This information is intended for use by health professionals

1. Name of the medicinal product

Formoterol Easyhaler® 12 micrograms/dose inhalation powder

2. Qualitative and quantitative composition

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).

Excipient with known effect: Lactose monohydrate

For the full list of excipients, see Section 6.1.

3. Pharmaceutical form

Inhalation powder.

White to yellowish white powder.

4. Clinical particulars
4.1 Therapeutic indications

Formoterol Easyhaler 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.

Formoterol Easyhaler 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.

4.2 Posology and method of administration

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

Formoterol Easyhaler 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 Formoterol Easyhaler 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 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.

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

4.3 Contraindications

Hypersensitivity to formoterol fumarate dihydrate or to the excipient listed in section 6.1 (lactose monohydrate, which contains small amounts of milk proteins).

4.4 Special warnings and precautions for use

Formoterol Easyhaler 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 Easyhaler 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 Formoterol Easyhaler may be introduced as add-on therapy when inhaled corticosteroids do not provide adequate control of asthma symptoms, patients should not be initiated on Formoterol Easyhaler 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 Formoterol Easyhaler. Patients should be asked to continue treatment but seek medical advice if asthma symptoms remain uncontrolled or worsen after initiation on Formoterol Easyhaler. Once asthma symptoms are controlled, consideration may be given to gradually reducing the dose of Formoterol Easyhaler. Regular review of patients as treatment is stepped down is important. The lowest effective dose of Formoterol Easyhaler should be used.

The maximum daily dose should not be exceeded. The long term safety of regular treatment at higher metered doses than 48 micrograms per day in adults with asthma, 24 micrograms per day in children with asthma and 24 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 beta2-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.

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 QTc interval (QTc> 0.44 sec.; see Section 4.5) 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 (see Section 4.5). 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 (see section 4.8) .

Formoterol Easyhaler 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 Formoterol Easyhaler, as no sufficient experience is available for this group.

4.5 Interaction with other medicinal products and other forms of interaction

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

There is a theoretical risk that concomitant treatment with other drugs known to prolong the QTc-interval may give rise to a pharmacodynamic interaction with formoterol and increase the possible risk of ventricular arrhythmias. Examples of such drugs include certain antihistamines (e.g. terfenadine, astemizole, mizolastine), certain antiarrhythmics (e.g. quinidine, disopyramide, procainamide), erythromycin and tricyclic antidepressants. In addition, levodopa, levothyroxine, oxytocin and alcohol can impair cardiac tolerance towards beta2-agonists.

Concomitant administration of other sympathomimetic agents such as other beta2 –agonists or ephedrine has the potential to produce additive effects both in respect of the desirable effects and the undesirable effects of Formoterol Easyhaler. Therefore titration of the dose may be required.

Concomitant treatment with xanthine derivatives, steroids, or diuretics such as thiazides and loop diuretics may potentiate a possible hypokalaemic adverse effect of beta2-agonists. Hypokalaemia may increase susceptibility to cardiac arrhythmias in patients treated with digitalis glycosides (see section 4.4).

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

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.

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

The bronchodilating effects of formoterol can be enhanced by anticholinergic drugs.

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.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no adequate data from the use of formoterol in pregnant women. In animal studies formoterol has caused implantation losses as well as decreased early postnatal survival and birth weight. The effects appeared at considerably higher systemic exposures than those reached during clinical use of formoterol. Treatment with formoterol may be considered at all stages of pregnancy if needed to obtain asthma control, and if the expected benefit to the mother is greater than any possible risk to the fetus. The potential risk for human is unknown.

Breastfeeding

It is not known whether formoterol passes into human breast milk. In rats, small amounts of formoterol have been detected in maternal milk. Administration of formoterol to women who are breast-feeding should only be considered if the expected benefit to the mother is greater than any possible risk to the child.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

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).

Immune system disorders

Rare

Hypersensitivity reactions such as bronchospasm, severe hypotension, urticaria, angioedema, pruritus, exanthema, peripheral oedema

Metabolism and nutrition disorders

Rare

Hypokalaemia

Very rare

Hyperglycaemia

Psychiatric disorders

Uncommon

Agitation, restlessness, sleep disturbances, anxiety

Nervous system disorders

Common

Headache, tremor

Very rare

Dizziness, taste disturbance

Cardiac disorders

Common

Palpitations

Uncommon

Tachycardia

Rare

Cardiac arrhythmias, e.g atrial fibrillation, supraventricular tachycardia, extrasystoles

Very rare

Angina pectoris, prolongation of QTc interval

Vascular disorders

Very rare

Variation in blood pressure

Respiratory, thoracic and mediastinal disorders

Rare

Aggravated bronchospasm, paradoxical bronchospasm (see Section 4.4), oropharyngeal irritation

Gastrointestinal disorders

Rare

Nausea

Musculoskeletal, connective tissue and bone disorders

Uncommon

Muscle cramps, myalgia

As with all inhalation therapy, paradoxical bronchospasm may occur in very rare cases (see section 4.4).

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.

4.9 Overdose

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.

5. Pharmacological properties
5.1 Pharmacodynamic properties

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.

5.2 Pharmacokinetic properties

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.

5.3 Preclinical safety data

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.

6. Pharmaceutical particulars
6.1 List of excipients

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

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

As packaged for sale: 2 years.

After first opening the laminate pouch: 4 months. Do not store above 30°C and protect from moisture.

6.4 Special precautions for storage

Before the first use store in the unopened laminate pouch.

For storage conditions after first opening of the medicinal product, see section 6.3

6.5 Nature and contents of container

The multidose 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, styrene butadiene, 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/dose inhalation powder:

• 120 doses + protective cover

• 120 doses

• 2 x 120 doses

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

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

7. Marketing authorisation holder

Orion Corporation

Orionintie 1,

FI-02200 Espoo,

Finland

8. Marketing authorisation number(s)

PL 27925/0050.

9. Date of first authorisation/renewal of the authorisation

17 September 2011

10. Date of revision of the text

28/04/2015