Symptoms
There is no clinical experience to date on the management of overdose, however, an overdosage of Forair (Formoterol) 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, prolonged QTc-interval, hypertension.
Treatment
Supportive and symptomatic treatment is indicated. Serious cases should be hospitalised.
Use of cardioselective beta-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.
None known.
Adverse reactions (Table 1) are ranked in descending order of frequency, as follows: very common (> 1/10); common (> 1/100, < 1/10); uncommon (> 1/1,000, < 1/100); rare (> 1/10,000, <1/1,000); very rare (< 1/10,000); unknown (frequency cannot be estimated from available data). Within each frequency grouping, adverse reactions are ranked in order of decreasing seriousness.
Table 1
| Immune system disorders | |
| Very rare: | Hypersensitivity (including hypotension, angioneurotic oedema) |
| Rare | Hypersensitivity reactions e.g. bronchospasm, exanthema, urticaria, pruritus |
| Metabolism and nutrition disorders | |
| Rare | Hypokalaemia, |
| Very Rare | Hyperglycaemia |
| Psychiatric disorders | |
| Uncommon: | Agitation, anxiety, nervousness, restlessness, insomnia |
| Central Nervous system disorders | |
| Common: | Headache, tremor |
| Uncommon: | Dizziness |
| Very rare: | Dysgeusia |
| Cardiac disorders | |
| Common: | Palpitations |
| Uncommon: | Tachycardia |
| Rare: | Cardiac arrhythmias, e.g. atrial fibrillation, supraventricular tachycardia, extrasystoles |
| Very rare: | Peripheral oedema. Angina pectoris, prolongation of QTc-interval |
| Respiratory, thoracic and mediastinal disorders | |
| Uncommon: Unknown: | Bronchospasm, throat irritation, including paradoxical bronchospasm, acute asthma exacerbation* Cough** |
| Skin and subcutaneous tissue disorders | |
| Unknown: | Rash** |
| Gastrointestinal disorders | |
| Uncommon Rare: | Dry mouth Nausea |
| Musculoskeletal and connective tissue disorders | |
| Uncommon | Muscle cramps, myalgia |
| Investigations | |
| Unknown | Increased blood pressure (including hypertension)** |
| Vascular Disorders | |
| Very rare | Variations in blood pressure |
*The percent of patients with serious asthma exacerbations in clinical studies was higher for Forair (Formoterol) than for placebo, and the biggest numerical imbalance was observed in children 5-12 years old.
** These adverse events were reported in patients treated with Forair (Formoterol) during the post-marketing experience.
As with all inhalation therapy, paradoxical bronchospasm may occur in very rare cases. Treatment with β2-agonists may result in an increase in blood levels of insulin, free fatty acids, glycerol and ketone bodies. The excipient lactose contains small amounts of milk proteins. These may cause allergic reactions.
Reporting of suspected adverse reactions
Reporting 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.
Mutagenicity
Mutagenicity tests covering a broad range of experimental endpoints have been conducted. No genotoxic effects were found in any of the in vitro or in vivo tests performed.
Carcinogenicity
Two-year studies in rats and mice did not show any carcinogenic potential.
Male mice treated at very high dose levels showed a slightly higher incidence of benign adrenal subcapsular cell tumours, which are considered to reflect alterations in the physiological ageing process.
Two studies in rats, covering different dose ranges, showed an increase in mesovarial leiomyomas. These benign neoplasms are typically associated with long-term treatment of rats at high doses of β2-adrenergic drugs. Increased incidences of ovarian cysts and benign granulosa/theca cell tumours were also seen; β-agonists are known to have effects on the ovary in rats in which are very likely specific to rodents. A few other tumour types noted in the first study using the higher doses were within the incidences of the historical control population, and were not seen in the lower-dose experiment.
None of the tumour incidences were increased to a statistically significant extent at the lowest dose of the second study, a dose leading to a systemic exposure 10 times higher than that expected from the maximum recommended dose of formoterol.
On the basis of these findings and the absence of a mutagenic potential, it is concluded that use of formoterol at therapeutic doses does not present a carcinogenic risk.
Reproductive toxicity
Animal tests have shown no teratogenic effects. Formoterol was evaluated for its effect on fertility and general reproductive performance in sexually mature male and female rats. Reproduction studies in rats revealed no impairment of fertility or effect on early embryonic development at oral doses up to 3 mg/kg (approximately 1200 times the maximum recommended daily inhalation powder dose in human on a mg/m2 basis).
After oral administration, formoterol was excreted in the milk of lactating rats.
Forair (Formoterol) is indicated in asthma (including nocturnal asthma and exercise-induced symptoms) for those treated with inhaled corticosteroids who also require a long-acting beta agonist in accordance with current treatment guidelines.
Forair (Formoterol) is indicated for the relief of reversible airways obstruction in patients with chronic obstructive pulmonary disease (COPD) requiring long-term bronchodilatory therapy.
Pharmacotherapeutic group: Selective beta2-adrenergic agonist, ATC code: R03AC13.
Formoterol is a potent selective β2-adrenergic stimulant. It exerts a bronchodilator effect in patients with reversible airways obstruction. The effect sets in rapidly (within 1-3 minutes) and is still significant 12 hours after inhalation.
In man, Forair (Formoterol) has been shown to be effective in preventing bronchospasm induced by exercise and methacholine.
Formoterol has been studied in the treatment of conditions associated with COPD, and has been shown to improve symptoms and pulmonary function and quality of life. Formoterol acts on the reversible component of the disease.
Serious asthma exacerbations
Placebo-controlled clinical studies of at least 4 weeks treatment duration with Forair (Formoterol) suggested a higher incidence of serious asthma exacerbations in patients who received Forair (Formoterol) than in those who received placebo, particularly in patients 5-12 years of age.
| Placebo | Forair (Formoterol) 12 ug bd | Forair (Formoterol) 24 ug bd | Albuterol | |
| Placebo controlled clinical studies of at least 4 weeks treatment duration. | 0.3 % | 0.9 % (Forair (Formoterol) 10 - 12 ug bd) | 1.9 % | |
| Combined data from two 12-week double-blind, randomized, placebo-controlled, parallel-group studies. Age >12 y n=1095 | 0.7 % ( 2/277 ) | 0.4 % ( 1/275 ) | 3.3 % ( 9/271 ) | 0.7 % ( 2/272 ) |
| Multi-centre, randomized, parallel-group, double-blind, placebo-controlled 16 week trial. Age >12 y n=2085 | 0.2 % ( 1/514 ) | 0.6 % ( 3/527 ) 0.2 % ( 1/517 ) Open label treatment group - 12 ug bd plus up to two additional doses per day | 0.4 % ( 2/527 ) | |
| Randomized, placebo-controlled double-blind 52-week trial. Age 5-12 y n=518 | 0.0 % ( 0/176 ) | 4.7 % ( 8/171 ) | 6.4 % ( 11/171 ) |
Experience in children aged 5-12 years with asthma
The safety of Forair (Formoterol) 12 microgram twice daily compared to Forair (Formoterol) 24 microgram twice daily and placebo was investigated in one large, multicenter, randomized, double-blind, 52-week clinical trial in 518 children with asthma (ages 5 to 12 years) in need of daily bronchodilators and anti-inflammatory treatment. More children who received Forair (Formoterol) 24 microgram twice daily (11/171, 6.4%) or Forair (Formoterol) 12 microgram twice daily (8/171, 4.7%) than children who received placebo (0/176, 0.0%) experienced serious asthma exacerbations.
Forair (Formoterol) has a therapeutic dose range of 12 to 24 micrograms b.i.d. Data on the plasma pharmacokinetics of formoterol were collected in healthy volunteers after inhalation of doses higher than the recommended range and in COPD patients after inhalation of therapeutic doses. Urinary excretion of unchanged formoterol, used as an indirect measure of systemic exposure, correlates with plasma drug disposition data. The elimination half-lives calculated for urine and plasma are similar.
Absorption
Following inhalation of a single 120 microgram dose of formoterol fumarate by healthy volunteers, formoterol was rapidly absorbed into plasma, reaching a maximum concentration of 266 pmol/l within 5 minutes of inhalation. In COPD patients treated for 12 weeks with formoterol fumarate 12 or 24 micrograms b.i.d. the plasma concentrations of formoterol ranged between 11.5 and 25.7 pmol/L and 23.3 and 50.3 pmol/L respectively at 10 minutes, 2 hours and 6 hours post inhalation.
Studies investigating the cumulative urinary excretion of formoterol and/or its (R,R) and (S,S)-enantiomers, after inhalation of dry powder (12-96 micrograms) or aerosol formulations (12-96 micrograms), showed that absorption increased linearly with the dose.
After 12 weeks administration of 12 micrograms or 24 micrograms formoterol powder b.i.d., the urinary excretion of unchanged formoterol increased by 63-73% in adult patients with asthma, by 19-38% in adult patients with COPD and by 18-84% in children, suggesting a modest and self-limiting accumulation of formoterol in plasma after repeated dosing.
As reported for other inhaled drugs, it is likely that about 90% of formoterol administered from an inhaler will be swallowed and then absorbed from the gastrointestinal tract. This means that the pharmacokinetic characteristics of the oral formulation largely apply also to the inhalation powder. When 80 micrograms of 3H-labelled formoterol fumarate was orally administered to two healthy volunteers, at least 65% of the drug was absorbed.
Distribution
The plasma protein binding of formoterol is 61-64% (34% primarily to albumin).
There is no saturation of binding sites in the concentration range reached with therapeutic doses.
Biotransformation
Formoterol is eliminated primarily by metabolism, direct glucuronidation being the major pathway of biotransformation, with O-demethylation followed by further glucuronidation being another pathway. Minor pathways involve sulphate conjugation of formoterol and deformylation followed by sulphate conjugation. Multiple isozymes catalyze the glucuronidation (UGT1A1, 1A3, 1A6, 1A7, 1A8, 1A9, 1A10, 2B7 and 2B15) and O-demethylation (CYP2D6, 2C19, 2C9, and 2A6) of formoterol, and so consequently the potential for metabolic drug-drug interaction is low. Formoterol did not inhibit cytochrome P450 isozymes at therapeutically relevant concentrations. The kinetics of formoterol are similar after single and repeated administration, indicating no auto-induction or inhibition of metabolism.
Elimination
In asthmatic and COPD patients treated for 12 weeks with 12 or 24 micrograms formoterol fumarate b.i.d., approximately 10% and 7% of the dose, respectively, were recovered in the urine as unchanged formoterol. In asthmatic children, approximately 6% of the dose was recovered in the urine as unchanged formoterol after multiple dosing of 12 and 24 micrograms. The (R,R) and (S,S)-enantiomers accounted, respectively, for 40% and 60% of urinary recovery of unchanged formoterol, after single doses (12 to 120 micrograms) in healthy volunteers and after single and repeated doses in asthma patients.
After a single oral dose of 3H-formoterol, 59-62% of the dose was recovered in the urine and 32-34% in the faeces. Renal clearance of formoterol is 150 mL/min.
After inhalation, plasma formoterol kinetics and urinary excretion rate data in healthy volunteers indicate a biphasic elimination, with the terminal elimination half-lives of the (R,R)- and (S,S)-enantiomers being 13.9 and 12.3 hours, respectively.
Approximately 6.4-8% of the dose was recovered in the urine as unchanged formoterol, with the (R,R) and (S,S)-enantiomers contributing 40% and 60% respectively.
Asthma-related death
Formoterol fumarate dihydrate, the active ingredient of Forair (Formoterol), belongs to the class of long-acting beta2-adrenergic agonists (LABAs). In a study with salmeterol, a different long-acting beta2-agonist, a higher rate of death due to asthma was observed in the patients treated with salmeterol (13/13,176) than in the placebo group (3/13,179). No study adequate to determine whether the rate of asthma-related death is increased with Forair (Formoterol) has been conducted.
In the treatment of asthma
Forair (Formoterol) should not be used (and is not sufficient) as the first treatment for asthma.
When treating patients with asthma, use Forair (Formoterol) only as an add-on to an inhaled corticosteroid (ICS) for patients who are not adequately controlled on an ICS alone or whose disease severity clearly warrants initiation of treatment with both an ICS and a LABA.
Children up to the age of 6 years should not be treated with Forair (Formoterol) as sufficient experience is not available for this group. For children 6-12 years of age, when treatment with an ICS and LABA is required, it is recommended to use a combination product, except in cases where a separate ICS and LABA are more appropriate.
Forair (Formoterol) should not be used in conjunction with another LABA
Whenever Forair (Formoterol) is prescribed, patients should be evaluated for the adequacy of the anti-inflammatory therapy they receive. Patients must be advised to continue taking anti-inflammatory therapy unchanged after the introduction of Forair (Formoterol), even when their symptoms improve.
The daily dose of Forair (Formoterol) should not be increased beyond the maximum recommended dose.
Once asthma symptoms are controlled, consideration may be given to gradually reducing the dose of Forair (Formoterol). Regular review of patients as treatment is stepped down is important. The lowest effective dose of Forair (Formoterol) should be used.
Serious asthma-related adverse events and exacerbations may occur during treatment with Forair (Formoterol). Clinical studies with Forair (Formoterol) suggested a higher incidence of serious asthma exacerbations in patients who received Forair (Formoterol) than in those who received placebo, particularly in patients 5-12 years of age. These studies do not allow precise quantification of the differences in serious asthma exacerbation rates between treatment groups.
Patients should be advised that if, after initiation of Forair (Formoterol), their symptoms persist, or if the number of doses of Forair (Formoterol) required to control their symptoms increases, this usually indicates a worsening of the underlying condition. In these circumstances, they should be advised to continue treatment but to seek medical advice as soon as possible.
Patients should not be initiated on Forair (Formoterol) or the dose increased during an acute severe asthma exacerbation, or if they have significantly worsening or acutely deteriorating asthma.
Forair (Formoterol) must not be used to relieve acute asthma symptoms. In the event of an acute attack, a short-acting beta2-agonist should be used. Patients must be informed of the need to seek medical treatment immediately if their asthma deteriorates suddenly.
Concomitant conditions
Special care and supervision, with particular emphasis on dosage limits, is required in patients receiving Forair (Formoterol) when the following conditions may exist:
Ischaemic heart disease, cardiac arrhythmias, especially third degree atrioventricular block, severe cardiac decompensation, idiopathic subvalvular aortic stenosis, severe hypertension, aneurysm, phaeochromocytoma, hypertrophic obstructive cardiomyopathy, thyrotoxicosis, or other severe cardiovascular disorders, such as tachyarrhythmias or severe heart failure.
Formoterol may induce prolongation of the QTc-interval. Caution should be observed when treating patients with prolongation of the QTc-interval and in patients treated with drugs affecting the QTc-interval.
Caution should be used when co-administering theophylline and formoterol in patients with pre-existing cardiac conditions
Due to the hyperglycaemic effect of β2-stimulants, including formoterol, additional blood glucose controls are recommended in diabetic patients.
Hypokalaemia
Potentially serious hypokalaemia may result from β2-agonist therapy, including formoterol. Particular caution is advised in severe asthma as this effect may be potentiated by hypoxia and concomitant treatment. It is recommended that serum potassium levels be monitored in such situations.
Paradoxical bronchospasm
As with other inhalation therapy, the potential for paradoxical bronchospasm should be kept in mind. If it occurs, the preparation should be discontinued immediately and alternative therapy substituted.
Forair (Formoterol) contains lactose monohydrate less than 500 micrograms per delivered dose. This amount does not normally cause problems in lactose intolerant patients. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Incorrect route of administration
There have been reports of patients who have mistakenly swallowed Forair (Formoterol) capsules instead of placing the capsules in the inhalation device. The majority of these ingestions were not associated with side effects. Healthcare providers should discuss with the patient how to correctly use Forair (Formoterol). If a patient who is prescribed Forair (Formoterol) does not experience breathing improvement, the healthcare provider should ask how the patient is using Forair (Formoterol).
Patients experiencing dizziness or other similar side effects should be advised to refrain from driving or using machines.
Posology
For use in adults (including the elderly) and in children 6 years of age and older
Adults (including the elderly)
Asthma
Forair (Formoterol) should only be prescribed as an add-on to an inhaled corticosteroid.
Regular maintenance therapy: 1 inhalation capsule (equivalent to 12 micrograms formoterol fumarate dihydrate) to be inhaled twice daily. For more severe cases 2 inhalation capsules to be inhaled twice daily. This dosing regimen provides symptomatic relief throughout day and night. The recommended maximum daily dose is 48 micrograms per day.
Forair (Formoterol) should not be used to relieve the acute symptoms of an asthma attack. In the event of an acute attack, a short-acting beta2-agonist should be used.
Chronic Obstructive Pulmonary Disease
For regular maintenance therapy, 1 inhalation capsule (equivalent to 12 micrograms formoterol fumarate dihydrate) to be inhaled twice daily.
Children aged 6 years and above
Asthma
Forair (Formoterol) should only be prescribed as an add-on to an inhaled corticosteroid.
For regular maintenance therapy: 1 inhalation capsule (equivalent to 12 micrograms formoterol fumarate dihydrate) to be inhaled twice daily.
The recommended maximum daily dose is 24 micrograms per day.
For children 6-12 years of age, when treatment with an inhaled corticosteroid and long-acting beta2-agonist (LABA) is required, it is recommended to use a combination product, except in cases where separate inhaled corticosteroid and long-acting beta2-agonist inhalers are more appropriate.
Forair (Formoterol) should not be used to relieve the acute symptoms of an asthma attack. In the event of an acute attack, a short-acting beta2-agonist should be used.
Chronic Obstructive Pulmonary Disease
Not appropriate
Children under 6 years
Forair (Formoterol) is not recommended in children under the age of 6 years
Special populations
Renal and hepatic impairment
There is no theoretical reason to suggest that Forair (Formoterol) dosage requires adjustment in patients with renal or hepatic impairment, however no clinical data have been generated to support its use in these groups.
Elderly Patients (older than 65 years)
The pharmacokinetics of Forair (Formoterol) has not been studied in the elderly population. The available data from clinical trials performed in elderly patients do not suggest that the dosage should be different than in other adults.
Method of administration
Forair (Formoterol) inhalation powder capsules should be used only with the inhaler device provided in the Forair (Formoterol) pack. There is no safety or efficacy data on the use of Forair (Formoterol) inhalation powder capsules with other marketed inhalation devices.
To ensure proper administration of the drug, the patient should be shown how to use the inhaler by a physician or other health professional. A child should be shown how to use the inhaler correctly and should only use it with the help of an adult.
It is important for the patient to understand that the gelatin capsule may very occasionally break up and small pieces of gelatin might reach the mouth or throat after inhalation. The patient may be reassured that gelatin is harmless and will soften in the mouth and can be swallowed. The tendency for the capsule to break up is minimised by not piercing the capsule more than once.
Instructions for use
1. Pull off the cap from the mouthpiece of the inhaler
2. Hold the base of the inhaler firmly and turn the mouthpiece in the direction of the arrow on the bottom of the mouthpiece to open.
3. Take one of the capsules out of the blister strip for the appropriate day. Place it in the capsule shaped compartment in the base of the inhaler. It is important that the capsule is removed from the blister pack only immediately before use.
4. Twist the mouthpiece to the closed position until it clicks.
5. Keeping the inhaler upright, firmly squeeze the two blue buttons once only. This will pierce the capsule. Release the buttons. Although the capsule is now pierced, the powder will not be released.
6. The patient should breathe out fully.
7. The patient should place the mouthpiece in the mouth and tilt their head slightly back. The lips should be placed around the mouthpiece and the patient should inhale as quickly and as deeply as is possible. As the patient breathes in, the medicine will be inhaled into the lungs.
8. The capsule should be heard spinning in the inhaler. If the whirring noise is not heard, the capsule may be stuck in the compartment. If this occurs, open the inhaler and loosen the capsule by prising it out of the compartment. Do not try to loosen the capsule by repeatedly pressing the buttons.
9. If the whirring noise has been heard the patient should hold their breath for as long as they comfortably can while taking the inhaler out of the mouth. Then the patient should breathe normally. The inhaler should be opened to see if any powder is still in the capsule. If there is still powder in the capsule steps 6 to 8 should be repeated.
10. After use, the empty capsule should be tipped out and the mouthpiece closed.
11. Replace the cap.
12. If the inhaler needs to be cleaned, wipe the mouthpiece and capsule compartment with a dry cloth or a clean soft brush.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
