Recommended Topic Related To:

Dymista

"April 24, 2014 -- As many as 4 in 10 Americans have sneezing, runny nose, and watery eyes due to allergies. If you're one of them, allergy shots can help ease your reaction to the plants, insects, or animals that trigger your symptoms. But they r"...

Dymista

CLINICAL PHARMACOLOGY

Mechanism of Action

Dymista Nasal Spray

Dymista Nasal Spray contains both azelastine hydrochloride and fluticasone propionate; therefore, the mechanisms of actions described below for the individual components apply to Dymista Nasal Spray. 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 Nasal Spray 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.

Pharmacodynamics

Cardiac Effects

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.

Pharmacokinetics

Absorption

After intranasal administration of two sprays per nostril (548 mcg of azelastine hydrochloride and 200 mcg of fluticasone) of Dymista Nasal Spray, 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 Nasal Spray following intranasal administration was comparable with monotherapy azelastine hydrochloride (Astelin® ) nasal spray (i.e., approximately 40%). Systemic 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 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.

Metabolism

Azelastine hydrochloride is oxidatively metabolized to the principal active metabolite, desmethylazelastine, 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 17β-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 and negligible pharmacological activity in animal studies. 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.

Special Populations

Dymista Nasal Spray was not studied in any special populations, and no gender-specific pharmacokinetic data have been obtained.

Hepatic Impairment: Following oral administration of azelastine hydrochloride, pharmacokinetic parameters were not influenced by hepatic impairment.

Renal Impairment: Based on oral, single-dose studies of azelastine hydrochloride, renal impairment (creatinine clearance < 50 mL/min) resulted in a 70-75% higher Cmax and AUC compared to healthy subjects. Time to maximum concentration was unchanged.

Age: Following oral administration of azelastine hydrochloride, pharmacokinetic parameters were not influenced by age.

Gender: Following oral administration of azelastine hydrochloride, pharmacokinetic parameters were not influenced by gender.

Race: The effect of race has not been evaluated.

Drug-Drug Interactions

No formal drug interaction studies have been performed with Dymista Nasal Spray. The drug interactions of the combination are expected to reflect those of the individual components.

Erythromycin: Coadministration of orally administered azelastine (4 mg twice daily) with erythromycin (500 mg three times daily for 7 days) resulted in Cmax of 5.36 ± 2.6 ng/mL and AUC of 49.7 ± 24 ng•h/mL for azelastine, whereas, administration of azelastine alone resulted in Cmax of 5.57 ± 2.7 ng/mL and AUC of 48.4 ± 24 ng•h/mL for azelastine.

In another multiple-dose drug interaction study, coadministration of orally inhaled fluticasone propionate (500 mcg twice daily) and erythromycin (333 mg three times daily) did not affect fluticasone propionate pharmacokinetics.

Cimetidine and Ranitidine: In a multiple-dose, steady-state drug interaction trial in healthy subjects, cimetidine (400 mg twice daily) increased orally administered mean azelastine hydrochloride (4 mg twice daily) concentrations by approximately 65%. Coadministration of orally administered azelastine hydrochloride (4 mg twice daily) with ranitidine hydrochloride (150 mg twice daily) resulted in Cmax of 8.89 ± 3.28 ng/mL and AUC of 88.22 ± 40.43 ng•h/mL for azelastine hydrochloride, whereas, administration of azelastine hydrochloride alone resulted in Cmax of 7.83 ± 4.06 ng/mL and AUC of 80.09 ± 43.55 ng•h/mL for azelastine hydrochloride.

Theophylline: No significant pharmacokinetic interaction was observed with the coadministration of an oral 4 mg dose of azelastine hydrochloride twice daily and theophylline 300 mg or 400 mg twice daily.

Ritonavir: Coadministration of fluticasone propionate and the strong CYP3A4 inhibitor, ritonavir, is not recommended based upon a multiple-dose, crossover drug interaction study in 18 healthy subjects. Fluticasone propionate aqueous nasal spray (200 mcg once daily) was coadministered for 7 days with ritonavir (100 mg twice daily). Plasma fluticasone propionate concentrations following fluticasone propionate aqueous nasal spray alone were undetectable ( < 10 pg/mL) in most subjects, and when concentrations were detectable, peak levels (Cmax) averaged 11.9 pg/mL (range, 10.8 to 14.1 pg/mL) and AUC(0-τ) averaged 8.43 pg•hr/mL (range, 4.2 to 18.8 pg•hr/mL). Fluticasone propionate Cmax and AUC(0-τ) increased to 318 pg/mL (range, 110 to 648 pg/mL) and 3,102.6 pg•hr/mL (range, 1,207.1 to 5,662.0 pg•hr/mL), respectively, after coadministration of ritonavir with fluticasone propionate aqueous nasal spray. This significant increase in plasma fluticasone propionate exposure resulted in a significant decrease (86%) in plasma cortisol area under the plasma concentration versus time curve (AUC).

Caution should be exercised when other strong CYP3A4 inhibitors are coadministered with fluticasone propionate. In a drug interaction study, coadministration of orally inhaled fluticasone propionate (1,000 mcg) and ketoconazole (200 mg once daily) resulted in increased fluticasone propionate exposure and reduced plasma cortisol AUC, but had no effect on urinary excretion of cortisol. [see DRUG INTERACTIONS]

Clinical Studies

The efficacy and safety of Dymista Nasal Spray in seasonal allergic rhinitis was evaluated in 3 randomized, multicenter, double-blind, placebo-controlled clinical trials in 853 adult and adolescent patients 12 years and older with seasonal allergic rhinitis. The population of the trials was 12 to 78 years of age (64% female, 36% male; 80% white, 16% black, 2% Asian, 1% other).

Patients were randomized to one of four treatment groups: one spray per nostril twice daily of Dymista Nasal Spray, azelastine hydrochloride nasal spray, fluticasone propionate nasal spray, and vehicle placebo. The azelastine hydrochloride and fluticasone propionate comparators use the same device and vehicle as Dymista Nasal Spray and are not commercially marketed.

Assessment of efficacy was based on the reflective total nasal symptom score (rTNSS), in addition to the instantaneous total nasal symptom score (iTNSS) and other supportive secondary efficacy variables. TNSS is calculated as the sum of the patients' scoring of the 4 individual nasal symptoms (rhinorrhea, nasal congestion, sneezing, and nasal itching) on a 0 to 3 categorical severity scale (0 = absent, 1 = mild, 2 = moderate, 3 = severe). Patients were required to record symptom severity daily reflecting over the previous 12 hours (morning, AM, and evening, PM). For the primary efficacy endpoint, the combined AM+PM rTNSS (maximum score of 24) was assessed as a change from baseline for each day and then averaged over a 2week treatment period. The primary efficacy endpoint was the mean change from baseline in combined AM+PM rTNSS over 2 weeks. The iTNSS was recorded immediately prior to the next dose.

In these trials, Dymista Nasal Spray demonstrated statistically significant greater decreases in rTNSS as compared to azelastine hydrochloride and to fluticasone propionate, as well as to placebo. The differences between the monotherapies and placebo also were statistically significant. Representative results from one of the trials are shown below (Table 2).

Table 2: Mean Change from Baseline in Reflective Total Nasal Symptom Scores over 2 Weeks* in Adults and Children ≥ 12 years with Seasonal Allergic Rhinitis

Treatment (one spray /nostril twice daily) N Baseline Change from Baseline Difference From Dymista Nasal Spray
LS Mean LS Mean LS Mean 95% CI P-value
Dymista Nasal Spray 207 18.3 -5.6 - - -
Azelastine HCl Nasal Spray† 208 18.3 -4.3 -1.4 (-2.2, -0.5) 0.002
Fluticasone Propionate Nasal Spray† 207 18.2 -4.7 -1 (-1.8, -0.2) 0.022
Placebo 209 18.6 -2.9 -2.7 (-3.5, -1.9) < 0.001
* Sum of AM and PM rTNSS for each day (Maximum Score =24) and averaged over the 14 day treatment period
† Not commercially marketed
LS Mean, 95% CI, and p-value are obtained from the repeated-measures analysis of covariance model using observed data.

In these trials, Dymista Nasal Spray also demonstrated statistically significant, greater decreases in iTNSS as compared to placebo, as did the azelastine hydrochloride and fluticasone propionate comparators. Representative results from one of the trials are shown below (Table 3).

Table 3: Mean Change from Baseline in Instantaneous Total Nasal Symptom Scores over 2 Weeks* in Adults and Children ≥ 12 years with Seasonal Allergic Rhinitis

Treatment (one spray /nostril twice daily) N Baseline Change from Baseline Difference From Placebo
LS Mean LS Mean LS Mean 95% CI P-value
Dymista Nasal Spray 207 17.2 -5.2 -2.6 (-3.4, -1.8) < 0.001
Azelastine HCl Nasal Spray† 208 16.8 -3.9 -1.3 (-2.0, -0.6) < 0.001
Fluticasone Propionate Nasal Spray† 207 16.8 -4.5 -1.9 (-2.6, -1.2) < 0.001
Placebo 209 17.3 -2.7 - - -
* Sum of AM and PM iTNSS for each day (Maximum Score =24) and averaged over the 14 day treatment period
† Not commercially marketed
LS Mean, 95% CI, and p-value are obtained from the repeated-measures analysis of covariance model using observed data.

Onset of action, defined as the first timepoint at which Dymista Nasal Spray was statistically superior to placebo in the mean change from baseline in iTNSS and which was sustained thereafter, was assessed in each of the three trials. Onset of action was observed as early as 30 minutes following the initial dose of Dymista Nasal Spray.

The subjective impact of seasonal allergic rhinitis on patient's health-related quality of life was evaluated by the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) (28 items in 7 domains (activities, sleep, non-nose/eye symptoms, practical problems, nasal symptoms, eye symptoms, and emotional) evaluated on a 7-point scale where 0=no impairment and 6=maximum impairment), which was administered to patients 18 years of age and older. An overall RQLQ score is calculated from the mean of all items in the instrument. A change from baseline of at least 0.5 points is considered a clinically meaningful improvement. In each of these trials, Dymista Nasal Spray demonstrated a statistically significant greater decrease from baseline in the overall RQLQ than placebo, which ranged from -0.55 (95% CI -0.72, -0.39) to -0.80 (95% CI -1.05, -0.55). In these trials, the treatment differences between Dymista Nasal Spray and the monotherapies were less than the minimum important difference of 0.5 points.

Last reviewed on RxList: 9/13/2012
This monograph has been modified to include the generic and brand name in many instances.

A A A

Report Problems to the Food and Drug Administration

 

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.


Allergies & Asthma

Improve treatments & prevent attacks.


NIH talks about Ebola on WebMD