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S UMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

Formoterol 12 microgram, hard capsules with inhalation powder

2. QUALITATIVE AND QUANTITATIVE COMPOS ITION

One capsule contains 12 micrograms of formoterol fumarate equivalent to 12.5 µg formoterol fumarate dihydrate. This corresponds to a delivered dose of 10.3 micrograms of formoterol fumarate.

Excipient: Each capsule contains 24.0 mg of lactose monohydrate. For excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Inhalation powder, hard capsule.

Colourless transparent gelatin capsules containing white powder.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Symptomatic long-term treatment of persistent moderate and severe bronchial asthma in combination with a long-term antiinflammatory therapy (eg. ).

Relief of broncho-obstructive symptoms in patients with chronic obstructive pulmonary disease (COPD).

Treatment of other airways diseases with a reversible obstructive component such as chronic bronchitis with or without emphysema.

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Prevention of bronchospasm as a result of inhaled allergens or exertion.

Note: There are no indications to date that formoterol can replace treatment with corticosteroids. In any case formoterol must be combined with corticosteroids by inhalation in bronchial asthma.

4.2 Posology and method of administration

Capsules are Ffor inhalation use only.

The effect of formoterol is still significant 12 hours after inhalation. Therefore, in most cases, administration twice daily will be adequate to control the symptoms associated with asthma and other airways diseases with a reversible or irreversible obstructive component both during the day and at night.

Children from 6 years, adolescents and adults (including elderly):

Bronchial asthma and other airways diseases with a reversible obstructive component such as chronic bronchitis with or without emphysema and COPD:

Normal maintenance dose is 1 inhalation capsule (12 micrograms) twice a day. If it is necessary to relieve possible acute or chronic symptoms, a further 1-2 capsules per day may be used. The maximum daily dose is 2 inhalation capsules twice daily (48 micrograms). The patient should be informed that if the extra dosage is necessary more than twice a week, the doctor should be consulted and treatment reassessed, as it is possible that the condition has deteriorated.

Prevention of bronchospasm as a result of inhaled allergens or exertion:

The contents of 1 inhalation capsule (12 micrograms) is inhaled 15 minutes before expected activity or exposure to the allergen. In adult patients with serious asthma, 2 capsules (24 micrograms) may be necessary.

Is not recommended in children under the age of 6 years.

Renal and hepatic impairment

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

It should be ensured that the patient is instructed in the use of the inhaler by doctor or pharmacist.

Instructions for use:

1. Pull off the cap.

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

3. Place one capsule with dry hands in the capsule-shaped compartment in the base of the inhaler.

4. Twist the mouthpiece to the closed position.

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5. Keeping the inhaler upright (mouthpiece to top), firmly squeeze the two buttons at the same time once only. This will pierce the capsule. Release the buttons.

6. Breathe out fully.

7. Place the mouthpiece in your mouth and tilt your head slightly backwards. Close your lips around the mouthpiece and breathe in as quickly and as deeply as you can.

8. Hold your breath for as long as you comfortably can while taking the inhaler out of your mouth. Then breathe normally. Open the inhaler to see if any powder is still in the capsule. If there is still powder in the capsule, repeat steps 6 to 8.

9. After use, tip out the empty capsule and close the mouthpiece. Note: It is possible that gelatin capsule might fragment and that small pieces of gelatin end up in the mouth and throat during inhalation. Gelatin is harmless and will soften in the mouth and can be swallowed. The risk of fragmentation of gelatin capsule will be minimised by squeezing the two buttons only once and therefore by not perforating the capsule more than once.

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The capsules should remain in the blister pack until required for use and should only be removed from the blister strip immediately before use.

Inhaler cleaning: In order to remove residual powder, clean mouthpiece and capsule compartment with a dry cloth. Also a clean soft brush can be used.

4.3 Contraindications

 Hypersensitivity to Formoterol formoterol, lactose (which contains small amounts of milk proteins)or beta-2 agonists in general or to any of the excipients (e. g. lactose- monohydrate which contains small amounts of milk proteins).

4.4 S pecial warnings and precautions for use

Formoterol should not be used (and is not sufficient) as the first treatment for asthma. Formatiert: Schriftart: 12 Pt., Englisch (Großbritannien) Formatiert: Einzug: Links: 1,5 cm, Zeilenabstand: einfach, Tabstopps: 1,5 cm, Links + Nicht an 1 cm Asthmatic patients who require therapy with long-acting 2-agonists, should also receive optimal maintenance anti-inflammatory therapy with corticosteroids. Patients must be Formatiert: Schriftart: 12 Pt., Englisch (Großbritannien) advised to continue taking their anti-inflammatory therapy after the introduction of Formatiert: Schriftart: 12 Pt., Englisch (Großbritannien) formoterol even when symptoms decrease. Should symptoms persist, or treatment with 2- Formatiert: Schriftart: 12 Pt., Englisch (Großbritannien) agonists need to be increased, this indicates a worsening of the underlying condition and Formatiert: Schriftart: 12 Pt., Englisch (Großbritannien) warrants a reassessment of the maintenance therapy.

Although formoterol 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 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. Patients should be asked to continue treatment but to seek medical advice if asthma symptoms remain uncontrolled or worsen after initiation on formoterol. Once asthma symptoms are controlled, consideration may be given to gradually reducing the dose of formoterol. Regular review of patients as treatment is stepped down is important. The lowest effective dose of formoterol 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.

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Frequent need of (i.e. prophylactic treatment e.g. corticosteroids and long- acting 2-agonists) for the prevention of exercise-induced bronchoconstriction several Formatiert: Schriftart: 12 Pt., Englisch (Großbritannien) times every week, despite an adequate maintenance treatment, can be a sign of suboptimal Formatiert: Schriftart: 12 Pt., Englisch (Großbritannien) asthma control, and warrants a reassessment of the asthma therapy and an evaluation of the compliance.

Caution should be observed when treating patients with thyrotoxicosis, Formatiert: Schriftart: 12 Pt., Nicht Kursiv, Englisch phaeochromocytoma, hypertrophic obstructive cardiomyopathy, idiopathic subvalvular (Großbritannien) aortic stenosis, severe hypertension, aneurysm or other severe cardiovascular disorders, Formatiert: Schriftart: 12 Pt., Englisch (Großbritannien) such as ischaemic heart disease, 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 affecting the QTc-interval (see section 4.5).

Due to the hyperglycaemic effects of 2-agonists, additional glucose monitoring is Formatiert: Schriftart: 12 Pt., Englisch (Großbritannien) recommended initially in diabetic patients. Formatiert: Schriftart: 12 Pt., Englisch (Großbritannien)

Potentially serious hypokalaemia may result from 2-agonist therapy. Particular caution is Formatiert: Schriftart: 12 Pt., Englisch (Großbritannien) recommended in acute severe asthma as the associated risk may be augmented by hypoxia. Formatiert: Schriftart: 12 Pt., Englisch (Großbritannien) The hypokalaemic effect may be potentiated by concomitant treatment with xanthine- derivatives, steroids and . The serum potassium levels should therefore be monitored.

As with other inhalation therapy, the potential for paradoxial bronchospasm should be considered. If it occurs, the treatment should be discontinued immediately and alternative therapy started (see section 4.8).

Caution should be observed, with particular attention paid to the dose, when treating patients with any of the following conditions:

 cardiac arrhythmias e.g. tachyarrhythmias, third degree atrioventricular block or prolongation of QT-interval severe cardiovascular disorders or ischaemic heart disease, e.g. idiopathic subvalvular aortic stenosis or hypertrophic obstructive cardiomyopathy  arteriosclerosis hypertension  hyperthyroidism or thyreotoxicosis  adrenal tumour hypokalaemia

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 prior to narcosis with halogenated anaesthetics, the product should not be applied for at least 12 hours.

Blood glucose should be checked more often in diabetic patients because of the hyperglycaemic effect of beta-2 agonists.

Hypokalaemia: Treatment with beta-2 agonists can lead to potentially serious hypokalaemia. Special caution should be exercised in acute severe asthma as hypoxia increases the risk of hypokalaemia. The hypokalaemic effect may be potentiated by concomitant treatment with other medicinal products, such as xanthine-derivatives, steroids and diuretics (see Section 4.5 Interaction with other medicinal products and other forms of interaction). Therefore serum potassium levels should be monitored in such situations.

Paradoxical bronchospasm: As with other inhalation therapy, there is a risk of paradoxical bronchospasm (see section 4.8 Undesirable effects). If this occurs the patient will experience an immediate increase in wheezing after dosing which should be treated straightaway with a fast-acting inhaled bronchodilator. Formoterol 12 micrograms inhalation powder should be discontinued immediately, the patient should be assessed and, if necessary, alternative treatment instituted.

Anti-inflammatory therapy: Asthmatic patients who require therapy with long-acting 2-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 when symptoms decrease. Should symptoms persist, or treatment with 2- agonists need to be increased, this indicates a worsening of the underlying condition and warrants a reassessment of the maintenance therapy.

Although Formoterol may be introduced as add-on therapy when inhaled corticosteroids to not provide adequate control of asthma symptoms, patients should not be initiated on Formoterol 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. Patients should be asked to continue treatment but to seek medical advice if asthma symptoms remain uncontrolled or worsen after initiation on Formoterol. Formoterol should not be used (and is not sufficient) as the first treatment for asthma. Once asthma symptoms are controlled, consideration may be given to gradually reducing the

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dose of Formoterol. Regular review of patients as treatment is stepped down is important. The lowest effective dose of Formoterol should be used.

Formoterol inhalation powder should not be used therapeutically in the event of premature birth or threatened abortion.

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

Paediatric population Formatiert: Schriftart: Fett Administration of this product to children must be supervised by an adult. Children up to the age of 6 years should not be treated with Fformoterol, as no sufficient experience is available for this group.

This medicinal product contains lactose monohydrate (less than 500 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 medicinal producte.

4.5 Interaction with other medicinal products and other forms of interaction

No specific interaction studies have been carried out with formoterol.

Concomitant treatment with other sympathomimetic substances such as other β2-agonists or ephedrine may potentiate the undesirable effects of formoterol and may require titration of the dose.

Concomitant treatment with xanthine derivatives, steroids or diuretics such as thiazides and loop diuretics may potentiate a rare hypokalaemic adverse effect of β2-agonists. Hypokalaemia may increase the disposition towards arrhythmias in patients who are treated with digitalis glycosides.

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 (e.g. terfenadine, astemizole, mizolastine), certain antiarrhythmics (e.g. quinidine, disopyramide, procainamide), erythromycin and tricyclic .

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

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

Beta-adrenergic blockers can weaken or inhibit the effect of formoterol. Formoterol should therefore not be given together with β-adrenergic blockers (including eye drops) unless there are compelling reasons. Beta-adrenergic substances: Effect and undesirable effects may be potentiated by simultaneous ingestion of other sympathomimetic agents.

Anticholinergic agents: The effect may be exacerbated by anticholinergic agents.

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

Monoamine oxidase inhibitors:

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.

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

Cardiac glycosides: Increased risk of arrhythmias may occur due to formoterol-induced hypokalaemia in patients who are also receiving treatment with cardiac glycosides.

Corticosteroids: Corticosteroids may cause a fall in serum potassium level. Such hypokalaemia can be increased by the concomitant administration of formoterol. Similarly the concomitant administration of formoterol and corticosteroids may increase the hyperglycaemic effect seen with these active substances. The bronchodilator effect of formoterol may be increased by corticosteroids.

Diuretics:

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Hypokalaemia, which may be formoterol-induced, may be increased by simultaneous use of non-potassium-sparing diuretics. The arrhythmogenic potential of such concomitant treatment may be particularly significant in patients with ischaemic heart disease.

Xanthines: An increased hypokalaemic effect can be seen following concomitant use of formoterol and xanthine derivatives such as aminophylline, theophylline etc. The bronchodilator effect of formoterol can be increased by xanthine derivatives.

Other agents: Active substances such as quinidine, disopyramide, procainamide, phenothiazines, antihistamines and tricyclic antidepressants, may be associated with QT interval prolongation and increased risk of ventricular arrhythmias (see section 4.4 Special warnings and precautions for use).

Increase in sympathomimetic effects by L-Ddopa, L-thyroxine, oxytoxin and alcohol may be potentiated by concomitant administration with formoterol. There is an increased risk of arrhythmias and fall in blood pressure in patients treated with formoterol and receiving concomitant anaesthesia with halogenated hydrocarbons.

4.6 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. Clinical experience in pregnant women is limited. During pregnancy, formoterol should until further experience is available, only be used after special consideration, especially during the first three months and shortly before delivery.

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

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4.7 Effects on ability to drive and use machines

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

The occurrence of adverse reactions, such as tremor and nervousness, can affect the ability to drive and use machines.

4.8 Undesirable effects

S ummary 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 days of treatment.

List of adverse reactions Adverse reactions, which have been associated with formoterol, are given below, listed by system organ class and frequency. The frequencies of adverse events are ranked according to the following: very common ( 1/10), common ( 1/100 to < 1/10), uncommon ( 1/1,000 to < 1/100), rare ( 1/10,000 to < 1/1,000), very rare (< 1/10,000; including isolated reports), not known (cannot be estimated from the available data). Up to 10 % of treated patients can expect to experience undesirable effects. The most common undesirable effects are headache, dyspnoea, palpitations and tremor. Tremor and palpitations are often transient and reduce with regular treatment.

Immune disorders Rare (>1/10,000, <1/1,000) Hypersensitivity reactions: e.g. bronchospasm, exanthema, urticaria, pruritus, Ssevere hypotension, angioedema.

Very rare (<1/10,000, including isolated Peripheral oedema reports)

Metabolism and nutrition disorders Rare (>1/10,000, <1/1,000) Hypokalaemia/ hyperkalaemia

Very rare (<1/10,000, including isolated Hyperglycaemia reports) Psychiatric disorders

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Uncommon Agitation, restlessness, sleep disturbances

Nervous system disorders Common (>1/100, <1/10) Headache, Tremortremor Uncommon (>1/1,000, <1/100) Agitation, dizziness, aAnxiety, nervousness, insomnia, restlessness Very rare Taste disturbance, dizziness Formatiert: Schriftart: Nicht Fett Cardiac disorders Common (>1/100, <1/10) Palpitations Uncommon (>1/1,000, <1/100) Tachycardia, QT-prolongation

Rare Cardiac arrhythmias, e.g. atrial fibrillation, supraventricular tachycardia, extrasystoles Very rare (<1/10,000, including isolated Angina pectoris, prolongation of QTc interval reports)

Vascular (extracardiac) disorders Very rare (<1/10,000, including isolated Fluctuating Variations in blood pressure reports)

Respiratory, thoracic and mediastinal disorders Common (>1/100, <1/10) Dyspnoea Uncommon (>1/1,000, <1/100) Aggravated bronchospasm Rare (>1/10,000, <1/1,000) Paradoxical bronchospasm

Gastrointestinal disorders Uncommon (>1/1,000, <1/100) oOropharyngeal irritation Rare (>1/10,000, <1/1,000) Nausea, taste disturbances

S kin and subcutaneous tissue dermatological disorders Rare (>1/10,000, <1/1,000) Urticaria, itch, exanthema.

Musculoskeletal and connective tissue disorders

Uncommon (>1/1,000, <1/100) Muscle cramps, myalgia

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

Treatment with β2-agonists may result in an increaseIncreases in blood levels of insulin, free fatty acids, glycerol and ketone bodies following treatment with beta-2 sympathomimetics have been observed.

The excipient lactose Lactoselactose-monohydrate contains small amounts of milk proteins. and can thereforeThese may cause allergic reactions.

4.9 Overdose

Symptoms: There is limited clinical experience on the management of overdose. An overdose will probablywould likely lead to symptoms effects that are typical of 2-beta-2 agonists.: Nausea, vomiting, tachycardia, tremor, headache, somnolence, palpitations,. ventricular arrhythmias, metabolic acidosis, hypotension, . Symptoms reported from isolated cases are tachycardia, hyperglycaemia, hypokalaemia, prolonged QTc-interval, arrhythmia, nausea and vomiting. hyperglycaemia may occur. Beta-2 agonists may provoke ischaemic heart disease by acute reduction of the diastolic blood pressure or precipitation of heart arrhythmias. Supportive and symptomatic treatment is indicated.

Treatment: Symptomatic. In serious cases, the patient should be admitted to hospital. Use of cardioselective beta-blockers may be considered, but only subject toshould be used with extreme caution since the use of β-adrenergic blocker medication, as they may provoke bronchospasm. Serum potassium should be monitored.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: drugs for obstructive airway diseases, adrenergics, inhalants, selective beta-2-adrenoreceptor agonists, ATC code: R 03 AC 13. Formoterol is a powerful selective beta-2 adrenergic receptor agonist. Formoterol exhibits a bronchodilator effect in patients with reversible and irreversible airways obstruction. The effect sets in quickly (within 1-3 minutes) and is still significant 12 hours after inhalation. With therapeutic doses, the cardiovascular effects are small and appear only occasionally.

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Formoterol inhibits the release of histamine and leukotrienes from passively sensitised human lung. Certain anti-inflammatory properties, such as inhibition of oedema and inflammatory cell accumulation, are observed in experiments with animals.

In humans, formoterol has been shown to be effective in the prevention of bronchospasm induced by inhaled allergens, physical activity, cold air, histamine and metacholine.

In patients with stable chronic obstructive pulmonary disease with a reversible or irreversible component, formoterol inhaled in doses of 12 and 24 micrograms twice daily has proven to have a bronchodilator effect of rapid onset that lasts for at least 12 hours. In addition, the treatment gave rise to a subjective improvement in quality of life evaluated using Saint George’s Respiratory Questionnaire.

5.2. Pharmacokinetic properties

Absorption: As reported for other inhaled active substances, it is likely that about 90 % of formoterol administered from an inhaler will be swallowed and then absorbed from the . 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 radiolabeled 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 active substance. 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

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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 , direct glucuronidation being the major pathway of biotransformation, with O-demethylation followed by further glucuronidation being another pathway. Multiple CYP450 isozymes catalyze the transformation (2D6, 2C19, 2C9, and 2A6) and so consequently the potential for metabolic -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

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and 24 micrograms. As in healthy volunteers, the (R,R) and (S,S)-enantiomers contributed approximately 40 % and 60 % of unchanged active substance 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

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. The effects are known pharmacological manifestations seen after administration of high doses of beta-2 agonists.

Mutagenicity: Mutagenicity experiments have been conducted with a wide range of experimental end- points. No genotoxic effect has been found in any of the in-vitro or in-vivo experiments conducted.

Carcinogenicity: 2-year studies with rats and mice show no carcinogenic potential.

Male mice treated with very high doses of formoterol had a slightly higher incidence of benign adrenal subcapsular cell tumours. This is presumably due to changes in the physiological ageing process.

Two studies with rats, covering two different dose ranges showed an increase in the number of cases of mesovarial leiomyoma. These benign neoplasms were typically associated with prolonged treatment of rats, with high concentrations of beta-2 adrenergic . Similarly, a great number of cases of ovarian cysts and benign granulomas/thecal cell tumours were observed; beta-agonists are known to affect the rat's ovaries, and this is probably specific to rodents. Few other tumour types were observed at higher doses, but they were within the frequency in the historical control population and were not seen in experiments with low doses.

None of the tumour incidences were increased to a statistically significant degree with the lowest dose, a dose that provides 10 times greater systemic exposure than that expected from the maximum recommended dose of formoterol.

On the basis of these findings and the lack of mutagenic potential, it is concluded that formoterol exhibits no carcinogenic risk at therapeutic doses.

Reproductive toxicity: Formatiert: Schriftart: Fett, Nicht Kursiv

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DE/H/1891/001/MR Formoterol 12 microgram, hard capsules DE/H/1892/001/MR with inhalation powder Variation CSP-adoption-highlighted Changes due to Renewal DE/H/1892/001/R/01 shaded in yellow 01.2013

New proposed S ummary of Product Characteristics

Data by experiments with animals – see section 4.6.Experiments with animals have not shown any teratogenic effect. After oral administration, formoterol is secreted in the milk of lactating rats.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Capsule content: Lactose monohydrate (which contains small amounts of milk protein). Capsule Shellshell: Gelatin

6.2 Incompatibilities

Not applicable

6.3 S helf life

2 years

6.4 S pecial precautions for storage

Do not store above 25 °C. Store in the original package.

6.5 Nature and contents of container

PVC + PVDC/Aluminium blister and single dose dry powder inhaler.

Pack sizes: 1 inhaler + 10, 20, 30, 50, 56, 60, 100, 120, 180 or 200 capsules. 2 inhalers + 100 capsules. 4 inhalers + 200 capsules. 50 inhalers + 500 capsules. 50 or 60 capsules without inhaler.

Not all pack sizes may be marketed

6.6 S pecial precautions for disposal

No special requirements.

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DE/H/1891/001/MR Formoterol 12 microgram, hard capsules DE/H/1892/001/MR with inhalation powder Variation CSP-adoption-highlighted Changes due to Renewal DE/H/1892/001/R/01 shaded in yellow 01.2013

New proposed S ummary of Product Characteristics

7. MARKETING AUTHORISATION HOLDER

8. MARKETING AUTHORISATION NUMBER

9. DATE OF FIRS T AUTHORISATION / RENEWAL OF THE AUTHORISATION

10. DATE OF REVISION OF THE TEXT

June 2011January 2013

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