Consumer medicine information

Symbicort Turbuhaler

Budesonide; Formoterol (eformoterol) fumarate dihydrate

BRAND INFORMATION

Brand name

Symbicort Turbuhaler

Active ingredient

Budesonide; Formoterol (eformoterol) fumarate dihydrate

Schedule

SUMMARY CMI

SYMBICORT^® TURBUHALER^®

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 Symbicort Turbuhaler?

Symbicort Turbuhaler contains two active ingredients in one inhaler: budesonide and formoterol (eformoterol) fumarate dihydate. Symbicort Turbuhaler is used for treatment of asthma in adults and adolescents (12 years and over) or Chronic Obstructive Pulmonary Disease (COPD) in adults (18 years and over).

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

2. What should I know before I use Symbicort Turbuhaler?

Do not use if you have ever had an allergic reaction to any medicine containing budesonide or formoterol, 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 Symbicort Turbuhaler? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Symbicort Turbuhaler 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 Symbicort Turbuhaler?

Symbicort Turbuhaler should be inhaled into your lungs through the mouth.
Follow all directions given to you by your doctor or pharmacist.

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

5. What should I know while using Symbicort Turbuhaler?

Things you should do	If you have an Asthma Action Plan agreed with your doctor, follow it closely at all times. Have your reliever medicine available at all times. As advised by your doctor, this may be your Symbicort Turbuhaler (100/6 or 200/6) or another reliever medicine. Rinse your mouth out with water after taking your daily morning and/or evening dose of Symbicort Turbuhaler and spit this out. Remind any doctor, dentist or pharmacist you visit that you are using Symbicort Turbuhaler.
Things you should not do	Do not stop using this medicine suddenly without checking with your doctor
Driving or using machines	Symbicort Turbuhaler may cause dizziness, light-headedness, tiredness or drowsiness in some people when they first start using it.
Looking after your medicine	Keep your Turbuhaler in a cool dry place where the temperature stays below 30°C, with the cover firmly in place. The Turbuhaler mouthpiece must be wiped with a clean dry cloth/tissue and must never get wet.

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

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. These include sore, yellowish, raised patches in the mouth (thrush), hoarse voice, unpleasant taste in your mouth, pounding heart, headache, trembling or muscle cramps. However, some side effects may need medical attention. These include severe allergic reactions such as difficulty breathing, swelling of the face, lips or tongue, severe rash or pneumonia (lung infection), signs include fever or chills, increased phlegm or a change in colour, increased cough or difficulties breathing. Serious side effects are rare.

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

SYMBICORT^® TURBUHALER^®

Active ingredient(s): budesonide / formoterol (eformoterol) fumarate dihydrate

Consumer Medicine Information (CMI)

This leaflet provides important information about using Symbicort Turbuhaler. 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 Symbicort Turbuhaler.

Where to find information in this leaflet:

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

1. Why am I using Symbicort Turbuhaler?

Symbicort Turbuhaler contains two active ingredients in one inhaler: budesonide and formoterol (as formoterol fumarate dihydrate, which was previously known as eformoterol fumarate dihydrate).

Budesonide belongs to a group of medicines called corticosteroids. Budesonide acts directly on your airways to reduce inflammation.
Formoterol belongs to a group of medicines called beta-2-agonists. Formoterol opens up the airways to help you breathe more easily.

The medicine inside Symbicort Turbuhaler is inhaled into the lungs for the treatment of asthma in adults and adolescents (12 years and over) or Chronic Obstructive Pulmonary Disease (COPD) in adults (18 years and over).

Asthma

Asthma is a disease where the airways of the lungs become narrow and inflamed (swollen), making it difficult to breathe. This may for example be due to exercise, or exposure to allergens (eg. an allergy to house dust mites, smoke or air pollution), or other things that irritate your lungs.

The budesonide in Symbicort Turbuhaler helps to improve your condition and to prevent asthma attacks from occurring.

The formoterol in Symbicort Turbuhaler helps you breathe more easily.

Some people can take Symbicort Turbuhaler when they need it – they use Symbicort Turbuhaler as an anti-inflammatory reliever to treat their symptoms when their asthma gets worse and to help prevent asthma attacks, or to help prevent symptoms from happening (eg before exercise or exposure to other triggers such as allergens).

Some people need to take Symbicort Turbuhaler every day – they use their Symbicort Turbuhaler as a daily maintenance preventer to help maintain control of their asthma symptoms and help prevent asthma attacks.

Chronic Obstructive Pulmonary Disease (COPD)

COPD (which includes chronic bronchitis and emphysema) is a long-term lung disease. There is often permanent narrowing and persistent inflammation of the airways. Symptoms may include difficulty in breathing (breathlessness or wheezing), coughing and increased sputum (phlegm).

Symbicort Turbuhaler when used as prescribed will help to control your COPD symptoms (ie breathing difficulties).

2. What should I know before I use Symbicort Turbuhaler

Warnings

Do not use Symbicort Turbuhaler if:

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

Check with your doctor if you:

have any allergies to any other medicines or foods.
have, or have had, any of the following medical conditions, as it may not be safe for you to take Symbicort Turbuhaler:
- thyroid problems
- diabetes
- heart problems
- liver problems
- tuberculosis (TB)
- low levels of potassium in the blood.
currently have an infection. If you take Symbicort Turbuhaler while you have an infection, the medicine may hide some of the signs of an infection. This may make you think, mistakenly, that you are better or that it is not serious.
have any other medical conditions.
have any questions about how you should be using your Symbicort Turbuhaler.

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.

Your doctor will discuss the possible risks and benefits of using Symbicort Turbuhaler during pregnancy and while breastfeeding.

Children

Do not give Symbicort Turbuhaler to a child under 12 years, unless directed to by the child's doctor.

Symbicort Turbuhaler is not recommended for use in children under 12 years.

Asthma Action Plan

If you have asthma, ask your doctor or pharmacist if you have any questions about your Asthma Action Plan.

Your healthcare professional should give you a personal Asthma Action Plan to help manage your asthma. This plan will include what medicines to take as a reliever when you have symptoms or sudden attacks of asthma, medicines you can take to prevent symptoms from occurring (eg prior to exercise or allergen exposure) and if you need to take daily maintenance medicines to help control your asthma. It will also provide advice on when to seek urgent medical attention such as when your asthma suddenly worsens or worsens over a period of time.

It is important that you discuss with your doctor both your exposure to triggers and how often your exercise, as these could impact how your doctor prescribes your Symbicort Turbuhaler.

3. What if I am taking other medicines?

Some medicines may interfere with Symbicort Turbuhaler and affect how it works. These include:

medicines used to treat heart problems or high blood pressure such as beta-blockers, diuretics and antiarrhythmics (disopyramide, procainamide and quinidine)
medicines used to treat glaucoma such as beta-blockers
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
medicines used to treat fungal infections (eg ketoconazole)
xanthine derivatives (eg theophylline) which are a class of medicines used to treat asthma and COPD
medicines used to treat Addison's disease (when there is inadequate production of a natural steroid hormone by the adrenal gland) or another condition where there is too much salt lose in the urine (eg fludrocortisone)

These medicines may be affected by Symbicort Turbuhaler or may affect how well it works. You may need different amounts of your medicine, or you may need to use different medicines. Your doctor or pharmacist will advise you.

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

Your doctor and pharmacist have more information on medicines to be careful with or avoid while using Symbicort Turbuhaler.

4. How do I use Symbicort Turbuhaler?

How to use your Turbuhaler

Follow all directions given to you by your doctor or pharmacist carefully.

They may differ from the information contained in this leaflet.

Each pack of Symbicort Turbuhaler contains an instruction for use leaflet that tells you the correct way to use it. Please read this carefully.

If you are not sure how to use the Turbuhaler, ask your doctor or pharmacist to show you how.

How much to take

Asthma (Adults and children 12 years and over)

Your healthcare professional should give you a personal Asthma Action Plan to help manage your asthma. This plan will include what medicines to take as a reliever when you have symptoms or sudden attacks of asthma, medicines you take prevent symptoms from occurring (eg prior to exercise or allergen exposure) and if you need to take daily maintenance medicines to help control your asthma.

It is important that you discuss with your doctor both your exposure to triggers and how often you exercise, as these could impact how your doctor prescribes your Symbicort Turbuhaler.

Your doctor may have prescribed Symbicort Turbuhaler for you to use as:

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

If your asthma has been under control for some time, your doctor may tell you to take less inhalations of Symbicort Turbuhaler, prescribe you a lower strength of Symbicort Turbuhaler or recommended that you use Symbicort Turbuhaler in a different way.

If you are using more inhalations of your reliever medicine or you are wheezing or breathless more than usual tell your doctor as your asthma may be getting worse.

Ask your doctor if you have any questions about how you should be using your Symbicort Turbuhaler.

Anti-inflammatory reliever only (Symbicort Turbuhaler 200/6)

For patients aged 12 years and over, Symbicort Turbuhaler 200/6 can be used to treat asthma symptoms when they happen and to help stop asthma symptoms from happening (eg just before exercise or before you get exposed to other triggers).

If you get asthma symptoms, take 1 inhalation and wait a few minutes. If you do not feel better, take another inhalation.

Your doctor will tell you how many inhalations to take before exercising or exposure to other triggers to help stop symptoms from happening.

Do not use more than 6 inhalations on a single occasion or more than 12 inhalations in any day. If your symptoms continue to worsen over 3 days, despite using additional inhalations, tell your doctor.

Have your Symbicort Turbuhaler reliever with you at all times.

Anti-inflammatory reliever plus maintenance therapy (Symbicort Turbuhaler 100/6 and 200/6)

For patients aged 12 years and over, Symbicort Turbuhaler 100/6 and 200/6 can be used to treat asthma symptoms when they happen. Symbicort Turbuhaler 200/6 can also be used to help stop asthma symptoms from happening (eg just before exercise or before you get exposed to other triggers).

If you get asthma symptoms, take 1 inhalation of Symbicort Turbuhaler 100/6 or 200/6 and wait a few minutes. If you do not feel better, take another inhalation.

Your doctor will tell you how many inhalations of Symbicort Turbuhaler 200/6 to take before exercising or exposure to other triggers to help stop symptoms from happening.

Have your Symbicort Turbuhaler 100/6 or 200/6 reliever with you at all times.

You also need to take your Symbicort Turbuhaler (100/6 or 200/6) daily as your maintenance preventer. The usual maintenance dose is 2 inhalations per day (given either as 1 inhalation in the morning and evening or as 2 inhalations in either the morning or evening). Your doctor may prescribe a maintenance dose of Symbicort Turbuhaler 200/6, 2 inhalations twice a day.

NOTE: Symbicort Turbuhaler 400/12 is not recommended to be used as anti-inflammatory reliever medicine.

Daily fixed dose maintenance therapy (Symbicort Turbuhaler 100/6, 200/6 and 400/12)

For patients aged 12 years and over, Symbicort Turbuhaler 100/6 and 200/6 can be used as a daily fixed-dose maintenance preventer. The usual dose is 1-2 inhalations twice a day.

Symbicort Turbuhaler 400/12 is recommended only for patients aged 18 years and over who need a higher daily dose.

The usual dose is 2 inhalations twice a day. Your doctor may also tell you to take 1 inhalation twice a day if your asthma has been under control.

Do not take more than 2 inhalations twice a day of Symbicort Turbuhaler 100/6, 200/6 or 400/12.

Have your separate reliever with you at all times.

COPD (Adults)

The usual dose (also maximum recommended dose) is:

2 inhalations of Symbicort Turbuhaler 200/6 twice daily or
1 inhalation of Symbicort Turbuhaler 400/12 twice daily.

Your doctor should tell you the best way to manage your symptoms and any flare ups. This may include additional medicines (such as reliever medicines) to use when you have sudden attacks of breathlessness.

If you are using more inhalations of your reliever medicine or you are wheezing or breathless more than usual tell your doctor.

If your COPD gets worse, your doctor may give you some additional medicines (such as oral corticosteroids or antibiotics).

How long to use your Symbicort Turbuhaler

If your doctor has told you to take Symbicort Turbuhaler daily, it is important that you use it every day even if you feel well.

Symbicort Turbuhaler helps control your asthma or COPD but does not cure it.

Keep using it for as long as your doctor tells you to. Do not stop using it unless your doctor tells you to.

If you forget to use Symbicort Turbuhaler

If you miss a dose of Symbicort Turbuhaler, take your dose as soon as you remember.

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

This may increase the chance of you getting an unwanted side effect.

If you are using Symbicort Turbuhaler as a reliever medicine, consult your doctor on the correct use of the product.

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

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

If you use too much Symbicort Turbuhaler

If you think that you have used too much Symbicort Turbuhaler, 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.

If you use too much Symbicort Turbuhaler, you may feel sick or vomit, have a fast or irregular heartbeat, a headache, tremble, feel shaky, agitated, anxious, tense, restless, excited or be unable to sleep.

5. What should I know while using Symbicort Turbuhaler?

Things you should do

If you have an Asthma Action Plan that you have agreed with your doctor, follow it closely at all times.
Keep using Symbicort Turbuhaler for as long as your doctor tells you to, even if you are feeling well.
See your doctor regularly to make sure that your asthma or COPD is not getting worse.
Have your reliever medicine available at all times.
As advised by your doctor, this may be your Symbicort Turbuhaler (100/6 or 200/6) or another reliever medicine.
If you become pregnant while using Symbicort Turbuhaler, tell your doctor.
Rinse your mouth out with water after taking your daily morning and/or evening dose of Symbicort Turbuhaler and spit this out. If you don't rinse your mouth, you are more likely to develop thrush in your mouth. You do not have to rinse mouth if you have to take occasional doses of Symbicort Turbuhaler for relief of asthma symptoms (ie as an anti-inflammatory reliever).

Call your doctor straight away if you:

notice any signs of pneumonia (infection of the lung).
Signs include fever or chills, increased phlegm/sputum production or change in colour, increased cough or increased breathing difficulties. Pneumonia is a serious medical condition and will require urgent medical attention.

Remind any doctor, dentist or pharmacist you visit that you are using Symbicort Turbuhaler.

Things you should not do

Do not stop using this medicine suddenly without checking with your doctor.
Do not take any other medicines for your asthma or COPD without checking with your doctor.
Do not give Symbicort Turbuhaler to anyone else, even if they have the same condition as you.
Do not use Symbicort Turbuhaler to treat any other complaints unless your doctor tells you to.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how Symbicort Turbuhaler affects you.

Symbicort Turbuhaler may cause dizziness, light-headedness, tiredness or drowsiness in some people when they first start using it.

Looking after your medicine

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

Storage

Keep your Turbuhaler in a cool dry place where the temperature stays below 30°C, with the cover firmly in place

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.

Cleaning

The Turbuhaler mouthpiece must be wiped with a clean dry cloth/tissue and must never get wet.

Full instructions on the right way to use and clean Symbicort Turbuhaler are inside each pack.

Getting rid of any unwanted medicine

Since some medicine may remain inside your Symbicort Turbuhaler you should always return it to your pharmacist for disposal including:

when you have taken all your doses and the dose indicator is on zero (‘0’ – see instructions in the pack), or
it is damaged or past its expiry date, or
your doctor/pharmacist have told you to stop using it.

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.

If you get any side effects, do not stop using Symbicort Turbuhaler without first talking to your doctor or pharmacist.

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

Less serious side effects

Less serious side effects	What to do
Mouth/throat-related: sore, yellowish, raised patches in the mouth (thrush) hoarse voice irritation of the tongue and mouth coughing	These are less likely to happen if you rinse your mouth out after every time you use your usual morning and/or evening dose of Symbicort Turbuhaler. Speak to your doctor if you have any of these less serious side effects and they worry you.
Heart-related: fast or irregular heart rate or pounding heart chest pain Nervous system-related: feeling anxious, nervous, restless or upset headache trembling or shakiness feeling light-headed or dizzy thirsty unpleasant taste in your mouth tiredness Gut-related: nausea (feeling sick) diarrhoea Skin-related: skin rash skin bruising Others: difficulty sleeping muscle twitching or cramps weight gain	Speak to your doctor if you have any of these less serious side effects and they worry you.
mood changes	Speak to your doctor if you notice any of these. You may need urgent medical attention.

Serious side effects

Serious side effects

What to do

Allergic Reaction:

difficulty breathing or worsening of your breathing problems
swelling of the face, lips, tongue or other parts of the body
severe rash

Pneumonia (lung infection):

signs include fever or chills, increased phlegm/sputum production or a change in colour, increased cough or difficulties breathing

Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.
You may need urgent medical attention. Serious side effects are rare.

Potential eye problem:
Any issues with your eyes such as blurred vision or other problems with your eyesight.

Speak to your doctor if you notice any of these.
Your doctor may need to send you to an ophthalmologist (eye doctor) to check that you don't have eye problems such as cataracts (clouding of the eye lens), glaucoma (increased pressure in your eyeballs) or other rare eye conditions reported with corticosteroids use.

Other side effects

Growth

Corticosteroids taken into the lungs for long periods (eg 12 months) may affect how children/adolescents grow. In rare cases, some children/adolescents may be sensitive to the growth effects of corticosteroids, so the doctor may monitor a child's/adolescent's height.

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.

Some of these side effects (for example, changes in blood sugars) can only be found when your doctor does test from time to time to check your progress.

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 Symbicort Turbuhaler contains

Active ingredients (main ingredient)	budesonide formoterol (eformoterol) fumarate dihydrate
Other ingredients (inactive ingredients)	Lactose monohydrate
Potential allergens	Lactose (which may contain milk protein residue). The amount of lactose contained in Symbicort Turbuhaler is very small and does not normally cause problems in lactose intolerant people.

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

What Symbicort Turbuhaler looks like

Symbicort Turbuhaler is a plastic inhaler containing the medicine as a dry powder.

Symbicort Turbuhaler is registered in the following presentations*:

100/6: Each Turbuhaler contains 60 (sample) or 120 inhalations of the medicine. [AUST R 80875]
200/6: Each Turbuhaler contains 30 (sample), 60 or 120 inhalations of the medicine. [AUST R 80876]
400/12: Each Turbuhaler contains 60 inhalations of the medicine, presented in packs of 1 (sample), 1 or 2 Turbuhalers. [AUST R 80877]

*not all registered presentations might be available in Australia

Who distributes Symbicort Turbuhaler

AstraZeneca Pty Ltd
ABN 54 009 682 311
66 Talavera Road
MACQUARIE PARK NSW 2113

Telephone: 1800 805 342

This leaflet was prepared on 27 June 2022.

® Symbicort and Turbuhaler are registered trade marks of the AstraZeneca group of companies.

Doc ID-000378998 v10.0

Published by MIMS August 2022

BRAND INFORMATION

Brand name

Symbicort Turbuhaler

Active ingredient

Budesonide; Formoterol (eformoterol) fumarate dihydrate

Schedule

1 Name of Medicine

Budesonide.
Formoterol (eformoterol) fumarate dihydrate.

2 Qualitative and Quantitative Composition

Symbicort Turbuhaler is available in a multidose inspiratory flow driven, metered dose dry powder inhaler (Turbuhaler). 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:

Symbicort Turbuhaler 100/6.

Each delivered dose (the dose that leaves the mouthpiece) contains as active constituents: budesonide 80 microgram/inhalation and formoterol 4.5 microgram/inhalation.

Symbicort Turbuhaler 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.

Symbicort Turbuhaler 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 Symbicort Turbuhaler is labelled as the metered dose of the corresponding monoproducts (Pulmicort (budesonide)/Oxis (formoterol) Turbuhaler M2 version). Pulmicort and Oxis Turbuhaler are also labelled as metered doses. Table 1 gives the corresponding dose delivered to the patient.

Excipient(s) with known effect.

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

3 Pharmaceutical Form

Powder for inhalation.

4 Clinical Particulars

4.1 Therapeutic Indications

Asthma.

Symbicort Turbuhaler 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).

Symbicort 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. Symbicort is not indicated for the initiation of bronchodilator therapy in COPD.

4.2 Dose and Method of Administration

Asthma.

Symbicort Turbuhaler can be used according to different treatment approaches.
A. Symbicort anti-inflammatory reliever therapy (patients with mild disease).
B. Symbicort anti-inflammatory reliever plus maintenance therapy.
C. Symbicort maintenance therapy (fixed dose).
Symbicort anti-inflammatory reliever therapy (patients with mild disease). Symbicort Turbuhaler 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 Symbicort Turbuhaler 200/6 available for relief of symptoms.
Preventative use of Symbicort Turbuhaler 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 Symbicort Turbuhaler 200/6 as needed in response to symptoms. If symptoms persist after a few minutes, 1 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 3-day period of deteriorating symptoms after taking additional as needed inhalations, the patient should be reassessed for alternative explanations of persisting symptoms.
Symbicort 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 Symbicort anti-inflammatory reliever therapy and in addition take a daily maintenance dose of Symbicort Turbuhaler. The as needed inhalations provide both rapid relief of symptoms and improved overall asthma control. Patients should be advised to have Symbicort Turbuhaler available for relief of symptoms at all times.
Preventative use of Symbicort Turbuhaler 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 400/12 strength should not be used for Symbicort anti-inflammatory reliever plus maintenance therapy regimen.

Adults and adolescents (12 years and older).

Patients should take 1 inhalation of Symbicort Turbuhaler 100/6 or 200/6 as needed in response to symptoms to control asthma. If symptoms persist after a few minutes, 1 additional inhalation should be taken. No more than 6 inhalations should be taken on any single occasion.
Patients also take the recommended maintenance dose of Symbicort Turbuhaler 100/6 or 200/6, which is 2 inhalations per day, given as either 1 inhalation in the morning and evening or as 2 inhalations in either the morning or evening. For some patients, a maintenance dose of Symbicort Turbuhaler 200/6 2 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 3-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.
Symbicort maintenance therapy (fixed dose). When maintenance treatment with a combination of ICS and LABA is required, Symbicort Turbuhaler 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 Symbicort Turbuhaler 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).

Symbicort Turbuhaler 100/6.

1 or 2 inhalations of Symbicort Turbuhaler 100/6 twice daily. The maximum recommended daily maintenance dose is 4 inhalations (2 inhalations twice daily corresponding to 400 microgram budesonide/24 microgram formoterol).

Symbicort Turbuhaler 200/6.

1 or 2 inhalations of Symbicort Turbuhaler 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).

Symbicort Turbuhaler 400/12.

2 inhalations of Symbicort Turbuhaler 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.

Symbicort Turbuhaler 200/6.

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

Symbicort Turbuhaler 400/12.

1 inhalation of Symbicort Turbuhaler 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 Symbicort Turbuhaler 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 Symbicort Turbuhaler as a maintenance therapy, they should be instructed that Symbicort Turbuhaler must be used even when asymptomatic for optimal benefit.

Special patient populations.

Renal impairment.

There are no data available for use of Symbicort Turbuhaler in patients with renal impairment.

Hepatic impairment.

There are no data available for use of Symbicort Turbuhaler 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.

Symbicort Turbuhaler is not recommended for children below 12 years of age.

Instruction for correct use of Symbicort Turbuhaler.

Turbuhaler is inspiratory flow driven which means that when the patient inhales through the mouthpiece, the substance will follow the inspired air into the airways.

Note.

It is important to instruct the patient to:
Check the expiry date.
Carefully read the instructions for use in the patient information leaflet that are provided with each pack of Symbicort Turbuhaler.
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.
Replace the cover of Symbicort Turbuhaler after use.
Rinse their mouth out with water after inhaling the maintenance dose to minimise the risk of oropharyngeal thrush.
The patient may not taste or feel any medication when using Symbicort Turbuhaler due to the small amount of drug delivered.

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 Symbicort Turbuhaler (for asthma patients on Symbicort anti-inflammatory reliever therapy and Symbicort anti-inflammatory reliever plus maintenance therapy) or a separate short acting bronchodilator (for other asthma patients using Symbicort Turbuhaler 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 Symbicort Turbuhaler.
It is recommended that the maintenance dose be 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.

Symbicort should not be used to initiate treatment with inhaled steroids in patients being transferred from oral steroids. Care should be taken when commencing Symbicort 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 Symbicort Turbuhaler 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 via Turbuhaler 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.

Symbicort Turbuhaler contains lactose (< 1 mg/inhalation) which may contain milk protein residue. 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.

Symbicort Turbuhaler 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 Symbicort 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 nonselective, 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 by another company 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 an AstraZeneca 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, in studies undertaken by another company.
(Category B3)
For Symbicort Turbuhaler 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.
Symbicort Turbuhaler should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Only after special consideration should Symbicort Turbuhaler 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, Symbicort Turbuhaler 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 birthweight 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 Symbicort Turbuhaler in nursing mothers. Administration of Symbicort Turbuhaler 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 Symbicort Turbuhaler on the individual is established. Symbicort Turbuhaler does not generally affect the ability to drive or use machinery.

4.8 Adverse Effects (Undesirable Effects)

Since Symbicort Turbuhaler 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 antifungal therapy whilst still continuing with Symbicort Turbuhaler 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 Symbicort, 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 the Symbicort (as Turbuhaler or Rapihaler 200/6) and comparative placebo arms.

In these placebo-controlled studies, the incidence of pneumonia was low.

Symbicort anti-inflammatory reliever therapy (SYGMA 1 and 2).

Overall, Symbicort 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 Symbicort Turbuhaler 200/6 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 Symbicort Turbuhaler 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 Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Symbicort Turbuhaler 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 antianaphylactic 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 hyper-reactive 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.

Symbicort Turbuhaler 100/6 and 200/6 refers to the metered dose of the corresponding monoproducts (budesonide and formoterol Turbuhalers (M2 version) 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, Symbicort Turbuhaler 400/12 refers to the metered dose of the corresponding monoproducts i.e. 400 microgram of budesonide and 12 microgram formoterol fumarate dihydrate. See Section 2 Qualitative and Quantitative Composition, Table 1.

Asthma.

Symbicort anti-inflammatory reliever therapy. A total of 8,064 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 3,384 patients were randomised to Symbicort 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 Symbicort anti-inflammatory reliever therapy (Symbicort Turbuhaler 200/6 used as needed in response to symptoms) to budesonide Turbuhaler 200 microgram (1 inhalation twice daily) given with as needed SABA. SYGMA 1 also compared Symbicort 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, Symbicort anti-inflammatory reliever therapy was comparable to a maintenance dose of budesonide Turbuhaler 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 Symbicort anti-inflammatory reliever therapy 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, Symbicort 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 Symbicort anti-inflammatory reliever therapy compared to a maintenance dose of budesonide Turbuhaler 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 Symbicort 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 Symbicort anti-inflammatory reliever therapy compared to a maintenance dose of budesonide Turbuhaler 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 Symbicort anti-inflammatory reliever therapy compared to patients on as needed SABA alone. Statistically significantly smaller increases were observed for Symbicort anti-inflammatory reliever therapy compared to a maintenance dose of budesonide Turbuhaler 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 Symbicort anti-inflammatory reliever therapy is a more effective treatment than SABA as needed in patients with mild asthma. In addition, these studies suggest that Symbicort 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 Symbicort 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 Symbicort anti-inflammatory reliever therapy and a maintenance dose of budesonide given with SABA as needed.
Symbicort anti-inflammatory reliever plus maintenance therapy. The safety and efficacy of Symbicort in the Symbicort anti-inflammatory reliever plus maintenance therapy regimen have been investigated in six clinical trials using two dose strengths (100/6 and 200/6) of Symbicort Turbuhaler in patients with asthma. A total of 14,219 patients (1134 elderly, 11,144 adults, 1,595 adolescents and 345 children) were randomised into the studies, of which 5,514 were treated with Symbicort 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 Symbicort 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 Tables 5 and 6). In the 5 double blind long-term studies, patients receiving Symbicort 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. Symbicort anti-inflammatory reliever plus maintenance therapy: Symbicort Turbuhaler 200/6, 1 inhalation twice daily plus additional inhalations as needed.
2. Symbicort 200/6, 1 inhalation twice daily with formoterol Turbuhaler as needed.
3. Symbicort Turbuhaler 200/6, 1 inhalation twice daily with terbutaline Turbuhaler as needed.
The primary efficacy variable, time to first severe exacerbation, was significantly increased with Symbicort anti-inflammatory reliever plus maintenance therapy compared with Symbicort plus formoterol and Symbicort plus terbutaline (see Table 5).
Use of oral steroids due to exacerbations was lower in the Symbicort anti-inflammatory reliever plus maintenance therapy group (1204 days total vs 2063 and 2755 days in the Symbicort plus formoterol and Symbicort plus terbutaline groups, respectively).
The majority of secondary variables supported the superiority of Symbicort anti-inflammatory reliever plus maintenance therapy over both comparators (see Table 7). The average daily as needed use in the Symbicort anti-inflammatory reliever plus maintenance therapy group was 1.02 inhalations/day and the frequency of high as needed use was lower for Symbicort anti-inflammatory reliever plus maintenance therapy compared to both comparators.

The study specifically demonstrates that both the budesonide and the formoterol components of Symbicort contribute to improved asthma control achieved through the as needed dosing of Symbicort within the Symbicort 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. Symbicort anti-inflammatory reliever plus maintenance therapy: Symbicort Turbuhaler 200/6, 1 inhalation twice daily plus additional inhalation as needed.
2. Seretide Inhaler 125/25, 2 inhalations twice daily with terbutaline Turbuhaler as needed.
3. Symbicort Turbuhaler 400/12, 1 inhalation twice daily with terbutaline Turbuhaler as needed.
The primary efficacy variable, time to first severe exacerbation, was significantly increased with Symbicort anti-inflammatory reliever plus maintenance therapy compared with both Seretide plus terbutaline and Symbicort at a higher maintenance dose plus terbutaline (see Table 5).
Use of oral steroids due to exacerbations was lower in the Symbicort anti-inflammatory reliever plus maintenance therapy group compared to Seretide plus terbutaline and Symbicort 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 Symbicort anti-inflammatory reliever plus maintenance therapy and the other two groups. The average daily as needed use in the Symbicort anti-inflammatory reliever plus maintenance therapy group was 1.02 inhalations/day.
Since the mean daily dose in the Symbicort anti-inflammatory reliever plus maintenance therapy group remained lower than in the Symbicort plus terbutaline group, the study specifically confirms the benefit of as needed administration of part of the Symbicort dose.

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

In studies 673, 668 and 667, Symbicort anti-inflammatory reliever plus maintenance therapy prolonged the time to the first exacerbation compared to Symbicort 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 Symbicort anti-inflammatory reliever plus maintenance therapy with Seretide plus Ventolin 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 Symbicort anti-inflammatory reliever plus maintenance therapy treatment is more effective than adjustable therapy with Seretide plus Ventolin in controlling asthma in adults and adolescents. Symbicort 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 Seretide at a similar daily ICS dose.

Safety in the combined studies.

Symbicort anti-inflammatory reliever plus maintenance therapy treatment has a safety profile that is similar to budesonide and Symbicort maintenance therapy with a decrease in asthma related adverse events.
Exercise-induced and allergen-induced bronchoconstriction. The use of Symbicort Turbuhaler 200/6 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 Symbicort Turbuhaler 200/6, 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 Symbicort Turbuhaler 200/6 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 Symbicort Turbuhaler 200/6.
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, Symbicort Turbuhaler 200/6 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 Symbicort Turbuhaler 200/6 than with formoterol.
Symbicort maintenance therapy. The efficacy and safety of Symbicort Turbuhaler 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 Symbicort Turbuhaler.

Symbicort Turbuhaler 100/6 and 200/6.

In one study, the maximum recommended maintenance dose of Symbicort Turbuhaler 200/6 (2 inhalations twice daily) was compared to corresponding doses of the free combination (budesonide Turbuhaler 200 microgram + formoterol Turbuhaler 6 microgram, two inhalations twice daily) and budesonide Turbuhaler 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, Symbicort Turbuhaler 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%) Symbicort Turbuhaler 100/6 (1 inhalation twice daily) was compared with budesonide Turbuhaler 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 Symbicort Turbuhaler 100/6 than with a doubled dose of budesonide.

Symbicort Turbuhaler 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%), Symbicort Turbuhaler 400/12 (2 inhalations twice daily) was compared to corresponding doses of the free combination (formoterol Turbuhaler 12 microgram + budesonide Turbuhaler 400 microgram, two inhalations twice daily) and budesonide Turbuhaler 400 microgram (2 inhalations twice daily) only. Table 14 details the efficacy results after 12 weeks treatment.

When administered twice daily, Symbicort Turbuhaler 400/12 is a more effective treatment for the majority of clinical endpoints than the corresponding budesonide dose.

COPD.

The efficacy and safety of Symbicort in the treatment of patients with moderate to severe COPD (prebronchodilator FEV₁ ≤ 50% predicted normal) has been evaluated in four randomised, double blind, placebo and active controlled, parallel group, multicentre clinical studies. Two 12 month studies were performed with the dry powder inhaler Symbicort Turbuhaler (studies 629 and 670), and one 12 month and one 6 month study were performed with the pressurised metered dose inhaler (pMDI) Symbicort Rapihaler (studies 001 and 002, respectively).
Studies 629 and 670. In both studies, Symbicort Turbuhaler 200/6 was compared with placebo and the corresponding monoproducts (budesonide Turbuhaler 200 microgram and formoterol Turbuhaler 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 Symbicort Turbuhaler. 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 Symbicort Rapihaler.
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. Symbicort Rapihaler 200/6, fixed combination of 200 microgram budesonide and 6 microgram formoterol per actuation, administered as 2 actuations twice daily.
2. Symbicort Rapihaler 100/6, fixed combination of 100 microgram budesonide and 6 microgram formoterol per actuation, administered as 2 actuations twice daily.
3. Formoterol Turbuhaler, 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 Turbuhaler 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 Symbicort Rapihaler 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 coprimary endpoints of postdose 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).
Symbicort Turbuhaler significantly improved mean FEV₁ compared with placebo and budesonide by 15% (p < 0.001) and 9% (p < 0.001), respectively.
Symbicort Turbuhaler 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 Symbicort Turbuhaler compared with formoterol was 2.4.
Study 670. In study 670, efficacy was evaluated over 12 months using the coprimary endpoints of postdose 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).
Symbicort Turbuhaler 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.
Symbicort Turbuhaler 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.
Symbicort Turbuhaler 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 coprimary efficacy variables of change from baseline in average predose and 1 hour postdose FEV₁ over the treatment period.

Primary endpoints.

Symbicort Rapihaler 100/6 produced a significantly greater change in postdose FEV₁ compared to placebo (LS mean = 0.16 L; p < 0.001); however the change in predose FEV₁ was not significantly different to formoterol 6 microgram (LS mean = 0.02 L; p = 0.161).
Symbicort Rapihaler 200/6 significantly improved 1 hour predose FEV₁ compared with formoterol and placebo by 0.04 L (p = 0.008) and 0.09 L (p < 0.001), respectively.
Symbicort Rapihaler 200/6 significantly improved postdose 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 Symbicort Rapihaler 200/6 (N = 121). Maximum improvement in FEV₁ occurred at approximately 2 hours postdose, and postdose bronchodilator effect was maintained over 12 hours.

Exacerbations (secondary variable).

Symbicort Rapihaler 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: Symbicort Rapihaler 200/6, 30.8%; Symbicort Rapihaler 100/6, 32.6%; placebo 37.2%. The majority of exacerbations were treated with oral glucocorticosteroids: Symbicort Rapihaler 200/6, 96.5% of exacerbations; Symbicort Rapihaler 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. Symbicort Rapihaler 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. Symbicort Rapihaler 100/6 reduced the exacerbation rate by 41% compared with placebo (p < 0.001).
Symbicort Rapihaler 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 Symbicort Rapihaler compared with formoterol was 5.4.
Study 002. In Study 002, efficacy was evaluated over 6 months using the coprimary efficacy variables of change from baseline in average predose and 1 hour postdose FEV₁ over the treatment period.
Symbicort Rapihaler 100/6. Postdose FEV₁ increased significantly from baseline to the average of the treatment period (LS mean (95% CI) = 0.19 (0.17, 0.22)). Symbicort Rapihaler 100/6 caused a significantly greater change from baseline compared to budesonide (LS mean = 0.16; p < 0.001). Predose 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 predose FEV₁ was not statistically significant, LS mean = 0.02 (-0.02, 0.05; p = 0.335).
Symbicort Rapihaler 200/6 significantly improved predose 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.
Symbicort Rapihaler 200/6 significantly improved 1 hour postdose 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 Symbicort Rapihaler 200/6 (N = 101). Maximal improvement in FEV₁ occurred at approximately 2 hours postdose, and postdose bronchodilator effect was generally maintained over 12 hours.

5.2 Pharmacokinetic Properties

Symbicort Turbuhaler and the corresponding monoproducts (budesonide Turbuhaler and formoterol Turbuhaler (M2 version) (see Section 2 Qualitative and Quantitative Composition, Table 1)) 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 Symbicort Turbuhaler.

Absorption.

After inhalation of budesonide via Turbuhaler the mean lung deposition ranged from 26 to 34% of the metered dose. The systemic bioavailability of budesonide inhaled via Turbuhaler is approximately 40% of the metered dose.
In studies the mean lung deposition of formoterol after inhalation via Turbuhaler 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 (approx 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 (approximately 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 of formoterol via a Turbuhaler 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 in patients with renal failure is unknown. The systemic availability of budesonide and formoterol may be increased in patients with liver disease.

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 performed by AstraZeneca, 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 β-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 (also see Section 2 Qualitative and Quantitative Composition).

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

Do not store above 30°C. Replace cap firmly after use.

6.5 Nature and Contents of Container

The following pack sizes are registered^ for Symbicort Turbuhaler.
100/6: 60 (sample pack) or 120 inhalations.
200/6: 30 (sample pack), 60 or 120 inhalations.
400/12: 60 inhalations of single Turbuhaler (sample pack), single or double Turbuhaler pack.
^ Not all pack sizes may be available in Australia.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Chemical structure.

Budesonide.

Chemical name: 16α, 17α - 22 R, S-propylmethylenedioxypregna- 1,4-diene- 1β, 21-diol-3, 20-dione.

Formoterol fumarate dihydrate.

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.

CAS number.

Budesonide.

51333-22-3.

Formoterol fumarate dihydrate.

183814-30-4.

7 Medicine Schedule (Poisons Standard)

Prescription only medicine (Schedule 4).

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Symbicort Turbuhaler

Budesonide; Formoterol (eformoterol) fumarate dihydrate

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BRAND INFORMATION

Symbicort 100/6 mcg per dose Turbuhaler

Symbicort 200/6 mcg per dose Turbuhaler

Symbicort 400/12 mcg per dose Turbuhaler