Consumer medicine information

Foradile

Formoterol (eformoterol) fumarate dihydrate

BRAND INFORMATION

Brand name

Foradile

Active ingredient

Formoterol (eformoterol) fumarate dihydrate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Foradile.

What is in this leaflet

This leaflet answers some common questions about Foradile capsules.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

The information in this leaflet was last updated on the date listed on the final page. More recent information on the medicine may be available.

You should ensure that you speak to your pharmacist or doctor to obtain the most up to date information on the medicine. Those updates may contain important information about the medicine and its use of which you should be aware.

All medicines have risks and benefits. Your doctor has weighed the risks of you using this medicine 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 the medicine. You may need to read it again.

What Foradile is used for

Foradile capsules for inhalation belong to a group of medicines called bronchodilators. These medicines are used to keep the air passages in the lungs open.

Foradile capsules for inhalation contain the active ingredient, formoterol fumarate dihydrate in a capsule form.

Foradile capsules make breathing easier by opening the small air passages in the lungs and helping them to remain relaxed and open.

Foradile is a long acting bronchodilator. Each dose of Foradile will keep your air passages open and relieve chest tightness and wheezing for up to 12 hours. It is especially helpful if you have breathing problems during exercise or at night.

The capsules are for oral inhalation only. The powder from the capsule is inhaled (breathed into the lungs), using the Aerolizer® inhalation device provided with the medicine. Foradile capsules are for the treatment of asthma and chronic obstructive pulmonary disease, also called COPD.

Asthma is a disease where the lining of the lungs becomes inflamed (red and swollen), making it difficult to breathe. This may be due to an allergy to house dust mites, smoke or other irritants.

COPD is a serious lung condition that can cause difficulty in breathing, wheezing and constant coughing.

Foradile capsules for inhalation are used for people who need to take medicine every day for their asthma. Foradile is always used together with other medicines called inhaled corticosteroids (also known as "preventer" medicines.)

Ask your doctor if you have any questions about why Foradile has been prescribed for you. Your doctor may have prescribed it for another purpose.

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

It is not addictive.

Before you use Foradile

When you must not use it

Do not use Foradile if you have ever had an allergic reaction after using:

  • formoterol fumarate dihydrate (the active ingredient in Foradile)
  • any of the other ingredients listed at the end of this leaflet

You may get a skin rash, difficulty in breathing, hay fever, swelling of the face, faintness or other symptoms if you use it.

Do not use Foradile to relieve sudden wheezing or other acute attacks of asthma.

Your doctor will have given you a "reliever puffer" to use when you have a sudden problem with breathing.

Carry that medicine with you at all times.

Do not use Foradile if you:

  • are well controlled with an inhaled corticosteroid,
  • only need short-acting beta2-agonist medicines once in a while.

Do not give Foradile to children under 5 years of age. There is not enough experience to recommend its use in children under 5 years of age.

Do not use Foradile after the use by (expiry) date printed on the pack. If you take this medicine after the expiry date has passed, it may not work as well as it should.

Do not use Foradile if the packaging is torn or shows signs of tampering. In that case, return it to your pharmacist.

If you are not sure whether you should start using Foradile, contact your doctor or pharmacist.

Before you start to use it

Tell your doctor if you have any of these medical conditions:

  • a heart disorder called "prolongation of the QT interval"
  • any other heart problem
  • aneurysm (area where an artery is swollen like a balloon because the wall of the artery is weak)
  • pheochromocytoma (a tumor of the adrenal gland that can affect blood pressure)
  • diabetes
  • an overactive thyroid gland

Your doctor may want to take special precautions if you have any of these conditions.

Tell your doctor if you have allergies to:

  • lactose (milk sugar)
  • any other medicines
  • any other substances such as foods, preservatives or dyes.

Talk to your doctor about the benefits and possible risks of treating your asthma with Foradile.

A large study with a different long-acting bronchodilator (salmeterol) showed an increase in the risk of death due to asthma compared to the risk in patients who used a placebo (dummy) puffer. No study has been conducted to find out if Foradile could have the same effect.

If you have asthma: Do not use Foradile as your only asthma medicine. Use Foradile only with an inhaled corticosteroid (ICS).

Tell your doctor if you are pregnant or intend to become pregnant. Foradile is not recommended for use during pregnancy. If it is necessary for you to use Foradile, your doctor will discuss with you the benefits and risks of using it during pregnancy.

Tell your doctor if you are breast-feeding or plan to breast-feed. It is not known if the active ingredient of Foradile passes into the breast milk and could affect your baby.

If you have not told your doctor about any of these things, tell him/her before you start using Foradile.

Taking other medicines

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

Some medicines and Foradile may interfere with each other. These include any of the following medicines:

  • monoamine oxidase inhibitors (MAO inhibitors) or tricyclic antidepressants, which are types of medicines used to treat depression (sad mood)
  • sympathomimetic agents, which are adrenaline-like medicines used to treat asthma and nasal congestion.
  • antihistamines, which are common anti-allergy medicines used to prevent or treat the major symptoms of an allergic response and hay fever
  • steroids, which are often used to treat asthma and other inflammatory diseases
  • diuretics, which are used to increase the amount of urine produced to treat oedema (water retention), heart failure and high blood pressure
  • beta blockers, which are a type of medicine used to treat high blood pressure, heart failure, angina, anxiety and abnormal heart rhythm. Certain eye drops used to treat glaucoma (high pressure in the eye) may contain beta blockers.
  • quinidine, disopyramide, and procainamide, which are medicines used to treat abnormal heart rhythm
  • phenothiazine derivatives, which are a group of medicines used to control mental disorders such as schizophrenia, mania, psychotic conditions and anxiety, and mood disorders
  • digitalis, a medicine used to treat heart failure and abnormal heart rhythm
  • xanthine derivatives, which are a class of medicines used to treat asthma and chronic obstructive airways diseases.
  • macrolide antibiotics (e.g. erythromycin; azithromycin)
  • inhaled anaesthetics such as halogenated hydrocarbons (e.g. halothane), used during surgery. Inform your doctor that you use Foradile if you are to have surgery under anaesthesia.

These medicines may be affected by Foradile or they may affect how well Foradile works. Your doctor may need to change the dose of your medicines or may ask you to take different medicines.

If you are not sure if you are taking any of these medicines, ask your doctor or pharmacist. Your doctor and pharmacist have more information on medicines to be careful with or avoid while you are using Foradile.

Your doctor may have given you other medicines to take regularly for your lung condition. If so, it is important that you:

  • continue to take these regularly
  • DO NOT STOP or reduce the dose even if you feel much better.

How to use Foradile

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

Always use the Foradile Aerolizer exactly as your doctor or pharmacist has told you. Ask one of them for advice if you are not sure how to use the Aerolizer.

These directions may differ from the information contained in this leaflet.

If you do not understand the instructions on the label, ask your doctor or pharmacist for help.

How much to use

Your doctor will tell you how often to use Foradile and how much to take, depending on your needs.

If you are aged 65 years or over, you can use Foradile at the same dose as other adults.

1. For Asthma

Adults

The usual dose is 1 or 2 capsules inhaled twice a day.

The maximum recommended adult dose is 4 capsules for inhalation per day.

For asthma therapy, you will always be prescribed Foradile in addition to an inhaled corticosteroid (ICS).

Tell your doctor if you need to use any extra capsules more than 2 days a week, as soon as possible, because it may be that your condition is getting worse.

Children 5 years and over

The usual dose is 1 capsule inhaled twice a day.

The maximum recommended dose per day for children aged 5 years or older is 2 capsules.

2. For chronic obstructive pulmonary disease (COPD)

Adults

The usual maintenance dose is 1 capsule inhaled twice a day.

When to use it

Usually the doses are inhaled about 12 hours apart (eg. in the morning and evening) so that your breathing problems are relieved for the whole day and night.

How to use the Aerolizer

Use the capsules only with the Aerolizer inhalation device provided in the pack. This Aerolizer has been specially developed for use with Foradile capsules only.

Follow the instructions and pictures inside the carton which show you how to use the inhalation device.

Children should only use the device with the help of an adult. At times small children may have trouble breathing in strongly enough to get the entire dose out of the capsule.

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

Follow these steps:

  1. Pull off the cap of the Aerolizer inhalation device.
  2. To open the capsule chamber, hold the base of the device firmly and turn the mouthpiece in the direction shown by the arrow.
  3. Make sure your fingers are completely dry, so that the capsule does not get wet. Remove the capsule from the foil pack immediately before you are going to use it.
  4. Do not swallow the capsule.

The capsule should be used by inhaling the content with the Aerolizer inhaler.
  1. Place the capsule flat on the bottom of the capsule-shaped slot.
  2. Close the capsule chamber by twisting the mouthpiece back until you hear the "click" at the closed position.
  3. To pierce the capsule, hold the Aerolizer upright and firmly squeeze the two blue buttons at the same time and then release.
Pierce the capsule only once.
Note that if you pierce it more often, the capsule may break and small pieces of gelatin from the capsule shell may be inhaled into your mouth or throat. However the gelatin is edible and is not harmful.
  1. While holding the Aerolizer in an upright position, open the mouthpiece again and make sure that the capsule is loose in the slot so that when you inhale, the capsule is able to spin around in the circular area above the slot.
  2. Close the mouthpiece.
  3. Breathe out fully (as far as you can).
  4. Place the mouthpiece in your mouth and tilt your head slightly backwards.
  5. Close your lips firmly around the mouthpiece and then breathe in quickly but evenly, as deep as you can. Note that you should hear a whirring noise as the capsule spins around in the space above the capsule chamber. If you do not hear this noise, open the capsule chamber and check that the capsule lies loose in the capsule chamber. Then repeat step 11. DO NOT try to loosen the capsule by pressing the buttons repeatedly.
  6. After breathing in through the Aerolizer, hold your breath for as long as you comfortably can.
  7. Take the Aerolizer out of your mouth, and then breathe out through your nose.
  8. Open the capsule chamber to check whether there is any powder left in the capsule. If there is, repeat steps 10 to 15.
  9. After you have used up all the powder in the Aerolizer, open the capsule chamber and remove the empty capsule.
  10. Check the Aerolizer to see if there is any dry powder remaining in the device.
  11. To remove any remaining powder, wipe the mouthpiece and capsule slot with a dry cloth or a clean soft brush.
Do not use water to clean the device.
  1. Close the mouthpiece and put the cap on again.

Each time you get a FORADILE prescription filled, discard the old Aerolizer and use the Aerolizer provided in the new pack.

How long to use it

Continue to use Foradile for as long as your doctor tells you to.

If Foradile helps your breathing problems, your doctor may want you to keep using it for quite a long time.

This medicine helps to control your condition but it does not cure it.

If you forget to use it

If it almost time for your next dose, skip the one 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 one that you missed. This may increase the chance of you getting an unwanted side effect.

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

If you use too much (Overdose)

Immediately telephone your doctor or Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at your nearest hospital if you think that you or anyone else may have used too much Foradile. Take the medicine pack with you.

Do this even if there are no signs of discomfort or poisoning.

If you use too much Foradile, you may feel sick or vomit, feel shaky or sleepy, have a headache or a fast or irregular heartbeat.

While you are using Foradile

Things you must do

Use Foradile exactly as your doctor has prescribed. Try not to miss any doses and use the medicine even if you feel well. If you do not follow your doctor's instructions, you may not get relief from your breathing problems or you may have unwanted side effects.

If you have been prescribed Foradile for asthma, continue using your "preventer" medicine unchanged after you start using Foradile. It should be used with a "preventer" medicine, even if you feel that your symptoms have improved.

If you find that the usual dose of Foradile is not giving as much relief as before, or does not last as long as usual, contact your doctor so that your condition can be checked. This is important to ensure your asthma is controlled properly.

Visit your doctor regularly to check on your condition. Your doctor will want to check on your progress regularly. Treatment with Foradile may lead to lowering of your blood potassium level. This may make you more susceptible to an abnormal heart beat. Therefore, your doctor may monitor your blood potassium level, especially if you have severe asthma.

If you have an Asthma Action Plan that you have agreed with your doctor, follow it closely at all times. This medicine is only one part of a general plan to help you manage your condition.

If you become pregnant while using Foradile, tell your doctor. Your doctor can discuss with you the risks of using it while you are pregnant.

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

Tell any other doctor, dentist or pharmacist who treats you that you are using Foradile.

Things you must not do

Do not use Foradile to relieve acute attacks of asthma. If you become wheezy or tight in the chest before the next dose of Foradile is due, use a "reliever puffer" in the usual way. Your doctor will have given you a "reliever puffer" to use when you have a sudden problem with breathing. Carry that medicine with you at all times.

Do not use other medicines that contain long-acting beta2-agonists such as salmeterol, when you are taking Foradile.

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.

Foradile is intended to be used with "preventer" medicines. It is very important to keep your breathing problems under control. Your doctor can only do this if you follow instructions carefully.

Do not stop any of your medicines or lower the dosage even if you feel much better.

It is very important to keep your breathing problems under control. Your doctor can only do this if you follow instructions carefully.

Do not change or stop any of your medicines to control or treat your breathing problems including your inhaled corticosteroid. Your doctor will adjust your medicines as needed.

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

Do not give this medicine to anyone else, even if their condition seems similar to yours.

Things to be careful of

Be careful driving, operating machinery or doing jobs that require you to be alert until you know how Foradile affects you. This medicine may cause dizziness in some people. Make sure you know how you react to Foradile before you drive a car, operate machinery, or do anything else that could be dangerous. If you are dizzy, do not drive. If you drink alcohol, dizziness could be worse.

Side effects

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

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.

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

Tell your doctor if you notice any of the following side effects and they worry you:

  • trembling or shakiness
  • muscle aching or cramps
  • palpitations (feeling that your heartbeat is unusually fast or irregular)
  • headache
  • dizziness
  • feeling anxious, nervous or upset
  • being unable to sleep
  • sore mouth or throat from inhaling the powder in the capsule
  • changed sense of taste
  • nausea (feeling sick)
  • dry mouth

The above side effects are usually mild.

Tell your doctor immediately or go to Accident and Emergency at your nearest hospital if you experience any of the following serious side effects:

  • an irregular heart beat
  • excessive thirst, frequent urination and tiredness over an extended period of time (a possible indication of high blood sugar)
  • tight chestedness or breathing problems, with wheezing or coughing and difficulty in breathing
  • sudden worsening of breathing problems after having a dose of Foradile
  • muscle weakness, muscle spasms, or an abnormal heart rhythm (these could mean you have a low blood potassium level).
  • allergic reaction, such as severe dizziness or fainting (caused by very low blood pressure); red itchy skin rash (hives); swelling of the face, lips, tongue, eyelids or other parts of the body.

You may need urgent medical attention.

Tell your doctor if you notice anything else that is making you feel unwell. Other side effects not listed above may happen in some people.

Some side effects, such as a low level of potassium in the blood, may only be found when your doctor orders blood tests from time to time.

After using Foradile

Storage

  • Keep your capsules in the foil packs inside the cardboard carton until it is time to use them.
  • Store the capsules in a cool dry place at or below 25°C.
  • Do not store Foradile or any other medicine in the bathroom or near a sink.
  • Do not leave it in the car or on window sills.

Heat and dampness can destroy some medicines. Foradile will keep well if it is cool and dry.

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

Disposal

Always discard the old Aerolizer and use the new one provided with each new prescription.

If your doctor tells you to stop using Foradile or the capsules have passed their expiry date, ask your pharmacist what to do with any capsules you have left over.

Product description

What it looks like

Foradile: clear capsule containing a fine, white powder; one half of the capsule shell is marked CG and the other half is marked FXF. The capsules come in foil packs containing 60 capsules in a cardboard carton.

A blue and white plastic Aerolizer inhalation device is also supplied in the pack.

Ingredients

Active Ingredient

Each capsule contains 12 micrograms of formoterol fumarate dihydrate.

Inactive ingredients

Foradile capsules also contain lactose. The capsule shell is made of gelatin, an edible material.

Sponsor

Foradile is supplied in Australia by:

Sandoz Pty Ltd
ABN 60 075 449 553
100 Pacific Highway
North Sydney
NSW 2060
Tel: 1800 726 369

® = registered trademark

This leaflet was revised in November 2023.

Australian Registration Number
AUST R 58673

Published by MIMS February 2024

BRAND INFORMATION

Brand name

Foradile

Active ingredient

Formoterol (eformoterol) fumarate dihydrate

Schedule

S4

 

1 Name of Medicine

Formoterol (eformoterol) fumarate dihydrate.

2 Qualitative and Quantitative Composition

Foradile is supplied in a size 3 gelatin capsule shell.
Each capsule contains 12 microgram of Formoterol (eformoterol) fumarate (as dihydrate).
Excipient with known effect: lactose (as monohydrate).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Powder for inhalation in hard capsules.
A size 3 hard gelatin capsule, colourless transparent body and cap, marked in black ink with "CG" on one part and "FXF" on the other part of the capsule shell; containing a fine, white powder.

4 Clinical Particulars

4.1 Therapeutic Indications

Foradile is indicated for the long-term, regular treatment of reversible airways obstruction in asthma (including nocturnal asthma and exercise induced asthma) in patients aged 5 years or more who are receiving inhaled or oral corticosteroids. It should not be used in patients whose asthma can be managed by occasional use of short acting inhaled beta-2 agonists.
Foradile is also indicated for the prophylaxis and treatment of bronchoconstriction in patients with reversible or irreversible chronic obstructive pulmonary disease (COPD).

4.2 Dose and Method of Administration

Foradile is for inhalation only.
The dose of Foradile should be individualised to the patient's needs and should be at the lowest possible dose to fulfil the therapeutic objective. It should not be increased beyond the maximum recommended dose.

Adults.

Asthma.

1 to 2 capsules (12 to 24 microgram) to be inhaled twice daily. The total daily dose should not exceed 48 microgram.
Foradile should only be prescribed as an add-on to an inhaled corticosteroid.

COPD.

1 capsule (12 microgram) to be inhaled twice daily.

Children aged 5 years and over.

1 capsule (12 microgram) to be inhaled twice daily. Foradile should only be prescribed as an add-on to an inhaled corticosteroid. The total daily dose should not exceed 24 microgram.

Patients 65 years and over.

No dosage adjustment from the adult dose is required in this patient population.

Instructions for use.

The capsules should only be removed from the blister pack and placed in the device immediately before use. Failure to observe this instruction may result in insufficient medication being released by the device due to possible unfavourable storage of the capsules.
It is important for the patient to understand that the gelatin capsule might fragment and small pieces of gelatin might reach the mouth or throat after inhalation. The tendency for this to happen is minimised by not piercing the capsule more than once.
The patient should also be instructed to check that they have inhaled the entire content of the capsule shell before discarding the shell.

4.3 Contraindications

Hypersensitivity to any ingredients of the preparation.
Foradile capsules contain lactose. Therefore, patients with rare hereditary problems of galactose intolerance, severe lactase deficiency or glucose/ galactose malabsorption should not take this medicine.

4.4 Special Warnings and Precautions for Use

General.

Foradile should not be initiated in patients with unstable or acutely deteriorating asthma. The management of asthma should normally follow a stepwise programme, and patient response should be monitored clinically and by lung function tests.

Anti-inflammatory therapy.

Foradile should not be used in conjunction with another long acting β2-adrenoceptor agonist.
Foradile is not a substitute for anti-inflammatory therapy. When treating patients with asthma, use Foradile, a long acting beta-2 agonist (LABA) only as additional therapy for patients not adequately controlled on an inhaled corticosteroid (ICS) alone or whose disease severity clearly warrants initiation of treatment with both an ICS and a LABA.
In patients not currently receiving anti-inflammatory therapy, this must be initiated at the same time as Foradile. Whenever Foradile is prescribed, patients should be evaluated for the adequacy of the anti-inflammatory therapy they receive. Patients must be advised to continue taking their anti-inflammatory therapy unchanged after the introduction of Foradile, even when their symptoms improve. Should symptoms persist, or should the number of doses of rescue medication required to control symptoms increase, this usually indicates a worsening of the underlying condition and warrants a reassessment of asthma therapy by the physician.
Once asthma symptoms are controlled, consideration may be given to gradually reducing the dose of Foradile. Regular monitoring of patients as treatment is stepped down is important. The lowest effective dose of Foradile should be used.

Acute asthma.

Foradile should not be used for the management of acute episodes or exacerbation of asthma. Although Foradile has a rapid onset of action, current asthma management guidelines recommend that long acting inhaled bronchodilators should be used as maintenance bronchodilator therapy. They further recommend that in the event of an acute attack, a β2-adrenoceptor agonist with a short duration of action should be used. Patients should be advised to have such rescue medication available. Effective drug delivery through dry powder inhalation devices is dependent on inspiratory airflow. Some younger children (i.e. 5 years or younger) may not be able to use such devices effectively. This difficulty may be aggravated in acute attacks.

Asthma exacerbations.

Clinical studies with Foradile suggested a higher incidence of serious asthma exacerbations in patients who received Foradile than those who received placebo (see Section 4.8 Adverse Effects (Undesirable Effects)). These studies do not allow precise quantification of the differences in serious asthma exacerbation rates between research groups.

Deterioration.

Increasing use of bronchodilators indicates deterioration of asthma control. If patients find that relief from short acting bronchodilators becomes less effective or they need more inhalations than usual, medical attention must be sought. In this situation, patients should be reassessed and consideration be given to the need for increased anti-inflammatory therapy (e.g. higher doses of inhaled corticosteroids or a course of oral corticosteroids). Patients should be advised to have such medication available. Severe exacerbations of asthma must be treated in the normal way with nebulised or parenteral bronchodilators and parenteral corticosteroids, together with supportive measures.

Paradoxical bronchospasm.

As with other inhalation therapy, the potential for paradoxical bronchospasm should be kept in mind. If this occurs, Foradile should be discontinued and alternative therapy substituted.

Incorrect route of administration.

There have been reports of patients who have mistakenly swallowed Foradile capsules instead of placing the capsules in the Aerolizer inhalation device. The majority of these ingestions were not associated with side effects. Healthcare providers should discuss with the patient how to correctly use Foradile Aerolizer (see Section 4.2 Dose and Method of Administration). If a patient who is prescribed Foradile Aerolizer does not experience breathing improvement, the healthcare provider should ask how the patient is using Foradile Aerolizer.

Concomitant conditions.

Special care and supervision, with particular emphasis on dosage limits, is required in patients receiving Foradile who have the following conditions.
Ischaemic heart disease, cardiac arrhythmias (especially third degree atrioventricular block), severe cardiac decompensation, idiopathic subvalvular aortic stenosis, severe hypertension, aneurysm, phaeochromocytoma, hypertrophic obstructive cardiomyopathy, known or suspected prolongation of the QT interval (QTc > 0.44 seconds). (See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.)
Thyrotoxicosis.
Due to the hyperglycaemic effect of β2-adrenoceptor agonists, including Foradile, additional blood glucose controls are recommended in diabetic patients.

Hypokalaemia.

Potentially serious hypokalaemia may result from β2-adrenoceptor agonist therapy, including Foradile. Particular caution is advised in severe asthma as this effect may be potentiated by hypoxia and concomitant medications (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Hypokalaemia may increase susceptibility to cardiac arrhythmias. It is recommended that serum potassium levels be monitored in such situations.

Asthma related deaths.

Formoterol, the active ingredient of Foradile, belongs to the class of long acting β2-adrenoceptor agonists. In a study with salmeterol, a different long acting β2 agonist, a higher rate of death due to asthma was observed in the patients treated with salmeterol (13/13,176) than in the placebo group (3/13,179). No study adequate to determine whether the rate of asthma related death is increased with Foradile has been conducted.

Use in the elderly.

No data available.

Paediatric use.

Foradile is not recommended in children under 5 years. For the dosage in children 5 years and over (see Section 4.2 Dose and Method of Administration).

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

The undesirable cardiovascular effects of Foradile may be potentiated by its concomitant administration with a number of drugs. This should be kept in mind when treating patients on monoamine oxidase inhibitors or tricyclic antidepressants as well as those on quinidine, disopyramide, procainamide, phenothiazines or antihistamines, macrolides or any drugs known to be associated with QTc interval prolongation and an increased risk of ventricular arrhythmia (see Section 4.4 Special Warnings and Precautions for Use).
Concomitant administration of other sympathomimetic amines may also potentiate the undesirable effects of Foradile.
Concomitant treatment with xanthine derivatives, steroids or diuretics may potentiate a possible hypokalaemic effect of β2-adrenoceptor agonists. Hypokalaemia may increase susceptibility to cardiac arrhythmias.
There is an elevated risk of arrhythmias in patients receiving concomitant anesthesia with halogenated hydrocarbons.
Beta-adrenoceptor blockers may weaken or antagonise the effect of Foradile. Therefore, Foradile should not be given together with β2-adrenoceptor blockers (including eye drops) unless there are compelling reasons for their use.

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 beta-agonist properties of the compound. No effect was seen on fertility of female rats dosed orally with formoterol fumarate at 60 mg/kg/day for two 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.
(Category B3)
No teratogenic effects were observed in rats receiving formoterol fumarate at oral doses of up to 60 mg/kg/day or in rabbits given formoterol fumarate at oral doses of up to 500 mg/kg/day over the period of organogenesis. Decreased birthweight and increased perinatal mortality were observed when formoterol fumarate was given to rats at oral doses greater than 3 mg/kg/day during late gestation.
The safety of Foradile during pregnancy has not yet been established. Until further experience has been acquired, use in pregnancy should be avoided unless there is no safer alternative. Beta2-adrenoceptor agonists including formoterol may inhibit labour due to a relaxant effect on uterine smooth muscle.
 It is not known whether formoterol passes into human breast milk. Formoterol fumarate and/or its metabolites was excreted in the breast milk of lactating rats given oral doses of 50 microgram/kg of drug, and growth and survival of the pups were decreased when lactating rats were given formoterol fumarate at oral doses greater than 1 mg/kg/day. Women who are breastfeeding should not use Foradile unless in the opinion of the physician the benefits of therapy outweigh the risks.

4.7 Effects on Ability to Drive and Use Machines

Patients experiencing dizziness or other similar side effects should be advised to refrain from driving or using machinery.

4.8 Adverse Effects (Undesirable Effects)

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.

Serious asthma exacerbations.

Placebo controlled clinical studies of at least 4 weeks treatment duration with Foradile suggested a higher incidence of serious asthma exacerbations in patients who received Foradile (0.9% for 10-12 microgram twice daily, 1.9% for 24 microgram twice daily) than in those who received placebo (0.3%).

Experience in adolescent and adult patients with asthma.

In two pivotal 12 week controlled trials conducted for US registration with combined enrolment of 1095 patients 12 years of age and older, serious asthma exacerbations (acute worsening of asthma resulting in hospitalisation) occurred more commonly with Foradile 24 microgram twice daily (9/271, 3.3%) than with Foradile 12 microgram twice daily (1/275, 0.4%), placebo (2/277, 0.7%) or salbutamol (2/272, 0.7%).
A subsequent clinical trial to address this observation enrolled 2085 patients to compare asthma related serious adverse events in the higher and lower dose groups. The results from this 16 week trial did not show an apparent dose relationship for Foradile. The percent of patients with serious asthma exacerbations in this study was somewhat higher for Foradile than for placebo (for the three double blind treatment groups: Foradile 24 microgram twice daily (2/527, 0.4%), Foradile 12 microgram twice daily (3/527, 0.6%) and placebo (1/514, 0.2%), and for the open label treatment group: Foradile 12 microgram twice daily plus up to two additional doses/day (1/517, 0.2%).

Experience in children aged 5-12 years with asthma.

The safety of Foradile 12 microgram twice daily compared to Foradile 24 microgram twice daily and placebo was investigated in one large, multicentre, randomised, double blind, 52 week clinical trial in 518 children with asthma (ages 5-12) in need of daily bronchodilators and anti-inflammatory treatment. More children who received Foradile 24 microgram twice daily (11/171, 6.4%) or Foradile 12 microgram twice daily (8/171, 4.7%) than children who received placebo (0/176, 0.0%) experienced serious asthma exacerbations.

Other adverse effects.

Adverse reactions are defined according to frequency as follows: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000); very rare (< 1/10,000), including isolated reports.

Musculoskeletal system.

Common: tremor; uncommon: muscle cramps, myalgia.

Cardiac disorders.

Common: palpitations; uncommon: tachycardia; very rare: peripheral oedema.

Psychiatric disorders.

Uncommon: agitation, anxiety, nervousness, insomnia.

Central nervous system disorders.

Common: headache, dizziness, tremor; uncommon: fatigue, insomnia, dizziness; very rare: dysgeusia.

Respiratory tract, thoracic and mediastinal disorders.

Common: cough, pharyngitis, dysphonia, dyspnoea; uncommon: chest pain, increased sputum, bronchospasm, including paradoxical bronchospasm.

Local irritation.

Common: throat irritation, dry mouth.

Immune system disorders.

Very rare: hypersensitivity reactions including hypotension, urticaria, angioneurotic oedema, oedema (including conjunctival irritation and eyelid oedema), pruritus, exanthema.

Gastrointestinal disorders.

Very rare: nausea.

Post-marketing.

The following post-marketing events have been reported in patients treated with Foradile. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency which is therefore categorized as not known. Adverse drug reactions are listed according to system organ classes in MedDRA. Within each system organ class, ADRs are presented in order of decreasing seriousness.

Metabolism and nutrition disorders.

Hypokalaemia, hyperglycaemia.

Investigations.

Electrocardiogram QT prolonged, blood pressure increased (including hypertension).

Skin and subcutaneous tissue disorders.

Rash.

Cardiac disorders.

Angina pectoris, cardiac arrhythmias, e.g. atrial fibrillation, ventricular extrasystoles, tachyarrhythmia.

Respiratory, thoracic and mediastinal disorders.

Cough.

4.9 Overdose

For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).
An overdosage of Foradile is likely to lead to effects that are typical of β-adrenoceptor stimulants: nausea, vomiting, headache, tremor, somnolence, palpitations, tachycardia, ventricular arrhythmias, metabolic acidosis, hypokalaemia, hyperglycaemia, hypertension.
Supportive and symptomatic treatment is indicated. Serious cases should be hospitalised. Use of cardioselective beta-blockers may be considered, but only subject to extreme caution since the use of β-adrenoceptor blocker medication may provoke bronchospasm.
Contact Poisons Information Centre on 131126 for advice on management of overdosage.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Formoterol belongs to a new class of potent, long acting, selective β2-adrenoceptor agonists. It exerts a bronchodilator effect in patients with reversible airways obstruction.
Formoterol inhibits the release of histamine and leukotrienes from passively sensitised human lung. Some anti-inflammatory properties, such as inhibition of oedema and inflammatory cell accumulation, have been observed in animal experiments.
The onset of bronchodilation occurs within 1 to 3 minutes and is still significant 12 hours after inhalation. The time to peak effect is 1 to 2 hours.
In man, Foradile has been shown to be effective in preventing bronchospasm induced by inhaled allergens, exercise, cold air, histamine or methacholine. At therapeutic doses cardiovascular effects are minor and occur only occasionally.

Clinical trials.

Clinical trials in asthma.

Foradile powder for inhalation has been studied in several controlled multiple dose trials (in adults and children) and 3 open follow-up studies (2 in adults and 1 in children). All controlled multiple dose studies began with a run-in or baseline period either one or two weeks, followed by a double blind treatment period of within patient (crossover) or between patient (parallel group) design conducted with double dummies. Placebo and/or 400 microgram salbutamol (given four times a day or three times a day) were used as reference therapies. The studies included 258 asthmatic children (aged 5-15 years) and 1238 adults with reversible or partly reversible airways obstruction, 262 of which were elderly and aged 64 to 82 years.
Four of the controlled trials assessed the efficacy of Foradile given twice daily over a 12 week period. Table 1 lists the treatment differences of the primary efficacy parameter (predose morning PEFR) in these trials.
These trials have shown that Foradile is a significantly better bronchodilator than salbutamol. In the adult studies, mean predose morning PEFR increased by approximately 40-50 L/min with Foradile. This increase was maintained for the duration of the studies. In two of the studies (DP/RD1 and DP/RD2) FEV1 values did not increase significantly more with Foradile than with salbutamol but did in the third study (DP/RD3). Using the overall mean predose morning PEFR, although there was a trend in favour of 24 microgram twice daily Foradile, this dose was not significantly more effective than 12 microgram twice daily in trial DP/RD2 and DP/RD3. The effect of Foradile in the elderly was found to be similar to younger adults. In study DP/PD2 (children), the morning PEFR improved significantly more with Foradile 12 microgram twice daily than with salbutamol 400 microgram three times a day. This dose of Foradile was also found to be more effective than Foradile 6 microgram twice daily. Compared with regularly inhaled salbutamol, the use of Foradile resulted in significantly better predose evening PEFR, the need for significantly less rescue medication, significantly fewer day and night-time asthma symptoms, significantly less sleep disturbance and was judged to be better overall by patients and investigators.
375 adults and 69 children from the 3 month double blind studies completed a further 12 month open treatment period with Foradile. The doses of Foradile was 12-24 microgram twice daily. The improvement in airways obstruction observed in the 3 month studies was maintained in adults and showed a tendency for further improvement in children over the 12 month follow-up period.
A crossover study in 78 adults with nocturnal asthma was also conducted (DP/NA1). Foradile 12 microgram twice daily was compared with salbutamol 400 microgram four times a day during 2 week treatment periods with no wash out between. The night time scores, morning tightness score, predose PEFR, night rescue medication and overall assessment were significantly better with Foradile than salbutamol.

Clinical trials in COPD.

Two large multinational, multicenter, randomized, double blind, parallel group, controlled trials have been carried out in the target population of patients with COPD (protocols 056 and 058). Both were placebo controlled and included an active comparator arm. The primary objective in both trials was to assess the efficacy of formoterol 12 and 24 microgram twice daily by Aerolizer device compared with placebo. In both trials further analysis was made of patients classified as reversible or irreversible at baseline based on a cut-off of 15% increase in FEV1 30 minutes after inhalation of 200 microgram salbutamol. Approximately 50% of patients had reversible COPD in both trials. Subjective measurement of quality of life (QoL) was made using the Saint George's Respiratory Questionnaire.
In protocol 056, both doses of formoterol produced statistically significant and clinically relevant bronchodilation compared to placebo over 3 months in a modified intention to treat analysis involving 194 patients receiving 12 microgram twice daily, 192 that received 24 microgram twice daily and 200 placebo. The mean increase in FEV1 in the 12 microgram group was 224 mL (95% confidence interval: 174, 273), and in the 24 microgram group, 194 mL (95% confidence interval: 145, 243). The mean increases were 241 mL and 213 mL for reversible and irreversible patients, respectively, at 12 microgram, and 244 mL and 137 mL for reversible and irreversible patients, respectively, at 24 microgram.
Formoterol treatment was associated with improved quality of life, lower use of rescue salbutamol and 10% fewer 'bad days' compared to placebo; 'bad days' being days with scores > 2 (out of 3) on 2 or more symptoms or > 20% reduction in peak expiratory flow rate. Bronchodilation was maintained over the 12 hour dosing interval.
There were no significant differences between the two doses of formoterol, nor were there clinically relevant differences between inhaled ipratropium bromide 40 microgram four times a day and formoterol.
Similar results were obtained in protocol 058, which involved 191 patients who received formoterol 12 microgram twice daily, 197 that received 24 microgram twice daily and 186 placebo for 12 months. The mean increase in FEV1 at 3 months in the 12 microgram group was 200 mL, 95% confidence interval (144, 257), and in the 24 microgram group, 208 mL, 95% confidence interval (152, 264). The mean increases were 331 and 109 mL for reversible and irreversible patients, respectively, at 12 microgram, and 271 and 166 mL for reversible and irreversible patients, respectively, at 24 microgram. The increases were sustained at 12 months, being 207 mL, (95% confidence interval (143, 272) in the 12 microgram group and 170 mL, 95% confidence interval (107, 233) in the 24 microgram group. There were no clinically relevant differences between sustained release theophylline tablets 200-400 mg twice daily and formoterol.

5.2 Pharmacokinetic Properties

Absorption.

The pharmacokinetics of formoterol fumarate dihydrate have been elucidated from oral administration of the drug. Administration of up to 300 microgram orally of formoterol fumarate dihydrate showed that the drug is readily absorbed from the gastrointestinal tract. Peak plasma levels of unchanged drug are reached within 0.5 to 1 hour after administration. The absorption of an oral dose of 80 microgram is 65% or more, although 70% of this dose undergoes presystemic or first pass metabolism. The pharmacokinetics of formoterol appear linear in the range of oral doses studied, i.e. 20 to 300 microgram. Repeated oral administration of 40 to 160 microgram daily did not lead to significant accumulation of the drug.
Formoterol acts locally in the lung, therefore, plasma levels are not predictive of therapeutic effect. Analysis of urinary excretion rates suggests that inhaled formoterol is rapidly absorbed. The maximum excretion rate after administration of 12 to 96 microgram is reached within 1 to 2 hours of inhalation in healthy young adults. At a higher than therapeutic dose (120 microgram single dose), the peak plasma concentration (266 picomol/L) is observed at 5 minutes postinhalation. In COPD patients treated for 12 weeks with formoterol fumarate 12 or 24 microgram twice daily, the peak plasma concentrations occurred between 10 minutes and 2 hours after inhalation. On day 84, mean plasma concentrations were 7.6, 21.3, 25.7 and 11.5 picomol/L at 0, 10 minutes, 2 hours and 6 hours after inhalation in patients on 12 microgram twice daily and 30.9, 43.2, 50.3 and 23.3 picomol/L at 0, 10 minutes, 2 hours and 6 hours in patients on 24 microgram twice daily. Six to nine percent of an inhaled dose is excreted unchanged in the urine. Cumulative urinary excretion of formoterol after administration of the inhalation powder showed the amount of formoterol in the circulation to increase in proportion to dose.

Distribution.

Plasma protein binding of formoterol is 61 to 64% and no saturation of binding sites occurs with the concentration range reached with therapeutic doses.

Metabolism.

The major pathway for elimination is by direct glucuronidation and O-demethylation followed by glucuronidation, a minor pathway. The plasma concentration versus time profile of formoterol is polyphasic. On the basis of plasma or blood concentrations up to 6, 8 or 12 hours after oral administration, an elimination half-life of about 2 to 3 hours was determined. From urinary excretion rates between 3 and 16 hours after inhalation, a half-life of about 5 hours was calculated.

Excretion.

The drug and its metabolites are completely eliminated from the body; about two-thirds of an oral dose appear in the urine and one-third in the faeces. Renal clearance of formoterol from blood is 150 mL/min (2.2 mL/min/kg).

Special populations.

Elderly patients.

The pharmacokinetics of formoterol have not been studied in the elderly population.

Hepatic impairment.

The pharmacokinetics of formoterol have not been studied in patients with hepatic impairment.

Renal impairment.

The pharmacokinetics of formoterol have not been studied in patients with renal impairment.

5.3 Preclinical Safety Data

Genotoxicity.

Mutagenicity tests covering a broad range of experimental endpoints have been conducted. No genotoxic effects were found in any of the in vitro or in vivo tests.

Carcinogenicity.

In carcinogenicity studies, 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 or 72 mg/kg/day. The results of these studies must be treated with caution in view of the excessive dose levels used, which resulted in systemic exposure levels 200-1200 fold higher than those expected upon clinical use of formoterol fumarate (based on a 72 microgram daily dose). As a consequence of this the studies were repeated. In the repeated studies 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; 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 cells in the ovaries of rats 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 and smooth muscle tumours in the female reproductive system and effects on the ovary have been reported in rats or mice treated with other beta2-adrenoceptor agonists, and are likely to be secondary to prolonged stimulation of beta2-adrenoceptors in these tissues. Thyroid C cell tumours were only seen at doses resulting in systemic exposure several hundred 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 beta-agonist induced anabolic effects on skeletal muscle at excessive formoterol fumarate 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 fumarate is not mutagenic, 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

Capsule fill.

Lactose monohydrate.

Capsule shell.

Gelatin, Opacode monogramming ink S-1-277002 Black.

6.2 Incompatibilities

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

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C, Protect from moisture.

6.5 Nature and Contents of Container

Foradile capsules are available in Al/Al blister packs of 10 capsules without the inhalation device; 30 and 60 with an Aerolizer inhalation device to allow oral inhalation of the content of the capsule shell.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Formoterol fumarate dihydrate is a white to yellowish odourless powder. It is freely soluble in glacial acetic acid; soluble in methanol; sparingly soluble in ethanol and isopropyl alcohol, slightly soluble in water; and practically insoluble in acetone, ethyl acetate and diethylether.
Chemical name: (±)-2'-hydroxy-5'- [(RS)-1-hydroxy-2- [[(RS)-p-methoxy- α-methylphenethyl]- amino]ethyl] formanilide fumarate dihydrate.
Molecular formula: (C19H24N2O4)2.C4H4O4.2H2O.

Chemical structure.

Formoterol fumarate dihydrate is a racemic mixture of two isomers with the configurations R,R and S,S.

CAS number.

43229-80-7.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription medicine.

Summary Table of Changes