Consumer medicine information

Oxis Turbuhaler

Formoterol (eformoterol) fumarate dihydrate

BRAND INFORMATION

Brand name

Oxis Turbuhaler

Active ingredient

Formoterol (eformoterol) fumarate dihydrate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Oxis Turbuhaler.

SUMMARY CMI

OXIS® 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 Oxis Turbuhaler?

Oxis Turbuhaler contains the active ingredient formoterol fumarate dihydrate. Oxis Turbuhaler is inhaled into the lungs and opens up the airway in people with asthma so that they can breathe more easily. For more information, see Section 1. Why am I using Oxis Turbuhaler? in the full CMI.

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

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

3. What if I am taking other medicines?

Some medicines may interfere with Oxis 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 Oxis Turbuhaler?

  • Oxis Turbuhaler should be inhaled into your lungs through the mouth.
  • Oxis Turbuhaler can be used regularly to prevent asthma attacks (ie maintenance treatment). It can also be used when needed to treat your symptoms when your asthma control gets worse.
  • Follow all directions given to you by your doctor or pharmacist.

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

5. What should I know while using Oxis 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.
  • Continue using Oxis Turbuhaler and your preventer medicine for as long as your doctor or pharmacist tells you.
  • If you find that the usual dose of Oxis Turbuhaler is not giving as much relief as before, or you are needing to use it more often, contact your doctor so that your condition can be checked.
Things you should not do
  • Do not stop using this medicine suddenly without checking with your doctor or pharmacist.
  • Do not stop taking any other medicines you have been given for your asthma, even if you are feeling better, without checking with your doctor first.
  • Do not use other medicines that contain long-acting beta-2-agonists such as salmeterol, when you are taking Oxis Turbuhaler.
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 Oxis 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 tremor, muscle cramps, agitation, sleep disturbances, headache, fast/irregular heart rate, chest pain, nausea or taste disturbances. However, some side effects may need medical attention. These include severe allergic reactions such as difficulty breathing, swelling of the face, lips or tongue or severe rash. 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

OXIS® TURBUHALER®

Active ingredient(s): formoterol fumarate dihydrate

Consumer Medicine Information (CMI)

This leaflet provides important information about using Oxis 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 Oxis Turbuhaler.

Where to find information in this leaflet:

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

1. Why am I using Oxis Turbuhaler?

Oxis Turbuhaler contains the active ingredient formoterol fumarate dihydrate. Formoterol is a bronchodilator and belongs to a group of medicines called beta-2-agonists.

Oxis Turbuhaler is inhaled into the lungs and opens up the airway in people with asthma so that they can breathe more easily.

Oxis Turbuhaler will start to work soon after you take it and the effects will last up to 12 hours. It should be taken regularly to help control your symptoms. It may also be used if you have difficulty breathing at night or before exercise to keep your airways open if you start to wheeze or have difficulty breathing each time you exert yourself.

In patients already taking regular Oxis Turbuhaler, it can also be used when needed to treat your symptoms when your asthma control gets worse.

Oxis Turbuhaler is used together with other regular preventer medicines called inhaled corticosteroids (ICS).

Asthma

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

Symptoms of asthma include shortness of breath, wheezing, chest tightness and cough.

The formoterol in Oxis Turbuhaler helps you breathe more easily.

2. What should I know before I use Oxis Turbuhaler

Warnings

Do not use Oxis Turbuhaler if:

  • you are allergic to any medicine containing formoterol, or lactose (the only inactive ingredient in Oxis Turbuhaler). 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, foods, preservations or dyes.
  • have, or have had, any of the following medical conditions, as it may not be safe for you to take Oxis Turbuhaler:
    - thyroid problems
    - diabetes
    - heart problems
    - liver problems
    - low levels of potassium in the blood.
  • have any other medical conditions.
  • have any questions about how you should be using your Oxis 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 Oxis Turbuhaler during pregnancy and while breastfeeding.

Children

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

Oxis 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 regularly to control your asthma (eg preventer and controller medicines), as well as what reliever medicines to use when you have sudden attacks of asthma. Your doctor may have prescribed Oxis Turbuhaler for you to use as a regular controller and as a reliever medicine.

3. What if I am taking other medicines?

Some medicines may interfere with Oxis 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 (including eye drops) 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
  • erythromycin (an antibiotic)
  • xanthine derivatives (eg theophylline) which are a class of medicines used to treat asthma and chronic obstructive airways disease

These medicines may be affected by Oxis 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.

Tell your doctor or pharmacist if you are taking any other medicines, including any that you buy without a prescription from your pharmacy, supermarket or health food shop including vitamins or supplements. Check with your doctor if you are not sure.

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

4. How do I use Oxis 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 Oxis 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.

Oxis Turbuhaler can be used regularly to prevent asthma attacks (ie maintenance treatment). It can also be used when needed to treat your symptoms when your asthma control gets worse.

How much to take

Please note that Oxis Turbuhaler is labelled as the metered dose (amount of active ingredient from the meter inside the mouthpiece of the original version). The delivered dose (amount of active ingredient from the mouthpiece) is also included on the label. The doses below are metered doses with the corresponding delivered dose in brackets.

Regular maintenance treatment

The usual maintenance dose is one inhalation of Oxis Turbuhaler (6 mcg [4.5 mcg] or 12 mcg [9 mcg]) twice a day. Some patients may need to take 2 inhalations twice a day.

For adults, the maintenance dose should not exceed:

  • 4 inhalations of Oxis Turbuhaler 6 mcg [4.5 mcg] twice a day, or
  • 2 inhalations of Oxis Turbuhaler 12 mcg [9 mcg] twice a day

For children 12 years and over, the maintenance dose should not exceed:

  • 2 inhalations of Oxis Turbuhaler 6 mcg [4.5 mcg] twice a day, or
  • 1 inhalations of Oxis Turbuhaler 12 mcg [9 mcg] twice a day

As-needed use (to relieve asthma symptoms) for adults over 18 years

In addition to your maintenance dose, your doctor may advise you to take additional doses, if necessary, to relieve your asthma symptoms.

If you are using Oxis Turbuhaler for both maintenance treatment and as-needed use (to relief of asthma symptoms), the total daily dose should not exceed:

  • 12 inhalations per day of Oxis Turbuhaler 6 mcg [4.5 mcg], or
  • 6 inhalations per day of Oxis Turbuhaler 12 mcg [9 mcg]

Tell your doctor if your symptoms continue to worsen over three days, despite using more than:

  • 8 inhalations per day of Oxis Turbuhaler 6 mcg [4.5 mcg], or
  • 4 inhalations per day of Oxis Turbuhaler 12 mcg [9 mcg]

As-needed use is not recommended for patients under the age of 18 years.

How long to use your Oxis Turbuhaler

Continue using Oxis Turbuhaler for as long as your doctor tells you.

Oxis Turbuhaler helps control your condition, but does not cure it. It is important to keep using Oxis Turbuhaler every day even if you feel well.

If you forget to use Oxis Turbuhaler

If it is almost time for your next maintenance dose, skip the dose you missed and use the next dose when you are meant to. Otherwise, use it as soon as you remember, and then go back to using it as you would normally.

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 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 Oxis Turbuhaler

If you think that you have used too much Oxis 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 Oxis Turbuhaler, you may feel sick or vomit, have a fast or irregular heartbeat, a headache, trembling or feel shaky.

5. What should I know while using Oxis 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.
  • Have your reliever medicine available at all times.
  • Continue using Oxis Turbuhaler and your preventer medicine for as long as your doctor or pharmacist tells you. Oxis Turbuhaler should be used with a preventer medicine, even if you feel that your symptoms have improved.
  • If you find that the usual dose of Oxis Turbuhaler is not giving as much relief as before, or you are needing to use it more often, contact your doctor so that your condition can be checked. This is important to ensure that your breathing problem is controlled properly.
  • Visit your doctor regularly to check your asthma condition.
  • If you are about to be started on any new medicine, tell your doctor or pharmacist that you are using Oxis Turbuhaler.
  • If you become pregnant while using Oxis Turbuhaler, tell your doctor or pharmacist.

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

Things you should not do

  • Do not stop using Oxis Turbuhaler suddenly without checking with your doctor or pharmacist.
  • Do not stop taking any other medicines you have been given for your asthma, even if you are feeling better, without checking with your doctor first. Oxis Turbuhaler is intended to be used with preventer medicines.
  • Do not use other medicines that contain long-acting beta-2-agonists such as salmeterol, when you are taking Oxis Turbuhaler.
  • Do not give Oxis Turbuhaler to anyone else, even if they have the same condition as you.
  • Do not use Oxis Turbuhaler to treat any other complaints unless your doctor tells you to.

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 tissue and must never get wet.

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

Getting rid of any unwanted medicine

Since some medicine may remain inside your Oxis 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. Sometimes they are serious, most of the time they are not. 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 Oxis 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. Do not be alarmed by the following lists of side effects. You may not experience any of them.

Less serious side effects

Less serious side effectsWhat to do
  • tremor
  • muscle cramps
  • agitation, restlessness
  • sleep disturbances
  • headache, dizziness
  • palpitations, fast/irregular heart rate
  • chest pain
  • nausea
  • taste disturbances
  • skin rash
  • changes in blood pressure
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat 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
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.

Other side effects

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, low potassium levels in the blood or increase in blood sugar levels) may only be found when your doctor does tests 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 Oxis Turbuhaler contains

Active ingredient
(main ingredient)
  • formoterol fumarate dihydrate
Other ingredients
(inactive ingredients)		Lactose monohydrate
Potential allergensLactose (which may contain milk protein residue)

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

What Oxis Turbuhaler looks like

Oxis Turbuhaler is a multidose, breath activated metered dose dry powder inhaler. Turbuhaler is made up of plastic parts.

Oxis Turbuhaler is registered in the following presentations*:

  • 6 mcg: Each carton contains one Oxis Turbuhaler of 60 doses of the medicine. [AUST R 60142]
  • 12 mcg: Each carton contains one Oxis Turbuhaler of 60 doses of the medicine. [AUST R 60141]

*not all registered presentations might be available in Australia

Who distributes Oxis 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 December 2024.

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

© AstraZeneca 2024

VV-RIM-01321141 v8.0

Published by MIMS February 2025

BRAND INFORMATION

Brand name

Oxis Turbuhaler

Active ingredient

Formoterol (eformoterol) fumarate dihydrate

Schedule

S4

 

1 Name of Medicine

Formoterol (eformoterol) fumarate dihydrate.

2 Qualitative and Quantitative Composition

Oxis is available in a multi-dose, inspiratory flow driven, metered dose dry powder inhaler (Turbuhaler). For convenience the term formoterol has been used throughout this document.
The original Oxis Turbuhaler (M2 version) was labelled as the metered dose (amount of formoterol from the metering unit) - 6 and 12 microgram/inhalation. The original and current (M3 version) Oxis Turbuhaler versions both deliver (amount of formoterol leaving the mouthpiece) the same dose to the patient (4.5 and 9 microgram/inhalation respectively), however the metered dose cannot be measured in the M3 version. To avoid confusion the current Oxis Turbuhaler version is labelled with the corresponding metered dose of the original Oxis Turbuhaler in addition to the delivered dose.
Table 1 provides 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.
White to off-white rounded granules in a specially designed inhaler made of plastic. The turning grip is greenish blue with a braille code embossed on the base.

4 Clinical Particulars

4.1 Therapeutic Indications

Long-term treatment of reversible airways obstruction in asthma (including nocturnal asthma and exercise induced asthma) in adults and children aged 12 years and over who are receiving inhaled or oral corticosteroids and who require bronchodilator therapy.
Oxis Turbuhaler can be used on-demand (prn) in asthmatics over the age of 18 years who are receiving inhaled or oral corticosteroids. It should not be used in patients whose asthma can be managed alone by occasional use of short acting inhaled β2-agonists.

4.2 Dose and Method of Administration

The doses below are provided as the metered dose of the original Oxis Turbuhaler (M2 version) with the corresponding delivered dose (original and current Oxis Turbuhaler) in brackets afterwards. See Section 2 Qualitative and Quantitative Composition for further details.
The dosage of formoterol via Oxis Turbuhaler should be individualised. The treatment should always aim for the lowest effective dose.
The recommended dose is 6-12 microgram (corresponding to 4.5-9 microgram delivered dose) twice daily, however some patients may require a dose of up to 24 microgram (corresponding to 18 microgram delivered dose) twice daily. During regular twice daily dosing, a total daily dose of 48 microgram (corresponding to 36 microgram delivered dose) in adults and 24 microgram (corresponding to 18 microgram delivered dose) in children 12 years and over should not be exceeded.
In patients over the age of 18 years on regular corticosteroids and regular formoterol, additional doses of formoterol can be administered as required for the relief of symptoms. The maximum total daily dose should not normally exceed 72 microgram (corresponding to 54 microgram delivered dose). Prolonged use (more than 3 consecutive days) of more than 48 microgram (corresponding to 36 microgram delivered dose) is a sign of sub-optimal asthma control and treatment should be reassessed.
There is no evidence of efficacy of formoterol in acute severe asthma exacerbations.

Renal impairment.

No adjustment of dose should be required in patients with renal impairment at the recommended doses. However, no clinical studies have been performed in this group.

Hepatic impairment.

No adjustment of dose should be required in patients with hepatic impairment at the recommended doses. However, no clinical studies have been performed in this groups.

Instruction for correct use of 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:
carefully read the instructions for use in the patient information leaflet that are provided with each pack of Oxis Turbuhaler;
breathe in forcefully and deeply through the mouthpiece to ensure that an optimal dose is delivered to the lungs;
never breathe out through the mouthpiece;
replace the cover of Oxis Turbuhaler after use.
The patient may not taste or feel any medication when using Turbuhaler due to the small amount of medicine delivered.

4.3 Contraindications

Hypersensitivity to formoterol or lactose.

4.4 Special Warnings and Precautions for Use

Formoterol should not be initiated in patients to treat an acute severe asthma exacerbation, or if they have significantly worsening or acutely deteriorating asthma.

Asthma action plan.

Patients with asthma should have a personal asthma action plan designed in association with their general practitioner. This plan should incorporate a stepwise treatment regimen which can be instituted if the patient's asthma deteriorates. It should include advice as to when urgent medical attention is required and that patients should not stop other asthma treatments, even if they feel better, without seeking medical advice.

Anti-inflammatory therapy.

Formoterol is not a substitute for anti-inflammatory therapy with inhaled or oral corticosteroids. Asthmatic patients who require regular therapy with β2-adrenoceptor agonists should also receive regular and adequate doses of inhaled or oral corticosteroids. Whenever formoterol is prescribed, patients should be evaluated for the adequacy of their corticosteroid treatment. Patients must be advised to continue taking their corticosteroid therapy unchanged after the introduction of formoterol even when their symptoms improve.

Lack of response.

If a previously effective dosage regimen of bronchodilators no longer gives the same symptomatic relief the patient should seek medical advice as soon as possible since this could be an indication of worsening asthma.

Sensitivity to sympathomimetic amines.

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

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.

Arrhythmogenic potential.

β2-agonists have an arrhythmogenic potential which must be considered before commencing treatment for bronchospasm.

Other cardiovascular conditions.

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 β-adrenoceptor agonists.
Patients with pre-existing cardiovascular conditions are at greater risk of developing adverse cardiovascular effects following administration of formoterol. Caution is advised when formoterol is administered to patients with severe cardiovascular disorder, such as ischaemic heart disease, tachyarrhythmias or severe heart failure.

Hypokalaemia.

Potentially serious hypokalaemia may result from β2-stimulant therapy. Particular caution is advised in acute severe asthma 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 observed in such situations.

Lactose.

Oxis Turbuhaler contains lactose monohydrate (< 0.9 mg/inhalation delivered dose) 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 is not known. As formoterol is primarily eliminated via hepatic metabolism, increased plasma levels of formoterol would be expected in patients with severe liver cirrhosis.

Use in renal impairment.

The effect of decreased kidney function on the pharmacokinetics of formoterol is not known.

Use in the elderly.

No data available.

Paediatric use.

Oxis is not recommended for children under 12 years old.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

β-receptor blocking agents.

β-receptor blocking agents, especially those which are non-selective, may partly or totally inhibit the effect of β-agonists. These medicines may also increase airway resistance, therefore, the use of these medicines 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, such as thiazide and loop diuretics (see Section 4.4 Special Warnings and Precautions for Use, Other cardiovascular conditions).

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

The adverse cardiovascular effects of formoterol may be exacerbated by concurrent administration of medicines 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, erythromycin or antihistamines (e.g. astemizole, terfenadine, mizoblastine).

4.6 Fertility, Pregnancy and Lactation

Effects 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 2 weeks.
Testicular atrophy was observed in mice given formoterol fumarate in the diet at 0.2-50 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)
No teratogenic effects were observed in rats receiving formoterol fumarate at doses up to 60 mg/kg/day orally or 1.2 mg/kg/day by inhalation. Fetal cardiovascular malformations were observed in one study in which pregnant rabbits were dosed orally at 125 or 500 mg/kg/day during the period of organogenesis, but similar results were not obtained in another study at the same dose range. In a third study, an increased incidence of subcapsular hepatic cysts was observed in fetuses from rabbits dosed orally at 60 mg/kg/day. Decreased birth weight and increased peri/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.
Clinical experience with Oxis Turbuhaler in pregnant women is limited. Effects seen in animal studies were at considerably higher systemic exposures than those in clinical use. Since asthma control is important for maternal and fetal health, use of Oxis Turbuhaler in pregnancy should be considered when indicated.
β2-adrenoceptor agonists including formoterol may inhibit labour due to a relaxant effect on uterine smooth muscle.
 Formoterol has been detected in small amounts in the milk of lactating rats, but it is not known whether formoterol passes into human breast milk.
A study in rats showed increased postnatal mortality at maternal oral doses of 0.2 mg/kg/day or greater, and retardation of pup growth at 15 mg/kg/day.
Since asthma control is important for maternal and foetal health, use of Oxis Turbuhaler in women who are breastfeeding should be considered when indicated.

4.7 Effects on Ability to Drive and Use Machines

Oxis Turbuhaler does not affect the ability to drive or use machines. However, adverse effects of this medicine include dizziness which could affect the ability to drive or use machines (see Section 4.8 Adverse Effects (Undesirable Effects)).

4.8 Adverse Effects (Undesirable Effects)

Pharmacologically predictable side-effects of β2-agonist therapy, such as tremor and palpitations, may occur, but tend to be transient and are reduced with regular therapy. See 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.

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

Possible symptoms and signs.

An overdose would be likely to lead to effects typical of β2-adrenergic agonists such as tremor, headache, palpitations, and tachycardia. Hypotension, metabolic acidosis, hypokalaemia, hyperglycaemia, prolonged QTc-interval, arrhythmia, nausea and vomiting may also occur. The symptoms and signs are those characteristic of excessive sympathetic stimulation.

Laboratory findings.

Monitoring of serum potassium concentrations may be warranted. β2-agonists may cause hypokalaemia as a result of redistribution of potassium, but this usually requires no treatment.

Treatment.

There is no clinical experience on the management of overdose with formoterol, however supportive and symptomatic treatment may be indicated. β-blockers should be used with care because of the possibility of inducing bronchospasm in sensitive individuals.
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.

Formoterol is a potent selective β2-adrenergic stimulant 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 sets in rapidly, within 1-3 minutes after inhalation and has a mean duration of 12 hours following a single dose.

Clinical trials.

Oxis Turbuhaler.

The clinical data provided below refers to the metered dose (amount of formoterol from the metering unit) of the original Oxis Turbuhaler (M2 version). The corresponding delivered doses (amount of formoterol from the Turbuhaler mouthpiece) are discussed, see Section 2 Qualitative and Quantitative Composition.
The current Oxis Turbuhaler (M3 version; see Section 2 Qualitative and Quantitative Composition) has been shown to be therapeutically equivalent to the original Oxis Turbuhaler M2 version.

Asthma - continuous prophylactic use.

The clinical efficacy studies conducted with Oxis Turbuhaler (M2 version) include 7 blinded controlled trials (parallel group and crossover). A total of 1353 adult patients with bronchial asthma were randomised and treated with treatment periods ranging from 2 to 24 weeks. Two open, uncontrolled, long-term trials were also performed in 201 patients who had participated in short-term treatment.
The primary objective of the controlled clinical studies was to evaluate the efficacy of Oxis Turbuhaler in comparison with placebo and/or an active control (terbutaline, formoterol pMDI and budesonide).
Efficacy has also been studied in three single-dose, placebo-controlled, crossover studies performed in a total of 87 patients with asthma, to determine the dose-response relationship for doses of 3 microgram up to 48 microgram of Oxis Turbuhaler.

Asthma - 'as needed' use.

Two large double-blind, randomised, parallel studies have been conducted in moderate to severe asthmatic patients on continual prophylactic corticosteroid therapy with Oxis Turbuhaler (M2 version; 72 microgram metered dose maximal daily dose) as prn ('as needed' use) treatment for 12 weeks.
One study compared prn Oxis Turbuhaler to prn terbutaline Turbuhaler (6 mg maximal daily dose) in 362 adult patients on prophylactic inhaled corticosteroid therapy. The other study compared prn Oxis Turbuhaler to prn terbutaline Turbuhaler (6 mg maximal daily dose) in 357 adult patients on prophylactic inhaled Oxis Turbuhaler (12 microgram metered dose bid) and inhaled corticosteroids. The two trials showed that Oxis Turbuhaler could replace terbutaline Turbuhaler for rescue treatment without loss of efficacy. There were no differences of clinical significance with respect to prn inhalations per day, peak expiratory flow rate, incidence of exacerbations or asthma score.

5.2 Pharmacokinetic Properties

Absorption.

Inhaled formoterol is rapidly absorbed and peak plasma concentrations are reached about 15 minutes after inhalation. In clinical studies, the mean lung deposition of formoterol after inhalation via Turbuhaler (original M2 version) ranged from 28-49% of the delivered dose (corresponding to 21-37% of the metered dose). The total systemic availability for the higher lung deposition was around 61% of the delivered dose (corresponding to 46% of the metered dose).
In a pharmacokinetic study with the M3 Turbuhaler version, the mean lung deposition of formoterol after inhalation via Turbuhaler was 43% of the delivered dose (corresponding to 32% of the metered dose).

Distribution.

Plasma protein binding is approximately 50%.

Metabolism.

Formoterol is metabolised via direct glucuronidation and O-demethylation.

Excretion.

The major part of the dose of formoterol is eliminated via metabolism. After inhalation, 8-13% of the delivered dose (corresponding to 6-10% of the metered dose of the M2 version) of formoterol is excreted unmetabolised in the urine. The terminal half-life after inhalation is estimated to 8 hours.

5.3 Preclinical Safety Data

Genotoxicity.

Mutagenicity tests covering a range of experimental endpoints have been conducted. No genotoxic effects were found in any of the in vitro or in vivo tests, except for a slight increase in reverse mutation frequency in Salmonella typhimurium at high concentrations of formoterol fumarate.

Carcinogenicity.

In 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.
In carcinogenicity studies performed by other companies, very high dose levels were used, resulting in systemic exposure levels 800-4800 fold higher than those expected upon clinical use of formoterol (based on an 18 microgram daily dose). The studies are summarised below.
In the initial studies performed by other companies, addition of formoterol fumarate to the drinking water caused adrenal subcapsular cell tumours in male mice dosed at 66-225 mg/kg/day, thyroid C-cell neoplasms in male rats dosed at 46 mg/kg/day, mesovarian leiomyomas in female rats dosed at 18-72 mg/kg/day, and an increased incidence of mammary adenocarcinoma in female rats dosed at 36-72 mg/kg/day.
In the repeated studies performed by other companies, drug was administered with the feed. Hepatocellular adenomas and carcinomas were observed in male and female mice at dose levels greater than 2 mg/kg/day, and leiomyomas and leiomyosarcomas were seen in the reproductive tract of female mice dosed at 2-50 mg/kg/day. Mesovarian leiomyomas were observed in rats dosed at 2-20 mg/kg/day, and benign granulosa/ theca cell tumours in the ovaries of rat dosed at 0.5-20 mg/kg/day. Plasma drug concentrations at dose levels associated with these carcinogenic effects, based on AUC values, were estimated to be at least ten times higher than the maximum systemic exposure anticipated in humans.
Mammary adenocarcinomas, smooth muscle tumours in the female reproductive system and effects on the ovary have been reported in rats or mice treated with other β2-adrenoceptor agonists, and are likely to be secondary to prolonged stimulation of β2-adrenoceptors in these tissues.
Thyroid C-cell tumours were only seen at doses resulting in systemic exposure several fold higher than that expected at the highest recommended human dose. They are thought to be a consequence of stimulation of calcitonin secretion as a result of bone growth, secondary to β-agonist induced anabolic effects on skeletal muscle at excessive formoterol doses. The mechanism underlying the induction of hepatocellular tumours and adrenal subcapsular tumours in the mouse is unclear.
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.

6 Pharmaceutical Particulars

6.1 List of Excipients

Lactose monohydrate.
The product is free from other additives such as propellants, lubricants, preservatives or carrier substances.

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. Replace the cover firmly after use.

6.5 Nature and Contents of Container

Oxis Turbuhaler is available in plastic dry powder inhaler containing 60 doses. See Section 2 Qualitative and Quantitative Composition.

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.

The chemical name is (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.

183814-30-4.

7 Medicine Schedule (Poisons Standard)

Prescription only medicine (Schedule 4).

Summary Table of Changes