in hyperreactive patients. Budesonide, when inhaled, has a rapid (within hours) and dose-dependent anti-inflammatory action in the airways, resulting in reduced symptoms and fewer exacerbations. Inhaled budesonide has less severe adverse effects than systemic corticosteroids. The exact mechanism responsible for the anti-inflammatory effect of glucocorticosteroids is unknown.

Formoterol.

Formoterol is a potent selective β2-adrenergic agonist that when inhaled results in rapid and long-acting relaxation of bronchial smooth muscles in patients with reversible airways obstruction. The bronchodilating effect is dose dependent with an onset of effect within 1-3 minutes after inhalation. The duration of effect is at least 12 hours after a single dose.

Clinical trials.

Budesonide/formoterol 100/6 and 200/6 refers to the metered dose of the monoproducts (budesonide and formoterol i.e. 100 microgram of budesonide and 6 microgram formoterol fumarate dihydrate and 200 microgram of budesonide and 6 microgram formoterol fumarate dihydrate respectively). Similarly, budesonide/formoterol 400/12 refers to the metered dose of the monoproducts i.e. 400 microgram of budesonide and 12 microgram formoterol fumarate dihydrate. Also see Table 1 in Section 2 Qualitative and Quantitative Composition.

Asthma.

Budesonide/formoterol anti-inflammatory reliever therapy. A total of 8064 patients aged 12 and above with mild asthma were included in 2 double-blind efficacy and safety studies (SYGMA 1 and SYGMA 2), of which 3384 patients were randomised to budesonide/formoterol anti-inflammatory reliever therapy for 12 months. Patients were required to be uncontrolled on only short-acting β2-agonist (SABA) as needed or controlled on low dose ICS or leukotriene receptor agonist plus SABA as needed.
Both studies compared budesonide/formoterol anti-inflammatory reliever therapy (budesonide/formoterol 200/6 used as needed in response to symptoms) to budesonide dry powder inhaler 200 microgram (1 inhalation twice daily) given with as needed SABA. SYGMA 1 also compared budesonide/formoterol anti-inflammatory reliever therapy to as needed SABA alone.
In SYGMA 1 and SYGMA 2, respectively, based on physician assessment before enrolment, 44.5% and 46.3% of patients were uncontrolled on SABA as needed, and 55.5% and 53.7% of patients were controlled on low dose ICS or leukotriene receptor antagonists plus SABA as needed. At baseline, patients in SYGMA 1 and SYGMA 2, respectively, had a median age of 40 and 41 years (overall range across both studies 12 to 85 years), 12.5% and 9.8% of patients were adolescents (≥ 12 to < 18 years) and approximately 7% and 9% of patients were over 65 years of age, 87.0% and 84.3% had never smoked, 10.3% and 13.1% were former smokers, 2.7% and 2.6% were current smokers, and 19.7% and 22.0% of patients had experienced a severe exacerbation within the 12 months prior to study enrolment.
In SYGMA 2, budesonide/formoterol anti-inflammatory reliever therapy was comparable to a maintenance dose of budesonide dry powder inhaler given with as needed SABA in terms of the rate of severe exacerbations (Table 4). Protection against severe exacerbation was achieved with a 75% reduction in median ICS load and without requiring adherence to maintenance ICS treatment.
SYGMA 1 showed that budesonide/formoterol provided a statistically significant and clinically meaningful reduction in the rate of annual severe exacerbations by 64% compared with SABA as needed alone (Table 4). Reduction in the annual rate of moderate to severe exacerbations was consistent (60%) with that observed for severe exacerbations (Risk Ratio (RR): 0.40 (95% Confidence Interval (CI): 0.32, 0.49); p < 0.001).
In SYGMA 1, budesonide/formoterol anti-inflammatory reliever therapy provided superior daily asthma symptom control compared to as needed SABA alone (Odds Ratio (OR): 1.14 (1.00 to 1.30); p = 0.046), showing a mean percentage of weeks with well-controlled asthma of 34.4% and 31.1%, respectively. Asthma symptom control was inferior for budesonide/formoterol anti-inflammatory reliever therapy compared to a maintenance dose of budesonide dry powder inhaler given with as needed SABA (OR: 0.64 (2-sided 95% CI 0.57, 0.73; lower limit of the CI ≥ 0.8 for non-inferiority), showing a mean percentage of well-controlled asthma weeks of 34.4% and 44.4%, respectively.
Improvements in asthma control (as defined by Asthma Control Questionnaire (ACQ-5)) in patients using budesonide/formoterol anti-inflammatory reliever therapy were superior to improvements in patients using as needed SABA alone (estimate for difference: -0.15 (-0.20, -0.11); p < 0.001). In accordance with the pre-specified hierarchical testing strategy, apart from well-controlled asthma weeks, all other efficacy results from this study were considered of nominal statistical significance. Improvements in asthma control were lower for budesonide/formoterol anti-inflammatory reliever therapy compared to a maintenance dose of budesonide dry powder inhaler given with SABA as needed (SYGMA 1 estimate for difference: 0.15 (0.10, 0.20); SYGMA 2: 0.11 (0.07, 0.15); both p < 0.001). For both comparisons, mean differences in treatments' effect upon ACQ-5 are not clinically meaningful (as assessed by a difference of greater than or equal to 0.5). These results were observed in a clinical study setting with considerably higher adherence to budesonide maintenance dosing than expected in real life.
In the SYGMA studies, increases in lung function compared to baseline (mean pre-bronchodilator FEV1) were statistically significantly larger for patients on budesonide/formoterol anti-inflammatory reliever therapy compared to patients on as needed SABA alone. Statistically significantly smaller increases were observed for budesonide/formoterol anti-inflammatory reliever therapy compared to a maintenance dose of budesonide dry powder inhaler given with SABA as needed. For both comparisons, mean differences in treatments' effect were small (approximately 30 to 55 mL, equating to approximately 2% of the baseline mean).
Overall, the results of the SYGMA studies show that budesonide/formoterol anti-inflammatory reliever therapy is a more effective treatment than SABA as needed in patients with mild asthma. In addition, these studies suggest that budesonide/formoterol anti-inflammatory reliever therapy may be considered an alternative treatment option for patients with mild asthma who are eligible for ICS treatment.
Analysis of time to first severe exacerbation in SYGMA 1 showed that the likelihood of experiencing a severe exacerbation was statistically significantly higher for SABA as needed use compared to budesonide/formoterol anti-inflammatory reliever therapy over the 1 year treatment period, with a risk reduction of 56% (Hazard Ratio (HR): 0.44 (0.33, 0.58); p < 0.001). There were no differences in the probability of experiencing a severe exacerbation between budesonide/formoterol anti-inflammatory reliever therapy and a maintenance dose of budesonide given with SABA as needed.
Budesonide/formoterol anti-inflammatory reliever plus maintenance therapy. The safety and efficacy of budesonide/formoterol anti-inflammatory reliever plus maintenance therapy regimen have been investigated in six clinical trials using two dose strengths (100/6 and 200/6) of budesonide/formoterol dry powder inhaler in patients with asthma. A total of 14,219 patients (1134 elderly, 11,144 adults, 1595 adolescents and 345 children) were randomised into the studies, of which 5514 were treated with budesonide/formoterol anti-inflammatory reliever plus maintenance therapy. Of the overall patient population 7% were smokers. In comparison with the usual patient proportions seen in practice, smokers and the elderly were under-represented in the trials. However, the results for these subgroups were generally consistent with the results for the whole study population. Patients with COPD were excluded.
The studies showed that budesonide/formoterol anti-inflammatory reliever plus maintenance therapy was significantly superior compared with fixed dose combination products or higher doses of ICS with a separate short-acting or long-acting β-agonist used as reliever (see Table 5 and Table 6). In the 5 double-blind long-term studies, patients receiving budesonide/formoterol anti-inflammatory reliever plus maintenance therapy used no reliever inhalations on 57% of treatment days and 0-2 reliever inhalations on 87% of treatment days.

Study 734 (SMILE).

A 12-month randomised, double-blind, parallel-group, trial in 3394 adult and adolescent patients aged 12 to 89 years with moderate to severe asthma. The study comprised of the following three arms:
1. Budesonide/formoterol anti-inflammatory reliever plus maintenance therapy - budesonide/formoterol dry powder inhaler 200/6, 1 inhalation twice daily plus additional inhalations as needed.
2. Budesonide/formoterol dry powder inhaler 200/6, 1 inhalation twice daily with formoterol dry powder inhaler as needed.
3. Budesonide/formoterol dry powder inhaler 200/6, 1 inhalation twice daily with terbutaline dry powder inhaler as needed.
The primary efficacy variable, time to first severe exacerbation, was significantly increased with budesonide/formoterol anti-inflammatory reliever plus maintenance therapy compared with budesonide/formoterol plus formoterol and budesonide/formoterol plus terbutaline (see Table 5).
Use of oral steroids due to exacerbations was lower in the budesonide/formoterol anti-inflammatory reliever plus maintenance therapy group (1204 days total vs 2063 and 2755 days in the budesonide/formoterol plus formoterol and budesonide/formoterol plus terbutaline groups, respectively).
The majority of secondary variables supported the superiority of budesonide/formoterol anti-inflammatory reliever plus maintenance therapy over both comparators (see Table 7). The average daily as needed use in the budesonide/formoterol anti-inflammatory reliever plus maintenance therapy group was 1.02 inhalations/day and the frequency of high as needed use was lower for budesonide/formoterol anti-inflammatory reliever plus maintenance therapy compared to both comparators.
The study specifically demonstrates that both the budesonide and the formoterol components contribute to improved asthma control achieved through the as needed dosing of budesonide/formoterol within the budesonide/formoterol anti-inflammatory reliever plus maintenance therapy concept.

Study 735 (COMPASS).

A 6-month randomised, double-blind, parallel-group trial in 3335 adult and adolescent patients aged 11 to 83 years. The study compared the following three arms:
1. Budesonide/formoterol anti-inflammatory reliever plus maintenance therapy - budesonide/formoterol dry powder inhaler 200/6, 1 inhalation twice daily plus additional inhalation as needed.
2. Fluticasone/salmeterol inhaler 125/25, 2 inhalations twice daily with terbutaline dry powder inhaler as needed.
3. Budesonide/formoterol dry powder inhaler 400/12, 1 inhalation twice daily with terbutaline dry powder inhaler as needed.
The primary efficacy variable, time to first severe exacerbation, was significantly increased with budesonide/formoterol anti-inflammatory reliever plus maintenance therapy compared with both fluticasone/salmeterol plus terbutaline and budesonide/formoterol at a higher maintenance dose plus terbutaline (see Table 5).
Use of oral steroids due to exacerbations was lower in the budesonide/formoterol anti-inflammatory reliever plus maintenance therapy group compared to fluticasone/salmeterol plus terbutaline and budesonide/formoterol plus terbutaline (619 days total use vs. 1132 and 1044 days, respectively).
Results for secondary variables, including lung function, mean use of as needed medication and symptom variables, were not significantly different between budesonide/formoterol anti-inflammatory reliever plus maintenance therapy and the other two groups. The average daily as needed use in the budesonide/formoterol anti-inflammatory reliever plus maintenance therapy group was 1.02 inhalations/day.
Since the mean daily dose in the budesonide/formoterol anti-inflammatory reliever plus maintenance therapy group remained lower than in the budesonide/formoterol plus terbutaline group, the study specifically confirms the benefit of as needed administration of part of the budesonide/formoterol dose.

Study 673 (STAY), study 668 (STEP) and study 667 (STEAM).

In studies 673, 668 and 667, budesonide/formoterol anti-inflammatory reliever plus maintenance therapy prolonged the time to the first exacerbation compared to budesonide/formoterol at the same maintenance dose with terbutaline as reliever and compared to a 2 to 4-fold higher maintenance dose of budesonide with terbutaline as reliever (see Table 5). Symptoms and reliever use were reduced and lung function improved compared with all other treatments (see Table 8, Table 9 and Table 10).

Study 691 (COSMOS).

A 12-month, randomised, open, parallel group trial that compared the effectiveness of budesonide/formoterol anti-inflammatory reliever plus maintenance therapy with fluticasone/salmeterol plus salbutamol in steroid-treated adult and adolescent patients (N = 2143) aged 12 to 84 years with asthma. Randomised treatment started with a 4-week period during which the maintenance doses were fixed, followed by 11 months where the maintenance dose was adjusted to the lowest dose required for symptom control (see Table 11).
This study showed that budesonide/formoterol anti-inflammatory reliever plus maintenance therapy treatment is more effective than adjustable therapy with fluticasone/salmeterol plus salbutamol in controlling asthma in adults and adolescents. Budesonide/formoterol anti-inflammatory reliever plus maintenance therapy increased the time to first severe asthma exacerbations, reduced the total number of severe asthma exacerbations (see Table 5 and Table 6), reduced use of oral steroids for severe asthma exacerbations, and reduced use of as needed medications as compared with fluticasone/salmeterol at a similar daily ICS dose.

Safety in the combined studies.

Budesonide/formoterol anti-inflammatory reliever plus maintenance therapy treatment has a safety profile that is similar to budesonide and budesonide/formoterol maintenance therapy with a decrease in asthma-related adverse events.
Exercise-induced and allergen-induced bronchoconstriction. The use of budesonide/formoterol 200/6 dry powder inhaler in relation to exercise-induced and allergen-induced bronchoconstriction has been studied in three clinical trials for patients with mild/intermittent asthma.
Study D5890L00032 was a 6-week, 3-arm study in 66 adults and adolescents with mild asthma and episodic exercise-induced bronchoconstriction, in which the primary variable was change in maximum decrease in post-exercise FEV1 calculated before and after 6 weeks of treatment. This study demonstrated that budesonide/formoterol 200/6 dry powder inhaler, taken as 1 inhalation before exercise plus additional inhalations as needed in response to symptoms, improved asthma control by reducing exercise-induced bronchoconstriction to the same order of magnitude as regular maintenance treatment with budesonide 400 microgram plus terbutaline 0.5 mg as needed, despite a substantially lower steroid dose. Both treatments were superior to terbutaline as needed when taken alone.
Study AF-039-0001 was a 6-month, 2-arm study in 92 adult and adolescents with mild intermittent asthma who used SABA for symptom relief, in which the primary variable of efficacy was the change in level of fractional exhaled nitric oxide (FENO) in the two treatment groups over the duration of the study. This study demonstrated that the budesonide component in budesonide/formoterol 200/6 dry powder inhaler taken before exercise and as needed, reduced airway inflammation and improved airway function, and showed the beneficial effect of the budesonide component when taken as needed together with formoterol (for symptom relief) as budesonide/formoterol 200/6 dry powder inhaler.
Study D5890L00007 was a 3-arm, placebo-controlled, cross-over study in 15 adult patients with mild allergic asthma, in which the primary efficacy variable was change in PD20 (the provocative dose causing a 20% fall in FEV1) methacholine (MCh) during each treatment period. This study showed that when administered 30 minutes after a low-dose allergen challenge, budesonide/formoterol 200/6 dry powder inhaler abolished allergen-induced components of asthma deterioration whilst improving baseline pulmonary function, whereas, formoterol 6 microgram alone inhibited the rise in symptoms but did not protect against allergen-induced airway inflammation. This study indicated that deteriorating asthma, provoked by low-dose allergen, is managed more effectively with budesonide/formoterol 200/6 dry powder inhaler than with formoterol.
Budesonide/formoterol maintenance therapy. The efficacy and safety of budesonide/formoterol dry powder inhaler for maintenance therapy has been evaluated in seven randomised, double-blind, double-dummy, active controlled, parallel group studies. All treatment arms in these studies used a SABA for relief of symptoms. Six studies were conducted for 12 weeks (100/6 and 200/6 presentations) while the 400/12 presentation study was conducted for 24 weeks (12 weeks efficacy and additional 12 weeks safety). Efficacy and safety data were collected for 3340 mild to moderate/severe asthmatic patients (2411 adults, 128 adolescents, 801 children aged 4 to 11 years old); 1704 were treated with budesonide/formoterol dry powder inhaler.

Budesonide/formoterol dry powder inhaler 100/6 and 200/6.

In one study, the maximum recommended maintenance dose of budesonide/formoterol dry powder inhaler 200/6 (2 inhalations twice daily) was compared to corresponding doses of the free combination (budesonide dry powder inhaler 200 microgram + formoterol dry powder inhaler 6 microgram, two inhalations twice daily) and budesonide dry powder inhaler 200 microgram (2 inhalations twice daily) only in adults with moderate asthma (mean FEV1 73.8% predicted normal and reversibility 22.5%). Table 12 details the efficacy results after 12 weeks treatment.
When administered twice daily, budesonide/formoterol dry powder inhaler 200/6 is a more effective treatment than budesonide, at corresponding budesonide doses.
In a study in adults with milder asthma (mean FEV1 81.7% predicted normal and reversibility 22.2%) budesonide/formoterol dry powder inhaler 100/6 (1 inhalation twice daily) was compared with budesonide dry powder inhaler 200 microgram (1 inhalation twice daily). Table 13 details the efficacy results after 12 weeks treatment.
In conclusion, there was a greater improvement in lung function and asthma control with budesonide/formoterol dry powder inhaler 100/6 than with a doubled dose of budesonide.

Budesonide/formoterol dry powder inhaler 400/12.

In a study in predominantly adult patients (< 3% of patients were adolescents) with moderate to severe asthma (mean FEV1 66% predicted normal and reversibility 28%) budesonide/formoterol dry powder inhaler 400/12 (2 inhalations twice daily) was compared to corresponding doses of the free combination (formoterol dry powder inhaler 12 microgram + budesonide dry powder inhaler 400 microgram, two inhalations twice daily) and budesonide dry powder inhaler 400 microgram (2 inhalations twice daily) only. Table 14 details the efficacy results after 12 weeks treatment.
When administered twice daily, budesonide/formoterol dry powder inhaler 400/12 is a more effective treatment for the majority of clinical endpoints than the corresponding budesonide dose.

COPD.

The efficacy and safety of budesonide/formoterol in the treatment of patients with moderate to severe COPD (pre-bronchodilator FEV1 ≤ 50% predicted normal) has been evaluated in four randomised, double-blind, placebo and active controlled, parallel-group, multi-centre clinical studies. Two 12-month studies were performed with the dry powder inhaler (studies 629 and 670), and one 12-month and one 6-month study were performed with the pressurised metered dose inhaler (pMDI) (studies 001 and 002, respectively).
Studies 629 and 670. In both studies, budesonide/formoterol dry powder inhaler 200/6 was compared with placebo and the corresponding mono-products (budesonide dry powder inhaler 200 microgram and formoterol dry powder inhaler 6 microgram), all taken as 2 inhalations twice daily. A total of 812 and 1022 patients with moderate to severe COPD were randomised, of which 208 and 254 were treated with budesonide/formoterol. Patients in both studies had a mean age of 64 years and FEV1 of 0.99 L or 36% of predicted normal at baseline.
Studies 001 and 002. The study plans were similar. Both studies used budesonide/formoterol pMDI.
For study 001, after a screening visit (visit 1), subjects entered a two weeks run-in period after which they were randomly assigned (visit 2) to one of the four following treatments:
1. Budesonide/formoterol pMDI 200/6, fixed combination of 200 microgram budesonide and 6 microgram formoterol per actuation, administered as 2 actuations twice daily;
2. Budesonide/formoterol pMDI 100/6, fixed combination of 100 microgram budesonide and 6 microgram formoterol per actuation, administered as 2 actuations twice daily;
3. Formoterol dry powder inhaler, 6 microgram per inhalation, administered as 2 actuations twice daily;
4. Placebo.
Study 002 had two additional treatment groups:
5. Budesonide pMDI 200 microgram per actuation, administered as 2 actuations twice daily;
6. Free combination of budesonide pMDI 200 microgram per actuation plus formoterol dry powder inhaler 6 microgram per actuation, administered as 2 actuations of each twice daily.
A total of 1964 (study 001) and 1704 (study 002) patients with moderate to severe COPD were randomised, of which 494 and 277 were treated with budesonide/formoterol pMDI 200/6. The study populations had a mean age of 63 years and mean FEV1 of 1.04-1.05 L or 34% of predicted normal at baseline.
Study 629. In study 629, efficacy was evaluated over 12 months using the co-primary endpoints of post-dose FEV1 and number of severe COPD exacerbations (defined as intake of a course of oral steroids and/or antibiotics and/or hospitalisation due to respiratory symptoms).
Budesonide/formoterol dry powder inhaler significantly improved mean FEV1 compared with placebo and budesonide by 15% (p < 0.001) and 9% (p < 0.001), respectively.
Budesonide/formoterol dry powder inhaler significantly reduced the number of severe exacerbations compared with placebo and formoterol by 24% (p = 0.035) and 23% (p = 0.043), respectively. The number needed to treat (NNT) to prevent one severe COPD exacerbation in a year for budesonide/formoterol dry powder inhaler compared with formoterol was 2.4.
Study 670. In study 670, efficacy was evaluated over 12 months using the co-primary endpoints of post-dose FEV1 and time to first severe COPD exacerbation (defined as intake of a course of oral steroids and/or antibiotics and/or hospitalisation due to respiratory symptoms).
Budesonide/formoterol dry powder inhaler significantly improved mean FEV1 compared with placebo, budesonide, and formoterol by 14% (p < 0.001), 11% (p < 0.001), and 5% (p = 0.002), respectively.
Budesonide/formoterol dry powder inhaler significantly prolonged the time to first severe COPD exacerbation compared to all comparator treatments. The instantaneous risk of experiencing a severe COPD exacerbation compared to placebo, budesonide, and formoterol was reduced by 29% (p = 0.006), 23% (p = 0.033), and 30% (p = 0.003), respectively.
Budesonide/formoterol dry powder inhaler also significantly reduced the number of severe COPD exacerbations compared to placebo and formoterol by 24% (p = 0.029) and 26% (p = 0.015), respectively. The NNT to prevent one COPD exacerbation in a year compared to formoterol was 2.1.
Study 001. In study 001, efficacy was evaluated over 12 months using the co-primary efficacy variables of change from baseline in average pre-dose and 1-hour post-dose FEV1 over the treatment period.

Primary endpoints.

Budesonide/formoterol pMDI 100/6 produced a significantly greater change in post-dose FEV1 compared to placebo (LS mean = 0.16 L; p < 0.001); however, the change in pre-dose FEV1 was not significantly different to formoterol 6 microgram (LS mean = 0.02 L; p = 0.161).
Budesonide/formoterol pMDI 200/6 significantly improved 1-hour pre-dose FEV1 compared with formoterol and placebo by 0.04 L (p = 0.008) and 0.09 L (p < 0.001), respectively.
Budesonide/formoterol pMDI 200/6 significantly improved post-dose FEV1 over the treatment period compared with formoterol and placebo by 0.03 L (p = 0.023) and 0.18 L (p < 0.001), respectively.
Serial FEV1 measures over 12 hours were obtained in a subset of patients (N = 491). The median time to onset of bronchodilation (> 15% improvement in FEV1) was seen within 5 minutes at the end of treatment time point in patients receiving budesonide/formoterol pMDI 200/6 (N = 121). Maximum improvement in FEV1 occurred at approximately 2 hours post-dose, and post-dose bronchodilator effect was maintained over 12 hours.

Exacerbations (secondary variable).

Budesonide/formoterol pMDI reduced the number of severe COPD exacerbations (defined as a worsening of COPD requiring oral steroid use and/or hospitalisation) to a statistically significant degree. Overall, 34.1% of subjects experienced 1159 exacerbations: Budesonide/formoterol pMDI 200/6, 30.8%; budesonide/formoterol pMDI 100/6, 32.6%; placebo 37.2%. The majority of exacerbations were treated with oral glucocorticosteroids: Budesonide/formoterol pMDI 200/6, 96.5% of exacerbations; budesonide/formoterol pMDI 100/6, 94.1%; placebo 97.4%. Treatment comparisons were by means of rate ratios estimates, CIs and p-values derived from a Poisson regression adjusted for treatment, country and differential treatment exposure. Budesonide/formoterol pMDI 200/6 demonstrated a statistically significant reduction of 37% (p < 0.001) and 25% (p = 0.004) in the rate of exacerbations per subject-treatment year compared with placebo and formoterol, respectively. Budesonide/formoterol pMDI 100/6 reduced the exacerbation rate by 41% compared with placebo (p < 0.001).
Budesonide/formoterol pMDI 200/6 significantly prolonged the time to first severe COPD exacerbation compared to placebo, reducing the instantaneous risk of experiencing a severe COPD exacerbation by 26% (p = 0.009). The NNT to prevent one severe COPD exacerbation in a year for Budesonide/formoterol pMDI compared with formoterol was 5.4.
Study 002. In study 002, efficacy was evaluated over 6 months using the co-primary efficacy variables of change from baseline in average pre-dose and 1-hour post-dose FEV1 over the treatment period.
Budesonide/formoterol pMDI 100/6: Post-dose FEV1 increased significantly from baseline to the average of the treatment period (LS mean (95% CI) = 0.19 (0.17, 0.22)). Budesonide/formoterol pMDI 100/6 caused a significantly greater change from baseline compared to budesonide (LS mean = 0.16; p < 0.001). Pre-dose FEV1 increased significantly from baseline to the average of the treatment period (LS mean = 0.06 (0.03, 0.08)). However, the change from baseline, compared to formoterol, for pre-dose FEV1 was not statistically significant (LS mean = 0.02 (-0.02, 0.05; p = 0.335)).
Budesonide/formoterol pMDI 200/6 significantly improved pre-dose FEV1 compared with formoterol by 0.04 L (p = 0.026) and compared with placebo and budesonide by 0.08 L (p < 0.001) for both comparators.
Budesonide/formoterol pMDI 200/6 significantly improved 1-hour post-dose FEV1 compared with formoterol by 0.04 L (p = 0.039) and compared with placebo and budesonide by 0.17 L (p < 0.001) for both comparators.
Study 002 was not powered for showing effect on severe COPD exacerbations.
Serial FEV1 measures over 12 hours were obtained in subsets of patients (n = 618). The median time to onset of bronchodilation (> 15% improvement in FEV1) was seen within 5 minutes at the end of treatment in patients receiving budesonide/formoterol pMDI 200/6 (N = 101). Maximal improvement in FEV1 occurred at approximately 2 hours post-dose, and post-dose bronchodilator effect was generally maintained over 12 hours.

5.2 Pharmacokinetic Properties

The fixed-dose combination of budesonide and formoterol, and the corresponding monoproducts have been shown to be bioequivalent with regard to systemic exposure of budesonide and formoterol, respectively.
There was no evidence of pharmacokinetic interactions between budesonide and formoterol.
Pharmacokinetic parameters for the respective substances were comparable after the administration of budesonide and formoterol as monoproducts or as the fixed-dose combination.

Absorption.

After inhalation of budesonide via dry powder inhaler the mean lung deposition ranged from 26 to 34% of the metered dose. The systemic bioavailability of budesonide inhaled via dry powder inhaler is approximately 40% of the metered dose.
In studies the mean lung deposition of formoterol after inhalation via dry powder inhaler ranged from 21-37% of the metered dose. The total systemic bioavailability for the higher lung deposition is approximately 46%.

Distribution.

Plasma protein binding of budesonide is approximately 90% with a volume of distribution of approximately 3 L/kg.
Plasma protein binding of formoterol is approximately 50% with a volume of distribution of approximately 4 L/kg.

Metabolism.

Budesonide undergoes an extensive degree (approximately 90%) of biotransformation on first passage through the liver to metabolites of low glucocorticosteroid activity.
Formoterol is metabolised by conjugation to inactive glucuronides. Active O-demethylated and deformylated metabolites are formed, however plasma levels of these are low.

Excretion.

Elimination of budesonide is via metabolism mainly catalysed by the enzyme CYP3A4. The metabolites are excreted in urine as such or in conjugated form with only negligible amounts of unchanged budesonide being detected in the urine. Budesonide has a high systemic clearance (approx. 1.2 L/min) and the plasma elimination half-life after i.v. dosing averages 4 hours.
Elimination of formoterol is via metabolism in the liver followed by renal excretion. After inhalation 6-10% of the metered dose is excreted unmetabolised in the urine. Formoterol has a terminal elimination half-life of approximately 17 hours.

Special patient populations - elderly, hepatic and/or renal impairment.

The pharmacokinetics of budesonide or formoterol in elderly and patients with renal failure is unknown. The systemic availability of budesonide and formoterol may be increased in patients with liver disease.

Bufomix Easyhaler pharmacokinetic profile.

Bufomix Easyhaler was evaluated by comparing it against the innovator fixed-dose combination inhalation product containing budesonide and formoterol and has been shown to be bioequivalent with regard to total systemic exposure and exposure via the lungs.

5.3 Preclinical Safety Data

Genotoxicity.

Individually, budesonide and formoterol were not genotoxic in a series of assays for gene mutations (except for a slight increase in reverse mutation frequency in Salmonella typhimurium at high concentrations of formoterol fumarate), chromosomal damage and DNA repair. The combination of budesonide and formoterol has not been tested in genotoxicity assays.

Carcinogenicity.

The carcinogenic potential of the budesonide/formoterol combination has not been investigated in animal studies.
In formoterol carcinogenicity studies there was a dose dependent increase in the incidence of uterine leiomyomas in mice dosed orally at 0.1, 0.5 and 2.5 mg/kg/day for two years, and a mesovarian leiomyoma was observed in a female rat dosed by inhalation at 0.13 mg/kg/day for two years. The effects observed are expected findings with high dose exposure to β2-agonists.
Formoterol carcinogenicity studies performed by other companies used systemic exposure levels 800 to 4800-fold higher than those expected upon clinical use of formoterol (based on an 18 microgram daily dose).
Some carcinogenicity activity was observed in rats and mice. However, in view of the dose levels at which these effects were observed and the fact that formoterol is not mutagenic (except for very weak activity at high concentrations in one test system), it is concluded that the cancer risk in patients treated with formoterol fumarate is no greater than for other beta-adrenoceptor agonists.
The carcinogenic potential of budesonide has been evaluated in the mouse and rat at oral doses up to 200 and 50 microgram/kg/day, respectively. In male rats dosed with 10, 25 and 50 microgram budesonide/kg/day, those receiving 25 and 50 microgram/kg/day showed an increased incidence of primary hepatocellular tumours. In a repeat study this effect was observed in a number of steroid groups (budesonide, prednisolone, triamcinolone acetonide) thus indicating a class effect of corticosteroids.

6 Pharmaceutical Particulars

6.1 List of Excipients

Lactose monohydrate.

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

Store below 25°C. Protect from moisture.
After removal from the foil bag, the Bufomix Easyhaler should be placed into the protective cover and remain enclosed inside the protective cover at all times until dosing.
The Bufomix Easyhaler inhaler should be discarded 1 month after first opening the foil bag.

6.5 Nature and Contents of Container

Bufomix Easyhaler 200/6.

1 inhaler per carton, each inhaler contains 60 inhalations.

Bufomix Easyhaler 400/12.

1 inhaler per carton, each inhaler contains 60 inhalations.
Each carton contains one Easyhaler multiple dose powder inhaler sealed in a foil bag and a protective cover.

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

Budesonide.

Budesonide is a white to off white crystalline powder. It is freely soluble in methylene chloride, sparingly soluble in ethanol and practically insoluble in water.
Chemical name: 16α, 17α-22 R, S-propylmethylenedioxypregna-1, 4-diene-1β, 21-diol-3, 20-dione.

Chemical structure.


Molecular formula: C25H34O6. Molecular weight: 430.5.

CAS number.

51333-22-3.

Formoterol fumarate dihydrate.

Formoterol fumarate dihydrate is a white or almost white or slightly yellow powder. It is slightly soluble in water, soluble in methanol, slightly soluble in 2-propanol and practically insoluble in acetonitrile.
Chemical name: (R*R*)-(±)-N-[2-hydroxy-5-[1-hydroxy-2-[[2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]phenyl]formamide, (E)-2-butendioate(2:1), dihydrate).

Chemical structure.


Molecular formula: C42H52N4O12,2H2O. Molecular weight: 841.

CAS number.

183814-30-4.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes