Atimos Modulite 12 micrograms/actuation pressurised inhalation solution

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

Pressurised inhalation solution

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

Glucocorticoid therapy should be continued on a regular basis.

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

The dosage depends on the type and severity of disease.

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

Asthma

Adults and adolescents aged 12 years and above:

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

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

Children younger than 12 years of age:

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

Chronic Obstructive Pulmonary Disease (COPD)

Adults (aged 18 years and above)

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

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

Patients should not use the inhaler beyond three months from the date of dispensing by the pharmacist (see section 6.4).

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

Atimos Modulite is not intended to relieve acute asthma attacks.

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

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

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

Renal or hepatic impairment

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

Instructions for Use

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

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

1. Remove the protecting cap from the mouthpiece.

2. Breathe out as deeply as possible.

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

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

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

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

After use, the mouthpiece should be closed with the protecting cap.

IMPORTANT: Steps 2 to 4 should not be performed too quickly.

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

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

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

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

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

Although Atimos may be introduced as add-on therapy when inhaled corticosteroids do not provide adequate control of asthma symptoms, patients should not be initiated on Atimos 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 Atimos. Patients should be asked to continue treatment but to seek medical advice if asthma symptoms remain uncontrolled or worsen after initiation of Atimos.

Atimos Modulite should be used strictly in accordance with the dosage recommendations (see section 4.2). Once asthma symptoms are controlled, consideration may be given to gradually reducing the dose of Atimos. Regular review of patients as treatment is stepped down is important. The lowest effective dose of Atimos should be used.

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

Concomitant conditions

Atimos Modulite 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, eg. 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, phaeochromocytoma.

Atimos Modulite may only be used with special precautions (eg. 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 Atimos Modulite 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.

Hypokalaemia

There is evidence that under formoterol therapy the decrease of blood potassium levels is higher than during treatment with short acting β₂-sympathomimetics (eg. 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 hypokalaemia 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 hypokalaemia is potentiated by hypoxia care should be taken in patients with acute severe asthma.

Drugs such as quinidine, disopyramide, procainamide, phenothiazines, antihistamines and tricyclic antidepressants may be associated both with QT-interval prolongations and an increased risk of ventricular arrhythmia (see section 4.3).

Concomitant administration of other sympathomimetic agents may potentiate the undesirable effects of Atimos Modulite.

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 Atimos Modulite 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 Atimos Modulite. Therefore, Atimos Modulite should not be given together with β-adrenergic blockers (including eye drops) unless there are compelling reasons for their use.

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 Atimos Modulite 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.

Atimos Modulite is unlikely to have any effect on the ability to drive and operate machinery.

The frequency of Adverse Reactions has been classified as follows:

Common ( 1/100 < 1/10 )

Uncommon ( 1/1,000 < 1/100 )

Rare ( 1/10,000 < 1/1,000 )

Very rare ( < 1/10,000 )

Blood and lymphatic system disorders

Very rare: thrombopenia

Metabolism and nutrition disorders

Uncommon: hypokalaemia, hyperglycaemia

Psychiatric disorders

Uncommon: restlessness

Very rare: abnormal behaviour, sleep disorders, hallucinations

Nervous system disorders

Common: tremor, headache

Uncommon: dizziness, dysgeusia

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.

Cardiac disorders

Common: palpitations

Uncommon: tachycardia, tachyarrhythmia

Rare: ventricular extrasystoles, angina pectoris

Very rare: atrial fibrillation

Respiratory, Thoracic and Mediastinal Disorders

Common: cough

Uncommon: throat irritation

Rare: bronchospasm paradoxical

Very rare: dyspnoea, exacerbation of asthma

Gastrointestinal disorders

Uncommon: nausea

Skin and Subcutaneous tissue disorders

Uncommon: pruritus, rash, hyperhidrosis

Rare: urticaria, angioedema

Musculoskeletal and connective tissue disorders

Uncommon: muscle cramps, myalgia

Renal and urinary disorders

Rare: Nephritis

General disorders and administration site conditions

Very rares: oedema peripheral

Investigations

Uncommon: blood insulin increased, free fatty acids increased, blood ketone body increased

Rare: blood pressure increased, blood pressure decreased

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

There is no clinical experience to date on the management of overdose, however, an overdosage of Atimos Modulite 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.

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

ATC code: R03A C13

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

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

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 Atimos Modulite pressurised inhalation solution in asthmatic patients, the peak plasma concentration is observed approximately 15 minutes after inhalation, earlier than that observed with a formoterol powder inhalation. Generally, absorption rate should be taken into account when switching patients from one formoterol formulation to another.

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

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

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

Repeated daily administration of 40 micrograms to 160 micrograms per day does not result in accumulation because of the short half-life. The pharmacokinetics of formoterol does 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 hours 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 hours after inhalation.

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

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

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

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

Norflurane

Ethanol anhydrous

Hydrochloric acid

Not applicable

18 months (see also section 6.4)

Prior to dispensing to the patient

Store in a refrigerator at 2°C to 8°C (for a maximum of 15 months)

After dispensing

Do not store above 30°C (for a maximum of 3 months)

A pressurised, aluminium container fitted with a metering valve, actuator and protective cap, containing a pressurised inhalation solution.

Each canister provides 50, 100 or 120 actuations.

Not all pack size may be marketed.

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.

Chiesi Limited

Cheadle Royal Business Park

Highfield

Cheadle

SK8 3GY

United Kingdom

PL 08829/0154

20/05/2011

20/05/2011

POM