Singapore Drugs Database

Indication

For use as long-term maintenance treatment of asthma in patients 6 years of age and older with reversible obstructive airways disease, including patients with symptoms of nocturnal asthma, who are using optimal corticosteroid treatment and experiencing regular or frequent breakthrough symptoms requiring use of a short-acting bronchodilator. Not indicated for asthma that can be successfully managed with occasional use of an inhaled, short-acting beta2-adrenergic agonist. Also used for the prevention of exercise-induced bronchospasm, as well as long-term treatment of bronchospasm associated with COPD.

Mechanism of Action

The pharmacologic effects of beta2-adrenoceptor agonist drugs, including formoterol, are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3', 5'-adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibits the release of pro-inflammatory mast-cell mediators such as histamine and leukotrienes. Formoterol also inhibits histamine-induced plasma albumin extravasation in anesthetized guinea pigs and inhibits allergen-induced eosinophil influx in dogs with airway hyper-responsiveness. The relevance of these in vitro and animal findings to humans is unknown.

Pharmacokinetics

Absorption

Rapidly absorbed into plasma following administration by oral inhalation. It is likely that the majority of the inhaled formoterol delivered is swallowed and then absorbed from the gastrointestinal tract.

Distribution

Metabolism

Metabolized primarily by direct glucuronidation at either the phenolic or aliphatic hydroxyl group and O-demethylation followed by glucuronide conjugation at either phenolic hydroxyl groups. Minor pathways involve sulfate conjugation of formoterol and deformylation followed by sulfate conjugation. The most prominent pathway involves direct conjugation at the phenolic hydroxyl group. The second major pathway involves O-demethylation followed by conjugation at the phenolic 2'-hydroxyl group. Four cytochrome P450 isozymes (CYP2D6, CYP2C19, CYP2C9 and CYP2A6) are involved in the O-demethylation of formoterol.

Elimination

Clearance

* Renal cl=150 mL/min [Healty subjects receiving oral administration of 80 mcg]

Toxicity

An overdosage is likely to lead to effects that are typical of ß2-adrenergic stimulants: nausea, vomiting, headache, tremor, somnolence, palpitations, tachycardia, ventricular arrhythmias, metabolic acidosis, hypokalemia, hyperglycemia.

Active Ingredient/Synonyms

2'-Hydroxy-5'-(1-hydroxy-2-((P-methoxy-alpha-methylphenethyl)amino)ethyl)formanilide | 2'-Hydroxy-5'-{1-hydroxy-2-[(P-methoxy-alpha-methylphenethyl)amino]ethyl}formanilide | Formoterolum | N-[2-Hydroxy-5-(1-hydroxy-2-{[2-(4-methoxyphenyl)-1-methylethyl]amino}ethyl)phenyl]formamide | Formoterol |

Indication

The inhaler is indicated for the maintenance treatment of asthma as prophylactic therapy. The nasal spray is indicated for the treatment of the nasal symptoms of seasonal allergic and perennial allergic rhinitis.

Mechanism of Action

Unbound corticosteroids cross cell membranes and bind with high affinity to specific cytoplasmic receptors. Inflammation is decreased by diminishing the release of leukocytic acid hydrolases, prevention of macrophage accumulation at inflamed sites, interference with leukocyte adhesion to the capillary wall, reduction of capillary membrane permeability, reduction of complement components, inhibition of histamine and kinin release, and interference with the formation of scar tissue. The antiinflammatory actions of corticosteroids are thought to involve phospholipase A₂ inhibitory proteins, lipocortins, which control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes. Mometasone furoate has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor which is approximately 12 times that of dexamethasone, 7 times that of triamcinolone acetonide, 5 times that of budesonide, and 1.5 times that of fluticasone.

Pharmacokinetics

Absorption

Nasal spray is virtually undetectable in plasma

Distribution

Metabolism

Hepatic. Extensive metabolism to multiple metabolites. There are no major metabolites detectable in plasma. Upon in vitro incubation, one of the minor metabolites formed is 6ß-hydroxy-mometasone furoate. In human liver microsomes, the formation of the metabolite is regulated by cytochrome P-450 3A4.

Elimination

Toxicity

The potential for acute toxic effects following overdose with the mometasone inhaler is low. However, habitual overuse of the product can cause symptoms of steroid overload, including menstrual irregularities, acne, obesity, and muscle weakness. Single oral doses up to 8000 µg have been studied on human volunteers with no adverse events reported.

Active Ingredient/Synonyms

(+)-Mometasone | Mometason | Mometasona | Mométasone | Mometasonum | Mometasone | Mometasone Furoate |