Dymista Mechanism of Action

Pharmacologic Category: Anti-allergic - Corticosteroid Combination.
Pharmacology: Pharmacodynamics: Mechanism of action and pharmacodynamic effects: Azelastine hydrochloride + Fluticasone propionate (Dymista) Nasal Spray contains azelastine hydrochloride and fluticasone propionate, which have different modes of action and show synergistic effects in terms of improvement of allergic rhinitis and rhino-conjunctivitis symptoms.
Fluticasone propionate: Fluticasone propionate is a synthetic trifluorinated corticosteroid that possesses a very high affinity for the glucocorticoid receptor and has a potent anti-inflammatory action, e.g. 3-5 fold more potent than dexamethasone in cloned human glucocorticoid receptor binding and gene expression assays.
Azelastine hydrochloride: Azelastine, a phthalazinone derivative is classified as a potent long-acting anti-allergic compound with selective H₁-antagonist, mast cell stabilizing and anti-inflammatory properties. Data from in vivo (preclinical) and in vitro studies show that azelastine inhibits the synthesis or release of the chemical mediators known to be involved in early and late stage allergic reactions, e.g. leukotrienes, histamine, platelet-activating factor (PAF) and serotonin.
A relief of nasal allergic symptoms is observed within 15 minutes after administration.
Azelastine hydrochloride + fluticasone propionate (Dymista) Nasal Spray: In 4 clinical studies in adults and adolescents with allergic rhinitis, one spray of Azelastine hydrochloride + Fluticasone propionate (Dymista) in each nostril twice daily significantly improved nasal symptoms (comprising rhinorrhoea, nasal congestion, sneezing and nasal itching) compared with placebo, azelastine hydrochloride alone and fluticasone propionate alone. It significantly improved ocular symptoms (comprising itching, tearing/watering and redness of the eyes) and the patients' disease-related quality of life (Rhinoconjunctivitis Quality of Life Questionnaire - RQLQ) in all 4 studies.
In comparison to a marketed fluticasone propionate nasal spray substantial symptom improvement (50% reduction in nasal symptoms severity) was achieved significantly earlier (3 days and more) with Azelastine hydrochloride + Fluticasone propionate (Dymista) Nasal Spray. The superior effect of Azelastine hydrochloride + Fluticasone propionate (Dymista) Nasal Spray to fluticasone propionate nasal spray was maintained throughout one-year study in patients with chronic persistent allergic rhinitis and nonallergic/vasomotor rhinitis.
Pharmacokinetics: Absorption: After intranasal administration of two sprays per nostril (548 mcg of azelastine hydrochloride and 200 mcg of fluticasone propionate) of Azelastine hydrochloride + Fluticasone propionate (Dymista) Nasal Spray, the mean (± standard deviation) peak plasma exposure (C_max) was 194.5 ± 74.4 pg/mL for azelastine and 10.3 ± 3.9 pg/mL for fluticasone propionate and the mean total exposure (AUC) was 4217 ± 2618 pg/mL*hr for azelastine and 97.7 ± 43.l pg/mL*hr for fluticasone propionate. The median time to peak exposure (t_max) from a single dose was 0.5 hours for azelastine and 1.0 hours for fluticasone propionate.
There was no evidence of pharmacokinetic interactions between azelastine hydrochloride and fluticasone propionate.
Distribution: Fluticasone propionate has a large volume of distribution at steady-state (approximately 318 litre). Plasma protein binding is 91 %.
The volume of distribution of azelastine is high indicating distribution predominantly into the peripheral tissue. The level of protein binding is 80-90%. Additionally, both drugs have broad therapeutic windows. Therefore, drug displacement reactions are unlikely.
Biotransformation: Fluticasone propionate is cleared rapidly from the systemic circulation, principally by hepatic metabolism to an inactive carboxylic acid metabolite, by the cytochrome P450 enzyme CYP3A4. Swallowed fluticasone propionate is also subject to extensive first pass metabolism. Azelastine is metabolized to N-desmethylazelastine via various CYP isoenzymes, mainly CYP3A4, CYP2D6 and CYP2C19.
Elimination: The elimination rate of intravenous administered fluticasone propionate is linear over the 250-1000 microgram dose range and are characterised by a high plasma clearance (CL=1.1 l/min). Peak plasma concentrations are reduced by approximately 98% within 3-4 hours and only low plasma concentrations were associated with the 7.8 h terminal half-life. The renal clearance of fluticasone propionate is negligible (<0.2%) and less than 5% as the carboxylic acid metabolite. The major route of elimination is the excretion of fluticasone propionate and its metabolites in the bile.
Plasma elimination half-lives after a single dose of azelastine are approximately 20-25 hours for azelastine and about 45 hours for the therapeutically active metabolite N-desmethylazelastine. Excretion occurs mainly via the faeces. The sustained excretion of small amounts of the dose in the faeces suggests that some enterohepatic circulation may take place.