Symptoms
There is limited clinical experience on the management of overdose. An overdose would likely lead to effects that are typical of beta2-agonists: tremor, headache, palpitations. Symptoms reported from isolated cases are tachycardia, hyperglycaemia, hypokalaemia, prolonged QTc-interval, arrhythmia, nausea and vomiting.
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 beta-adrenergic blocker medication may provoke bronchospasm. Serum potassium should be monitored.
(lactose monohydrate, which contains small amounts of milk proteins).
Not applicable.
The most commonly reported adverse events of beta2-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 given below, listed by system organ class and frequency. Frequencies are defined as: very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1000 to <1/100), rare (>1/10 000 to <1/1000), very rare (<1/10 000) and not known (cannot be estimated from the available data).
| Immune system disorders | Rare | Hypersensitivity reactions such as bronchospasm, severe hypotension, urticaria, angioedema, pruritus, exanthema, peripheral oedema |
| Metabolism and nutrition disorders | Rare | Hypokalaemia |
| Very rare | Hyperglycaemia | |
| Psychiatric disorders | Uncommon | Agitation, restlessness, sleep disturbances, anxiety |
| Nervous system disorders | Common | Headache, tremor |
| Very rare | Dizziness, taste disturbance | |
| Cardiac disorders | Common | Palpitations |
| Uncommon | Tachycardia | |
| Rare | Cardiac arrhythmias, e.g atrial fibrillation, supraventricular tachycardia, extrasystoles | |
| Very rare | Angina pectoris, prolongation of QTc interval | |
| Vascular disorders | Very rare | Variation in blood pressure |
| Respiratory, thoracic and mediastinal disorders | Rare | Aggravated bronchospasm, paradoxical bronchospasm , oropharyngeal irritation |
| Gastrointestinal disorders | Rare | Nausea |
| Musculoskeletal, connective tissue and bone disorders | Uncommon | Muscle cramps, myalgia |
As with all inhalation therapy, paradoxical bronchospasm may occur in very rare cases.
Treatment with beta2-agonists may result in an increase in blood levels of insulin, free fatty acids, glycerol and ketone bodies.
Lactose monohydrate contains small amounts of milk proteins and can therefore cause allergic reactions.
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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
Non-clinical data reveal no special hazard for humans in the therapeutic dose range based on conventional studies of repeated dose toxicity, genotoxicity, carcinogenicity and reproduction toxicity. A somewhat reduced fertility in male rats was observed at high systemic exposure to formoterol. In rats and mice a slight increase in the incidence of uterine leiomyomas has been observed. This effect is looked upon as a class-effect observed in rodents after long exposure to high doses of beta2-receptor agonists.
Oxis Turbuhaler 12 micrograms/dose inhalation powder is indicated for use in the treatment of asthma in patients treated with inhaled corticosteroids and who also require a long-acting beta2-agonist in accordance with current treatment guidelines.
Oxis Turbuhaler 12 micrograms/dose inhalation powder is indicated also for the relief of reversible airways obstruction in patients with chronic obstructive pulmonary disease (COPD) and requiring long-term bronchodilator therapy.
Pharmacotherapeutic group: Selective beta2-adrenoreceptor agonists.
ATC code: R03AC13.
Mechanism of action
Formoterol is a potent selective beta2-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.
Clinical efficacy and safety
In man, 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. Formoterol acts on the reversible component of the disease.
Absorption
As reported for other inhaled drugs, it is likely that about 80 % of formoterol administered from the Easyhaler 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. Following inhalation of therapeutic doses, formoterol cannot be detected in the plasma using current analytical methods.
Absorption is both rapid and extensive: At a higher than therapeutic dose (120 micrograms), the peak plasma concentration is observed at 5 minutes post inhalation whilst at least 65 % of a radiolabelled 80 micrograms oral dose is absorbed, and oral doses of up to 300 micrograms are readily absorbed with the peak concentrations of unchanged formoterol at 0.5-1 hour. 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.
The pharmacokinetics of formoterol appear linear in the range of oral doses investigated, i.e. 20-300 micrograms. Repeated oral administration of 40-160 micrograms daily does not lead to significant accumulation of the drug. The maximum excretion rate after administration of 12-96 micrograms is reached within 1-2 hours of inhalation.
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 and by 18-84 % in children, suggesting a modest and self-limiting accumulation of formoterol in plasma after repeated dosing.
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.
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. Multiple CYP450 isoenzymes (2D6, 2C19, 2C9, and 2A6) catalyze the transformation and so 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.
Elimination
Elimination of formoterol from the circulation seems to be polyphasic; the apparent half-life depends on the time interval considered. On the basis of plasma or blood concentrations up to 6, 8 or 12 hours after oral administration, an elimination half-life of about 2-3 hours was determined. From urinary excretion rates between 3 and 16 hours after inhalation, a half-life of about 5 hours was calculated.
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.
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.
In adult asthmatics, approximately 10 % and 15-18 % of the dose was recovered in the urine as unchanged and conjugated formoterol, respectively, after multiple doses of 12 and 24 micrograms. In children, approximately 6 % and 6.5-9 % of the dose was recovered in the urine as unchanged and conjugated formoterol, respectively, after multiple doses of 12 and 24 micrograms. As in healthy volunteers, the (R,R) and (S,S)-enantiomers contributed approximately 40 % and 60 % of unchanged drug excreted in the urine of adults, respectively, and there was no relative accumulation of one enantiomer over the other after repeated dosing.
Oxis Turbuhaler should not be used (and is not sufficient) as the first treatment for asthma.
Asthmatic patients who require therapy with long-acting ß2-agonists, should also receive optimal maintenance anti-inflammatory therapy with corticosteroids.) and in patients treated with drugs affecting the QTc interval. Formoterol itself may induce prolongation of 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 beta2-stimulants, additional blood glucose controls are recommended initially in diabetic patients.
Potentially serious hypokalaemia may result from beta2-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 other medicines, such as xanthine derivatives, steroids and diuretics. It is recommended that serum potassium levels are monitored in such situations.
As with other inhalation therapy there is a risk of paradoxical bronchospasm. If this occurs the patient will experience an immediate increase in wheezing and shortness of breath after dosing which should be treated straightaway with a fast-acting inhaled bronchodilator. Oxis Turbuhaler inhalation powder should be discontinued immediately, the patient should be assessed and, if necessary, alternative therapy instituted.
Oxis Turbuhaler contains approx. 8 mg of lactose per dose. This amount does not normally cause problems in lactose intolerant people. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Paediatric population
Children up to the age of 6 years should not be treated with Oxis Turbuhaler, as no sufficient experience is available for this group.
Formoterol has no or negligible influence on the ability to drive and use machines.
Posology
ADULTS (INCLUDING OLDER PEOPLE) AND ADOLESCENTS (ABOVE 12 YEARS)
Asthma
Regular maintenance therapy:
1 inhalation (12 micrograms) to be inhaled twice daily. For more severe disease this dose regimen can be increased to 2 inhalations (24 micrograms) to be inhaled twice daily.
The maximum daily dose is 4 inhalations (2 inhalations inhaled twice daily).
Chronic Obstructive Pulmonary Disease
Regular maintenance therapy:
1 inhalation (12 micrograms) to be inhaled twice daily.
The maximum daily dose is 2 inhalations (1 inhalation inhaled twice daily).
Paediatric population
CHILDREN 6 to 12 YEARS
Asthma
Regular maintenance therapy:
1 inhalation (12 micrograms) to be inhaled twice daily. The maximum daily dose is 24 micrograms.
Chronic Obstructive Pulmonary Disease
Not appropriate.
CHILDREN UNDER THE AGE OF 6 YEARS
Oxis Turbuhaler is not recommended for use in children under the age of 6 years.
Renal and hepatic impairment
There are no data available for use of Oxis Turbuhaler in patients with hepatic or renal impairment. As formoterol is primarily eliminated via liver metabolism an increased exposure can be expected in patients with severe liver cirrhosis.
The duration of action of formoterol has been shown to last for about 12 hours. The treatment should always aim for the lowest effective dose.
Current asthma management guidelines recommend that long-acting inhaled beta2-agonists should be used for maintenance bronchodilator therapy. They further recommend that in the event of an acute attack, a short-acting beta2-agonist should be used.
In accordance with the current asthma management guidelines, long-acting beta2-agonists may be added to the treatment regimen in patients experiencing problems with high dose inhaled steroids. Patients should be advised not to stop or change their steroid therapy when treatment with formoterol is introduced.
If the symptoms persist or worsen, or if the recommended dose of Oxis Turbuhaler fails to control symptoms (maintain effective relief), this is usually an indication of a worsening of the underlying condition.
When transferring a patient to Oxis Turbuhaler from other inhalation devices, the treatment should be individualised. The previous active substance, dose regimen, and method of delivery should be considered.
Method of administration
For inhalation use.
Precautions to be taken before handling or administering the medicinal product.
Instructions for use and handling
Easyhaler is an inspiratory flow driven inhaler, which means that when the patient inhales through the mouthpiece, the substance will follow the inspired air into the airways.
Note: It is important to instruct the patient
- To carefully read the instructions for use in the patient information leaflet which is packed together with each inhaler.
- That it is recommended to keep the device in the protective cover after opening the laminate pouch to enhance the stability of the product during use and make the inhaler more tamper proof.
- To shake and actuate the device prior to each inhalation.
- To breathe in forcefully and deeply through the mouthpiece to ensure that an optimal dose is delivered to the lungs.
- Never to breathe out through the mouthpiece as this will result in a reduction in the delivered dose. Should this happen the patient is instructed to tap the mouthpiece onto a table top or the palm of a hand to empty the powder, and then to repeat the dosing procedure.
- Never to actuate the device more than once without inhalation of the powder. Should this happen the patient is instructed to tap the mouthpiece onto a table top or the palm of a hand to empty the powder, and then to repeat the dosing procedure.
- To always replace the dust cap and close the protective cover after use to prevent accidental actuation of the device (which could result in either overdosing or underdosing the patient when subsequently used).
- To clean the mouthpiece with a dry cloth at regular intervals. Water should never be used for cleaning because the powder is sensitive to moisture.
- To replace Oxis Turbuhaler when the counter reaches zero even though powder can still be observed within the device.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
