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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.
Pharmacokinetics and Metabolism
After intranasal administration, the systemic bioavailability of azelastine hydrochloride is approximately 40%. Maximum plasma concentrations (Cmax) are achieved in 2-3 hours. Based on intravenous and oral administration, the elimination half-life, steady-state volume of distribution, and plasma clearance are 22 hours, 14.5 L/kg, 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. 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; however, clinical interaction studies with the known CYP3A4 inhibitor erythromycin failed to demonstrate a pharmacokinetic interaction. In a multiple-dose, steady-state drug interaction study in normal volunteers, cimetidine (400 mg twice daily), a nonspecific P450 inhibitor, raised orally administered mean azelastine (4 mg twice daily) concentrations by approximately 65%.
The major active metabolite, desmethylazelastine, was not measurable (below assay limits) after single-dose intranasal administration of azelastine hydrochloride. After intranasal dosing of azelastine hydrochloride to steady-state, plasma concentrations of desmethylazelastine range from 20-50% of azelastine concentrations. When azelastine hydrochloride is administered orally, desmethylazelastine has an elimination half-life of 54 hours. Limited data indicate that the metabolite profile is similar when azelastine hydrochloride is administered via the intranasal or oral route.
In vitro studies with human plasma indicate that the plasma protein binding of azelastine and desmethylazelastine are approximately 88% and 97%, respectively.
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. Studies in healthy subjects administered oral doses of azelastine hydrochloride demonstrated linear responses in Cmax and AUC.
Following oral administration, pharmacokinetic parameters were not influenced by age, gender, or hepatic 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.
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. At higher oral exposures ( 4 mg twice daily), a nonclinically significant mean change on the QTc (3-7 millisecond increase) was observed.
Interaction studies investigating the cardiac repolarization effects of concomitantly administered oral azelastine hydrochloride and erythromycin or ketoconazole were conducted. Oral erythromycin had no effect on azelastine pharmacokinetics or QTc based on analysis of serial electrocardiograms. Ketoconazole interfered with the measurement of azelastine plasma levels; however, no effects on QTc were observed (see PRECAUTIONS: DRUG INTERACTIONS).
Seasonal Allergic Rhinitis
Trials Supporting Two Sprays Per Nostril Twice Daily
U.S. placebo-controlled clinical trials of Astelin® Nasal Spray included 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. Astelin® Nasal Spray showed significant improvement compared to placebo in the two primary efficacy variables- the Total Symptom Complex (TSC) and the Major Symptom Complex (MSC).The results for the MSC are shown in Table 1 as the mean change from Baseline in 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.
Table 1: Summary of Primary Efficacy* Analyses for
Pivotal Studies Supporting Two Sprays Per Nostril Twice Daily.
|Astelin® Nasal Spray||Placebo Nasal Spray||Outcomes
Astelin® vs. Placebo
|Mean (SD)||Difference between Treatments||P value|
|Study 26: 12 Hour AM and PM Reflective MSC|
|Baseline||11.48 (4.13)||10.84 (4.53)|
|Change from Baseline||-3.05 (3.51)||-1.07 (3.52)||1.98||0.0024|
|Study 31: 12 Hour AM and PM Reflective MSC|
|Baseline||12.50 (4.5)||12.18 (4.64)|
|Change from Baseline||-4.10 (3.46)||-2.07 (4.01)||2.03||0.0023|
|Study 33: 12 Hour AM and PM Reflective MSC|
|Baseline||12.04 (4.03)||11.66 (3.96)|
|Change from Baseline||-3.31 (3.74)||-1.96 (3.57)||1.35||0.0374|
|* 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.|
Trials Supporting One Spray Per Nostril Twice Daily
Two hundred seventy five patients with seasonal allergic rhinitis received Astelin® Nasal Spray one spray per nostril twice daily for 2 weeks in two U.S. placebo-controlled trials. The primary efficacy endpoint was the change from Baseline to Day 14 in the Total Nasal Symptom Score [TNSS] (the average of individual scores of runny nose, sneezing, itchy nose, and nasal congestion) as assessed by patients on a 0-3 categorical scale. Compared to placebo, Astelin® Nasal Spray significantly improved the TNSS. The results are shown in Table 2.
Table 2: Summary of Primary Efficacy* Analyses for
Pivotal Studies Supporting One Spray Per Nostril Twice Daily.
|Astelin® Nasal Spray||Placebo Nasal Spray||Outcomes
Astelin® vs. Placebo
|LS Mean (SD)||Difference between Treatments||P value|
|Study 419: 12 Hour AM and PM Reflective TNSS|
|Baseline||16.34 (4.222)||17.21 (4.316)|
|Change from Baseline||-2.69 (4.789)||-1.31 (4.285)||1.38||0.0017|
|Study 420: 12 Hour AM and PM Reflective TNSS|
|Baseline||16.62 (4.197)||16.84 (4.768)|
|Change from Baseline||-3.68 (4.163)||-2.50 (4.011)||1.18||0.0173|
|* 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.
Other Supporting Studies
In dose-ranging trials, administration of Astelin® Nasal Spray, two sprays per nostril twice daily, resulted in a decrease in symptoms, which reached statistical significance from saline placebo within 3 hours after initial dosing and persisted over the 12-hour dosing interval.
There were no findings on nasal examination in an 8-week study that suggested any adverse effect of azelastine on the nasal mucosa.
Two hundred sixteen patients with vasomotor rhinitis received Astelin® Nasal Spray two sprays per nostril twice a day in two U.S. placebo controlled trials. 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 significantly improved a symptom complex comprised of rhinorrhea, post nasal drip, nasal congestion, and sneezing.
Last reviewed on RxList: 2/1/2012
This monograph has been modified to include the generic and brand name in many instances.
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