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Mechanism Of Action
Azelastine hydrochloride, a phthalazinone derivative, exhibits histamine H1-receptor antagonist activity in isolated tissues, animal models, and humans. Astelin 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.
In a placebo-controlled study (95 subjects with allergic rhinitis), there was no evidence of an effect of Astelin 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. At a dose approximately 8 times the maximum recommended dose, azelastine hydrochloride does not prolong the QTc interval to any clinically relevant extent.
After intranasal administration, the systemic bioavailability of azelastine hydrochloride is approximately 40%. Maximum plasma concentrations (Cmax) are achieved in 23 hours.
Azelastine hydrochloride administered intranasally at doses above two sprays per nostril twice daily for 29 days resulted in greater than proportional increases in Cmax and area under the curve (AUC) for azelastine.
Based on intravenous and oral administration, the steady-state volume of distribution is 14.5 L/kg. In vitro studies with human plasma indicate that the plasma protein binding of azelastine and its metabolite, desmethylazelastine, are approximately 88% and 97%, respectively.
Azelastine 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. After intranasal dosing of azelastine hydrochloride to steady-state, plasma concentrations of desmethylazelastine range from 20-50% of azelastine concentrations. Limited data indicate that the metabolite profile is similar when azelastine hydrochloride is administered via the intranasal or oral route.
Based on intravenous and oral administration, the elimination half-life and plasma clearance are 22 hours and 0.5 L/h/kg, respectively. Approximately 75% of an oral dose of radiolabeled azelastine hydrochloride was excreted in the feces with less than 10% as unchanged azelastine.
Hepatic Impairment: Following oral administration, pharmacokinetic parameters were not influenced by hepatic impairment.
Renal Impairment: Based on oral, single-dose studies, renal insufficiency (creatinine clearance < 50 mL/min) resulted in a 70-75% higher Cmax and AUC compared to normal subjects. Time to maximum concentration was unchanged.
Age: Following oral administration, pharmacokinetic parameters were not influenced by age.
Gender: Following oral administration, pharmacokinetic parameters were not influenced by gender.
Race: The effect of race has not been evaluated.
Erythromycin: No significant pharmacokinetic interaction was observed with the coadministration of orally administered azelastine (4 mg twice daily) with erythromycin (500 mg three times daily for 7 days). In this study, co-administration of orally administered azelastine with erythromycin 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.
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 (4 mg twice daily) concentrations by approximately 65%. No pharmacokinetic interaction was observed with co-administration of orally administered azelastine (4 mg twice daily) with ranitidine hydrochloride (150 mg twice daily). Oral co-administration of azelastine with ranitidine resulted in Cmax of 8.89 ±3.28 ng/mL and AUC of 88.22 ± 40.43 ng•h/mL for azelastine, whereas, azelastine when administered alone resulted in Cmax of 7.83 ± 4.06 ng/mL and AUC of 80.09 ± 43.55 ng•h/mL for azelastine.
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.
Seasonal Allergic Rhinitis
Two Sprays Per Nostril Twice Daily
The efficacy and safety of Astelin Nasal Spray were evaluated in three placebo-controlled clinical trials of Astelin Nasal Spray including 322 patients with seasonal allergic rhinitis who received two sprays per nostril twice a day for up to 4 weeks. These trials included 55 pediatric patients ages 12 to 16 years. Assessment of efficacy was based on the 12-hour reflective Total Symptom Complex (TSC) and Major Symptom Complex (MSC). The MSC was calculated as the average of individual symptoms of nose blows, sneezes, runny nose/sniffles, itchy nose, and watery eyes as assessed by patients on a 0-5 categorical scale. Astelin Nasal Spray two sprays per nostril twice daily demonstrated a greater decrease in the MSC than placebo (Table 3).
Table 3: Mean Change from Baseline in Reflective MSC*
in Adults and Adolescents ≥ 12 Years with Seasonal Allergic Rhinitis
Treated with Astelin Nasal Spray Two Sprays Per Nostril Twice Daily Versus
|Treatment||N||Baseline LS Mean (SD)||Change from Baseline (SD)||Treatment Difference||P-value|
|Trial 1: 12 Hour AM and PM Reflective MSC|
|Astelin Nasal Spray||63||11.48 (4.13)||-3.05 (3.51)||1.98||< 0.01|
|Placebo Nasal Spray||60||10.84 (4.53)||-1.07 (3.52)|
|Trial 2: 12 Hour AM and PM Reflective MSC|
|Astelin Nasal Spray||63||12.50 (4.5)||-4.10 (3.46)||2.03||< 0.01|
|Placebo Nasal Spray||63||12.18 (4.64)||-2.07 (4.01)|
|Trial 3: 12 Hour AM and PM Reflective MSC|
|Astelin Nasal Spray||66||12.04 (4.03)||-3.31 (3.74)||1.35||0.04|
|66||11.66 (3.96)||-1.96 (3.57)|
|* Major Symptom Comlex (MSC): Average of individual symptoms of nose blows, sneezes, runny nose/sniffles, itchy nose, and watery eyes as assessed by patients on a 0-5 categorical scale.|
In dose-ranging trials, administration of Astelin Nasal Spray two sprays per nostril twice daily resulted in a statistically significant decrease in symptoms compared to saline placebo within 3 hours after initial dosing and persisted over the 12-hour dosing interval.
One Spray Per Nostril Twice Daily
The efficacy and safety of Astelin Nasal Spray were evaluated in two placebo-controlled clinical trials of Astelin Nasal Spray including 275 patients with seasonal allergic rhinitis who received one spray per nostril twice a day for up to 2 weeks. Assessment of efficacy was based on the 12hour reflective Total Nasal Symptom Score [rTNSS]. rTNSS is calculated as the sum of the patients scoring of four individual nasal symptoms (runny nose, sneezing, itchy nose, and nasal congestion) as assessed by patients on a 0-3 categorical scale. The primary efficacy endpoint was the change from Baseline to Day 14 in rTNSS. The mean change from baseline in rTNSS was greater in patients receiving Astelin Nasal Spray one spray per nostril twice daily than those receiving placebo (Table 4).
Table 4: Mean Change from Baseline in Reflective TNSS*
in Adults and Adolescents ≥ 12 years with Seasonal Allergic Rhinitis
Treated with Astelin Nasal Spray One Spray Per Nostril Twice Daily Versus
|Treatment||N||Baseline LS Mean (SD)||Change from Baseline (SD)||Treatment Difference||P-value|
|Trial 4: 12 Hour AM and PM Reflective TNSS|
|Astelin Nasal Spray||138||16.34 (4.22)||-2.69 (4.79)||1.38||0.01|
|Placebo Nasal Spray||141||17.21 (4.32)||-1.31 (4.29)|
|Trial 5: 12 Hour AM and PM Reflective TNSS|
|Astelin Nasal Spray||137||16.62 (4.20)||-3.68 (4.16)||1.18||0.02|
|Placebo Nasal Spray||136||16.84 (4.77)||-2.50 (4.01)|
|* Total Nasal Symptom Score (TNSS): Average of individual symptoms of runny nose, sneezing, itchy nose, and nasal congestion as assessed by patients on a 0-3 categorical scale.|
Two-week studies comparing the efficacy (and safety) of Astelin Nasal Spray two sprays per nostril twice daily versus one spray per nostril twice daily were not conducted.
The efficacy and safety of Astelin Nasal Spray were evaluated in two placebo-controlled clinical trials of Astelin Nasal Spray including 216 patients with vasomotor rhinitis who received two sprays per nostril twice a day for up to 4 weeks. These patients had vasomotor rhinitis for at least one year, negative skin tests to indoor and outdoor aeroallergens, negative nasal smears for eosinophils, and negative sinus X-rays. Astelin Nasal Spray demonstrated a significantly greater decrease in a symptom complex comprised of rhinorrhea, post nasal drip, nasal congestion, and sneezing compared to placebo.
Last reviewed on RxList: 12/1/2014
This monograph has been modified to include the generic and brand name in many instances.
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