ANNEX I LIST OF THE INVENTED NAMES, PHARMACEUTICAL ...

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ANNEX I

LIST OF THE INVENTED NAMES, PHARMACEUTICAL FORM, STRENGTH OF THE MEDICINAL PRODUCTS, ROUTE OF ADMINISTRATION AND MARKETING

AUTHORISATION HOLDERS IN THE MEMBER STATES

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ATIFOR CHIESI 12 mcg AND ASSOCIATED NAMES WITH MARKETING AUTHORISATION IN THE EUROPEAN UNION Member State (EU/EEA)

Marketing Authorisation Holder

Invented Name Strength Pharmaceutical Form Route of administration

Austria Novartis Pharma GmBH Brunner Strasse 59

A-1235 Wien Austria

FORADIL 12 mcg/actuation Pressurised inhalation, solution Inhalation use

Belgium Chiesi Farmaceutici S.p.A. Via Palermo 26/A, 43100 Parma

Italy

ATIMOS 12 mcg/actuation Pressurised inhalation, solution Inhalation use

Czech Republic Torrex Chiesi Pharma s.r.o. CZ Na Kvetnici 33

CZ-140 00 Praha 4 Czech Republic


Denmark Chiesi Farmaceutici S.p.A. Via Palermo 26/A, 43100 Parma

Italy


Estonia Torrex Chiesi Pharma GmbH Gonzagagasse 16/16

A-1010 Vienna Austria


France Chiesi S.A. Immeuble le Doublon - 11 Avenue

Dubonnet, 92400 Courbevoie

France


Germany Chiesi Farmaceutici S.p.A. Via Palermo 26/A, 43100 Parma

Italy

ATIFOR CHIESI 12 mcg/actuation Pressurised inhalation, solution Inhalation use

Greece Novartis (Hellas) S.A.C.I. 12 klm National Road No 1 Athens-

Lamia – GR 14453 – Metamorphosis Greece

FORADIL 12 mcg/actuation Pressurised inhalation, solution Inhalation use

Hungary Torrex Chiesi Kft. Kristóf tér 4.

1052 Budapest Hungary


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Latvia Torrex Chiesi Pharma GmbH

Gonzagagasse 16/16 A-1010 Vienna

Austria


Lithuania Torrex Chiesi Pharma GmbH Gonzagagasse 16/16

A-1010 Vienna Austria


Poland Torrex Chiesi Polska Sp. z o.o. ul. Biala 3

00-895 Warszawa Poland


Portugal Chiesi Farmaceutici S.p.A. Via Palermo 26/A, 43100 Parma

Italy


Slovakia Torrex Chiesi Slovakia s.r.o. Sulekova 14

811 06 Bratislava Slovak Rep.


Slovenia Torrex Chiesi Slovenija, d.o.o. Trdinova ulica 4

SLO-1000 Ljubljana Slovenia


Spain Chiesi España S.A. Berlín, 38-48 7ª planta

08029 Barcelona Spain

BRONCORAL NEO

12 mcg/actuation Pressurised inhalation, solution Inhalation use

The Netherlands

Chiesi Farmaceutici S.p.A. Via Palermo 26/A, 43100 Parma

Italy


United Kingdom

Trinity-Chiesi Pharmaceuticals Ltd. Cheadle Royal Business Park, Highfield, Cheadle, SK8 3GY

UK

ATIMOS MODULITE

12 mcg/actuation Pressurised inhalation, solution Inhalation use

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ANNEX II

SCIENTIFIC CONCLUSIONS AND GROUNDS FOR AMENDMENT OF THE SUMMARY OF PRODUCT CHARACTERISTICS AND PACKAGE LEAFLET PRESENTED BY THE

EMEA

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SCIENTIFIC CONCLUSIONS OVERALL SUMMARY OF THE SCIENTIFIC EVALUATION OF ATIFOR CHIESI 12 MCG AND ASSOCIATED NAMES (see Annex I) 1. Introduction Formoterol is a potent selective beta2-adrenergic stimulant. It exerts a bronchodilator effect in patients with reversible airways obstruction. Formoterol is indicated as an add-on therapy in patients with moderate to severe asthma requiring regular bronchodilator therapy in combination with long term corticosteroid therapy. The authorised posology for the reference product formoterol DPI (dry powder inhaler) in children aged 5 years and over is 12 micrograms twice daily (b.i.d.). The MAHs submitted a variation application to include use in children of 5 years old and above via the MRP route. Following finalisation of the variation application the UK and the Netherlands considered that the justification of the MAHs on the therapeutic equivalence with the reference product in use in children 5 years old and above, were not satisfactory and initiated the referral procedures. 2. Efficacy issues The supporting studies for the extension of use of Atifor Chiesi (formoterol 12 micrograms pressurised inhalation solutions) and associated names to children of 5 years and older b.i.d. to control asthma symptoms in moderate to severe asthmatic children in ICS (Inhaled corticosteroids) maintenance therapy started in 2004. In the variation application the MAHs have presented two main studies. The description of the studies follows below. • Study CT01/Paed Study CT01/Paed was a double blind, double dummy, active controlled, two-arm, parallel group, multicentre, randomized, non-inferiority phase IIIa 12-week trial. There were 398 patients randomised all with persistent moderate to severe asthma under regular treatment with inhaled corticosteroids. The clinical primary outcome variable was the change from baseline in pre-dose morning peak expiratory flow (PEF) with a pre-specified margin of -15 L/min. The study design of study CT01/Paed was chosen to demonstrate clinical non-inferiority of Chiesi formoterol Hydrofluoroalkane (HFA) versus formoterol DPI, two different formulations containing the long-acting β2-agonists (LABAs) active formoterol for the treatment of patients with asthma. This study enrolled patients who were on current treatment with inhaled corticosteroids at a stable daily dose for at least one month prior to the screening visit and had to be free of inhaled long-acting β2-agonists treatment for at least one month before the screening visit. Effective Comparator: As for the approval of studies in adult asthmatics, Formoterol DPI was used as comparator. This DPI, as other DPI devices, provides equivalent potency and efficacy as the Chlorofluorocarbon propellant (CFC) pressurised metered dose inhaler (pMDI). Dose of the study: The single dose of 12mcg was used. • Study CT02/Paed The second study, CT02/Paed, was designed to demonstrate the value of a spacer device. Study CT02/Paed was a randomised, double blind, double dummy, single dose, placebo controlled, three period crossover phase II equivalence study (5 days washout). Forty patients with persistent moderate to severe asthma were entered and pMDI with AeroChamber PlusR and pMDI without were compared.

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The primary efficacy measure was the rise from pre-dose to the 3 hour post dose forced expiratory volume in the first second (FEV1). This study was again conducted in children on regular ICS over a two-week period. Supplementary Study: PK and Lung Deposition of formoterol DPI compared with formoterol HFA pMDI with and without spacer. This additional study investigated the effect of AeroChamber Plus spacer on lung deposition. The influence of AeroChamber PlusR spacer on Formoterol HFA performance was investigated in vivo using a scintigraphic technique. In this study, lung deposition and pharmacokinetics of Formoterol HFA MDI in comparison to formoterol DPI formulation were assessed in patients with COPD receiving a single dose of 24 mcg of formoterol. Furthermore, the influence of a spacer on Formoterol HFA pMDI performance was investigated.

3. Discussion The CHMP addressed at the start of this Article 36 referral procedure two scientific questions (LoQ) to the MAHs. In the first question the CHMP requested the MAHs to justify the therapeutic equivalence to the reference product in children aged 5 years and older. The CHMP noted that in study CT01/Paed change from baseline to endpoint in pre-dose morning PEF was below 15 L/min for formoterol-HFA. Considering the fact that only one dose of formoterol was studied and not much improvement was seen, this study lacked sensitivity. The MAHs presented that the 11.8 L/min and 14.9 L/min LSM increase in morning PEF on active treatments, and the large confidence interval for testing for non-inferiority was achieved; These justify their position on the CHMP concern against the low level of response in the patient’s lung function results with the treatments. Additionally the MAHs argued that the -15 L/min as non-inferiority limit for PEF was already accepted for a different application of HFA pMDI and this was supported by the data in the scientific literature. This limit was attained by the study CT01/Paed according to the MAHs. Therefore, the value in study CT01/Paed of -10.36 L/min, is much narrower than -15 L/min originally chosen and for which the study was powered. Furthermore, both the test treatment and the active control had increases from baseline greater than the observed lower limit for the 95% CI of the adjusted LS means (11.8 and 14.9 L/min for formoterol HFA and the reference product, respectively). The consistency of these results led the MAHs to conclude that formoterol HFA is non inferior to formoterol DPI. Furthermore the MAHs also argued that they achieved non-inferiority for the secondary measurement of the pre-treatment FEV1. With view to support the question on the single dose choice the MAHs presented the following additional arguments. Doses of 6mcg, 12 mcg, and 24 mcg of formoterol produce equivalent speed of onset and duration of bronchodilation without systemic side effects with a wide range of inhalation delivery devices. According to the MAHs the use of multiple doses of HFA formoterol would not have enhanced the assay sensitivity. Therefore, the MAHs believed that a potential small variability in the efficacy of 12 mcg b.i.d. HFA pMDI should not pose any risk, as the reference product is currently authorised in this dose, which in return justified the use of this dose only. In conclusion the MAHs reasoning to the first question of the CHMP was that the limits set for non-inferiority with both PEF and FEV1 were both precedent in earlier regulatory approval for HFA pMDI and also achieved in the MAH’s study. Furthermore the size of the rises in lung function was significant from a clinical perspective as they were associated with a marked improvement of symptoms. The MAHs stressed that LABAs are essentially used to enhance symptom control in patients already on maintenance ICS and that this was demonstrated in this study. The CHMP assessment of the responses to the first question concluded that the MAHs did not provide any new information or arguments. Change from baseline to endpoint in pre-dose morning PEF was below 15 L/min for formoterol-HFA. Furthermore, this study only evaluated one dose of test and

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reference product and due to the flat dose response curve of formoterol the assay sensitivity of this study is still questioned. It remained possible that the test formulation was more or less potent than the reference product and therefore evidence of therapeutic equivalence has not been provided. The CHMP noted that there are possible scientific ways to provide additional information on the sensitivity but that will entail additional studies from the side of the MAHs. In the second question the CHMP requested the MAHs to comment on the argument that for the CT02/Paed change in FEV1 from pre-dose to 3 hours post-dose was used as a primary endpoint which was not considered appropriate. No differences between the group using the spacer and the group not using the spacer was seen and it remained possible that the differences between the groups would have been seen if FEV1 had been measured to 12 hours instead of 3 hours. The CHMP expressed the concern that the patients did not have a long enough period of observation to demonstrate equivalent long duration; the relevance of having at least 8 hour of observation and determination of no difference in AUC was expressed by the Committee. The MAHs response to the second concern of the CHMP was on the basis of extensive literature reporting on the fixed relationship between the early bronchodilator responses to formoterol delivered by a variety of inhalation devices and the 12 hour value of FEV1. The MAHs added that it was unlikely that having achieved an equivalent rise in FEV1 at 3 hours the medicinal product would behave differently from earlier studies reported in the literature with a wide range of inhalation devices. In summary, according to the MAHs’ estimates of the 3 and 12 hour FEV1 values, the ratio between 3 hour and 12 hour values was remarkably constant irrespectively of the device and the age. This indicated that the device,age and disease did not influence the relationship between the pharmacodynamic effect of formoterol at 3 hour and that at 12 hour. Thus the MAHs concluded on the second question of the CHMP that the objection to the primary outcome measurement in CT02/Paed was unjustified as it implied that formoterol HFA pMDI would behave differently than all the other multiple DPIs and CFC HFA pMDIs. Further to these responses of the MAHs to the initial LoQ, the CHMP was not in agreement regarding the justifications provided and in its meeting in October 2008, a List of Outstanding Issues (LoOI) was adopted to further give the opportunity to the MAHs to support their application. The CHMP invited the MAHs to respond to the LoOI in writing and in an oral presentation to the committee in the November 2008 CHMP meeting. The MAHs responded to the LoOI questions in an Oral Explanation on 18 November 2008. The MAHs responses did not give additional clarification or justification on the issues. In November 2008 the CHMP has referred the issue to an ad hoc Expert group meeting asking the views on the acceptability of the clinical studies submitted for this procedure. In conclusion the Expert Group did not support the design and the outcome of both studies as submitted by the MAH. The Group was of the opinion that another study is needed to demonstrate therapeutic equivalence between formaterol HFA modulite 12mcg and the reference product.

Following the views of the ad hoc Expert Group meeting the CHMP concluded that the use of Atifof Chiesi 12 mcg in children less than 12 years of age is not recommended.

4. Benefit/risk

Taking all these elements into account, the CHMP concluded that the benefit/risk ratio for Atifor Chiesi 12 mcg (Formoterol HFA 12mcg) is unfavourable for use in children less than 12 years of age and recommended the variation of the Marketing Authorisation(s) in accordance to the amendments of the Summary of Product Characteristics, Labelling and Package Leaflet (see Annex III) for the medicinal product(s) referred to in Annex I.

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GROUNDS FOR AMENDMENT OF THE SUMMARY OF PRODUCT CHARACTERISTICS AND PACKAGE LEAFLET Whereas The CHMP considered the referral triggered by the UK and The Netherlands in relation to the use of formoterol HFA 12 mcg in children less than 12 years of age. - The CHMP concluded that therapeutic equivalence of formoterol HFA 12 mcg modulite with

the reference product for the use in children less than 12 years of age has not been established.

The CHMP noted that

a. The 12 week study failed to demonstrate assay sensitivity. Only one dose of the test was evaluated. It is considered that two dose levels should be studied in order to demonstrate assay sensitivity of a therapeutic equivalence study in LABAs.

b. the 3 hour FEV1 endpoint used in study CT02/Paed is not considered optimal and 12

hours should have been used instead. - the delivery of medicinal products for asthma through a MDI without a spacer device is

inappropriate in children under the age of 12. So it is inappropriate to consider the pharmacological action of an inhaled therapy for asthma without considering that medicinal product in the context of the delivery method used. In both of the presented trials, different delivery methods were used for the formoterol-HFA and the reference product.

In view of the above the CHMP concluded that given the lack of robustness of the 12 week study, the issues with the single dose study and the absence of any pharmacokinetic data in the study population, on the equivalence on safety and efficacy of Atifor Chiesi 12mcg with the reference product is lacking. Consequently the Summary of Product Characteristics, Labelling and the Package Leaflet of Atifor Chiesi 12mcg and associated names should not include the use in children less than 12 years of age. The CHMP has recommended the variation of the Marketing Authorisation(s) in accordance with the Summary of Product Characteristics, Labelling and the Package Leaflet set out in Annex III for Atifor Chiesi 12mcg and associated names (see Annex I).

ANNEX III

SUMMARY OF PRODUCT CHARACTERISTICS, LABELLING AND PACKAGE LEAFLET

SUMMARY OF PRODUCT CHARACTERISTICS

SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT {(Invented) name} 12 micrograms/actuation pressurised inhalation solution

2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each metered dose contains 12 micrograms of formoterol fumarate dihydrate. This corresponds

to a delivered dose of 10.1 micrograms. For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM Pressurised inhalation solution.

4. CLINICAL PARTICULARS

4.1 THERAPEUTIC INDICATIONS For the long-term symptomatic treatment of persistent, moderate to severe asthma in patients

requiring regular bronchodilator therapy in combination with long-term antiinflammatory therapy (inhaled and/or oral glucocorticoids).

Glucocorticoid therapy should be continued on a regular basis. {(Invented) name} is indicated for the relief of broncho-obstructive symptoms in patients with

chronic obstructive pulmonary disease (COPD).

4.2 POSOLOGY AND METHOD OF ADMINISTRATION 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 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 formoterol fumarate dihydrate).

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 (see section 6.4). Although {(Invented) name} has a rapid onset of action, long-acting inhaled bronchodilators

should be used for maintenance bronchodilator therapy. {(Invented) name} 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 {(Invented) name}

is introduced. If the symptoms persist or worsen, or if the recommended dose of {(Invented) name} fails to

control symptoms (maintain effective relief), this is usually an indication of a worsening of the underlying condition

Renal and hepatic impairment There is no theoretical reason to suggest that {(Invented) name} 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, keep the inhaler in vertical position for about half minute, then repeat step 2 to 5.

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 will be held with both index fingers and its lower part 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 with {(Invented) name} with spacers.

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

4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE {(Invented) name} should be used strictly in accordance with the dosage recommendations (see

section 4.2). If there is no satisfactory improvement or even a deterioration of the disease despite the prescribed therapy, a consultation of the physician will be necessary to modify the therapeutic program, if appropriate by adding additional medicinal products. 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.

Until extensive experience is available, {(Invented) name} should not be used in children. Concomitant conditions {(Invented) name} should only be used with caution and under strict conditions of indication in

patients with third degree atrioventricular block, idiopathic subvalvular aortic stenosis, hypertrophic obstructive cardiomyopathy, QT-interval prolongation, e.g. congenital or drug-induced (QTc > 0.44 seconds), thyrotoxicosis, severe heart disease, especially acute myocardial infarction, coronary heart disease, congestive heart failure, occlusive vascular diseases, especially arteriosclerosis, arterial hypertension and aneurysm, hyperthyreosis, refractory diabetes mellitus, pheochromocytoma.

{(Invented) name} may only be used with special precautions (e.g. monitoring) in patients with tachycardic arrhythmia (accelerated and/or irregular heart beat). The inhalation of high doses of formoterol may cause a rise in blood sugar levels. This parameter should therefore be closely monitored in diabetics. If anaesthesia with halogenated anaesthetics is planned, it should be ensured that {(Invented) name} is not administered for at least 12 hours before the start of anaesthesia.

Paradoxical bronchospasm As with every inhalation therapy, paradoxical bronchospasm can occur in rare cases. In such cases the medicinal product should be discontinued immediately and the therapeutic program should be modified by the physician. Hypokaelemia There is evidence that under formoterol therapy the decrease of blood potassium levels is higher than during treatment with short acting β2-sympathomimetics (e.g. salbutamol) 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. The hypokaelemia may be particularly distinctive in patients with severe asthma receiving concomitant treatment with theophylline, glucocorticoids and/or diuretics. Due to decreased serum potassium levels the effect of digitalis containing medicinal products is enhanced. As the risk related to hypokaelemia is potentiated by hypoxia care should be taken in patients with acute severe asthma

4.5 INTERACTIONS WITH OTHER MEDICINAL PRODUCTS AND OTHER FORMS OF INTERACTION 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 4.3).

Concomitant administration of other sympathomimetic agents may potentiate the undesirable effects of {(Invented) name}.

The simultaneous use of formoterol and theophylline can result in mutual potentiation of effects, and there is also the likelihood of increased undesirable effects such as cardiac dysrhythmia. Compounds which themselves potentiate sympathomimetic effects, such as L-

dopa, L-thyroxine, oxytocin or alcohol, can also affect cardiovascular regulation when taken at the same time as formoterol.

Administration of {(Invented) name} to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants should be performed with caution, since the action of β2-adrenergic stimulants on the cardiovascular system may be potentiated.

Concomitant treatment with xanthine derivatives, steroids, or diuretics may potentiate a possible hypokalaemic effect of β2-agonists. Hypokalaemia may increase susceptibility to cardiac arrhythmias in patients treated with digitalis (see section 4.4).

β-adrenergic blockers may weaken or antagonise the effect of {(Invented) name}. Therefore {(Invented) name} should not be given together with β-adrenergic blockers (including eye drops) unless there are compelling reasons for their use.

4.6 PREGNANCY AND LACTATION Insufficient experience is presently available with the use of formoterol during human

pregnancy. Although no embryotoxic or teratogenic effects were detected in animal studies, the use of formoterol during pregnancy, especially during the first 3 months, is only indicated if absolutely necessary.

The known tocolytic action of β2-sympathomimetic agents of the type contained in {(Invented) name} requires a close benefit-risk assessment before using this medicinal product shortly before delivery.

While it is not known whether formoterol passes into human breast milk, it has been detected in the milk of lactating animals. Mothers using formoterol should therefore refrain from breast feeding their infants.

4.7 EFFECTS ON ABILITY TO DRIVE AND USE MACHINES {(Invented) name} is unlikely to have any effect on the ability to drive and operate machinery.

4.8 UNDESIRABLE EFFECTS The frequency of Adverse Reactions has been classified as follows: Common (>1/100, <1/10),

Uncommon (>1/1000, <1/100) Rare (>1/10000, <1/1000), Very rare (<1/10000) including isolated reports.

BLOOD AND LYMPHATIC SYSTEM DISORDERS Very rare, including isolated reports: thrombopenia

CARDIAC DISORDERS Common: palpitations

Uncommon: tachycardia, tachyarrhythmia Rare: ventricular extrasystoles, angina pectoris Very rare including isolated reports: atrial fibrillation

GASTROINTESTINAL DISORDERS Uncommon : nausea, dysgeusia

GENERAL DISORDERS AND ADMNISTRATION SITE CONDITIONS Very rare including isolated reports:oedema peripheral

IMMUNE SYSTEM DISORDERS Rare: angioneurotic oedema

INVESTIGATIONS Uncommon: blood insulin increased, free fatty acids increased, blood ketone body increased Rare: blood pressure increased, blood pressure decreased.

METABOLISM AND NUTRITION DISORDERS Uncommon: hypokalaemia, hyperglycaemia

MUSCULOSKELETAL AND CONNETTIVE TISSUE DISORDERS Uncommon: muscle cramps, myalgia

NERVOUS SYSTEM DISORDERS Common: tremor, headache Uncommon: restlessness, dizziness Very rare, including isolated reports: CNS stimulating effects have been sporadically reported following inhalation of β2-sympathomimetics, manifesting as hyperexcitability. These effects were mainly observed in children up to 12 years of age.

PSYCHIATRIC DISORDERS: Very rare including isolated reports: abnormal behaviour, sleep disorders, hallucinations

RENAL AND URINARY DISORDERS Rare: Nephritis

RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS Common: cough Uncommon: throat irritation Rare: bronchospasm paradoxical Very rare including isolated reports: dyspnea, exacerbation of asthma

SKIN AND SUBCUTANEOUS TISSUE DISORDERS Uncommon: pruritus, exanthem, hyperidrosis Rare: urticaria Tremor, nausea, dysgeusia, throat irritation, hyperidrosis, restlessness, headache, dizziness and muscle cramps may resolve spontaneously within one to two weeks of continued treatment.

4.9 OVERDOSE There is no clinical experience to date on the management of overdose, however, an overdosage

of /{(Invented) name} 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

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.

5. PHARMACOLOGICAL PROPERTIES

5.1 PHARMACODYNAMIC PROPERTIES Pharmacotherapeutic group: Adrenergics, inhalants; selective β2-adrenoreceptor agonists ATC-code: R03 AC13 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 methacoline challenge.

5.2 PHARMACOKINETIC PROPERTIES 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 {(Invented) name} 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 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 20-300 micrograms (oral administration). Repeated daily administration of 40-160 micrograms/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 feces. Following inhalation of formoterol, a mean of 6 to 9% of the substance is eliminated unchanged with the urine. Renal clearance of formoterol is 150 ml/min.

5.3 PRECLINICAL SAFETY DATA 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 loocked upon as a class effect in rodents after long exposure to high doses of β2-agonists.

6. PHARMACEUTICAL PARTICULARS

6.1 LIST OF EXCIPIENTS Norflurane Ethanol anhydrous Hydrochloric acid.

6.2 INCOMPATIBILITIES Not applicable.

6.3 SHELF LIFE 18 months (see also section 6.4).

6.4 SPECIAL PRECAUTIONS FOR STORAGE Prior to dispensing to the patient: Store in a refrigerator at 2-8°C (for a maximum of 15 months). After dispensing: Do not store above 30°C (for a maximum of 3 months).

6.5 NATURE AND CONTENTS OF CONTAINER 1 pressurised aluminium container fitted with a metering valve, actuator and protective cap,

containing a pressurised inhalation solution. Each container provides 50, 100 or 120 actuations.

6.6 SPECIAL PRECAUTIONS FOR DISPOSAL AND OTHER HANDLING 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.

7. MARKETING AUTHORISATION HOLDER <[To be completed nationally]> <[See Annex I - To be completed nationally]> [For referral procedures] {Name and address} <{tel}> <{fax}> <{e-mail}>

8. MARKETING AUTHORISATION NUMBER <[To be completed nationally]>

9. DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION <{DD/MM/YYYY}> <{DD month YYYY}> <[To be completed nationally]>

10. DATE OF REVISION OF THE TEXT <{MM/YYYY}> <[To be completed nationally]>

LABELLING

Proposed wording for inner packaging (internal label):

1. Name of the medicinal product and route of administration {(Invented) name} 12 micrograms/actuation pressurised inhalation solution Formoterol fumarate dihydrate Each metered (ex-valve) actuation contains: formoterol fumarate dihydrate 12 micrograms List of excipients: anhydrous ethanol, hydrochloric acid, norflurane (HFA 134a) Pressurised inhalation solution of 50 actuations 100 actuations 120 actuations For inhalation use.

2. Name of the marketing authorisation holder ………………………. 3. Marketing authorisation number MA No……….

4. Expiry date Expiry date:……./……/……

5. Batch number Batch No Date of manufacture: 6. Other Prescription-only medicine Do not use your inhaler after three months from the dispensing date entered by your pharmacist on the label. Do not store above 30°C. The canister contains a pressurised liquid. Do not expose to temperature higher than 50°C Do not pierce the canister. Keep out of the reach and sight of children

Proposed wording for outer packaging (folding box): 3. Name of the medicinal product {(Invented) name} 12 micrograms/actuation pressurised inhalation solution Formoterol fumarate dihydrate 2. Statement of active substance Each metered (ex-valve) actuation contains: formoterol fumarate dihydrate 12 micrograms 3. List of excipients List of excipients: anhydrous ethanol, hydrochloric acid, norflurane (HFA 134a) 4. Pharmaceutical form and contents Pressurised inhalation solution 50 actuations 100 actuations 120 actuations 5. Method and route of administration For inhalation use. Please read the enclosed Patient Information Leaflet carefully before use. 6. Special warning that the medicinal product must be stored out of the reach and sight of children Keep out of the reach and sight of children 7. Other special warnings, if necessary Use regularly and only as directed by your doctor. Do not stop taking this medicine unless advised to do so by your doctor. Do not exceed the recommended dose. 8. Expiry date Expiry date:……./……/…… 9. Special storage conditions Prior to dispensing, store at 2°C to 8°C (for a maximum of 15 months from the date of manufacture)

Enter the date of dispensing to the patient on the sticky label 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. Space for the adhesive label:

Dispensing date ........../.................../......... For patients: Do not use your inhaler after 3 months from the dispensing date entered by your pharmacist on the label. After dispensing, do not store above 30°C The canister contains a pressurised liquid. Do not expose to temperatures higher than 50°C Do not pierce the canister. 10. Special precautions for disposal of unused medicinal products or waste materials derived from such medicinal products if appropriate 11. Name and address of the Marketing authorisation holder ………………… 12. Marketing authorisation number MA-No. 13. Batch number Batch No Date of manufacture: 14. General classification for supply

Prescription-only

PACKAGE LEAFLET

PACKAGE LEAFLET: INFORMATION FOR THE USER {(Invented) name} 12 micrograms/actuation pressurised inhalation solution

Formoterol fumarate dihydrate

Read all of this leaflet carefully before you start using this medicine. − Keep this leaflet. You may need to read it again. − If you have any further questions, ask your doctor, or pharmacist. − This medicine has been prescribed for you. Do not pass it on to others. It may harm them even if

their symptoms are the same as yours. − If any of the side effects become serious, or if you notice any side effects not listed in this leaflet,

please tell your doctor or pharmacist.

In this leaflet: 1. What is {(Invented) name} and what it is used for 2. Before you use {(Invented) name} 3. How to use {(Invented) name} 4. Possible side effects 5. How to store {(Invented) name} 6. Further information

1. What is {(Invented) name} and what is used for?

{(Invented) name} is an inhalation medicine delivering its active ingredient directly into your lungs where it is needed. It is used to treat the symptoms of wheezing and breathlessness in patients with moderate to severe asthma. Its active ingredient, formoterol fumarate, belongs to a group of medicines called bronchodilators: they make breathing easier by relaxing muscle spasms in the air passages of the lungs. Regular use of {(Invented) name} together with steroids (either by inhaler or by mouth), will help to prevent breathing problems over the long term. {(Invented) name} can also be used for the relief of symptoms such as cough, wheezing and shortness of breath in patients with chronic obstructive pulmonary disease (COPD) who require long-term regular bronchodilator therapy.

2. Before you use {(Invented) name}

Do not use {(Invented) name}:

• if you are allergic to formoterol or to any of the ingredients of {(Invented) name}

• to treat a sudden attack of breathlessness. It will not help. Use a reliever for this purpose and carry it with you at all times.

Take special care with {(Invented) name} and always inform your doctor if you:

• suffer from severe heart disease, especially a recent heart attack, a disease of the coronary vessels of the heart or severe weakness of the heart muscle (congestive heart failure)

• suffer from disorders of heart rhythm such as increased heart rate, heart valve defect or certain electrocardiogram abnormalities or any other heart disease

• have narrowing of the blood vessels, especially the arteries, or abnormal widening of the vessel wall

• suffer from high blood pressure

• have high sugar levels in the blood (diabetes mellitus)

• have low blood potassium levels

• have an overactive thyroid gland

• are suffering from epinephrine and nor-epinephrine producing tumours of the adrenal medulla.

• are going to have any surgery or receive halogenated anaesthetics Taking other medicines: Tell your doctor if you are taking or have recently taken any other medicines including medicines obtained without prescription. Some medicines may interfere with the action of {(Invented) name}, these include medicines:

for treating abnormal heart rhythms (for example quinidine, disopyramide, procainamide) for treating heart disease (for example digitalis) for treating nasal congestion ( for example ephedrine) called beta adrenergic blockers used to treat heart conditions or glaucoma (an increase of the

pressure in the eye), as tablets or eye drops for treating symptoms of depression: monoamine oxidase inhibitors (for example phenelzine and

isocarboxazid ) or tricyclic antidepressants (for example amitryptiline and imipramine ) to treat severe mental disorders (for example chloropromazine and trifluperazine) used to treat allergic reactions,( such as anti-histamines) used to treat bronchial asthma (for example theophylline, aminophylline or steroids) used to increase urine production (such as diuretics) for treating Parkinsonism (for example Levodopa) containing oxytocin, which causes uterus contraction. to treat an underactive thyroid gland (for example Thyroxine)

Other special warnings • You have also been prescribed corticosteroids for your breathing problems. It is very important to

keep using these regularly. Do not stop using them or change the dose when you start using {(Invented) name}.

Pregnancy and breast feeding If you are pregnant or breast feeding or could become pregnant, talk to your doctor before using {(Invented) name} The use of {(Invented) name} during pregnancy, especially during the first 3 months, is only indicated if absolutely necessary. Breast feeding is not recommended whilst using {(Invented) name}. Driving and using machines {(Invented) name} is unlikely to have any effect on the ability to drive and operate machinery. Important information about some of the ingredients of {(Invented) name} {(Invented) name} contains a small amount of alcohol: each puff of your inhaler contains about 9 mg of ethanol.

3. How to use {(Invented) name} Dosage

Asthma The dose of {(Invented) name} you must inhale will depend on the type of asthma you have and how severe it is.

Your dose will be decided by your doctor and it is important that you only take the prescribed dose, regularly.

The usual dose for adults including the elderly and adolescents 12 years and older is 1 puff in the morning and 1 puff in the evening. This means you need to take a total of 2 puffs (24 micrograms) of {(Invented) name} per day.

If you suffer for more severe asthma your doctor may prescribe 4 puffs per day (48 micrograms) 2 puffs in the morning and 2 puffs in the evening.. (4 puffs) 48 micrograms of {(Invented) name} is the maximum daily dose and it is important that you do not take more than the total daily dose that your doctor has told you to take . This product is not suitable for asthmatic children under 12 years old. For Chronic Obstructive Pulmonary Disease COPD The usual dose for adults (18 years and older) including the elderly is 1 puff in the morning and 1 puff in the evening . This means you need to take a total of 2 puffs (24 micrograms) of {(Invented) name} per day. If you suffer from more severe COPD your doctor may prescribe 4 puffs per day (48 micrograms), 2 puffs in the morning and 2 puffs in the evening.. (4 puffs) 48 micrograms of {(Invented) name} is the maximum daily dose and it is important that you do not take more than the total daily dose that your doctor has told you to take. Do not take more than 2 puffs at any one time. This product is not suitable for COPD patients under 18 years old. Do not use {(Invented) name} to treat a sudden attack of breathlessness. You should use a “reliever” inhaler prescribed by your doctor for this purpose, carry this medicine with you at all times. If you use more {(Invented) name} than you should: You may notice that your heart is beating faster than usual and that you feel shaky. You may also have a headache, tremor, feeling and being sick (nausea and vomiting) or feel sleepy. Contact your doctor as soon as possible for advice.

If you forget to use {(Invented) name}: If you forget to use {(Invented) name}, take it as soon as you remember. If it is almost time for your next dose, do not take the dose you have missed, just take the next dose at the usual time. Do not double the dose.

Do not stop or reduce the dose of {(Invented) name} or any other medicine for your breathing just because you feel better, without talking to your doctor first. It is very important to use these medicines regularly.

Do not increase your dose of {(Invented) name} without talking to your doctor first. If your asthma seems to be getting increasingly worse, perhaps you are more wheezy and short of breath than usual, or you do not seem to be getting better, tell your doctor immediately. The doctor may decide to change the dose of medicines or may wish to change your treatment by prescribing other medicines for you.

Instructions for use It is important that you know how to use your inhaler properly. Your doctor, nurse or pharmacist will show you how to use your inhaler correctly. You must follow their instructions carefully so that you know how, when and how many puffs to inhale. The correct instructions are given in this leaflet. If you are not sure what to do or have problems in inhaling then ask your doctor, nurse or pharmacist for advice. Testing your inhaler. If your inhaler is new or if it has not been used for 3 days or more, one puff should be released into the air before using it, to make sure that it works. You should be stand or sitting in upright position when using the inhaler.

1. Remove the mouthpiece cover from the inhaler and hold it between the thumb and forefinger as shown.

2. Breathe out as far as is comfortable. 3. Hold the inhaler upright as shown with your thumb on the base below the mouthpiece; place

the mouthpiece in your mouth between your teeth and close tightly your lips around it. 4. Breathe in deeply through your mouth and at the same time press down on the top of the

inhaler to release a puff.

5. Hold your breath as long as is comfortable, then take the inhaler from your mouth.

6. If you are to take another puff, keep the inhaler upright and wait about half a minute before

repeating steps 2 to 5. 7. After use always replace the mouthpiece cover to keep out dust and fluff. Replace firmly and

snap into position.

IMPORTANT Do not rush steps 2, 3, 4 and 5.

It is important that you start to breathe in as slowly as possible just before operating the inhaler.

If you see 'mist' coming from the top of the inhaler or the sides of your mouth, {(Invented) name} will not get into your lungs as it should. Take another puff carefully following the instructions from Step 2 onwards.

If you have weak hands it may be easier to hold the inhaler with both hands. Put the two forefingers on top of the inhaler and both thumbs on the bottom below the mouthpiece.

Tell your doctor, nurse or pharmacist if you have any difficulties.

Cleaning It is important to clean your inhaler regularly, at least once or twice a week to ensure that it works properly.

1 2-3 4

• Pull the metal canister out of the plastic case of the inhaler and remove the mouthpiece cover.

• Rinse the plastic case and the mouthpiece cover in warm water.

• Do not put the metal canister into water.

• Leave to dry thoroughly in a warm place. Avoid excessive heat.

• Replace the canister and mouthpiece cover.

If you have any further questions on the use of this product, ask your doctor or pharmacist. 4. Possible side effects

Like all medicines {(Invented) name} can cause side effects although not every body gets them. Possible side effects are listed below according to their frequency. If you are not sure what the side effects below are, ask your doctor to explain them to you.

If your breathing or wheezing gets worse after using your inhaler tell your doctor immediately. This is caused by narrowing of the airways in your lungs but it occurs only rarely.

Common side effects which may affect up to 1 in 10 people: unusually fast heart beat and palpitations, cough, trembling (fine tremor), headache

Uncommon side effects which may affect fewer than 1 in 100 people are: muscles cramps, pain in muscles, nausea, restlessness, dizziness, abnormal or impaired sense of taste, throat irritation, abnormal rapid heart beat, disorders of heart rhythm with increase heart rate, abnormal low levels of potassium in the blood, increase in blood sugar levels, increase in the blood level of insulin, free fatty acids, glycerol and ketones, skin itching, skin rash, excessive sweating.

Rare side effects which may affect fewer than 1 in 1,000 people are: missed heartbeats caused by too early contraction of the ventricles of the heart, feeling chest tightness, increase or decrease in blood pressure, wheezing immediately after using the inhaler, severe fall in blood pressure, swelling of skin and mucous membrane persisting for several days, nettle rash or hives, inflammation of the kidneys.

Very rare side effects which may affect fewer than 1 in 10,000 people are: worsening of asthma, difficulty breathing, swelling of the hands and/or feet, irregular heartbeat, reduced number of blood platelets, hyperexcitability (mainly in children below 12 years), abnormal behaviour, sleep disorders and hallucinations.

Some side effects, such as tremor, nausea, disgeusia, throat irritation, hyperhidosis, restlessness, headache, dizziness and muscle cramps, may ease during the course of one to two weeks of continued use of your asthma medication. If you experience any of the side effects and it causes you distress, is severe or lasts several days, or if you feel unwell or notice anything unusual or a side effect which is not mentioned in this leaflet, you should contact your doctor or pharmacist immediately.

5. How to store {(Invented) name}

• Keep out of the reach and sight of children.

• Do not use beyond three months from the date you get the inhaler from your pharmacist and never use after the expiry date which is stated on the carton and label. The expiry date refers to the last day of that month.

• Do not store the inhaler above 30oC.

• If the inhaler gets very cold, take the metal canister out of the plastic case and warm it in your hands for a few minutes before use. Never use anything else to warm it up.

• Warning. The canister contains a pressurised liquid. Do not expose to temperatures higher than 50°C. Do not pierce the canister.

• Medicines should not be disposed of via waste water or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measure will help to protect the environment.

6. Further information

What {(Invented) name} contains:

The active substance of {(Invented) name} is formoterol fumarate dihydrate. Each metered actuation provides 12 micrograms of formoterol fumarate dihydrate. This corresponds to a delivered dose of 10.1 micrograms.

The other ingredients are: hydrochloric acid, ethanol and norflurane (HFA 134a).

What {(Invented) name} looks like and content of the pack:

{(Invented) name} is a pressurised inhalation solution contained in a aluminium can with plastic actuator and protective cap.

Each pack contains 1 inhaler which provides 50, 100 or 120 puffs.

Marketing Authorisation Holder:

Chiesi Farmaceutici S.p.A., Via Palermo 26/A, 43100 Parma, Italy Manufacturer: Chiesi Farmaceutici S.p.A., Via Palermo 26/A, 43100 Parma, Italy

This medicinal product has been authorised in the member states of the EEA under the following tradenames:

Austria FORADIL

France ATIMOS

Germany ATIFOR CHIESI

Greece FORADIL

Denmark ATIMOS

Spain BRONCORAL NEO

Belgium ATIMOS

Holland ATIMOS

UK ATIMOS MODULITE

Czech Republic ATIMOS

Slovak Republic ATIMOS

Hungary ATIMOS

Portugal ATIMOS

Slovenia ATIMOS

Poland ATIMOS

Estonia ATIMOS

Latvia ATIMOS

Lithuania ATIMOS

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