Consumer medicine information

Symbicort Rapihaler

Budesonide; Formoterol (eformoterol) fumarate dihydrate

BRAND INFORMATION

Brand name

Symbicort Rapihaler

Active ingredient

Budesonide; Formoterol (eformoterol) fumarate dihydrate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Symbicort Rapihaler.

What is in this leaflet

This leaflet answers some common questions about Symbicort Rapihaler. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have benefits and risks. Your doctor has weighed the risks of you using Symbicort Rapihaler against the benefits they expect it will have for you.

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

Keep this leaflet with your Symbicort Rapihaler. You may need to read it again.

What Symbicort Rapihaler is used for?

Symbicort Rapihaler is a pressurised metered dose inhaler (pMDI) or puffer.

Symbicort Rapihaler 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).

Symbicort Rapihaler 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.

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 Rapihaler helps to improve your condition and to prevent asthma attacks from occurring.

The formoterol in Symbicort Rapihaler helps you breathe more easily.

Some people can take Symbicort Rapihaler when they need it - They use Symbicort Rapihaler 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 Rapihaler every day. They use their Symbicort Rapihaler 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.

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

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

Symbicort Rapihaler is not addictive.

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

Before you use Symbicort Rapihaler

When you must not use it

Do not use Symbicort Rapihaler if you have an allergy to:

  • any medicine containing formoterol or budesonide
  • any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

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

Do not give Symbicort Rapihaler to a child under 12 years, unless directed by the child's doctor. Symbicort Rapihaler is not recommended for use in children under 12 years.

Do not use Symbicort Rapihaler after the expiry date (EXP) printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

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

Before you start to use it

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 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 Rapihaler.

Your doctor may prescribe Symbicort Rapihaler 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 used as a reliever.

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

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

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

  • thyroid problems
  • diabetes
  • heart problems
  • liver problems
  • tuberculosis (TB)
  • low levels of potassium in the blood

It may not be safe for you to take Symbicort Rapihaler if you have, or have had, any of these conditions.

Tell your doctor if you currently have an infection. If you take Symbicort Rapihaler 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.

Tell your doctor if you are pregnant or intend to become pregnant or breastfeeding. Your doctor will discuss the possible risks and benefits of using Symbicort Rapihaler during pregnancy and while breastfeeding.

If you have not told your doctor or pharmacist about any of the above, tell them before you start using Symbicort Rapihaler.

Taking other medicines

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

Some medicines and Symbicort Rapihaler may interfere with each other. 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.

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

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

How to use Symbicort Rapihaler

How to use your Rapihaler

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 Rapihaler contains an instruction leaflet that tells you the correct way to use it. Please read this carefully.

If you are not sure how to use the Rapihaler, 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 can 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 Rapihaler.

Your doctor may prescribe Symbicort Rapihaler 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 used as a reliever.

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

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

Anti-inflammatory reliever only (Symbicort Rapihaler 100/3)

For patients aged 12 years and over, Symbicort Rapihaler 100/3 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 2 inhalations and wait a few minutes. If you do not feel better, take 2 more inhalations.

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 12 inhalations on a single occasion or more than 24 inhalations in any day. If your symptoms continue to worsen over 3 days, despite using additional inhalations, tell your doctor.

Have your Symbicort Rapihaler reliever with you at all times.

Anti-inflammatory reliever plus maintenance therapy (Symbicort Rapihaler 50/3 and 100/3)

For patients aged 12 years and over, Symbicort Rapihaler 50/3 and 100/3 can be used to treat asthma symptoms when they happen. Symbicort Rapihaler 100/3 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 2 inhalations of Symbicort Rapihaler 50/3 or 100/3 and wait a few minutes. If you do not feel better, take 2 more inhalations.

Your doctor will tell you how many inhalations of Symbicort Rapihaler 100/3 to take before exercising or exposure to other triggers to help stop symptoms from happening.

Have your Symbicort Rapihaler 50/3 or 100/3 reliever with you at all times. You also need to take you Symbicort Rapihaler (50/3 and 100/3) daily as your maintenance preventer. The usual maintenance dose is 4 inhalations per day (given either as 2 inhalations in the morning and evening or as 4 inhalations in either the morning or evening). Your doctor may prescribe a maintenance dose of Symbicort Rapihaler 100/3 4 inhalations twice a day.

Do not use more than 12 inhalations on a single occasion or more than 24 inhalations of Symbicort Rapihaler (as needed and daily dose) in any day. If your symptoms continue to worsen over 3 days, despite using additional inhalations, tell your doctor.

NOTE: Symbicort Rapihaler 200/6 is not recommended to be used as an anti-inflammatory reliever medicine.

Daily fixed dose maintenance therapy (Symbicort Rapihaler 50/3, 100/3 and 200/6)

For patients aged 12 years and over, Symbicort Rapihaler 50/3, 100/3 and 200/6 can be used as a daily fixed-dose maintenance preventer.

The usual dose of Symbicort Rapihaler 50/3 and 100/3 is 2 or 4 inhalations twice a day. Do not take more than 8 inhalations a day.

The usual dose of Symbicort Rapihaler 200/6 is 2 inhalations twice a day. Do not take more than 4 inhalations per day.

Symbicort Rapihaler 200/6 can also be given as a higher dose in patients aged 18 years and over. The usual dose is 4 inhalations twice a day. Do not take more than 8 inhalations per day.

Have your separate reliever with you at all times.

COPD (Adults)

The usual dose (also maximum recommended dose) is 2 puffs of Symbicort Rapihaler 200/6 twice a day.

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).

If you forget to use it

If you miss a dose of Symbicort Rapihaler, 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 Rapihaler 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.

How long to use it

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

Symbicort Rapihaler 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 take too much (overdose)

Telephone your doctor, pharmacist or the Poisons Information Centre (telephone 13 11 26) or go to Accident and Emergency at your nearest hospital if you think that you or anyone else may have used too much Symbicort Rapihaler.

Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

If you use too much Symbicort Rapihaler, 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.

While you are using Symbicort Rapihaler

Things you must do

If you have an Asthma Action Plan that you have agreed with your doctor, follow it closely at all times.

Keep using Symbicort Rapihaler 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 Rapihaler (50/3 or 100/3) or another reliever medicine.

Rinse your mouth out with water after taking your daily morning and/or evening dose of Symbicort Rapihaler 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 your mouth if you have to take occasional puffs of Symbicort Rapihaler for relief of asthma symptoms (ie as an anti-inflammatory reliever).

Tell any other doctors, dentists and pharmacists who are treating you that you are using Symbicort Rapihaler.

If you become pregnant while using Symbicort Rapihaler, tell your doctor.

Patients taking Symbicort Rapihaler for COPD should tell their doctor or pharmacist immediately if they notice any signs of pneumonia (infection of the lung). Signs include fever or chills, increased mucus production or change in mucus colour, increased cough or increased breathing difficulties. Pneumonia is a serious medical condition and will require urgent medical attention.

Things you must not do

Do not take any other medicines for your asthma or COPD without checking with your doctor.

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

Do not use Symbicort Rapihaler to treat any other complaints unless your doctor tells you to.

Do not stop using Symbicort Rapihaler without checking with your doctor.

Things to be careful of

Be careful driving or operating machinery until you know how Symbicort Rapihaler affects you.

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

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are using Symbicort Rapihaler.

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

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

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

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

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

  • 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 Rapihaler.

  • Trembling or shakiness
  • Feeling anxious, nervous, restless or upset
  • Fast or irregular heart rate or pounding heart
  • Chest pain
  • Headache
  • Feeling light-headed or dizzy
  • Thirsty
  • Unpleasant taste in your mouth
  • Nausea (feeling sick)
  • Diarrhoea
  • Difficulty sleeping
  • Muscle twitching or cramps
  • Skin rash
  • Tiredness
  • Weight gain
  • Skin bruising

These side effects are usually mild.

Tell your doctor or pharmacist immediately if you notice any of the following:

  • Difficulty breathing or worsening of your breathing problems
  • Swelling of the face, lips, tongue or other parts of the body
  • Severe rash
  • Mood changes

These may be serious side effects. You may need urgent medical attention. Serious side effects are rare.

Tell your doctor or pharmacist if you notice anything else that is making you feel unwell. Other side effects not listed above may occur in some patients.

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

Tell your doctor if you notice any issues with your eyes such as blurred vision or other problems with your eyesight. 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 corticosteroid use.

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.

After using Symbicort Rapihaler

Cleaning

The Rapihaler 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 Rapihaler are inside each pack.

Storage

Keep your Symbicort Rapihaler in a cool dry place where the temperature stays below 30°C.

Always replace the mouthpiece cover after using Symbicort Rapihaler.

Discard Symbicort Rapihaler within 3 months after removal from the foil pouch.

Do not store Symbicort Rapihaler or any other medicine in the bathroom or near a sink. Do not leave it in the car on hot days or on a windowsill. Heat and dampness can destroy some medicines.

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

WARNING:

The canister in Symbicort Rapihaler contains a pressurised liquid. Do not expose to temperatures high than 50°C. Do not pierce the canister. The canister should not be broken, punctured or burnt, even when it seems empty.

Disposal

Your Symbicort Rapihaler should always be returned to your pharmacist for disposal including:

  • when you have taken all your doses and the dose counter reaches zero ('0' - see instructions in the pack), or
  • 3 months after removal from the foil pouch, or
  • it is damaged or past its expiry date, or
  • your doctor/pharmacist has told you to stop using it.

Product description

What it looks like

Symbicort Rapihaler is a pressurised metered dose inhaler with a dose counter. The inhaler is comprised of a pressurised aluminium canister with an attached dose counter, a red plastic casing body with a white mouthpiece and attached grey mouthpiece cover. Each inhaler is individually wrapped in a foil laminate pouch (containing a sachet of drying agent).

Symbicort Rapihaler contains 120 puffs (inhalations) and is available in three strengths: 50/3, 100/3 and 200/6. Each pack contains 1 inhaler. Symbicort Rapihaler 200/6 also has a 60 puff (inhalation) pack size (sample).

Ingredients

Symbicort Rapihaler contains budesonide and formoterol (eformoterol) fumarate dihydrate as the active ingredients. The other ingredients are apaflurane (HFA-227), macrogol 1000 and povidone.

Symbicort Rapihaler does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

Sponsor

AstraZeneca Pty Ltd
ABN 54 009 682 311
66 Talavera Road
MACQUARIE PARK NSW 2113
Telephone: 1800 805 342

This leaflet was prepared on 18 July 2019

Australian Registration Numbers

50/3 - AUST R 158898

100/3 - AUST R 158899

200/6 - AUST R 115555

® Symbicort Rapihaler is a registered trademark of the AstraZeneca group of companies.

© AstraZeneca, 2019

Doc ID-000374359 v7

Published by MIMS October 2019

BRAND INFORMATION

Brand name

Symbicort Rapihaler

Active ingredient

Budesonide; Formoterol (eformoterol) fumarate dihydrate

Schedule

S4

 

1 Name of Medicine

Budesonide.
Eformoterol fumarate dihydrate is now known as formoterol fumarate dihydrate (hereafter referred to as formoterol).

6.7 Physicochemical Properties

Budesonide.

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

Chemical structure.


CAS number.

51333-22-3.

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.

Chemical structure.


CAS number.

183814-30-4.

2 Qualitative and Quantitative Composition

Symbicort Rapihaler is a pressurised metered dose inhaler (pMDI). The following strengths are registered:

Symbicort Rapihaler 50/3.

Each delivered dose (the dose that leaves the mouthpiece) contains as active constituents: budesonide 40 microgram/inhalation and formoterol 2.25 microgram/inhalation.

Symbicort Rapihaler 100/3.

Each delivered dose (the dose that leaves the mouthpiece) contains as active constituents: budesonide 80 microgram/inhalation and formoterol 2.25 microgram/inhalation.

Symbicort Rapihaler 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 Rapihaler 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.
To avoid confusion, Symbicort Rapihaler is labelled as metered dose like Symbicort Turbuhaler. Table 1 gives the corresponding dose delivered to the patient.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Inhalation, pressurised.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Symbicort Rapihaler 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 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 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 is a potent selective β2-adrenergic agonist that produces relaxation of bronchial smooth muscle. Therefore, it has a bronchodilating effect in patients with reversible airways obstruction and in patients with bronchospasm induced by direct (methacholine) and indirect (e.g. exercise) stimuli. The bronchodilating effect is dose dependent with an onset of effect within 1 to 3 minutes after inhalation. The duration of effect is at least 12 hours after a single dose.

Clinical trials.

Asthma.

Therapeutic equivalence between Symbicort Rapihaler and Symbicort Turbuhaler was demonstrated in three clinical efficacy and safety studies in adults and adolescents with asthma. They included two randomised, double-blind, active controlled, parallel-group studies, Studies 681 (12 weeks duration) and 003 (6 weeks duration); and one randomised, open-label, parallel group, long-term (12 months) study, Study 715.
No clinical studies have been conducted to directly compare the efficacy and safety of Symbicort Rapihaler 100/3 with Symbicort Turbuhaler 200/6.
In Study 681, Symbicort Rapihaler 200/6 (2 inhalations twice daily) was compared with the corresponding dose of budesonide pMDI (200 microgram; 2 inhalations twice daily), or Symbicort Turbuhaler (200/6; 2 inhalations twice daily) in adults and adolescents (≥ 12 years) with moderate to severe asthma [e.g. mean forced expiratory volume during the first second (FEV1) ≥ 50% and ≤ 90% of predicted normal (PN) and FEV1 reversibility ≥ 12%]. Symbicort Rapihaler was shown to significantly improve morning peak expiratory flow rate (primary efficacy variable), other lung function parameters, symptom scores and use of reliever medication compared to budesonide and was equivalent to Symbicort Turbuhaler (see Table 4).
Study 003 was a 6-week study with similar design to Study 681. In this study, Symbicort Rapihaler 50/3 (2 inhalations twice daily) was compared primarily (as regular therapy) with the corresponding dose of budesonide Turbuhaler 100 microgram (1 inhalation twice daily), or and secondarily with Symbicort Turbuhaler 100/6 (1 inhalation twice daily) in adults and adolescents (≥ 12 years) with asthma (mean FEV1 74% PN and FEV1 reversibility 24%). The primary efficacy variable was the change in morning peak expiratory flow (mPEF) from baseline (mean of the 10 last days of the run-in period) to the treatment period (mean of the 6-week treatment period). The primary objective was to demonstrate that Symbicort Rapihaler 50/3 was more efficacious than budesonide Turbuhaler 100 microgram. The adjusted mean mPEF increased by 12.2 L/min with Symbicort Rapihaler 50/3, 4.15 L/min with budesonide Turbuhaler, and 13.1 L/min with Symbicort Turbuhaler 100/6. The results showed that the mean change from baseline in mPEF was greater with Symbicort Rapihaler 50/3 than with budesonide Turbuhaler, and that the mean difference was statistically significant (mean difference of 8.07 L/min [95% CI: 3.26 to 12.9], p=0.001). The secondary objective was to demonstrate therapeutic equivalence of Symbicort Rapihaler 50/3 and Symbicort Turbuhaler 100/6. The results supported equivalence of the two Symbicort formulations as regular treatment in both the ITT and per-protocol analyses. There was no statistically significant difference between the two Symbicort formulations for any outcome variable in this study.
Study 715 investigated primarily the safety of Symbicort Rapihaler 200/6 (2 inhalations twice daily) during 12 months. The reference treatment was the corresponding dose of Symbicort Turbuhaler 200/6 and in a population consisting of adults and adolescents (≥ 12 years) with moderate to severe asthma (e.g. mean FEV1 of ≥ 50% of PN and FEV1 reversibility ≥ 12%). The study was of an open-label design.
There was no statistically significant difference between Symbicort Rapihaler and Symbicort Turbuhaler regarding FEV1 and FVC (forced vital capacity). The percentage of patients experiencing one or more severe asthma exacerbations did not differ between the two Symbicort groups: 11% in the Symbicort Rapihaler group and 13% in the Symbicort Turbuhaler group. The maximum number of severe exacerbations per patient was 6 in the Symbicort Rapihaler group and 4 in the Symbicort Turbuhaler group. There was no statistical significant difference in time to first severe asthma exacerbation between the two treatment groups.

COPD.

The efficacy and safety of Symbicort 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 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 mono-products (budesonide Turbuhaler 200 microgram and formoterol Turbuhaler 6 microgram), all taken as two 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 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).
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 co-primary 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 co-primary efficacy variables of change from baseline in average pre-dose and 1-hour post-dose FEV1 over the treatment period.

Primary endpoints.

Symbicort Rapihaler 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).
Symbicort Rapihaler 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.
Symbicort Rapihaler 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 Symbicort Rapihaler 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).

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 (RR) 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 co-primary efficacy variables of change from baseline in average pre-dose and 1-hour post-dose FEV1 over the treatment period.
Symbicort Rapihaler 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]). Symbicort Rapihaler 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].
Symbicort Rapihaler 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.
Symbicort Rapihaler 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 Symbicort Rapihaler 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 budesonide and formoterol bioavailability of Symbicort Rapihaler and Symbicort Turbuhaler were similar after single doses containing 1280 microgram budesonide and 36 microgram formoterol (8 inhalations) in healthy adult volunteers. The budesonide and formoterol bioavailability from Symbicort Rapihaler was also comparable with that from similar doses of the component products, Pulmicort (budesonide) Turbuhaler, Oxis (formoterol) Turbuhaler and a specially prepared budesonide HFA pressurised inhalation suspension.
There was no evidence of pharmacokinetic interactions between budesonide and formoterol.

Absorption.

Inhaled budesonide is rapidly absorbed and the maximum plasma concentration is reached within 30 minutes after inhalation.
Inhaled formoterol is rapidly absorbed and the maximum plasma concentration is reached within 10 minutes after inhalation.

Distribution.

Plasma protein binding is approximately 90% for budesonide and volume of distribution is 3 L/kg.
Plasma protein binding is approximately 50% for formoterol and volume of distribution is about 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. The glucocorticosteroid activity of the major metabolites, 6β-hydroxy-budesonide and 16α-hydroxy-prednisolone is less than 1% of that of budesonide.
Formoterol is inactivated via conjugation reactions (active-O-demethylated and deformylated metabolites are formed, but they are seen mainly as inactivated conjugates).

Excretion.

Budesonide is eliminated via metabolism mainly catalysed by the enzyme CYP3A4. The metabolites of budesonide are excreted in urine as such or in conjugated form. Only negligible amounts of unchanged budesonide have been detected in the urine. Budesonide has a high systemic clearance (approximately 1.2 L/min) and the plasma elimination half-life after i.v. dosing averages 4 hours.
The major part of a dose of formoterol is eliminated by metabolism in the liver followed by renal excretion. After inhalation of formoterol via a Turbuhaler, 8% to 13% of the delivered dose of formoterol is excreted unmetabolised in the urine. Formoterol has a high systemic clearance (approximately 1.4 L/min) and terminal elimination half-life averages 17 hours.

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

The pharmacokinetics of budesonide or formoterol in children, elderly patients, and 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), 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 2 years, and a mesovarian leiomyoma was observed in a female rat dosed by inhalation at 0.13 mg/kg/day for 2 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 β2-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.

4 Clinical Particulars

4.1 Therapeutic Indications

Asthma.

Symbicort Rapihaler 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 200/6 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.

4.3 Contraindications

Hypersensitivity to budesonide, formoterol or any other ingredients present in this formulation.

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 Rapihaler (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 patients using Symbicort Rapihaler 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 Rapihaler.
It is recommended that the 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.

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 switched from oral corticosteroids (see Section 4.4 Special Warnings and Precautions for Use, Oral corticosteroid usage) and patients administering concomitant medication metabolised by CYP3A4 (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Pharmacokinetic 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 to 6 years) studies of budesonide treatment in adults at recommended doses, have not demonstrated a negative effect on bone mass compared to placebo, including a 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 3 large, medium-to-long-term (12 months to 6 years) studies in children (5 to 16 years), no effects on bone mineral density were observed after treatment with budesonide (189 to 1322 microgram/day) compared to nedocromil, placebo or age matched controls. However, in a randomised 18-month paediatric study (n=176; 5 to 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 of growth (approximately 1 cm) has been observed. This generally occurs within the first year of treatment. Physicians should closely follow the growth of children and adolescents taking long-term corticosteroids.
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, Xanthine derivatives, mineralocorticosteroids and diuretics). 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).

Use in renal impairment.

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

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 the elderly.

See Section 5.1 Pharmacodynamic Properties, Clinical trials.

Paediatric use.

Symbicort Rapihaler is not recommended for children under the age of 12 years because of lack of data on efficacy and safety.

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. Inhibitors of this enzyme, e.g. ketoconazole, may therefore increase systemic exposure to budesonide. This is of limited clinical importance for short-term (1 to 2 weeks) treatment with ketoconazole, but should be taken into consideration during long-term treatment with ketoconazole or other potent CYP3A4 inhibitors.

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 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 2 years, but no effect on male fertility was observed in rats dosed orally at 60 mg/kg/day for 9 weeks, in studies undertaken by another company.
(Category B3)
For the concomitant treatment with budesonide and formoterol, no clinical data on exposed pregnancies are available. Fetal malformations (umbilical hernia and cleft palate), typical of glucocorticoid toxicity in animals, occurred in rats dosed with the Symbicort Rapihaler formulation at the inhaled dose of 12 microgram/kg/day budesonide and 0.66 microgram/kg/day formoterol, with plasma AUC values for both drugs below that expected in patients at the maximum recommended clinical dose. No teratogenic effect was detected at 2.5 microgram/kg/day of budesonide and 0.14 microgram/kg/day of formoterol.
Symbicort Rapihaler should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Only after special consideration should Symbicort Rapihaler 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 Rapihaler should be used during labour only if the potential benefit justifies the potential risk.

Budesonide.

Results from a large prospective epidemiological study and from world-wide post-marketing experience indicate no adverse effects of inhaled budesonide during pregnancy on the health of the fetus/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. Foetal 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 foetuses 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 passes into human breast milk. In rats, formoterol was excreted into breast milk. There are no studies in lactating animals using the budesonide/formoterol combination. Increased postnatal mortality at maternal formoterol doses of 0.2 mg/kg/day PO or greater, and retardation of pup growth at 15 mg/kg/day PO were observed in a rat study. There are no well-controlled human studies using Symbicort Rapihaler in nursing mothers. Because many drugs are excreted in human breast milk, administration of Symbicort Rapihaler 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.

4.8 Adverse Effects (Undesirable Effects)

Since Symbicort Rapihaler 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.
In the clinical program comparing Symbicort Rapihaler with Symbicort Turbuhaler, 679 adults and adolescents (Study 681 and Study 715) were exposed to Symbicort Rapihaler 800/24 microgram daily with a median duration of 359 days and a range of 1 to 427 days.
There were no apparent differences in the overall pattern of AE's between the Symbicort Rapihaler and Symbicort Turbuhaler groups in the clinical program. The AEs were generally mild to moderate in intensity and the pattern was that usually seen in a population with persistent asthma and dominated by symptoms of upper respiratory events.
Overall, the AE profile was similar for patients receiving Symbicort Rapihaler and Symbicort Turbuhaler with regard to total daily dose, age, sex and ethnic group and no new safety concerns were identified with Symbicort Rapihaler.
If oropharyngeal candidiasis develops, it may be treated with appropriate anti-fungal therapy whilst still continuing with Symbicort Rapihaler 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, with no consistent evidence of increased risk of pneumonia for Symbicort-treated patients compared to patients on placebo.

Symbicort anti-inflammatory reliever therapy.

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 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.

4.2 Dose and Method of Administration

Asthma.

Symbicort Rapihaler 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 Rapihaler 100/3 is taken as needed for the relief of asthma symptoms when they occur, and as preventative treatment of symptoms in those circumstances recognised by the patient to precipitate an asthma attack. Patients should be advised to always have Symbicort Rapihaler 100/3 available for relief of symptoms.
Preventative use of Symbicort Rapihaler 100/3 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 2 inhalations of Symbicort Rapihaler 100/3 as needed in response to symptoms. If symptoms persist after a few minutes, an additional 2 inhalations should be taken. No more than 12 inhalations should be taken on any single occasion.
A total daily dose of more than 16 inhalations is normally not needed, however a total daily dose of up to 24 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.

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 Rapihaler. The as-needed inhalations provide both rapid relief of symptoms and improved overall asthma control. Patients should be advised to have Symbicort Rapihaler available for relief of symptoms at all times.
Preventative use of Symbicort Rapihaler 100/3 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 2 inhalations of Symbicort Rapihaler 50/3 or 100/3 as needed in response to symptoms to control asthma. If symptoms persist after a few minutes, 2 additional inhalations should be taken. No more than 12 inhalations should be taken on any single occasion.
Patients also take the recommended maintenance dose of Symbicort Rapihaler 50/3 or 100/3, four inhalations per day, given as either two inhalations in the morning and evening or as four inhalations in either the morning or evening. For some patients, a maintenance dose of Symbicort Rapihaler 100/3 four 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 16 inhalations is normally not needed, however a total daily dose of up to 24 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.

Symbicort maintenance therapy (fixed dose).

When maintenance treatment with a combination of ICS and LABA is required, Symbicort Rapihaler 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 Rapihaler 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 Rapihaler 50/3. 2 or 4 inhalations of Symbicort Rapihaler 50/3 twice daily. The maximum recommended daily maintenance dose is 8 inhalations (4 inhalations twice daily corresponding to 400 microgram budesonide/24 microgram formoterol).
Symbicort Rapihaler 100/3. 2 or 4 inhalations of Symbicort Rapihaler 100/3 twice daily. The maximum recommended daily maintenance dose is 8 inhalations (4 inhalations twice daily corresponding to 800 microgram budesonide/24 microgram formoterol).
Symbicort Rapihaler 100/6**. 2 inhalations of Symbicort Rapihaler 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 Rapihaler 200/6. 2 inhalations of Symbicort Rapihaler 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).
For adults 18 years and over who require a higher daily maintenance dose, the maximum recommended maintenance dose may be increased to 4 inhalations of Symbicort Rapihaler 200/6 twice daily (corresponding to 1600 microgram budesonide/48 microgram formoterol).

COPD.

Adults.

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

Special patient populations.

Renal impairment.

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

Hepatic impairment.

There are no data available for use of Symbicort Rapihaler 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.

Elderly.

There is no need to adjust the dose in elderly patients.

Use in paediatric patients.

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

General information.

If patients take Symbicort Rapihaler 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 Rapihaler as a maintenance therapy, they should be instructed to take Symbicort Rapihaler even when asymptomatic for optimal benefit.

Instruction for correct use of Rapihaler.

On actuation of the Symbicort Rapihaler, a volume of the suspension is expelled from the canister at high velocity. When the patient inhales through the mouthpiece at the same time as actuating the inhaler, the substance will follow the inspired air into the airways.

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 Rapihaler.
Shake the inhaler well prior to each use to mix its contents properly.
Prime the inhaler by actuating it twice for Symbicort Rapihaler 100/6** and 200/6, or three times for Symbicort Rapihaler 50/3 and 100/3, into the air when the inhaler is new, if it has not been used for more than one week or if it has been dropped.
Place the mouthpiece into the mouth. While breathing in slowly and deeply, press the inhaler firmly to release the medication. Continue to breathe in and hold the breath for approximately 10 seconds or as long as is comfortable. Shake the inhaler again and repeat this step for the second inhalation.
Rinse the mouth with water after inhaling the maintenance dose to minimise the risk of oropharyngeal thrush.
Clean the mouthpiece of the inhaler regularly, at least once a week with a clean dry cloth. Do not put the inhaler into water.
**Not supplied in Australia; not all presentations may be available in Australia.

4.7 Effects on Ability to Drive and Use Machines

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

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 3 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 Rapihaler 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).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Symbicort Rapihaler contains the inactive ingredients povidone (polyvinylpyrolidone K25), macrogol (polyethylene glycol) 1000 and apaflurane (known as hydrofluroalkane (HFA)-227).

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 30°C.
The inhaler should be discarded within 3 months after removal from the foil pouch.

6.5 Nature and Contents of Container

Symbicort Rapihaler is a pressurised metered dose inhaler with an actuation counter. The inhaler is comprised of a pressurised aluminium canister with an attached actuation counter, a red plastic actuation body with a white mouthpiece and attached grey mouthpiece cover. Each inhaler is individually wrapped in a foil laminate pouch with desiccant sachet.
Four strengths of Symbicort Rapihaler are registered (50/3, 100/3, 100/6** and 200/6 - see Section 2 Qualitative and Quantitative Composition) in packs of one inhaler containing 120 inhalations. In addition, Symbicort Rapihaler 200/6 has a 60 inhalation (sample) pack registered and Symbicort 50/3, 100/3 and 100/6** also have packs of two** 120 inhalation inhalers registered.
**Not supplied in Australia; not all presentations 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.
Always be sure to dispose of Symbicort Rapihaler responsibly, since some of the medicine may remain inside it. The canister in Symbicort Rapihaler contains a pressurised liquid. The canister should not be broken, punctured or burnt, even when it seems empty.

Summary Table of Changes