Dymista Mechanism of Action

ATC Code: R01AD58.
Pharmacology: Pharmacodynamics: Azelastine hydrochloride, a phthalazinone derivative, inhibits histamine H1 receptor activity in blood vessels and respiratory tract providing hyper-reactivity of airway reduction, bronchial epithelial cilia motility increase and mucociliary transport improvement. The onset of action will be achieved within 30 minutes to 1 hour and reached the maximum effect in 3 hours. The inhibition is lasting for 12 hours.
Fluticasone propionate: It is a synthetic trifluorinated corticosteroid. The precise mechanism for allergic rhinitis symptoms is not known but corticosteroids have been shown a wide range of effects on mediator cells (e.g., basophils, eosinophils, T-helper cells, mast cells, neutrophils) in nasal mucosa, nasal reactivity for allergens, and release of inflammatory mediators and proteolytic enzymes. Additionally, fluticasone propionate may decrease histamine and tryptase releasing from nasal mucosa. The maximum effect of fluticasone propionate may take several days after regular use.
Pharmacokinetics: Absorption: After intranasal administration of two sprays per nostril (548 mcg of azelastine hydrochloride and 200 mcg of fluticasone propionate) of Dymista Nasal Spray, the mean (± standard deviation) peak plasma exposure (Cmax) was 194.5 ± 74.4 pg/mL for azelastine hydrochloride and 10.3±3.9 pg/mL for fluticasone propionate and the AUC was 4217 ± 2618 pg/mL*hr for azelastine hydrochloride and 97.7 ± 43.1 pg/mL*hr for fluticasone propionate. The median time to peak exposure (tmax) from a single dose was 0.5 hours for azelastine hydrochloride and 1.0 hours for fluticasone propionate.
Bioavailability of azelastine from Dymista Nasal Spray following intranasal administration was comparable with monotherapy azelastine hydrochloride (Astelin) nasal spray (i.e., approximately 40%).
Bioavailability of fluticasone from Dymista Nasal Spray following intranasal administration was 44-61% higher than monotherapy fluticasone propionate (bioavailability for monotherapy fluticasone nasal spray was less than 2%). Due to the low intranasal bioavailability, pharmacokinetic data for fluticasone propionate were obtained via other routes of administration. Studies using oral dosing of radiolabeled fluticasone propionate showed negligible oral bioavailability and high extraction from plasma. The majority of the circulating radioactivity was due to an inactive metabolite.
Distribution: Based on intravenous and oral administration, the steady-state volume of distribution of azelastine hydrochloride is 14.5 L/kg. In vitro, indicate that the plasma protein binding of azelastine hydrochloride and its metabolite, desmethylazelastine, are approximately 88% and 97%, respectively.
Following intravenous administration, the volume of distribution averaged 4.2L/kg. The percentage of fluticasone propionate bound to human plasma proteins averaged 91%.
Metabolism: Azelastine hydrochloride is oxidatively metabolized to the principal active metabolite, desmethyl-azelastine, by the cytochrome P450 enzyme system. The specific P450 isoforms responsible for the biotransformation of azelastine have not been identified. The total clearance of azelastine is approximately 0.50 L/kg/hr.
For fluticasone propionate, the only circulating metabolite detected in man is the 17-Beta carboxylic acid derivative, which is formed through the CYP3A4 pathway. This inactive metabolite had less affinity (approximately 1/2,000) than the parent drug for the glucocorticoid receptor of human lung cytosol (In vitro). Other metabolites detected in vitro using cultured human hepatoma cells have not been detected in man. The average total clearance of fluticasone propionate is relatively high (approximately 66 L/hr).
Elimination: Following intranasal administration of Dymista Nasal Spray, the elimination half-life of azelastine hydrochloride is approximately 25 hours. Approximately 75% of an oral dose of radiolabeled azelastine hydrochloride was excreted in the feces with less than 10% as unchanged azelastine.
Following intravenous dosing, fluticasone propionate showed polyexponential kinetics and had a terminal elimination half-life of approximately 7.8 hours. Less than 5% of a radiolabeled oral dose was excreted in the urine as metabolites, with the remainder excreted in the feces as parent drug and metabolites.
Toxicology: Preclinical safety data: Dymista Nasal Spray: No studies of carcinogenicity, mutagenicity, or fertility were conducted with Dymista Nasal Spray; however, studies are available for the individual active components, azelastine hydrochloride and fluticasone propionate, as described as follows.
Azelastine hydrochloride: the carcinogenicity studies in rats and mice, azelastine hydrochloride did not show evidence of carcinogenicity at oral doses up to 30 mg/kg and 25 mg/kg, respectively. These doses were approximately 240 and 100 times of the maximum recommended human daily intranasal dose on a mg/m² basis.
Additionally, there were no genotoxic effects in the Ames test, DNA repair test, mouse lymphoma forward mutation assay, mouse micronucleus test, or chromosomal aberration test in rat bone marrow.
Fertility studies in rats showed no effects on male or female fertility at oral doses up to 30 mg/kg (approximately 240 times of the maximum recommended human daily intranasal dose on a mg/m² basis). At 68.6 mg/kg (approximately 550 times of the maximum recommended human daily intranasal dose on a mg/m² basis), the duration of estrous cycles was prolonged and copulatory activity and the number of pregnancies were decreased. The numbers of corpora lutea and implantations were decreased; however, implantation ratio was not affected.
Fluticasone propionate: no tumorigenic potential in mice at oral doses up to 1,000 mcg/kg (approximately 20 times the maximum recommended daily (MRD) intranasal dose in adults and approximately 10 times the maximum recommended daily intranasal dose in children) for 78 weeks or in rats at inhaled doses up to 57 mcg/kg (approximately 2 times the MRD in adults and equal to MRD intranasal dose in children) for 104 weeks. Moreover, fluticasone propionate did not induce gene mutation in prokaryotic or eukaryotic cells In vitro. No evidence of fertility impairment in male and female rats received subcutaneous doses up to 50 mcg/kg (approximately 2 times the MRD intranasal dose in adults on a mcg/m² basis).