Formoterol Fumarate Dihydrate: Salt Form of Formoterol as a Long Acting Beta 2 Sympathomimetic (LABA)
Formoterol fumarate dihydrate is the salt form of the active substance formoterol used in inhaled medications, a long acting beta 2 agonist (LABA) with rapid onset of action. Known brand names include Foradil, Oxis Turbuhaler and in fixed combination products Symbicort (with budesonide), Foster (with beclomethasone dipropionate), DuoResp Spiromax (with budesonide), Trimbow (with beclomethasone dipropionate and glycopyrronium). The fumarate dihydrate salt form provides good stability in powder and pressurized gas inhalers.
The special characteristic of formoterol is the combination of 12 hours duration of action with rapid onset of action within 1 to 3 minutes. Unlike salmeterol, another LABA with slower onset of action, formoterol can also be used for acute treatment of an asthma attack, which forms the basis of the MART concept (Maintenance and Reliever Therapy).
Mechanism of Action and Salt Form
The fumarate dihydrate salt dissociates rapidly after inhalation into active formoterol and fumaric acid. Pharmacologically, the effect is exclusively due to formoterol.
Formoterol selectively binds to beta 2 adrenergic receptors in the smooth bronchial muscle. Via activation of adenylyl cyclase and increase of intracellular cAMP, the smooth muscle relaxes, leading to bronchodilation. The high lipophilic property of formoterol allows storage in the membrane space with reserve formation, explaining the long duration of action of approximately 12 hours. At the same time, the hydrophilic component is sufficient for rapid diffusion to the receptor binding site, mediating the rapid onset of action.
Additionally, formoterol has mast cell stabilizing properties and reduces histamine release, complementing the anti-inflammatory effect of concomitant inhaled glucocorticoids. The combined effect in fixed combination products (ICS LABA) is standard therapy for asthma and COPD.
Indications
- Asthma bronchiale: in combination with inhaled glucocorticoids (ICS LABA), not as monotherapy
- COPD (chronic obstructive pulmonary disease): as maintenance therapy, combined with ICS or LAMA
- MART therapy (Maintenance and Reliever Therapy) in asthma: Formoterol budesonide fixed combination as maintenance and as needed medication
- Exercise induced asthma: prophylaxis before sport
Dosage and Administration
Maintenance therapy: 4.5 to 12 micrograms formoterol per actuation, one to two actuations twice daily. Maximum daily dose 24 micrograms with pure LABA use, up to 48 micrograms in MART scheme.
MART scheme (Symbicort, DuoResp): 200/6 micrograms two actuations twice daily plus additionally as needed up to a maximum of 8 additional actuations per day (total maximum 12 actuations).
Administration: via powder or pressurized gas inhaler. Correct inhalation technique is essential for efficacy. Patients should be instructed by a physician or pharmacist. After inhalation, rinse mouth to avoid oral candidiasis and hoarseness.
In children from 6 years: lower doses, individually as prescribed.
Side Effects
Common: fine tremor (hands), tachycardia, palpitations, headache, dry mouth, local throat irritation, hoarseness, cough after inhalation.
Occasional to rare: hypokalemia (especially at high doses or combination with corticosteroids, diuretics), muscle cramps, hyperglycemia, sleep disturbances, nervousness, paradoxical bronchospasm on inhalation, arrhythmias.
Serious: with LABA monotherapy alone without ICS in asthma increased mortality risk (Black Box Warning from FDA), which is why LABA in asthma must always be prescribed in combination with ICS.
Important: the Black Box Warning for LABA monotherapy in asthma has been documented by large studies (SMART, AUSTRI, VESTRI). In fixed ICS LABA combinations, the risk is not increased. Pure formoterol monotherapy without ICS is not permitted in asthma.
Interactions
- Beta blockers (especially non selective such as propranolol): antagonism of bronchodilation, contraindicated in asthma, selective beta 1 blockers with caution
- Other sympathomimetics: additive cardiovascular effects
- Diuretics and glucocorticoids: additive hypokalemia
- Theophylline: additive tachycardia, tremor and hypokalemia
- MAO inhibitors and tricyclic antidepressants: enhanced cardiovascular effect
- Volatile inhalational anesthetics: risk of severe arrhythmias
Special Precautions
Pregnancy: data on use in pregnancy are limited, experience with asthma therapy supports safety. In asthma during pregnancy, adequate therapy is important because uncontrolled asthma is more dangerous for mother and fetus than the medications.
Children from 6 years: approved in this age group for asthma therapy, inhalation technique adjusted with spacer or powder inhaler.
Inhalation technique: correct inhalation is essential for efficacy. Powder inhalers require a forceful breath, pressurized gas inhalers a coordinated slow deep inhalation. Training in practice or pharmacy is highly recommended.
Asthma stewardship: if the reliever inhaler is used frequently (more than 2 times per week with pure reliever use, or high MART need), asthma control is insufficient and therapy should be adjusted. Current GINA recommendations prefer ICS LABA fixed combinations instead of SABA monotherapy.
You Might Also Be Interested In
- Formoterol, detailed pillar page on the active substance
- Salbutamol, short acting beta 2 sympathomimetic (SABA)
- Salmeterol, another LABA with slower onset of action
- Budesonide, inhaled glucocorticoid in combination products
- Beclomethasone dipropionate, another ICS in Foster and Trimbow
Frequently Asked Questions
What is the difference between formoterol and salmeterol?
Both are LABAs with approximately 12 hours duration of action. Formoterol has rapid onset of action within 1 to 3 minutes, salmeterol only after approximately 30 minutes. Therefore, formoterol can also be used for acute treatment of an asthma attack (in the MART scheme), salmeterol cannot. Both are used in asthma always in combination with ICS.
What is MART?
MART (Maintenance and Reliever Therapy) is a modern asthma therapy concept in which a formoterol budesonide fixed combination is used both as regular maintenance therapy and as as needed medication. With each as needed use, an additional dose of ICS is simultaneously inhaled, which improves asthma control and prevention of exacerbations.
Why can I not use formoterol alone in asthma?
Studies (SMART) have shown that LABA monotherapy alone in asthma increases the risk of severe asthma attacks and asthma related mortality. The FDA has issued a Black Box Warning. In combination with ICS in fixed combinations, the risk is not increased, which is why LABAs in asthma must always be combined with ICS.
What to do about tremor with formoterol?
Fine tremor of the hands is a common, harmless side effect of beta 2 stimulation and occurs especially at the beginning of therapy. It often improves after a few weeks of use. In case of intolerable tremor, dose reduction or switching to another LABA can be considered.
Sources
- Gelbe Liste, Formoterol active substance profile
- GINA Global Initiative for Asthma recommendations
- GOLD recommendations COPD
- BfArM, Federal Institute for Drugs and Medical Devices
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