asmanex (Mometasone Furoate) inhalant
[Schering Corporation]
PRODUCT INFORMATION
FOR ORAL INHALATION ONLY
DESCRIPTION
Mometasone furoate, the active component of the ASMANEX TWISTHALER product, is a corticosteroid with the chemical name 9,21-dichloro-11(Beta),17-dihydroxy-16 (alpha)-methylpregna-1,4-diene-3,20-dione 17-(2-furoate) and the following chemical structure:
Mometasone furoate is a white powder with an empirical formula of C27H30Cl2O6, and molecular weight 521.44 Daltons.
The ASMANEX TWISTHALER 220 mcg product is a cap-activated inhalation-driven multi-dose dry powder inhaler containing mometasone furoate and anhydrous lactose (which contains milk proteins). Each actuation of the ASMANEX TWISTHALER 220 mcg inhaler provides a measured dose of 1.5 mg mometasone furoate inhalation powder, containing 220 mcg of mometasone furoate. This results in delivery of 200 mcg mometasone furoate from the mouthpiece, based on in vitro testing at flow rates of 30 L/min and 60 L/min with constant volume (2 L). The amount of mometasone furoate emitted from the inhaler in vitro did not differ significantly for flow rates ranging from 28.3 L/min to 70 L/min for fixed intervals of 2 seconds. However, the amount of drug delivered to the lung will depend on patient factors such as inspiratory flow and peak inspiratory flow through the device. In adult and adolescent patients with varied asthma severity, mean peak inspiratory flow rate through the device was 69 L/min (range 54–77 L/min).
CLINICAL PHARMACOLOGY
Mechanism of Action
Mometasone furoate is a corticosteroid demonstrating potent anti-inflammatory activity. The precise mechanism of corticosteroid action on asthma is not known. Inflammation is an important component in the pathogenesis of asthma. Corticosteroids have been shown to have a wide range of inhibitory effects on multiple cell types (eg, mast cells, eosinophils, neutrophils, macrophages and lymphocytes) and mediators (eg, histamine, eicosanoids, leukotrienes, and cytokines) involved in inflammation and in the asthmatic response. These anti-inflammatory actions of corticosteroids may contribute to their efficacy in asthma.
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. The clinical significance of these findings is unknown.
In a three-way cross over study in 15 asthmatic patients receiving 50 or 100 mcg of mometasone furoate inhalation powder to placebo twice daily for two weeks, mometasone furoate inhalation powder reduced airway reactivity to adenosine monophosphate. In another study, pretreatment with mometasone furoate inhalation powder for 5 days attenuated the early and late phase reactions following inhaled allergen challenge and also reduced allergen-induced hyperresponsiveness to methacholine. Mometasone furoate inhalation powder was also shown to attenuate the increase in inflammatory cells (total and activated eosinophils) in induced sputum following allergen and methacholine challenge. The clinical significance of these findings is unknown.
Studies in asthmatic patients have demonstrated that ASMANEX TWISTHALER provides a favorable ratio of topical to systemic activity due to its primary local effect along with the extensive hepatic metabolism and the lack of active metabolites (see below).
Though effective for the treatment of asthma, glucocorticoids do not affect asthma symptoms immediately. Maximum improvement in symptoms following inhaled administration of mometasone furoate may not be achieved for 1 to 2 weeks or longer after starting treatment. When glucocorticoids are discontinued, asthma stability may persist for several days or longer.
Pharmacokinetics
Absorption
Following a 1000 mcg inhaled dose of tritiated mometasone furoate inhalation powder to 6 healthy human subjects, plasma concentrations of unchanged mometasone furoate were shown to be very low compared to the total radioactivity in plasma. Following an inhaled single 400 mcg dose of ASMANEX TWISTHALER treatment to 24 healthy subjects, plasma concentrations for most subjects were near or below the lower limit of quantitation for the assay (50 pcg/mL). The mean absolute systemic bioavailability of the above single inhaled 400 mcg dose, compared to an intravenous 400 mcg dose of mometasone furoate, was determined to be less than 1%. Following administration of the recommended highest inhaled dose (400
