Zafiron

Zafiron is indicated in asthma (including nocturnal asthma and exercise-induced symptoms) for those treated with inhaled corticosteroids who also require a long-acting beta agonist in accordance with current treatment guidelines.

Zafiron is indicated for the relief of reversible airways obstruction in patients with chronic obstructive pulmonary disease (COPD) requiring long-term bronchodilatory therapy.

For the long-term symptomatic treatment of persistent, moderate to severe asthma in patients requiring regular bronchodilator therapy in combination with long-term anti-inflammatory therapy (inhaled and / or oral glucocorticoids).

Glucocorticoid therapy should be continued on a regular basis.

Zafiron is indicated for the relief of broncho-obstructive symptoms in patients with chronic obstructive pulmonary disease (COPD).

Zafiron is indicated in adults, adolescents and children aged 6 years and older, as add on therapy to maintenance treatment with inhaled corticosteroids, for the relief of broncho-obstructive symptoms and prevention of exercise-induced symptoms, in patients with asthma when adequate treatment with corticosteroids is not sufficient.

Zafiron is also indicated in adults for the relief of broncho-obstructive symptoms in patients with chronic obstructive pulmonary disease (COPD).

Zafiron 12 micrograms/dose inhalation powder is indicated for use in the treatment of asthma in patients treated with inhaled corticosteroids and who also require a long-acting beta2-agonist in accordance with current treatment guidelines.

Zafiron 12 micrograms/dose inhalation powder is indicated also for the relief of reversible airways obstruction in patients with chronic obstructive pulmonary disease (COPD) and requiring long-term bronchodilator therapy.

Posology

For use in adults (including the elderly) and in children 6 years of age and older

Adults (including the elderly)

Asthma

Zafiron should only be prescribed as an add-on to an inhaled corticosteroid.

Regular maintenance therapy: 1 inhalation capsule (equivalent to 12 micrograms formoterol fumarate dihydrate) to be inhaled twice daily. For more severe cases 2 inhalation capsules to be inhaled twice daily. This dosing regimen provides symptomatic relief throughout day and night. The recommended maximum daily dose is 48 micrograms per day.

Zafiron should not be used to relieve the acute symptoms of an asthma attack. In the event of an acute attack, a short-acting beta2-agonist should be used.

Chronic Obstructive Pulmonary Disease

For regular maintenance therapy, 1 inhalation capsule (equivalent to 12 micrograms formoterol fumarate dihydrate) to be inhaled twice daily.

Children aged 6 years and above

Asthma

Zafiron should only be prescribed as an add-on to an inhaled corticosteroid.

For regular maintenance therapy: 1 inhalation capsule (equivalent to 12 micrograms formoterol fumarate dihydrate) to be inhaled twice daily.

The recommended maximum daily dose is 24 micrograms per day.

For children 6-12 years of age, when treatment with an inhaled corticosteroid and long-acting beta2-agonist (LABA) is required, it is recommended to use a combination product, except in cases where separate inhaled corticosteroid and long-acting beta2-agonist inhalers are more appropriate.

Zafiron should not be used to relieve the acute symptoms of an asthma attack. In the event of an acute attack, a short-acting beta2-agonist should be used.

Chronic Obstructive Pulmonary Disease

Not appropriate

Children under 6 years

Zafiron is not recommended in children under the age of 6 years

Special populations

Renal and hepatic impairment

There is no theoretical reason to suggest that Zafiron dosage requires adjustment in patients with renal or hepatic impairment, however no clinical data have been generated to support its use in these groups.

Elderly Patients (older than 65 years)

The pharmacokinetics of Zafiron has not been studied in the elderly population. The available data from clinical trials performed in elderly patients do not suggest that the dosage should be different than in other adults.

Method of administration

Zafiron inhalation powder capsules should be used only with the inhaler device provided in the Zafiron pack. There is no safety or efficacy data on the use of Zafiron inhalation powder capsules with other marketed inhalation devices.

To ensure proper administration of the drug, the patient should be shown how to use the inhaler by a physician or other health professional. A child should be shown how to use the inhaler correctly and should only use it with the help of an adult.

It is important for the patient to understand that the gelatin capsule may very occasionally break up and small pieces of gelatin might reach the mouth or throat after inhalation. The patient may be reassured that gelatin is harmless and will soften in the mouth and can be swallowed. The tendency for the capsule to break up is minimised by not piercing the capsule more than once.

Instructions for use

1. Pull off the cap from the mouthpiece of the inhaler

2. Hold the base of the inhaler firmly and turn the mouthpiece in the direction of the arrow on the bottom of the mouthpiece to open.

3. Take one of the capsules out of the blister strip for the appropriate day. Place it in the capsule shaped compartment in the base of the inhaler. It is important that the capsule is removed from the blister pack only immediately before use.

4. Twist the mouthpiece to the closed position until it clicks.

5. Keeping the inhaler upright, firmly squeeze the two blue buttons once only. This will pierce the capsule. Release the buttons. Although the capsule is now pierced, the powder will not be released.

6. The patient should breathe out fully.

7. The patient should place the mouthpiece in the mouth and tilt their head slightly back. The lips should be placed around the mouthpiece and the patient should inhale as quickly and as deeply as is possible. As the patient breathes in, the medicine will be inhaled into the lungs.

8. The capsule should be heard spinning in the inhaler. If the whirring noise is not heard, the capsule may be stuck in the compartment. If this occurs, open the inhaler and loosen the capsule by prising it out of the compartment. Do not try to loosen the capsule by repeatedly pressing the buttons.

9. If the whirring noise has been heard the patient should hold their breath for as long as they comfortably can while taking the inhaler out of the mouth. Then the patient should breathe normally. The inhaler should be opened to see if any powder is still in the capsule. If there is still powder in the capsule steps 6 to 8 should be repeated.

10. After use, the empty capsule should be tipped out and the mouthpiece closed.

11. Replace the cap.

12. If the inhaler needs to be cleaned, wipe the mouthpiece and capsule compartment with a dry cloth or a clean soft brush.

The dosage depends on the type and severity of disease.

The following dosages are recommended for adults, including elderly patients, and adolescents aged 12 years and above:

Asthma

Adults and adolescents aged 12 years and above

Usually one actuation in the morning and evening (24 micrograms of formoterol fumarate dihydrate per day). In severe cases, up to a maximum of two actuations in the morning and evening (48 micrograms of formoterol fumarate dihydrate per day).

The maximum daily dose is 4 actuations (48 micrograms of formoterol fumarate dihydrate).

Children younger than 12 years of age:

The safety and efficacy of Zafiron Modulite in children younger than 12 years of age has not been established yet, therefore Zafiron Modulite should not be used in children.

Chronic Obstructive Pulmonary Disease (COPD)

Adults (aged 18 years and above)

The usual dose is one actuation twice daily (one in the morning and one in the evening, 24 micrograms formoterol fumarate dihydrate per day).

The daily dose for regular use should not exceed 2 inhalations. If required, additional inhalations above those prescribed for regular therapy may be used for relief of symptoms, up to a maximum total daily dose of 4 inhalations (regular plus required). More than 2 inhalations should not be taken on any single occasion.

Patients should not use the inhaler beyond three months from the date of dispensing by the pharmacist.

Although Zafiron Modulite has a rapid onset of action, long-acting inhaled bronchodilators should be used for maintenance bronchodilator therapy.

Zafiron Modulite is not intended to relieve acute asthma attacks.

In the event of an acute attack, a short-acting β₂-agonist should be used.

Patients should be advised not to stop or change their steroid therapy when Zafiron Modulite is introduced.

If the symptoms persist or worsen, or if the recommended dose of Zafiron Modulite fails to control symptoms (maintain effective relief), this is usually an indication of a worsening of the underlying condition.

Renal or hepatic impairment

There is no theoretical reason to suggest that Zafiron Modulite dosage requires adjustment in patients with renal or hepatic impairment, however, no clinical data have been generated to support its use in these groups.

Instructions for Use

To ensure proper administration of the drug, the patient should be shown how to use the inhaler by a physician or other health professional.

Before the first use of the inhaler and after 3 days or more of non-use one actuation should be discharged in the air in order to ensure a faultless function. As far as possible patients should stand or sit in an upright position when discharging the inhaler.

1. Remove the protecting cap from the mouthpiece.

2. Breathe out as deeply as possible.

3. Hold the canister vertically with its body upwards and put the mouthpiece between well-closed lips.

4. Deeply inspire through the mouth and, at the same time, press on the upper part of the inhaler to actuate the puff.

5. Hold breath as long as possible without any effort and, finally, remove the inhaler from the mouth.

Should a further puff be inhaled, the inhaler should be kept in a vertical position for about half a minute, then steps 2 to 5 repeated.

After use, close with the protecting cap.

IMPORTANT: do not perform steps 2 to 4 too quickly.

Should a part of gas be sprayed from the upper part of the inhaler or from the mouth side, operations should be performed again starting from step 2.

For patients with weak hand-grip it could be easier to hold the inhaler with both hands. Therefore, the upper part of the inhaler is held with both index fingers and its lower part is held with both thumbs.

The use of a spacer device with the inhaler is usually recommended for patients who have difficulty in coordinating inhalation with actuation, however, no clinical data are available for Zafiron Modulite with spacers.

Posology

Use of doses above those normally required by the individual patient on more than 2 days per week, is a sign of suboptimal disease control and maintenance treatment should be reassessed.

Asthma:In asthma, Zafiron can be used once or twice daily ('regular dosage') and as 'relief medication' to relieve acute broncho-obstructive symptoms.

Adults aged > 18 years:

Relief medication: 1 inhalation for the relief of acute broncho-obstructive symptoms.

Regular dosage: 1 inhalation once or twice daily. Some patients may need 2 inhalations once or twice daily.

Prevention of exercise-induced bronchoconstriction: 1 inhalation before exercise.

The daily dose for regular use should not exceed 4 inhalations, however occasionally up to a maximum of 6 inhalations may be allowed within a 24-hour period. No more than 3 inhalations should be taken on any single occasion.

Children and adolescents 6 years and older:

Relief medication: 1 inhalation for the relief of acute broncho-obstructive symptoms.

Regular dosage: 1 inhalation once or twice daily.

Prevention of exercise-induced bronchoconstriction: 1 inhalation before exercise.

The regular daily dose should not exceed 2 inhalations, however, occasionally up to a maximum of 4 inhalations may be allowed within a 24-hour period. No more than 1 inhalation should be taken on any single occasion.

COPD:

Adults aged > 18 years:

Regular dosage: 1 inhalation once or twice daily.

The daily dose for regular use should not exceed 2 inhalations.

If required, additional inhalations above those prescribed for regular therapy may be used for relief of symptoms, up to a maximum total daily dose of 4 inhalations (regular plus as required). More than 2 inhalations should not be taken on any single occasion.

Special populations:

Elderly

There are no special dosing requirements for elderly patients.

Patients with hepatic or renal impairment:

).

Paediatric population:

Zafiron is not recommended for use in children below 6 years due to insufficient data on safety and efficacy.

NB! A lower strength (6 micrograms/dose) is also available.

Method of administration

Instructions for correct use of Zafiron

Zafiron 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 breathe in forcefully and deeply through the mouthpiece to ensure that an optimal dose is obtained.

It is important to instruct the patient never to chew or bite on the mouthpiece and never to use the inhaler if it has been damaged or if the mouthpiece has become detached.

The patient may not taste or feel any medication when using Zafiron due to the small amount of drug dispensed.

Detailed instructions for use are packed together with each inhaler.

Posology

ADULTS (INCLUDING OLDER PEOPLE) AND ADOLESCENTS (ABOVE 12 YEARS)

Asthma

Regular maintenance therapy:

1 inhalation (12 micrograms) to be inhaled twice daily. For more severe disease this dose regimen can be increased to 2 inhalations (24 micrograms) to be inhaled twice daily.

The maximum daily dose is 4 inhalations (2 inhalations inhaled twice daily).

Chronic Obstructive Pulmonary Disease

Regular maintenance therapy:

1 inhalation (12 micrograms) to be inhaled twice daily.

The maximum daily dose is 2 inhalations (1 inhalation inhaled twice daily).

Paediatric population

CHILDREN 6 to 12 YEARS

Asthma

Regular maintenance therapy:

1 inhalation (12 micrograms) to be inhaled twice daily. The maximum daily dose is 24 micrograms.

Chronic Obstructive Pulmonary Disease

Not appropriate.

CHILDREN UNDER THE AGE OF 6 YEARS

Zafiron is not recommended for use in children under the age of 6 years.

Renal and hepatic impairment

There are no data available for use of Zafiron in patients with hepatic or renal impairment. As formoterol is primarily eliminated via liver metabolism an increased exposure can be expected in patients with severe liver cirrhosis.

The duration of action of formoterol has been shown to last for about 12 hours. The treatment should always aim for the lowest effective dose.

Current asthma management guidelines recommend that long-acting inhaled beta₂-agonists should be used for maintenance bronchodilator therapy. They further recommend that in the event of an acute attack, a short-acting beta₂-agonist should be used.

In accordance with the current asthma management guidelines, long-acting beta₂-agonists may be added to the treatment regimen in patients experiencing problems with high dose inhaled steroids. Patients should be advised not to stop or change their steroid therapy when treatment with formoterol is introduced.

If the symptoms persist or worsen, or if the recommended dose of Zafiron fails to control symptoms (maintain effective relief), this is usually an indication of a worsening of the underlying condition.

When transferring a patient to Zafiron from other inhalation devices, the treatment should be individualised. The previous active substance, dose regimen, and method of delivery should be considered.

Method of administration

For inhalation use.

Precautions to be taken before handling or administering the medicinal product.

Instructions for use and handling

Easyhaler is an inspiratory flow driven inhaler, 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 which is packed together with each inhaler.

- That it is recommended to keep the device in the protective cover after opening the laminate pouch to enhance the stability of the product during use and make the inhaler more tamper proof.

- To shake and actuate the device prior to each inhalation.

- To breathe in forcefully and deeply through the mouthpiece to ensure that an optimal dose is delivered to the lungs.

- Never to breathe out through the mouthpiece as this will result in a reduction in the delivered dose. Should this happen the patient is instructed to tap the mouthpiece onto a table top or the palm of a hand to empty the powder, and then to repeat the dosing procedure.

- Never to actuate the device more than once without inhalation of the powder. Should this happen the patient is instructed to tap the mouthpiece onto a table top or the palm of a hand to empty the powder, and then to repeat the dosing procedure.

- To always replace the dust cap and close the protective cover after use to prevent accidental actuation of the device (which could result in either overdosing or underdosing the patient when subsequently used).

- To clean the mouthpiece with a dry cloth at regular intervals. Water should never be used for cleaning because the powder is sensitive to moisture.

- To replace Zafiron when the counter reaches zero even though powder can still be observed within the device.

Known hypersensitivity to the active substance or to any of the excipients.

(lactose monohydrate, which contains small amounts of milk proteins).

Asthma-related death

Formoterol fumarate dihydrate, the active ingredient of Zafiron, belongs to the class of long-acting beta2-adrenergic agonists (LABAs). In a study with salmeterol, a different long-acting beta2-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 Zafiron has been conducted.

In the treatment of asthma

Zafiron should not be used (and is not sufficient) as the first treatment for asthma.

When treating patients with asthma, use Zafiron only as an add-on to an inhaled corticosteroid (ICS) for patients who are not adequately controlled on an ICS alone or whose disease severity clearly warrants initiation of treatment with both an ICS and a LABA.

Children up to the age of 6 years should not be treated with Zafiron as sufficient experience is not available for this group. For children 6-12 years of age, when treatment with an ICS and LABA is required, it is recommended to use a combination product, except in cases where a separate ICS and LABA are more appropriate.

Zafiron should not be used in conjunction with another LABA

Whenever Zafiron is prescribed, patients should be evaluated for the adequacy of the anti-inflammatory therapy they receive. Patients must be advised to continue taking anti-inflammatory therapy unchanged after the introduction of Zafiron, even when their symptoms improve.

The daily dose of Zafiron should not be increased beyond the maximum recommended dose.

Once asthma symptoms are controlled, consideration may be given to gradually reducing the dose of Zafiron. Regular review of patients as treatment is stepped down is important. The lowest effective dose of Zafiron should be used.

Serious asthma-related adverse events and exacerbations may occur during treatment with Zafiron. Clinical studies with Zafiron suggested a higher incidence of serious asthma exacerbations in patients who received Zafiron than in those who received placebo, particularly in patients 5-12 years of age. These studies do not allow precise quantification of the differences in serious asthma exacerbation rates between treatment groups.

Patients should be advised that if, after initiation of Zafiron, their symptoms persist, or if the number of doses of Zafiron required to control their symptoms increases, this usually indicates a worsening of the underlying condition. In these circumstances, they should be advised to continue treatment but to seek medical advice as soon as possible.

Patients should not be initiated on Zafiron or the dose increased during an acute severe asthma exacerbation, or if they have significantly worsening or acutely deteriorating asthma.

Zafiron must not be used to relieve acute asthma symptoms. In the event of an acute attack, a short-acting beta2-agonist should be used. Patients must be informed of the need to seek medical treatment immediately if their asthma deteriorates suddenly.

Concomitant conditions

Special care and supervision, with particular emphasis on dosage limits, is required in patients receiving Zafiron when the following conditions may exist:

Ischaemic heart disease, cardiac arrhythmias, especially third degree atrioventricular block, severe cardiac decompensation, idiopathic subvalvular aortic stenosis, severe hypertension, aneurysm, phaeochromocytoma, hypertrophic obstructive cardiomyopathy, thyrotoxicosis, or other severe cardiovascular disorders, such as tachyarrhythmias or severe heart failure.

Formoterol may induce prolongation of the QTc-interval. Caution should be observed when treating patients with prolongation of the QTc-interval and in patients treated with drugs affecting the QTc-interval.

Caution should be used when co-administering theophylline and formoterol in patients with pre-existing cardiac conditions

Due to the hyperglycaemic effect of β2-stimulants, including formoterol, additional blood glucose controls are recommended in diabetic patients.

Hypokalaemia

Potentially serious hypokalaemia may result from β2-agonist therapy, including formoterol. Particular caution is advised in severe asthma as this effect may be potentiated by hypoxia and concomitant treatment. It is recommended that serum potassium levels be monitored in such situations.

Paradoxical bronchospasm

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

Zafiron contains lactose monohydrate less than 500 micrograms per delivered dose. This amount does not normally cause problems in lactose intolerant patients. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Incorrect route of administration

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

Zafiron Modulite should not be used (and is not sufficient) as the first treatment for asthma.

Asthmatic patients who require therapy with long-acting ß₂-agonists, should also receive optimal maintenance anti-inflammatory therapy with corticosteroids. Patients must be advised to continue taking their anti-inflammatory therapy after the introduction of formoterol even when symptoms decrease. Should symptoms persist, or treatment with ß₂-agonists need to be increased, this indicates a worsening of the underlying condition and warrants a reassessment of the maintenance therapy.

Although Zafiron may be introduced as add-on therapy when inhaled corticosteroids do not provide adequate control of asthma symptoms, patients should not be initiated on Zafiron during an acute severe asthma exacerbation, or if they have significantly worsening or acutely deteriorating asthma.

Serious asthma-related adverse events and exacerbations may occur during treatment with Zafiron. Patients should be asked to continue treatment but to seek medical advice if asthma symptoms remain uncontrolled or worsen after initiation of Zafiron.

Zafiron Modulite should be used strictly in accordance with the dosage recommendations. Once asthma symptoms are controlled, consideration may be given to gradually reducing the dose of Zafiron Modulite. Regular review of patients as treatment is stepped down is important. The lowest effective dose of Zafiron Modulite should be used.

The maximum daily dose should not be exceeded.

A sudden and progressive deterioration of the asthmatic disorder can be life-threatening and requires immediate medical intervention. Considerably exceeding the prescribed individual doses or the total daily dose can be hazardous due to the effects on the heart (cardiac arrhythmia, rise in blood pressure), in combination with changes in the salt concentrations in body fluids (electrolyte shifts), and must therefore be avoided.

Concomitant conditions

Caution should be observed when treating patients with third degree atrioventricular block, refractory diabetes mellitus, thyrotoxicosis, phaeochromocytoma, hypertrophic obstructive cardiomyopathy, idiopathic subvalvular aortic stenosis, severe hypertension, aneurysm or other severe cardiovascular disorders, such as ischaemic heart disease, tachyarrhythmias or severe heart failure and occlusive vascular diseases, especially arteriosclerosis.

Formoterol may induce prolongation of the QTc-interval. Caution should be observed when treating patients with prolongation of the QTc-interval, eg. congenital or drug-induced (QTc > 0.44 seconds) and in patients treated with drugs affecting the QTc-interval.

Due to the hyperglycaemic effects of ß₂-agonists, additional blood glucose monitoring is recommended initially in diabetic patients.

If anaesthesia with halogenated anaesthetics is planned, it should be ensured that Zafiron Modulite is not administered for at least 12 hours before the start of anaesthesia.

Paradoxical bronchospasm

As with every inhalation therapy, the potential for paradoxical bronchospasm should be considered. If it occurs, the treatment should be discontinued immediately and alternative therapy started.

Hypokalaemia

Potentially serious hypokalaemia may result from ß₂-agonist therapy. Particular caution is recommended in acute severe asthma as the associated risk may be augmented by hypoxia. The hypokalaemic effect may be potentiated by concomitant treatment with xanthine-derivatives, steroids and diuretics. The serum potassium levels should therefore be monitored.

Therefore potassium levels have to be regularly monitored particularly in patients with low basic potassium values or peculiar risks for decreased blood potassium levels. The monitoring should also be conducted if no decreased levels occurred under previous treatment with short acting β₂-sympathomimetics. Where applicable, potassium has to be substituted.

Due to decreased serum potassium levels the effect of digitalis containing medicinal products is enhanced.

General

Zafiron should not be used (and is not sufficient) as the first treatment for asthma.

Asthmatic patients who require therapy with long acting β₂-agonists, should also receive optimal maintenance anti-inflammatory therapy with corticosteroids. Patients must be advised to continue taking their anti-inflammatory therapy after the introduction of Zafiron even when symptoms decrease. Should symptoms persist, or treatment with β₂-agonists need to be increased, this indicates a worsening of the underlying condition and warrants a reassessment of the maintenance therapy.

Although Zafiron may be introduced as add-on therapy when inhaled corticosteroids do not provide adequate control of asthma symptoms, patients should not be initiated on Zafiron during an acute severe asthma exacerbation, or if they have significantly worsening or acutely deteriorating asthma. Serious asthma-related adverse events and exacerbations may occur during treatment with Zafiron. Patients should be asked to continue treatment but to seek medical advice if asthma symptoms remain uncontrolled or worsen after initiation on Zafiron. Once asthma symptoms are controlled, consideration may be given to gradually reducing the dose of Zafiron. Regular review of patients as treatment is stepped down is important. The lowest effective dose of Zafiron should be used.

The maximum daily dose should not be exceeded. The long-term safety of regular treatment at higher doses than 36 micrograms per day in adults with asthma, 18 micrograms per day in children with asthma and 18 micrograms per day in patients with COPD, has not been established.

Frequent need of medication (i.e. prophylactic treatment e.g. corticosteroids and long-acting β₂-agonists)for the prevention of exercise-induced bronchoconstriction several times every week, despite an adequate maintenance treatment, can be a sign of suboptimal asthma control, and warrants a reassessment of the asthma therapy and an evaluation of the compliance.

Cardiovascular and endocrine disorders

Caution should be observed when treating patients with thyrotoxicosis, phaeochromocytoma, hypertrophic obstructive cardiomyopathy, idiopathic subvalvular aortic stenosis, severe hypertension, aneurysm or other severe cardiovascular disorders, such as ischaemic heart disease, tachyarrhythmias or severe heart failure.

QTc prolongation

Formoterol may induce prolongation of the QTc-interval. Caution should be observed when treating patients with prolongation of the QTc-interval and in patients treated with drugs affecting the QTc-interval.

Diabetic patients

Due to the hyperglycaemic effects of β₂-agonists, additional blood glucose monitoring is recommended initially in diabetic patients.

Hypokalaemia

Potentially serious hypokalaemia may result from β₂-agonist therapy. Particular caution is recommended in acute severe asthma as the associated risk may be augmented by hypoxia. The hypokalaemic effect may be potentiated by concomitant treatment with xanthine-derivatives, steroids and diuretics. The serum potassium levels should therefore be monitored.

Bronchospasm

As with other inhalation therapy, the potential for paradoxical bronchospasm should be considered. If it occurs, the treatment should be discontinued immediately and alternative therapy started.

Lactose intolerance

Zafiron contains lactose monohydrate 891 micrograms per delivered dose. This amount does not normally cause problems in lactose intolerant people. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Paediatric population

Children up to the age of 6 years should not be treated with Zafiron, as no sufficient experience is available for this group.

Zafiron should not be used (and is not sufficient) as the first treatment for asthma.

Asthmatic patients who require therapy with long-acting ß₂-agonists, should also receive optimal maintenance anti-inflammatory therapy with corticosteroids.) and in patients treated with drugs affecting the QTc interval. Formoterol itself may induce prolongation of QTc interval.

Caution should be used when co-administering theophylline and formoterol in patients with pre-existing cardiac conditions.

Due to the hyperglycaemic effect of beta2-stimulants, additional blood glucose controls are recommended initially in diabetic patients.

Potentially serious hypokalaemia may result from beta₂-agonist therapy. Particular caution is recommended in acute severe asthma as the associated risk may be augmented by hypoxia. The hypokalaemic effect may be potentiated by concomitant treatment with other medicines, such as xanthine derivatives, steroids and diuretics. It is recommended that serum potassium levels are monitored in such situations.

As with other inhalation therapy there is a risk of paradoxical bronchospasm. If this occurs the patient will experience an immediate increase in wheezing and shortness of breath after dosing which should be treated straightaway with a fast-acting inhaled bronchodilator. Zafiron inhalation powder should be discontinued immediately, the patient should be assessed and, if necessary, alternative therapy instituted.

Zafiron contains approx. 8 mg of lactose per dose. This amount does not normally cause problems in lactose intolerant people. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Paediatric population

Children up to the age of 6 years should not be treated with Zafiron, as no sufficient experience is available for this group.

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

Zafiron Modulite has no influence on the ability to drive and use machines.

Zafiron has no or negligible influence on the ability to drive and use machines.

Formoterol has no or negligible influence on the ability to drive and use machines.

Adverse reactions (Table 1) are ranked in descending order of 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); unknown (frequency cannot be estimated from available data). Within each frequency grouping, adverse reactions are ranked in order of decreasing seriousness.

Table 1

*The percent of patients with serious asthma exacerbations in clinical studies was higher for Zafiron than for placebo, and the biggest numerical imbalance was observed in children 5-12 years old.

** These adverse events were reported in patients treated with Zafiron during the post-marketing experience.

As with all inhalation therapy, paradoxical bronchospasm may occur in very rare cases. Treatment with β2-agonists may result in an increase in blood levels of insulin, free fatty acids, glycerol and ketone bodies. The excipient lactose contains small amounts of milk proteins. These may cause allergic reactions.

Reporting of suspected adverse reactions

Reporting adverse reactions after authorisation 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 via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

The most commonly reported adverse events of β₂-agonist therapy, such as tremor and palpitations, tend to be mild and disappear within a few days of treatment. Adverse reactions, which have been associated with formoterol, are listed below by system organ class and frequency. Frequency is defined as: Very Common (>1/10), Common (>1/100, <1/10), Uncommon (>1/1000, <1/100), Rare (>1/10000, <1/1000), Very rare (<1/10000)

Nausea, dysgeusia, throat irritation, hyperhidrosis, restlessness, headache, dizziness and muscle cramps may resolve spontaneously within one to two weeks of continued treatment.

Central nervous system stimulating effects have been sporadically reported following inhalation of ß₂-sympathomimetics, manifesting as hyperexcitability. These effects were mainly observed in children up to 12 years of age.

Treatment with ß₂-agonists may result in an increase in blood levels of insulin, free fatty acids, glycerol and ketone bodies.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard.

Summary of the safety profile

The most commonly reported adverse events of β₂-agonist therapy, such as tremor and palpitations, tend to be mild and disappear within a few days of treatment.

Tabulated list of adverse reactions

Adverse reactions, which have been associated with formoterol are given below, listed by system organ class and frequency. Frequency are defined as: very common (>1/10), common (>1/100 and <1/10), uncommon (>1/1 000 and <1/100), rare (>1/10 000 and <1/1000) and very rare <1/10 000).

* Headache occurred in 6.5% of patients in OXIS and 6.2% on placebo.

Description of selected adverse reactions

As with all inhalation therapy, paradoxical bronchospasm may occur in very rare cases.

Treatment with β₂-agonists may result in an increase in blood levels of insulin, free fatty acids, glycerol and ketone bodies.

The excipient lactose contains small amounts of milk proteins. These may cause allergic reactions.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via the Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard

The most commonly reported adverse events of beta₂-agonist therapy, such as tremor and palpitations, tend to be mild and disappear within a few days of treatment.

Adverse reactions, which have been associated with formoterol, are given below, listed by system organ class and frequency. Frequencies are defined as: very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1000 to <1/100), rare (>1/10 000 to <1/1000), very rare (<1/10 000) and not known (cannot be estimated from the available data).

As with all inhalation therapy, paradoxical bronchospasm may occur in very rare cases.

Treatment with beta2-agonists may result in an increase in blood levels of insulin, free fatty acids, glycerol and ketone bodies.

Lactose monohydrate contains small amounts of milk proteins and can therefore cause allergic reactions.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

Symptoms

There is no clinical experience to date on the management of overdose, however, an overdosage of Zafiron would be likely to lead to effects that are typical of β2-adrenergic agonists: nausea, vomiting, headache, tremor, somnolence, palpitations, tachycardia, ventricular arrhythmias, metabolic acidosis, hypokalaemia, hyperglycaemia, prolonged QTc-interval, hypertension.

Treatment

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-adrenergic blocker medication may provoke bronchospasm.

Serum potassium should be monitored.

There is limited clinical experience on the management of overdose. An overdosage of Zafiron Modulite would be likely to lead to effects that are typical of β₂-adrenergic agonists: headache, tremor, palpitations. Symptoms reported from isolated cases are tachycardia, prolonged QTc interval, ventricular arrhythmias, metabolic acidosis, hypokalaemia, hyperglycaemia, nausea, vomiting and somnolence.

Treatment of Overdose

Supportive and symptomatic treatment is indicated. Serious cases should be hospitalised. Use of cardioselective β-adrenergic blockers may be considered, but only subject to extreme caution since the use of β-adrenergic blocker medication may provoke bronchospasm.

Serum potassium should be monitored.

There is limited clinical experience on the management of overdose.

Symptoms

An overdose would likely lead to effects that are typical of β₂-agonists: tremor, headache, palpitations. Symptoms reported from isolated cases are tachycardia, hyperglycaemia, hypokalaemia, prolonged QTc-interval, arrhythmia, nausea and vomiting. Supportive and symptomatic treatment is indicated.

Management

Use of cardioselective beta-blockers may be considered, but only subject to extreme caution since the use of β-adrenergic blocker medication may provoke bronchospasm. Serum potassium should be monitored.

Symptoms

There is limited clinical experience on the management of overdose. An overdose would likely lead to effects that are typical of beta2-agonists: tremor, headache, palpitations. Symptoms reported from isolated cases are tachycardia, hyperglycaemia, hypokalaemia, prolonged QTc-interval, arrhythmia, nausea and vomiting.

Treatment

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 beta-adrenergic blocker medication may provoke bronchospasm. Serum potassium should be monitored.

Pharmacotherapeutic group: Selective beta2-adrenergic agonist, ATC code: R03AC13.

Formoterol is a potent selective β2-adrenergic stimulant. It exerts a bronchodilator effect in patients with reversible airways obstruction. The effect sets in rapidly (within 1-3 minutes) and is still significant 12 hours after inhalation.

In man, Zafiron has been shown to be effective in preventing bronchospasm induced by exercise and methacholine.

Formoterol has been studied in the treatment of conditions associated with COPD, and has been shown to improve symptoms and pulmonary function and quality of life. Formoterol acts on the reversible component of the disease.

Serious asthma exacerbations

Placebo-controlled clinical studies of at least 4 weeks treatment duration with Zafiron suggested a higher incidence of serious asthma exacerbations in patients who received Zafiron than in those who received placebo, particularly in patients 5-12 years of age.

Experience in children aged 5-12 years with asthma

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

Pharmacotherapeutic Group: Adrenergics, inhalants; selective β₂-adrenoreceptor agonists

ATC code: R03A C13

Formoterol is a predominantly selective β₂-stimulator. Formoterol has bronchodilator activity in patients with reversible obstructive airway diseases. The onset of action is observed within one to three minutes. Significant bronchodilation is still present 12 hours after inhalation.

In humans formoterol is effective in the prophylaxis of bronchospasm induced by methacholine challenge.

Pharmacotherapeutic group: selective β₂-agonist, formoterol, ATC code: R03A C13.

Mechanism of action and pharmacodynamic effects

Formoterol is a selective β₂-adrenoceptor agonist that produces relaxation of bronchial smooth muscle. Formoterol thus has a bronchodilating effect in patients with reversible airways obstruction. The bronchodilating effect sets in rapidly, within 1-3 minutes after inhalation and has a mean duration of 12 hours after a single dose.

Pharmacotherapeutic group: Selective beta₂-adrenoreceptor agonists.

ATC code: R03AC13.

Mechanism of action

Formoterol is a potent selective beta2-adrenergic stimulant. It exerts a bronchodilator effect in patients with reversible airways obstruction. The effect sets in rapidly (within 1-3 minutes) and is still significant 12 hours after inhalation.

Clinical efficacy and safety

In man, formoterol has been shown to be effective in preventing bronchospasm induced by exercise and methacholine.

Formoterol has been studied in the treatment of conditions associated with COPD, and has been shown to improve symptoms and pulmonary function. Formoterol acts on the reversible component of the disease.

Zafiron has a therapeutic dose range of 12 to 24 micrograms b.i.d. Data on the plasma pharmacokinetics of formoterol were collected in healthy volunteers after inhalation of doses higher than the recommended range and in COPD patients after inhalation of therapeutic doses. Urinary excretion of unchanged formoterol, used as an indirect measure of systemic exposure, correlates with plasma drug disposition data. The elimination half-lives calculated for urine and plasma are similar.

Absorption

Following inhalation of a single 120 microgram dose of formoterol fumarate by healthy volunteers, formoterol was rapidly absorbed into plasma, reaching a maximum concentration of 266 pmol/l within 5 minutes of inhalation. In COPD patients treated for 12 weeks with formoterol fumarate 12 or 24 micrograms b.i.d. the plasma concentrations of formoterol ranged between 11.5 and 25.7 pmol/L and 23.3 and 50.3 pmol/L respectively at 10 minutes, 2 hours and 6 hours post inhalation.

Studies investigating the cumulative urinary excretion of formoterol and/or its (R,R) and (S,S)-enantiomers, after inhalation of dry powder (12-96 micrograms) or aerosol formulations (12-96 micrograms), showed that absorption increased linearly with the dose.

After 12 weeks administration of 12 micrograms or 24 micrograms formoterol powder b.i.d., the urinary excretion of unchanged formoterol increased by 63-73% in adult patients with asthma, by 19-38% in adult patients with COPD and by 18-84% in children, suggesting a modest and self-limiting accumulation of formoterol in plasma after repeated dosing.

As reported for other inhaled drugs, it is likely that about 90% of formoterol administered from an inhaler will be swallowed and then absorbed from the gastrointestinal tract. This means that the pharmacokinetic characteristics of the oral formulation largely apply also to the inhalation powder. When 80 micrograms of ³H-labelled formoterol fumarate was orally administered to two healthy volunteers, at least 65% of the drug was absorbed.

Distribution

The plasma protein binding of formoterol is 61-64% (34% primarily to albumin).

There is no saturation of binding sites in the concentration range reached with therapeutic doses.

Biotransformation

Formoterol is eliminated primarily by metabolism, direct glucuronidation being the major pathway of biotransformation, with O-demethylation followed by further glucuronidation being another pathway. Minor pathways involve sulphate conjugation of formoterol and deformylation followed by sulphate conjugation. Multiple isozymes catalyze the glucuronidation (UGT1A1, 1A3, 1A6, 1A7, 1A8, 1A9, 1A10, 2B7 and 2B15) and O-demethylation (CYP2D6, 2C19, 2C9, and 2A6) of formoterol, and so consequently the potential for metabolic drug-drug interaction is low. Formoterol did not inhibit cytochrome P450 isozymes at therapeutically relevant concentrations. The kinetics of formoterol are similar after single and repeated administration, indicating no auto-induction or inhibition of metabolism.

Elimination

In asthmatic and COPD patients treated for 12 weeks with 12 or 24 micrograms formoterol fumarate b.i.d., approximately 10% and 7% of the dose, respectively, were recovered in the urine as unchanged formoterol. In asthmatic children, approximately 6% of the dose was recovered in the urine as unchanged formoterol after multiple dosing of 12 and 24 micrograms. The (R,R) and (S,S)-enantiomers accounted, respectively, for 40% and 60% of urinary recovery of unchanged formoterol, after single doses (12 to 120 micrograms) in healthy volunteers and after single and repeated doses in asthma patients.

After a single oral dose of ³H-formoterol, 59-62% of the dose was recovered in the urine and 32-34% in the faeces. Renal clearance of formoterol is 150 mL/min.

After inhalation, plasma formoterol kinetics and urinary excretion rate data in healthy volunteers indicate a biphasic elimination, with the terminal elimination half-lives of the (R,R)- and (S,S)-enantiomers being 13.9 and 12.3 hours, respectively.

Approximately 6.4-8% of the dose was recovered in the urine as unchanged formoterol, with the (R,R) and (S,S)-enantiomers contributing 40% and 60% respectively.

As with other substances administered by inhalation, 90% of the inhaled formoterol dose is swallowed and absorbed from the gastrointestinal tract. The pharmacokinetic characteristics of the oral formulation can thus be extrapolated to the inhalation of metered aerosol.

Absorption is both rapid and extensive; after inhalation of a therapeutic dose (12 micrograms) of Zafiron Modulite pressurised inhalation solution in asthmatic patients, the peak plasma concentration is observed approximately 15 minutes after inhalation, earlier than that observed with a formoterol powder inhalation. Generally, absorption rate should be taken into account when switching patients from one formoterol formulation to another.

Absorption of formoterol is linear following inhalation of 12 micrograms to 96 micrograms of formoterol fumarate dihydrate.

Oral doses of up to 300 micrograms of formoterol are rapidly absorbed from the gastrointestinal tract. The peak plasma concentration of the unchanged substance is reached after 30 minutes to 1 hour. More than 65% of an oral dose of 80 micrograms is absorbed.

Dose linearity is present within a dose range of 20 micrograms to 300 micrograms (oral administration).

Repeated daily administration of 40-160 micrograms per day does not result in accumulation because of the short half-life. The pharmacokinetics of formoterol do not differ significantly between men and women.

Plasma protein binding is 61% to 64% (34% to albumin); binding sites are not saturated at therapeutic dose levels.

Formoterol is metabolised primarily via direct glucuronisation and is eliminated completely. A further route of biotransformation is O-demethylation followed by glucuronisation with consecutive complete elimination.

Multiple CYP450 isozymes catalyze the transformation (2D6, 2C19, 2C9, and 2A6) and consequently the potential for metabolic drug-drug interaction is low. The kinetics of formoterol are similar after single and repeated administration, indicating no auto-induction or inhibition of metabolism.

The elimination of formoterol apparently follows a polyphasic pattern, and the half-life described is therefore dependent on the time intervals considered. Based on plasma or blood concentrations measured 6, 8 or 12 h after oral administration, an elimination half-life of 2 to 3 hours was determined. A half-life of 5 hours was calculated from the renal excretion rate between 3 and 16 h after inhalation.

The active substance and metabolites are eliminated completely, two thirds of an oral administered dose with the urine, one third with the faeces. Following inhalation of formoterol, a mean of 6% to 9% of the substance is eliminated unchanged with the urine. Renal clearance of formoterol is 150ml/min.

Absorption

Inhaled formoterol is rapidly absorbed. Peak plasma concentration is reached about 10 minutes after inhalation.

In a pharmacokinetic study, the mean lung deposition of formoterol after inhalation via Turbohaler was 43% of the delivered dose. The total systemic availability was around 60% of the delivered dose.

Distribution and biotransformation

Plasma protein binding is approximately 50%.

Formoterol is metabolised via direct glucuronidation and O-demethylation. The enzyme responsible for O-demethylation has not been identified.

Elimination

The major part of the dose of formoterol is eliminated via metabolism. Total plasma clearance and volume of distribution has not been determined. After inhalation 8-13% of the delivered dose of formoterol is excreted unmetabolised in the urine. About 20% of an intravenous dose is excreted unchanged in the urine. The terminal half-life after inhalation is estimated to be 17 hours.

Linearity/non-linearity

Systemic exposure for formoterol correlates in a linear fashion to administered dose.

Special populations

The effect of decreased liver or kidney function on the pharmacokinetics of formoterol and the pharmacokinetics in the elderly is not known. As formoterol is primarily eliminated via liver metabolism an increased exposure can be expected in patients with severe liver cirrhosis.

Absorption

As reported for other inhaled drugs, it is likely that about 80 % of formoterol administered from the Easyhaler inhaler will be swallowed and then absorbed from the gastrointestinal tract. This means that the pharmacokinetic characteristics of the oral formulation largely apply also to the inhalation powder. Following inhalation of therapeutic doses, formoterol cannot be detected in the plasma using current analytical methods.

Absorption is both rapid and extensive: At a higher than therapeutic dose (120 micrograms), the peak plasma concentration is observed at 5 minutes post inhalation whilst at least 65 % of a radiolabelled 80 micrograms oral dose is absorbed, and oral doses of up to 300 micrograms are readily absorbed with the peak concentrations of unchanged formoterol at 0.5-1 hour. In COPD patients treated for 12 weeks with formoterol fumarate 12 or 24 micrograms b.i.d. the plasma concentrations of formoterol ranged between 11.5 and 25.7 pmol/L and 23.3 and 50.3 pmol/L respectively at 10 minutes, 2 hours and 6 hours post inhalation.

The pharmacokinetics of formoterol appear linear in the range of oral doses investigated, i.e. 20-300 micrograms. Repeated oral administration of 40-160 micrograms daily does not lead to significant accumulation of the drug. The maximum excretion rate after administration of 12-96 micrograms is reached within 1-2 hours of inhalation.

After 12 weeks administration of 12 micrograms or 24 micrograms formoterol powder b.i.d., the urinary excretion of unchanged formoterol increased by 63-73 % in adult patients and by 18-84 % in children, suggesting a modest and self-limiting accumulation of formoterol in plasma after repeated dosing.

Studies investigating the cumulative urinary excretion of formoterol and/or its (R,R) and (S,S)-enantiomers, after inhalation of dry powder (12-96 micrograms) or aerosol formulations (12- 96 micrograms), showed that absorption increased linearly with the dose.

Distribution

The plasma protein binding of formoterol is 61- 64 % (34 % primarily to albumin). There is no saturation of binding sites in the concentration range reached with therapeutic doses.

Biotransformation

Formoterol is eliminated primarily by metabolism, direct glucuronidation being the major pathway of biotransformation, with O-demethylation followed by further glucuronidation being another pathway. Multiple CYP450 isoenzymes (2D6, 2C19, 2C9, and 2A6) catalyze the transformation and so consequently the potential for metabolic drug-drug interaction is low. The kinetics of formoterol are similar after single and repeated administration, indicating no auto-induction or inhibition of metabolism.

Elimination

Elimination of formoterol from the circulation seems to be polyphasic; the apparent half-life depends on the time interval considered. On the basis of plasma or blood concentrations up to 6, 8 or 12 hours after oral administration, an elimination half-life of about 2-3 hours was determined. From urinary excretion rates between 3 and 16 hours after inhalation, a half-life of about 5 hours was calculated.

After inhalation, plasma formoterol kinetics and urinary excretion rate data in healthy volunteers indicate a biphasic elimination, with the terminal elimination half-lives of the (R,R)- and (S,S)-enantiomers being 13.9 and 12.3 hours, respectively. Approximately 6.4-8 % of the dose was recovered in the urine as unchanged formoterol, with the (R,R) and (S,S)-enantiomers contributing 40 % and 60 % respectively.

After a single oral dose of 3H-formoterol, 59-62 % of the dose was recovered in the urine and 32-34 % in the faeces. Renal clearance of formoterol is 150 ml/min.

In adult asthmatics, approximately 10 % and 15-18 % of the dose was recovered in the urine as unchanged and conjugated formoterol, respectively, after multiple doses of 12 and 24 micrograms. In children, approximately 6 % and 6.5-9 % of the dose was recovered in the urine as unchanged and conjugated formoterol, respectively, after multiple doses of 12 and 24 micrograms. As in healthy volunteers, the (R,R) and (S,S)-enantiomers contributed approximately 40 % and 60 % of unchanged drug excreted in the urine of adults, respectively, and there was no relative accumulation of one enantiomer over the other after repeated dosing.

Mutagenicity

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 performed.

Carcinogenicity

Two-year studies in rats and mice did not show any carcinogenic potential.

Male mice treated at very high dose levels showed a slightly higher incidence of benign adrenal subcapsular cell tumours, which are considered to reflect alterations in the physiological ageing process.

Two studies in rats, covering different dose ranges, showed an increase in mesovarial leiomyomas. These benign neoplasms are typically associated with long-term treatment of rats at high doses of β2-adrenergic drugs. Increased incidences of ovarian cysts and benign granulosa/theca cell tumours were also seen; β-agonists are known to have effects on the ovary in rats in which are very likely specific to rodents. A few other tumour types noted in the first study using the higher doses were within the incidences of the historical control population, and were not seen in the lower-dose experiment.

None of the tumour incidences were increased to a statistically significant extent at the lowest dose of the second study, a dose leading to a systemic exposure 10 times higher than that expected from the maximum recommended dose of formoterol.

On the basis of these findings and the absence of a mutagenic potential, it is concluded that use of formoterol at therapeutic doses does not present a carcinogenic risk.

Reproductive toxicity

Animal tests have shown no teratogenic effects. Formoterol was evaluated for its effect on fertility and general reproductive performance in sexually mature male and female rats. Reproduction studies in rats revealed no impairment of fertility or effect on early embryonic development at oral doses up to 3 mg/kg (approximately 1200 times the maximum recommended daily inhalation powder dose in human on a mg/m2 basis).

After oral administration, formoterol was excreted in the milk of lactating rats.

The effects of formoterol in rats and dogs were largely confined to the cardiovascular system and consisted of known pharmacological manifestations of high β₂-agonist doses.

A somewhat reduced fertility in male rats was observed at very high systemic exposure of formoterol.

No genotoxic effects of formoterol have been observed in in-vitro or in-vivo tests. In rats and mice, a slight increase in the incidence of benign uterine leiomyomas has been observed. This effect is looked upon as a class effect in rodents after long exposure to high doses of β₂-agonists.

The effects of formoterol seen in toxicity studies in rats and dogs were mainly on the cardiovascular system and consisted of hyperaemia, tachycardia, arrhythmias and myocardial lesions. These effects are known pharmacological manifestations seen after the administration of high doses of β₂-agonists.

No genotoxic effects of formoterol have been observed in in-vitro or in vivo tests. In rats and mice a slight increase in the incidence of benign uterine leiomyomas has been observed. This effect is looked upon as a class-effect observed in rodents after long exposure to high doses of β₂-agonists.

Non-clinical data reveal no special hazard for humans in the therapeutic dose range based on conventional studies of repeated dose toxicity, genotoxicity, carcinogenicity and reproduction toxicity. A somewhat reduced fertility in male rats was observed at high systemic exposure to formoterol. In rats and mice a slight increase in the incidence of uterine leiomyomas has been observed. This effect is looked upon as a class-effect observed in rodents after long exposure to high doses of beta₂-receptor agonists.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

For pharmacies

Enter the date of dispensing to the patient on the pack.

Ensure that there is a period of at least 3 months between the date of dispensing and the expiry date printed on the pack.

No special requirements.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.