Formoterol
Long acting beta 2 sympathomimetic with rapid onset
Formoterol is a long acting β2 sympathomimetic (LABA) with a notable feature: onset of action in 1 to 3 minutes, as fast as short acting β2 agonists. The substance was patented in 1986 by Yamanouchi and today appears in numerous inhalation devices (Foradil, Oxis, Formatris, generics). Formoterol is particularly important as a combination partner in fixed dose combinations with inhaled glucocorticoids such as budesonide (Symbicort), mometasone (Dulera) or beclomethasone (Foster).
Its rapid onset makes formoterol the basis of the MART strategy (Maintenance and Reliever Therapy), in which patients use one and the same budesonide formoterol combination as maintenance and reliever medication. This concept has taken a central place in the GINA recommendations and in national care guidelines in recent years, progressively replacing the previously common monotherapy with short acting β2 agonists.
Mechanism of Action
Formoterol selectively activates β2 adrenoceptors on bronchial smooth muscle. The G protein coupled signalling cascade raises intracellular cAMP, activates protein kinase A and lowers free calcium. Bronchial smooth muscle relaxes, the lumen widens and airway resistance and work of breathing decrease. Unlike short acting salbutamol or fenoterol, the effect of formoterol lasts about 12 hours.
The combination of rapid onset and long duration is based on molecular chemistry. Formoterol has moderate lipophilicity, so some of the drug is quickly available at the receptor site, while a depot in the cell membrane ensures sustained receptor activation. Salmeterol, another LABA, is considerably more lipophilic, acts more slowly and cannot be used as reliever medication.
As with all β2 agonists, formoterol at higher doses also stimulates β2 receptors outside the airways, for example in the heart, blood vessels, skeletal muscle and metabolism. Typical systemic effects are tachycardia, tremor, hypokalaemia and rise in blood glucose. With inhaled use at therapeutic doses, systemic action generally remains low.
Indications
- Bronchial asthma: in fixed combination with an inhaled glucocorticoid as maintenance therapy, increasingly also as MART reliever medication
- COPD: as maintenance therapy in fixed or free combination with LAMA (e.g. tiotropium) and inhaled glucocorticoids
- Exercise induced asthma: prophylaxis 15 minutes before exertion
- Severe nocturnal asthma symptoms: as addition to maintenance therapy
Dosage and Administration
Asthma maintenance: 6 or 12 µg twice daily in combination with an inhaled glucocorticoid. MART regimen (budesonide formoterol): 2 puffs twice daily plus 1 puff as needed, maximum 12 puffs per day. COPD: 12 µg twice daily, often in fixed combination with LAMA and inhaled glucocorticoid.
Inhalation technique: correct use is critical for therapeutic success. Powder inhaler or metered dose inhaler must be demonstrated before use; spacers for metered dose inhalers increase pulmonary deposition and reduce oropharyngeal deposition. After each inhalation of a glucocorticoid, rinse the mouth.
Renal and hepatic impairment: no formal dose adjustment, caution in severe hepatic impairment because of possible accumulation. Older patients: dose within usual limits, attention to arrhythmia and electrolyte balance.
Side Effects
Common (1 to 10 percent): tremor, palpitations, headache, nervousness, sleep disturbance, muscle cramps, dryness of mouth and throat, hoarseness, cough.
Uncommon (0.1 to 1 percent): tachycardia, hypokalaemia (especially in combination with diuretics or corticosteroids), dizziness, nausea, rash, pruritus.
Rare: paradoxical bronchoconstriction immediately after inhalation (immediate discontinuation, use SABA rescue spray, medical review), cardiac arrhythmias, angina pectoris, peripheral oedema, hyperglycaemia.
LABA monotherapy warning: formoterol as monotherapy without an inhaled glucocorticoid is contraindicated in asthma. A meta analysis of LABA monotherapy showed an increased risk of severe asthma exacerbations and deaths. Combination with an inhaled glucocorticoid offsets this risk.
Interactions
- Other β sympathomimetics: additive cardiac and metabolic effects, avoid combination
- Non selective beta blockers (propranolol): antagonism of bronchodilation, avoid combination
- Diuretics (loop diuretics, thiazides): enhanced hypokalaemia
- Corticosteroids, theophylline: enhanced hypokalaemia and tachycardia
- MAO inhibitors, tricyclic antidepressants: enhanced sympathomimetic side effects
- QT prolonging drugs (quinidine, class III antiarrhythmics, macrolides): additive QT prolongation possible
- Inhalation anaesthetics (halothane, enflurane): increased perioperative arrhythmia risk
Special Notes
Contraindications: hypersensitivity to formoterol, severe arrhythmias, recent myocardial infarction, hypertrophic cardiomyopathy, pheochromocytoma, untreated hyperthyroidism. Asthma monotherapy without ICS is prohibited.
Pregnancy: inhaled formoterol at therapeutic doses is considered acceptable because uncontrolled asthma is riskier for mother and child. Systemic exposure is low. Breastfeeding: passage into breast milk is not fully quantified, breastfeeding during inhaled therapy at usual doses is possible.
Monitoring: check asthma control with the ACT or GINA questionnaire regularly. Check blood count and potassium in severe asthma and combination therapy, heart rate and blood pressure in cardiovascular risk. Review inhalation technique annually because misuse is frequent and clinically relevant.
Rising demand? An increasing need for reliever inhalation or for emergency medication means the underlying disease is uncontrolled. Therapy adjustment and search for causes (allergen exposure, infections, adherence) are required.
You might also be interested in
- Budesonide, most important combination partner in asthma therapy
- Fenoterol, short acting β2 agonist as reliever medication
- Montelukast, leukotriene receptor antagonist as add on
- Ambroxol, secretolytic for productive cough
- Erdosteine, mucolytic in COPD exacerbations
Frequently Asked Questions
How quickly does formoterol work compared to salbutamol?
Formoterol works about as quickly as salbutamol, within 1 to 3 minutes, but the effect lasts up to 12 hours. This is why, in combination with an inhaled glucocorticoid, it can serve as both maintenance and reliever medication, which makes the MART strategy possible.
What is MART therapy?
MART stands for Maintenance and Reliever Therapy. Patients use a budesonide formoterol preparation as daily maintenance and additionally as needed. The regimen reduces severe exacerbations and is a recommended strategy in the GINA guidelines from asthma step 3. A maximum of 12 puffs per day is allowed.
Why must I not take formoterol alone?
Formoterol relieves bronchospasm but does not treat the chronic airway inflammation. Without an inhaled glucocorticoid the risk of severe asthma attacks and asthma related deaths rises. LABA monotherapy in asthma is therefore banned worldwide; combination with an ICS is mandatory.
What should I do in sudden shortness of breath?
During acute breathlessness on formoterol, take an additional inhalation according to your action plan, sit upright and breathe calmly. If there is no improvement after 10 to 15 minutes, marked wheezing, cyanosis or a persistently rapid pulse, call emergency services on 112 immediately. Asthma attacks are often underestimated.
Sources
- Global Initiative for Asthma (GINA)
- AWMF, National Care Guidelines on Asthma and COPD
- Gelbe Liste, Formoterol active substance profile
- BfArM, Federal Institute for Drugs and Medical Devices
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The information provided on this page is for general informational purposes only and does not constitute medical advice, diagnosis or treatment recommendation. It does not replace consultation with a licensed physician or pharmacist. Medicines should only be taken on medical prescription or via a pharmacy. All information is based on product information and recognised scientific sources published at the time of creation; the manufacturer's current summary of product characteristics is always authoritative. Sanoliste assumes no liability for the completeness, timeliness or accuracy of the information presented. In a medical emergency, call the emergency number 112 (Europe).