FORMOTEROL EG 12 µg Powder for Inhalation (Capsule) Bottle/60 + inhaler

Powder for inhalation in capsule.

Formoterol fumarate.......................................................................................................... 12 micrograms

For one capsule.

Excipient with known effect: lactose (16,792 mg/capsule), lactose monohydrate (7,196 mg/capsule) (may contain milk proteins).

Excipients:

• Continuous symptomatic treatment of asthma
  • in patients requiring daily doses of short-acting, rapid-acting beta2 agonists,
  • and/or in case of nocturnal symptoms, in combination with continuous anti-inflammatory treatment such as inhaled corticosteroids.
• Preventive treatment of exercise-induced asthma.

N.B.: formoterol is not a treatment for an asthma attack. In case of an asthma attack, use a short-acting, rapid-acting beta2 mimetic of short duration by inhaled route or, depending on severity, by injectable route.

• Symptomatic treatment of bronchial obstruction in chronic obstructive pulmonary disease.

This medicinal product is particularly suitable for subjects in whom poor hand/lung coordination has been demonstrated, which is necessary for correct use of conventional metered-dose aerosols without an inhalation chamber.

The capsules must be administered by inhalation route only

1 capsule (used for 1 inhalation) contains 12 µg of formoterol fumarate

Dosage

Asthma:

Reserved for adults and children over 6 years:

Continuous symptomatic treatment of asthma:

• usual dose: 1 capsule to be inhaled 2 times per day, morning and evening (i.e. 12 µg 2 times per day)
• maximum dose:
  •  adult: 2 capsules to be inhaled 2 times per day, morning and evening (i.e. 24 µg 2 times per day)
  •  child over 6 years: 1 capsule to be inhaled 2 times per day, morning and evening (i.e. 12 µg 2 times per day)

Preventive treatment of exercise-induced asthma:

• adult: 1 to 2 capsules (i.e. 12 to 24 µg) to inhale approximately 15 minutes before exertion.
• child over 6 years: 1 capsule to inhale (i.e. 12 µg) to inhale approximately 15 minutes before exertion

In adults, if needed, 1 to 2 additional inhalations may be taken occasionally to relieve asthma symptoms, without however exceeding a maximum total dose of 4 capsules per day (i.e. 48 micrograms per day of continuous treatment and additional inhalations included) without exceeding 2 capsules per intake. However, if recourse to additional doses is more than occasional (e.g. more than 2 days per week), which may indicate deterioration of asthma, a reassessment of the therapeutic management should be considered.

Chronic obstructive pulmonary disease (COPD)

Adults (aged 18 years and over)

The usual dose is 1 to 2 capsules (12 to 24 micrograms) to inhale twice a day.

If needed, additional inhalations may be taken occasionally to relieve symptoms, without however exceeding a maximum total dose of 4 capsules per day (i.e. 48 micrograms per day of continuous treatment and additional inhalations included) without exceeding 2 capsules per intake.

Method of administration

Inhalation by dispenser with mouthpiece.

THE CAPSULES MUST NOT BE SWALLOWED.

They must be administered by inhalation using the appropriate device reserved for this purpose and supplied in the pack.

For correct use, it is advisable that the physician personally ensure the patient uses the device correctly:

1. remove the protective cap

2. hold the base firmly and turn the mouthpiece in the direction of the arrow

3. place the capsule in the compartment provided for this purpose. Important: remove the capsule from its blister only at the last moment

4. Close the inhaler by returning the mouthpiece to its initial position

5. Press the 2 push buttons while holding the inhaler in a vertical position, then release,

6. Exhale fully

7. Place the mouthpiece in the mouth and close the lips, tilt the head back, inhale rapidly and very deeply through the mouth

8. Remove the inhaler from the mouth while holding the breath for as long as possible. Then breathe normally. Open the inhaler to check that no powder remains. If powder remains, repeat the inhalation

9. After use, remove the empty capsule, replace the mouthpiece and put the protective cap back on.

Maintenance: clean the mouthpiece and the capsule compartment with a dry cloth in order to remove any powder residue.

Specific populations

No dose adjustment is  a priori necessary in elderly patients.

There are no data available on the use of Formoterol EG in patients with hepatic or renal impairment (see section Pharmacokinetics).

Hypersensitivity to the active substance or to any of the excipients listed in section Composition.

Warning

Formoterol is a long-acting β2 mimetic bronchodilator.

It does not constitute treatment for an asthma attack and should be reserved for continuous maintenance treatment. If, despite well-managed treatment, paroxysmal dyspnoea occurs, the patient will be advised to use an inhaled, fast-acting, short-acting beta2 mimetic bronchodilator to treat the symptoms. The physician must inform the patient that an immediate medical consultation is necessary if the relief usually obtained is not rapidly observed after inhalation of the short-acting bronchodilator.

If a patient develops, over a few days, a rapid increase in their use of inhaled, fast-acting, short-acting beta2 mimetic bronchodilators, one must fear (especially if peak flow meter values fall and/or become irregular) a decompensation of their disease and the possibility of progression to a status asthmaticus. The physician must therefore warn the patient that in this case an immediate consultation is necessary, without having previously exceeded the prescribed maximum doses. The therapeutic management must then be reassessed.

Formoterol, indicated for continuous treatment in patients requiring daily intakes of beta2 mimetics and/or in cases of nocturnal asthma, must be combined with maintenance treatment with inhaled corticosteroid and must in no case replace it.

Furthermore, the patient must be warned that improvement in their clinical condition must not lead to a change in their treatment, in particular to discontinuation of inhaled corticosteroid therapy without medical advice.

If symptoms persist, or if it is necessary to intensify treatment with beta‑2 mimetics, one must fear a worsening of asthma and a reassessment of maintenance treatment should be considered.

The recommended maximum daily dose must not be exceeded. The long-term safety of daily treatment at doses above 48 micrograms per day in adult asthmatics, 24 micrograms per day in asthmatic children and 24 micrograms per day in patients with COPD, has not been established.

FORMOTEROL EG must not be combined with another long-acting beta‑2 mimetic.

Paradoxical bronchospasm: as with any inhaled product, paradoxical bronchospasm may occur, manifesting as the onset of dyspnoea, cough or an increase in bronchial wheezing immediately after inhalation of the treatment. In this case, the treatment should be stopped immediately and other therapies or other forms of administration prescribed.

Athletes: Athletes' attention will be drawn to the fact that this specialty contains an active ingredient that may induce a positive result in tests carried out during anti-doping controls.

Precautions for use

In case of bronchial infection or abundant bronchorrhea, appropriate treatment is necessary in order to promote optimal distribution of the product in the airways.

Formoterol should be administered with caution in cases of hyperthyroidism, pheochromocytoma, or in patients with coronary insufficiency, ischaemic heart disease, rhythm disorders, severe heart failure, obstructive cardiomyopathy, or any cardiac condition, or uncontrolled severe arterial hypertension.

Formoterol may cause a prolongation of the QTc interval. Caution is recommended in patients with QTc interval prolongation and in patients treated with medicinal products having an effect on the QTc interval (see section Interactions).

Due to the hyperglycaemic effects of β2-sympathomimetics, increased monitoring of blood glucose is advised at the start of treatment in diabetic patients.

Treatment with β2-sympathomimetics may cause potentially serious hypokalaemia. Particular caution is advised in severe acute asthma, as the associated risks may be increased by hypoxia. The hypokalaemic effect may be potentiated by concomitant administration of xanthine derivatives, steroids and diuretics. In these situations, potassium levels should therefore be monitored.

Formoterol must not be administered to children under 6 years of age in the absence of clinical studies.

This specialty is not suitable for children whose inspiratory flow is less than 16 litres per minute, due to ineffective inhalation of the powder through the device.

This medicine contains lactose monohydrate (less than 500 micrograms per delivered dose). In general, this quantity is harmless in patients intolerant to lactose. However, its use is not recommended in patients with certain rare hereditary diseases of galactose intolerance: Lapp lactase deficiency or glucose/galactose malabsorption syndrome. In addition, lactose may contain traces of milk proteins that may trigger allergic reactions in patients allergic to milk proteins.

Concomitant treatment with other sympathomimetic agents such as other β2-sympathomimetics or ephedrine may potentiate adverse effects and may require a reduction in the dose of formoterol.

Concomitant treatment with xanthine derivatives, steroids or diuretics such as thiazides or loop diuretics may potentiate the risk of the rare adverse effect of hypokalaemia from β2-agonists.

There is a theoretical risk that concomitant treatment with other substances known to prolong the QTc interval may result in a pharmacodynamic interaction with formoterol and increase the potential risk of ventricular arrhythmia. Such substances may include, for example, certain antihistamines (such as terfenadine, astemizole, mizolastine), certain antiarrhythmics (such as quinidine, disopyramide, procainamide), erythromycin and tricyclic antidepressants.

The risk of arrhythmia is increased in patients receiving a halogenated volatile anesthetic.

Non-cardioselective beta-blockers may reduce or inhibit the effect of formoterol. Formoterol EG should therefore not be used at the same time as non-cardioselective beta-blockers (including eye drops), unless absolutely necessary.

Pregnancy

Studies carried out in animals have not shown any teratogenic effect. In the absence of a teratogenic effect in animals, a malformative effect in humans is not expected. Indeed, to date, substances responsible for malformations in humans have proven to be teratogenic in animals in well-conducted studies on two species.

There are currently no relevant clinical data on a possible teratogenic or foetotoxic effect of formoterol when administered during pregnancy.

Consequently, the use of formoterol will be considered during pregnancy only if necessary.

Breast-feeding

Formoterol administered orally may be found in breast milk. The impact of this passage on the newborn is not known.

Fertility

There are no available data concerning the effect of formoterol on human fertility.

Fertility studies conducted in male and female rats did not reveal any impairment of fertility (see section Preclinical safety).

Formoterol by inhalation has no effects on the ability to drive vehicles or use machines.

The adverse reactions most frequently reported for beta-2 agonists, such as tremor and palpitations, are rather moderate and disappear after a few days of treatment.

The excipient contained in this medicinal product, lactose, may contain small amounts of milk proteins, which may cause allergic reactions in subjects allergic to milk proteins.

Severe asthma exacerbations:

Placebo-controlled clinical studies conducted using a formoterol-based medicinal product for at least 4 weeks showed an increased incidence of severe exacerbations in the formoterol-treated group (0,9 % for a dose of 10 to 12 µg 2 times/day - 1,9 % for a dose of 24 µg 2 times/day) compared with the placebo group (0,3 %).

Clinical experience in adolescents and adults:

In 2 pivotal controlled studies conducted with another formoterol-based medicinal product for registration in the United States and including a total of 1095 patients aged 12 years and over, severe exacerbations (acute worsening of asthma leading to hospitalisation) occurred more frequently in the group of patients receiving formoterol 24 µg 2 times/day (9/271 - 3,3 %) than in the group receiving formoterol 12 µg 2 times/day (1/275 - 0.4 %), the placebo group (2/277 - 0,7 %) or the salbutamol group (2/272 - 0,7 %). Patients were not receiving concomitant corticosteroid treatment.

A further study was then conducted with this other formoterol-based medicinal product in 2085 patients in order to compare the occurrence of serious asthma-related adverse events in each group (low and high dose of formoterol). The results of this 16-week study did not show a dose-response relationship. The percentage of patients who experienced severe exacerbations in this study was slightly higher in the formoterol group than in the placebo group (for the 3 double-blind treated groups: formoterol 24 µg 2 times/day (2/527 - 0,4 %), formoterol 12 µg 2 times/day (3/527 - 0.6 %) and placebo (1/514 - 0,2 %) and for the open-label treated group: formoterol 12 µg 2 times/day and up to 2 additional inhalations (1/517 - 0,2 %).

Clinical experience in children over 5 years

The tolerability of a formoterol-based medicinal product 12 µg 2 times/day compared with 24 µg 2 times/day and placebo was evaluated in a large, multicentre, randomised, double-blind clinical study of 52 weeks including 518 asthmatic children (5 to 12 years) requiring daily bronchodilator and anti-inflammatory treatment. Children receiving formoterol 24 µg 2 times/day (11/271 - 6,4 %) and formoterol 12 µg 2 times/day (8/171 - 4,7 %) had more severe exacerbations than children receiving placebo (0/176 - 0 %).

FORMOTEROL EG is not recommended in children under 6 years due to the lack of sufficient clinical data for this population.

Tabulated summary of adverse reactions

Adverse reactions are listed by frequency, from most to least frequent, according to the following criteria: very common (≥ 1/10); common (≥ 1/100 and < 1/10), uncommon (≥ 1/1 000 and < 1/100), rare (≥ 1/10 000 and < 1/1 000), very rare (< 1/10 000), including isolated cases.

Table 1. Adverse reactions from clinical studies and from other sources

Immune system disorders:
Rare:	hypersensitivity reaction (including hypotension, bronchospasm, urticaria, angioedema, angio, pruritus, rash, skin reactions)
Metabolism and nutrition disorders:
Rare:	hypokalaemia
Very rare:	hyperglycaemia
Psychiatric disorders:
Uncommon:	agitation (including psychomotor agitation), anxiety, nervousness, sleep disorders (insomnia)
Nervous system disorders:
Common:	headache, tremor
Very rare:	dysgeusia (alteration of taste), dizzy sensations
Cardiac disorders:
Common:	palpitations
Uncommon:	tachycardia
Rare:	arrhythmias (including atrial fibrillation, supraventricular tachycardia, extrasystoles)
Very rare:	angina pectoris, prolongation of the QT interval, peripheral oedema
Vascular disorders:
Very rare:	variations in blood pressure
Respiratory, thoracic and mediastinal disorders:
Uncommon:	bronchospasm, throat irritation (with cough and hoarseness)
Very rare:	paradoxical bronchospasm (see section Warnings and precautions)
Gastrointestinal disorders:
Uncommon:	dry mouth
Rare:	nausea
Musculoskeletal and systemic disorders:
Uncommon:	muscle spasms, myalgia

Table 2. Adverse effects reported spontaneously or in the literature (frequency not known)

Metabolism and nutrition disorders:
	increase in blood levels of insulin, free fatty acids, glycerol and ketone bodies
Skin and subcutaneous tissue disorders:
	rash

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 reaction via the national reporting system: National Agency for the Safety of Medicines and Health Products (ANSM) and the network of Regional Centres of Pharmacovigilance - Website: https://signalement.social-sante.gouv.fr/.  

Symptoms

An overdose of formoterol induced by excessive repeated inhalations of formoterol may result in the adverse effects typically associated with beta-2 mimetics: headache, tremor, palpitations. In isolated cases, the following events have been reported: tachycardia, prolongation of the QTc interval, cardiac rhythm disorder (including ventricular arrhythmias), metabolic acidosis, hypokalaemia, hyperglycaemia, blood pressure variation, hypertension, nausea and vomiting. In these cases, symptomatic adjunctive treatment is indicated.

Treatment

The management is symptomatic treatment of the disorders.

The use of cardioselective beta-blockers may be considered but only under medical supervision and with caution, as the use of beta-blockers may cause bronchospasm. Serum potassium should be monitored.

Pharmacotherapeutic class: Long-acting beta-2 mimetic bronchodilator for inhalation, ATC code: R03AC

Long-acting beta-2 mimetic bronchodilator for inhalation, ATC code: R03AC

Formoterol is a selective beta-2 agonist.

After inhalation, formoterol exerts a stimulating action on the beta2 receptors of bronchial smooth muscle.

After inhalation of a single dose it produces rapid bronchodilation (1 to 3 minutes) in patients with reversible airway obstruction, maximum at 2 hours, persisting for approximately 12 hours.

As formoterol acts locally in the lung, plasma levels are not correlated with the therapeutic effect. At therapeutic doses, plasma concentrations of formoterol after inhalation are below the sensitivity limits of the analytical methods.

Absorption

Formoterol is rapidly absorbed after inhalation. Plasma peaks are reached approximately 5 to 10 minutes after inhalation. It is likely that the majority of the administered formoterol is swallowed and therefore absorbed in the gastrointestinal tract.

Distribution and biotransformation

Plasma protein binding is 61 to 64% (albumin: 34%). Formoterol is essentially metabolised by direct glucuronidation and is completely eliminated. Another metabolic pathway consists of O-demethylation followed by glucuronidation and then complete elimination. Several enzymes are involved in the glucuronidation and O-demethylation of formoterol, which suggests a low risk of drug interaction.

At therapeutic doses, formoterol does not inhibit cytochrome P450 isoenzymes.

Total plasma clearance and volume of distribution have not been determined.

Elimination

Formoterol and its metabolites are completely eliminated, two thirds of an oral dose being eliminated in the urine and one third in the faeces. The renal clearance of formoterol is 150 ml/min.

The majority of a dose of formoterol is eliminated by metabolism. After inhalation, 6 to 9% of the dose (on average) is eliminated unchanged in the urine. After intravenous injection, approximately 20% of the administered dose is excreted unchanged in the urine. The terminal half-life after inhalation is estimated at 17 hours.

Specific populations

The impact of decreased renal or hepatic function on the pharmacokinetics of formoterol in elderly subjects is not known. Given the essentially hepatic metabolism of formoterol, an increase in systemic exposure is expected in patients with severe hepatic impairment.

The effects of formoterol observed in toxicity studies in rats and dogs were mainly cardiovascular and consisted of hyperaemia, tachycardia, arrhythmias and myocardial lesions. These effects correspond to the known pharmacological effects following administration of high doses of beta-2 sympathomimetics.

Formoterol had no genotoxic effect in the tests in vitro and in vivo. In rats and mice, a slight increase in the incidence of benign uterine leiomyomas was observed. This observation is considered a class effect seen in rodents after prolonged exposure to high doses of beta-2 sympathomimetics.

Carcinogenicity

A slight increase in the occurrence of benign subcapsular adrenal tumours was observed in male mice treated with high doses of formoterol. However, this trend was not found in a second study, in which the pathological changes observed consisted of a slight increase in the occurrence of benign smooth muscle tumours in the genital tract of females and liver tumours in males and females. Smooth muscle tumours are known effects of beta-agonists administered at high doses in rodents..

Two studies conducted in rats, with a wide range of administered doses, showed an increase in leiomyoma of the mesovarium.. These benign tumours are typically associated with long-term treatment and high doses of drugs stimulating adrenergic receptors. An increase in the occurrence of ovarian cysts and benign granulosa/theca cell tumours was also observed. In rats, beta-agonists are known to have effects on the ovaries, these effects being specifically observed in rodents. Some other tumour types, observed in the 1year study with high doses, were found at frequencies close to those historically recorded in the control population, and were not found in experiments carried out at lower doses.

No statistically significant increase in the frequency of occurrence of these tumours was observed at the lowest dose used in the second study conducted in rats, a dose corresponding to a drug exposure 10 times higher than the maximum recommended in clinical practice in humans.

On the basis of these results and the absence of a mutagenic effect, it was concluded that the use of formoterol at therapeutic doses presented no carcinogenic risk.

Reproduction studies

A certain reduction in fertility was observed in male rats after high systemic exposure to formoterol. Experimental studies in animals did not reveal any teratogenic effect. The effect of formoterol on fertility and reproduction was assessed in male and female rats that had reached sexual maturity. No decrease in fertility or effect on early embryonic development was observed with doses up to 60 mg/kg/day administered orally to rats (i.e. approximately 12 000 times the estimated maximum recommended daily dose in humans based on the mg/m2, for the dry powder for inhalation form).

Formoterol administered orally was excreted into the milk of lactating female rats.

3 years.

Store at a temperature not exceeding 25° C.

Store in the original packaging, protected from moisture.

No special requirements.

List I

Marketing authorisation (AMM)

CIP 3400930128954 (Fl/60+inhal). CIP 3400930131121 (Fl/30+inhal).

Price:

11,16 euros (Fl/60+inhal). 5,61 euros (Fl/30+inhal).

Social Security reimbursement at 65% based on the TFR: 11.16 euros (Fl/60+inhal), 5.61 euros (Fl/30+inhal) in the indications:

• Indication(s) listed in the marketing authorisation at the date of publication of this order (Fl/60+inhal, Fl/30+inhal)

Collection.