DYMISTA (Page 5 of 8)

10 OVERDOSAGE

DYMISTA: DYMISTA contains both azelastine hydrochloride and fluticasone propionate; therefore, the risks associated with overdosage for the individual components described below apply to DYMISTA.

Azelastine Hydrochloride: There have been no reported overdosages with azelastine hydrochloride. Acute azelastine hydrochloride overdosage by adults with this dosage form is unlikely to result in clinically significant adverse reactions, other than increased somnolence, since one (1) 23 g bottle of DYMISTA contains approximately 23 mg of azelastine hydrochloride. General supportive measures should be employed if overdosage occurs. There is no known antidote to DYMISTA. Oral ingestion of antihistamines has the potential to cause serious adverse effects in children. Accordingly, DYMISTA should be kept out of the reach of children.

Fluticasone Propionate: Chronic fluticasone propionate overdosage may result in signs/symptoms of hypercorticism [see Warnings and Precautions (5.5)].

11 DESCRIPTION

Dymista (azelastine hydrochloride and fluticasone propionate) nasal spray is formulated as a white, uniform metered-spray suspension for nasal administration. It is a fixed dose combination product containing an antihistamine (H1 receptor antagonist) and a corticosteroid as active ingredients.

Azelastine hydrochloride active ingredient occurs as a white, odorless, crystalline powder with a bitter taste. It has a molecular weight of 418.37. It is sparingly soluble in water, methanol, and propylene glycol and slightly soluble in ethanol, octanol, and glycerin. It has a melting point of 225°C and the pH of 5.2. Its chemical name is (±)-1-(2H)-phthalazinone,4-[(4-chlorophenyl) methyl]-2-(hexahydro-1-methyl-1H-azepin-4-yl)-, monohydrochloride. Its molecular formula is C22 H24 ClN3 O•HCl with the following chemical structure:

Azelastine Hydrochloride Structural Formula
(click image for full-size original)

Fluticasone propionate active ingredient is a white powder with a melting point of 273°C, a molecular weight of 500.6, and the empirical formula is C25 H31 F3 O5 S. It is practically insoluble in water, freely soluble in dimethyl sulfoxide and dimethylformamide, and slightly soluble in methanol and 95% ethanol. Fluticasone propionate is a synthetic corticosteroid having the chemical name S-(fluoromethyl)-6α,9-difluoro-11β-17-dihydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioate, 17-propionate, and the following chemical structure:

Fluticasone Propionate Structural Formula
(click image for full-size original)

Dymista (azelastine hydrochloride and fluticasone propionate) nasal spray, 137 mcg/50 mcg contains 0.1% solution of azelastine hydrochloride and 0.037% suspension of micronized fluticasone propionate in an isotonic aqueous suspension containing glycerin, microcrystalline cellulose and carboxymethylcellulose sodium, phenylethyl alcohol (2.5 mg/g), edetate disodium, benzalkonium chloride (0.1 mg/g), polysorbate 80, and purified water. It has a pH of approximately 6.0.

After priming [see Dosage and Administration (2.2)] , each metered spray delivers a 0.137 mL mean volume of suspension containing 137 mcg of azelastine hydrochloride (equivalent to 125 mcg of azelastine base) and 50 mcg of fluticasone propionate. The 23 g bottle provides 120 metered sprays, after priming.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

DYMISTA

DYMISTA contains both azelastine hydrochloride and fluticasone propionate; therefore, the mechanisms of actions described below for the individual components apply to DYMISTA. These drugs represent two different classes of medications (histamine H1 -receptor antagonist and synthetic corticosteroid).

Azelastine Hydrochloride

Azelastine hydrochloride, a phthalazinone derivative, exhibits histamine H1 -receptor antagonist activity in isolated tissues, animal models, and humans. Azelastine hydrochloride in DYMISTA is administered as a racemic mixture with no difference in pharmacologic activity noted between the enantiomers in in vitro studies. The major metabolite, desmethylazelastine, also possesses H1 -receptor antagonist activity.

Fluticasone Propionate

Fluticasone propionate is a synthetic trifluorinated corticosteroid with anti-inflammatory activity. In vitro dose response studies on a cloned human glucocorticoid receptor system involving binding and gene expression afforded 50% responses at 1.25 and 0.17 nM concentrations, respectively. Fluticasone propionate was 3-fold to 5-fold more potent than dexamethasone in these assays. Data from the McKenzie vasoconstrictor assay in man also support its potent glucocorticoid activity. The clinical relevance of these findings is unknown.

The precise mechanism through which fluticasone propionate affects allergic rhinitis symptoms is not known. Corticosteroids have been shown to have a wide range of effects on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines) involved in inflammation.

12.2 Pharmacodynamics

Cardiac Electrophysiology

In a placebo-controlled trial (95 patients with allergic rhinitis), there was no evidence of an effect of azelastine hydrochloride nasal spray (2 sprays per nostril twice daily for 56 days) on cardiac repolarization as represented by the corrected QT interval (QTc) of the electrocardiogram. Following multiple dose oral administration of azelastine 4 mg or 8 mg twice daily, the mean change in QTc was 7.2 msec and 3.6 msec, respectively.

Interaction studies investigating the cardiac repolarization effects of concomitantly administered oral azelastine hydrochloride and erythromycin or ketoconazole were conducted. These drugs had no effect on QTc based on analysis of serial electrocardiograms.

12.3 Pharmacokinetics

Absorption

After nasal administration of two sprays per nostril (548 mcg of azelastine hydrochloride and 200 mcg of fluticasone) of DYMISTA, the mean (± standard deviation) peak plasma exposure (Cmax ) 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 ± 43.1 pg/mL*hr for fluticasone. The median time to peak exposure (tmax ) from a single dose was 0.5 hours for azelastine and 1.0 hours for fluticasone.

Systemic bioavailability of azelastine from DYMISTA following nasal administration was comparable with monotherapy azelastine hydrochloride (Astelin®) nasal spray (i.e., approximately 40%). Systemic bioavailability of fluticasone from DYMISTA following nasal administration was 44-61% higher than monotherapy fluticasone propionate (bioavailability for monotherapy fluticasone nasal spray was less than 2%). Due to the low nasal 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 studies with human plasma indicate that the plasma protein binding of azelastine hydrochloride and its metabolite, desmethylazelastine, are approximately 88% and 97%, respectively.

Following intravenous administration, the initial disposition phase for fluticasone propionate was rapid and consistent with its high lipid solubility and tissue binding. The volume of distribution averaged 4.2 L/kg.

The percentage of fluticasone propionate bound to human plasma proteins averaged 91% with no obvious concentration relationship. Fluticasone propionate is weakly and reversibly bound to erythrocytes and freely equilibrates between erythrocytes and plasma. Fluticasone propionate is not significantly bound to human transcortin.

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