Formoterol Easyhaler® 12 micrograms per actuation Inhalation Powder

One metered dose contains 12 micrograms of formoterol fumarate dihydrate.

With the Easyhaler device the delivered dose (ex-actuator) contains the same quantity of active substance as the metered dose (ex-reservoir).

For excipients, see Section 6.1.

Inhalation powder.

White to yellowish white powder.

Formoterol Easyhaler 12 micrograms per actuation 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.

Formoterol Easyhaler 12 micrograms per actuation 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.

For inhalation use.

ADULTS (INCLUDING THE ELDERLY) AND ADOLESCENTS

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).

CHILDREN 6 YEARS AND OLDER

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 but only after assessment by a physician.

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

Chronic Obstructive Pulmonary Disease

Not appropriate.

CHILDREN UNDER THE AGE OF 6 YEARS

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

Renal and hepatic impairment

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

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 Formoterol Easyhaler fails to control symptoms (maintain effective relief), this is usually an indication of a worsening of the underlying condition.

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

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 Formoterol Easyhaler when the counter reaches zero even though powder can still be observed within the device.

Hypersensitivity to formoterol fumarate dihydrate or to lactose monohydrate (which contains small amounts of milk proteins).

Patients with asthma who require regular treatment with a beta2-agonist should also be receiving regular and appropriate doses of an inhaled anti-inflammatory drug (e.g. corticosteroids and/or in children sodium cromoglycate) or oral corticosteroids. Formoterol Easyhaler should only be used in patients requiring long-term regular bronchodilator therapy and not as an alternative to short-acting beta2-agonists in the event of an acute asthma attack.

When treatment with formoterol is prescribed, patients should be assessed in respect of the appropriateness of the anti-inflammatory therapy they are receiving. Patients should be instructed to continue taking anti-inflammatory therapy and told that the dose of anti-inflammatory therapy should remain unchanged following the introduction of formoterol, even when symptoms improve. If there is no improvement in symptoms or the number of doses of formoterol required to control symptoms increases, this usually indicates deterioration of the underlying condition and the patients should be told to contact their doctor in order that their asthma and its treatment can be reassessed.

Therapy should not be initiated during an exacerbation. In the event of an acute asthma attack, a short-acting beta2-agonist should be used.

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

Severe hypertension, severe heart failure, ischaemic heart disease, cardiac arrhythmias, especially third degree atrioventricular block, idiopathic subvalvular aortic stenosis, hypertrophic obstructive cardiomyopathy, thyrotoxicosis, phaeochromocytoma, aneurysm, known or suspected prolongation of the QT interval (QT> 0.44 sec.; see Section 4.5 Interaction with other medicinal products and other forms of interaction) and in patients treated with drugs affecting the QT interval. Formoterol itself may induce prolongation of QT 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 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 (see Section 4.5 Interaction with other medicinal products and other forms of interaction). 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. Formoterol Easyhaler inhalation powder should be discontinued immediately, the patient should be assessed and, if necessary, alternative therapy instituted.

Formoterol Easyhaler contains approx. 8 mg of lactose per dose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

No specific interaction studies have been carried out with Formoterol Easyhaler.

Drugs such as quinidine, disopyramide, procainamide, phenothiazines, antihistamines and tricyclic antidepressants may be associated with QT interval prolongation and an increased risk of ventricular arrhythmia (see Section 4.4 Special warnings and precautions for use). In addition, levodopa, levothyroxine, oxytocin and alcohol can impair cardiac tolerance towards beta2-agonists.

Concomitant administration of other sympathomimetic agents has the potential to produce additive effects both in respect of the desirable effects and the undesirable effects of Formoterol Easyhaler.

Formoterol may interact with monoamine oxidase inhibitors and should not be given to patients receiving treatment with monoamine oxidase inhibitors or for up to 14 days after their discontinuation.

There may be an increased risk of arrhythmias in patients undergoing concomitant treatment with tricyclic antidepressants.

Concomitant administration of formoterol and corticosteroids may increase the hyperglycaemic effect seen with these drugs.

Concomitant treatment with xanthine derivatives, steroids, or potassium-depleting diuretics may potentiate a possible hypokalaemic effect of beta2-agonists. Hypokalaemia may increase susceptibility to cardiac arrhythmias in patients treated with digitalis (see Section 4.4 Special warnings and precautions for use).

There is an elevated risk of arrhythmias in patients receiving concomitant anaesthesia with halogenated hydrocarbons.

Beta-adrenergic blockers may weaken or antagonise the effect of Formoterol Easyhaler. Therefore Formoterol Easyhaler should not be given together with beta-adrenergic blockers (including eye drops) unless there are compelling reasons for their use.

Clinical experience with formoterol in pregnant women is limited. No teratogenic effects have been revealed in animal tests. However, until further experience is gained, Formoterol Easyhaler is not recommended for use during pregnancy (particularly at the end of pregnancy or during labour) unless there is no other (safer) established alternative. As with any medicine, use during pregnancy should only be considered if the expected benefit to the mother is greater than any risk to the foetus. The substance has been detected in the milk of lactating rats, but it is not known whether formoterol passes into human breast milk, therefore mothers using Formoterol Easyhaler should refrain from breast-feeding their infants.

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

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.

Symptoms:

There is no clinical experience to date on the management of overdose, however, an overdosage of Formoterol Easyhaler would be likely to lead to effects that are typical of beta2-adrenergic agonists: nausea, vomiting, headache, tremor, somnolence, palpitations, tachycardia, ventricular arrhythmias, metabolic acidosis, hypokalaemia, hyperglycaemia.

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-adrenoreceptor agonists.

ATC code: R03AC13.

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.

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.

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 radio-labelled 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.

Preclinical 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.

Lactose monohydrate

Not applicable.

As packaged for sale: 2 years.

After first opening the laminate pouch: 4 months.

After opening the pouch: Do not store above 30°C.

The multi-dose powder inhaler consists of seven plastic parts and a stainless steel spring. The plastic materials of the inhaler are: polybutylene terepthalate, low density polyethylene, polycarbonate, styrenebutadiene, polypropylene. The inhaler is sealed in a laminate pouch and packed with or without a protective cover in a cardboard box.

Packages:

Formoterol Easyhaler 12 micrograms per actuation inhalation powder:

• 120 actuations + protective cover

• 120 actuations

• 2 x 120 actuations

(Protective cover is available separately)

No special requirements.

Orion Corporation

Orionintie 1

FI-02200 Espoo

Finland

PL 27925/0050

February 2007

05 August 2009