Atimos Modulite
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Atimos Modulite 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 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).
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).
Children younger than 12 years of age:
The safety and efficacy of Atimos Modulite in children younger then 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 p2 - 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 and 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, 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 Atimos Modulite 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
Atimos Modulite should not be used (and is not sufficient) as the first treatment for asthma.
Asthmatic patients who require therapy with long-acting B2-agonists, should also receive optimal maintenance anti-inflammatory therapy with corticosteroids. Patients must be advised to continue taking their antiinflammatory therapy after the introduction of formoterol even when symptoms decrease. Should symptoms persist, or treatment with B2-agonists need to be increased, this indicates a worsening of the underlying condition and warrants a reassessment of the maintenance therapy.
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 Modulite. Regular review of patients as treatment is stepped down is important. The lowest effective dose of Atimos Modulite should be used.
The maximum daily dose should not be exceeded.
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
Caution should be observed when treating patients with third degree atrioventricular block, refractory diabetes mellitus, thyrotoxicosis, phaeochromocytoma, hypertrophic obstructive cardiomyopathy, idiopathic subvalvular aortic stenosis, severe hypertension, aneurysm or other severe cardiovascular disorders, such as ischaemic heart disease, tachyarrhythmias or severe heart failure and occlusive vascular diseases, especially arteriosclerosis.
Formoterol may induce prolongation of the QTc-interval. Caution should be observed when treating patients with prolongation of the QTc-interval, eg. congenital or drug-induced (QTc > 0.44 seconds) and in patients treated with drugs affecting the QTc-interval (see section 4.5).
Due to the hyperglycaemic effects of B2-agonists, additional blood glucose monitoring is recommended initially in diabetic patients.
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, the potential for paradoxical bronchospasm should be considered. If it occurs, the treatment should be discontinued immediately and alternative therapy started (see section 4.8).
Hypokalaemia
Potentially serious hypokalaemia may result from B2-agonist therapy. Particular caution is recommended in acute severe asthma as the associated risk may be augmented by hypoxia. The hypokalaemic effect may be potentiated by concomitant treatment with xanthine-derivatives, steroids and diuretics. The serum potassium levels should therefore be monitored.
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 p2-sympathomimetics. Where applicable, potassium has to be substituted.
Due to decreased serum potassium levels the effect of digitalis containing medicinal products is enhanced.
4.5 Interaction with other medicinal products and other forms of interaction
No specific interaction studies have been carried out with formoterol.
There is a theoretical risk that concomitant treatment with other drugs known to prolong the QTc-interval may give rise to a pharmacodynamic interaction with formoterol and increase the possible risk of ventricular arrhythmias. Examples of such drugs include certain antihistamines (e.g. terfenadine, astemizole, mizolastine), certain antiarrhythmics (e.g. quinidine, disopyramide, procainamide), erythromycin and tricyclic antidepressants.
Concomitant administration of other sympathomimetic substances such as other p2-agonists or ephedrine may potentiate the undesirable effects of Atimos Modulite and may require titration of the dose.
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 p2-adrenergic stimulants on the cardiovascular system may be potentiated.
Concomitant treatment with xanthine derivatives, steroids, or diuretics such as thiazides and loop diuretics may potentiate a rare hypokalaemic adverse effect of p2-agonists. Hypokalaemia may increase the disposition towards arrhythmias in patients who are treated with digitalis glycosides.
There is an elevated risk of arrhythmias in patients receiving concomitant anaesthesia with halogenated hydrocarbons.
The bronchodilating effects of formoterol can be enhanced by anticholinergic drugs.
P-adrenergic blockers may weaken or inhibit the effect of Atimos Modulite. Therefore, Atimos Modulite should not be given together with P-adrenergic blockers (including eye drops) unless there are compelling reasons for their use.
4.6 Fertility, pregnancy and lactation
Pregnancy
There are no adequate data from the use of formoterol in pregnant women. In animal studies formoterol has caused implantation losses as well as decreased early postnatal survival and birth weight. The effects appeared at considerably higher systemic exposures than those reached during clinical use of formoterol. Treatment with formoterol may be considered at all stages of pregnancy if needed to obtain asthma control, and if the expected benefit to the mother is greater than any possible risk to the fetus. The potential risk for humans is unknown.
Lactation
It is not known whether formoterol passes into human breast milk. In rats, small amounts of formoterol have been detected in maternal milk. Administration of formoterol to women who are breastfeeding should only be considered if the expected benefit to the mother is greater than any possible risk to the child.
4.7 Effects on ability to drive and use machines
4.8 Undesirable effects
The most commonly reported adverse events of p2-agonist therapy, such as tremor and palpitations, tend to be mild and disappear within a few days of treatment.
Adverse reactions, which have been associated with formoterol, are listed below by system organ class and frequency. Frequency is defined as: Very Common (> 1/10), Common ( 1/100, <1/10), Uncommon (>1/1000, <1/100), Rare (>1/10000, <1/1000), Very rare (<1/10000)
|
System organ Class |
Adverse Reaction |
Frequency |
|
Blood and lymphatic system disorders |
Thrombopenia |
Very rare |
|
Immune system disorders |
Hypersensitivity reactions, e.g. angioedema, bronchospasm, exanthema, urticaria, pruritus. |
Rare |
|
Metabolism and nutrition disorders |
Hypokalaemia, hyperglycaemia |
Uncommon |
|
Psychiatric disorders: |
Agitation, restlessness, sleep disorder |
Uncommon |
|
Abnormal behaviour, hallucination |
Very rare | |
|
Nervous system disorders |
Tremor, headache |
Common |
|
Dizziness, taste disturbances |
Uncommon | |
|
Central nervous system stimulation |
Very rare | |
|
Cardiac disorders |
Palpitations |
Common |
|
Tachycardia |
Uncommon | |
|
Cardiac arrhythmias, e.g. atrial fibrillation, supraventricular tachycardia, extrasystoles, Angina pectoris |
Rare | |
|
Prolongation of QTc interval |
Very rare | |
|
Vascular disorders |
Variation in blood pressure |
Rare |
|
Respiratory, thoracic and mediastinal disorders |
Cough |
Common |
|
Throat irritation |
Uncommon | |
|
Bronchospasm paradoxical (see section 4.4) |
Rare | |
|
Dyspnoea, exacerbation of asthma |
Very rare | |
|
Gastrointestinal disorders |
Nausea |
Uncommon |
|
Skin and subcutaneous tissue disorders |
Hyperhidrosis |
Uncommon |
|
System organ Class |
Adverse Reaction |
Frequency |
|
Musculoskeletal and connective tissue disorders |
Muscle cramps, myalgia |
Uncommon |
|
Renal and urinary disorders |
Nephritis |
Rare |
|
General disorders and admnistration site conditions |
Oedema peripheral |
Very rare |
Nausea, dysgeusia, throat irritation, hyperhidrosis, restlessness, headache, dizziness and muscle cramps may resolve spontaneously within one to two weeks of continued treatment.
Central nervous system stimulating effects have been sporadically reported following inhalation of B2-sympathomimetics, manifesting as hyperexcitability. These effects were mainly observed in children up to 12 years of age.
Treatment with B2-agonists may result in an increase in blood levels of insulin, free fatty acids, glycerol and ketone bodies.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard.
4.9 Overdose
There is limited clinical experience on the management of overdose. An overdosage of Atimos Modulite would be likely to lead to effects that are typical of p2-adrenergic agonists: headache, tremor, palpitations. Symptoms reported from isolated cases are tachycardia, prolonged QTc interval, ventricular arrhythmias, metabolic acidosis, hypokalaemia, hyperglycaemia, nausea, vomiting and somnolence.
Treatment of Overdose
Supportive and symptomatic treatment is indicated. Serious cases should be hospitalised. Use of cardioselective ^-adrenergic blockers may be considered, but only subject to extreme caution since the use of ^-adrenergic blocker medication may provoke bronchospasm.
Serum potassium should be monitored.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic Group: Adrenergics, inhalants; selective p2-adrenoreceptor agonists ATC code: R03A C13
Formoterol is a predominantly selective ^-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.
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 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 halflife 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.
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 P2-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 looked upon as a class effect in rodents after long exposure to high doses of p2-agonists.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Norflurane (HFA-134a)
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)
Nature and contents of container
6.5
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.
Not all pack size may be marketed.
6.6 Special precautions for disposal 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
Chiesi Limited
Cheadle Royal Business Park
Highfield
Cheadle
SK8 3GY
United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 08829/0154
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
29/09/2005 / 20/05/2011
10 DATE OF REVISION OF THE TEXT
29/07/2014