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Astepro

CLINICAL PHARMACOLOGY

Mechanism of Action

Azelastine hydrochloride, a phthalazinone derivative, exhibits histamine H1-­receptor antagonist activity in isolated tissues, animal models, and humans. ASTEPRO (azelastine hydrochloride nasal spray) 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.

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. 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 DRUG INTERACTIONS].

Pharmacokinetics

Absorption

After intranasal administration of 2 sprays per nostril (548 mcg total dose) of ASTEPRO (azelastine hydrochloride nasal spray) Nasal Spray 0.1%, the mean azelastine peak plasma concentration (Cmax) is 200 pg/mL, the mean extent of systemic exposure (AUC) is 5122 pg•hr/mL and the median time to reach Cmax (tmax) is 3 hours. After intranasal administration of 2 sprays per nostril (822 mcg total dose) of ASTEPRO (azelastine hydrochloride nasal spray) Nasal Spray 0.15%, the mean azelastine peak plasma concentration (Cmax) is 409 pg/mL, the mean extent of systemic exposure (AUC) is 9312 pg•hr/mL and the median time to reach Cmax (tmax) is 4 hours. The systemic bioavailability of azelastine hydrochloride is approximately 40% after intranasal administration.

Distribution

Based on intravenous and oral administration, the steady-state volume of distribution of azelastine 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.

Metabolism

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 a single-dose, intranasal administration of ASTEPRO (azelastine hydrochloride nasal spray) Nasal Spray 0.1% (548 mcg total dose), the mean desmethylazelastine Cmax is 23 pg/mL, the AUC is 2131 pg•hr/mL and the median tmax is 24 hours. After a single-dose, intranasal administration of ASTEPRO (azelastine hydrochloride nasal spray) Nasal Spray 0.15% (822 mcg total dose), the mean desmethylazelastine Cmax is 38 pg/mL, the AUC is 3824 pg•hr/mL and the median tmax is 24 hours. After intranasal dosing of azelastine to steady-state, plasma concentrations of desmethylazelastine range from 20-50% of azelastine concentrations.

Elimination

Following intranasal administration of ASTEPRO (azelastine hydrochloride nasal spray) Nasal Spray 0.1%, the elimination half-life of azelastine is 22 hours while that of desmethylazelastine is 52 hours. Following intranasal administration of ASTEPRO (azelastine hydrochloride nasal spray) Nasal Spray 0.15%, the elimination half-life of azelastine is 25 hours while that of desmethylazelastine is 57 hours. Approximately 75% of an oral dose of radiolabeled azelastine hydrochloride was excreted in the feces with less than 10% as unchanged azelastine.

Special Populations

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 healthy 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.

Drug-Drug Interactions

Erythromycin: Co-administration 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 [see DRUG INTERACTIONS].

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%. Co-administration of orally administered azelastine (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, whereas, administration of azelastine alone resulted in Cmax of 7.83 ± 4.06 ng/mL and AUC of 80.09 ± 43.55 ng•h/mL for azelastine [see DRUG INTERACTIONS].

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

Animal Toxicology and/or Pharmacology

Reproductive Toxicology Studies

Azelastine hydrochloride has been shown to cause developmental toxicity. Treatment of mice with an oral dose of 68.6 mg/kg (approximately 170 times the maximum recommended human daily intranasal dose [MRHDID] on a mg/m² basis) caused embryo-fetal death, malformations (cleft palate; short or absent tail; fused, absent or branched ribs), delayed ossification, and decreased fetal weight. This dose also caused maternal toxicity as evidenced by decreased body weight. Neither fetal nor maternal effects occurred at a dose of 3 mg/kg (approximately 7 times the MRHDID on a mg/m² basis).

In rats, an oral dose of 30 mg/kg (approximately 150 times the MRHDID on a mg/m² basis) caused malformations (oligo-and brachydactylia), delayed ossification and skeletal variations, in the absence of maternal toxicity. At 68.6 mg/kg (approximately 340 times the MRHDID on a mg/m² basis) azelastine hydrochloride also caused embryo-fetal death and decreased fetal weight; however, the 68.6 mg/kg dose caused severe maternal toxicity. Neither fetal nor maternal effects occurred at a dose of 3 mg/kg (approximately 15 times the MRHDID on a mg/m² basis).

In rabbits, oral doses of 30 mg/kg and greater (approximately 300 times the MRHDID on a mg/m² basis) caused abortion, delayed ossification and decreased fetal weight; however, these doses also resulted in severe maternal toxicity. Neither fetal nor maternal effects occurred at a dose of 0.3 mg/kg (approximately 3 times the MRHDID on a mg/m² basis).

Clinical Studies

Seasonal Allergic Rhinitis

ASTEPRO (azelastine hydrochloride nasal spray) Nasal Spray 0.1%

The efficacy and safety of ASTEPRO (azelastine hydrochloride nasal spray) Nasal Spray 0.1% was evaluated in a 2-week, randomized, multicenter, double-blind, placebo-controlled clinical trial including 834 adult and adolescent patients 12 years of age and older with symptoms of seasonal allergic rhinitis. The population was 12 to 83 years of age (60% female, 40% male; 69% white, 16% black, 12% Hispanic, 2% Asian, 1% other).

Patients were randomized to one of six treatment groups: 1 spray per nostril of either ASTEPRO Nasal Spray 0.1%, Astelin (azelastine hydrochloride) Nasal Spray or vehicle placebo twice daily; or 2 sprays per nostril of ASTEPRO Nasal Spray 0.1%, Astelin (azelastine hydrochloride) Nasal Spray or vehicle placebo twice daily.

Assessment of efficacy was based on the 12-hour reflective total nasal symptom score (rTNSS) assessed daily in the morning and evening, 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 four 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). The rTNSS required patients to record symptom severity over the previous 12 hours. For the primary efficacy endpoint, the mean change from baseline rTNSS, morning (AM) and evening (PM) rTNSS scores were summed for each day (maximum score of 24) and then averaged over the 2 weeks. The iTNSS, recorded immediately prior to the next dose, were assessed as an indication of whether the effect was maintained over the dosing interval.

In this trial, ASTEPRO (azelastine hydrochloride nasal spray) Nasal Spray 0.1% two sprays twice a day demonstrated a greater decrease in rTNSS and iTNSS than placebo and the difference was statistically significant. The trial results are presented in Table 3 (Trial 1).

The efficacy of ASTEPRO (azelastine hydrochloride nasal spray) Nasal Spray 0.1% one spray per nostril twice daily for seasonal allergic rhinitis is supported by two, 2-week, placebo-controlled clinical trials with Astelin (azelastine hydrochloride) Nasal Spray in 413 patients with seasonal allergic rhinitis. In these trials, efficacy was assessed using the TNSS (described above). Astelin Nasal Spray demonstrated a greater decrease from baseline in the summed AM and PM rTNSS compared with placebo and the difference was statistically significant.

ASTEPRO (azelastine hydrochloride nasal spray) Nasal Spray 0.15%

The efficacy and safety of ASTEPRO (azelastine hydrochloride nasal spray) Nasal Spray 0.15% in seasonal allergic rhinitis was evaluated in five randomized, multicenter, double-blind, placebo-controlled clinical trials in 2499 adult and adolescent patients 12 years and older with symptoms of seasonal allergic rhinitis (Trials 2, 3, 4, 5, and 6). The population of the trials was 12 to 83 years of age (64% female, 36% male; 81% white, 12% black, < 2% Asian, 5% other; 23% Hispanic, 77% non-Hispanic). Assessment of efficacy was based on the rTNSS, iTNSS as described above, and other supportive secondary efficacy variables. The primary efficacy endpoint was the mean change from baseline in rTNSS over 2 weeks.

Two 2-week seasonal allergic rhinitis trials evaluated the efficacy of ASTEPRO (azelastine hydrochloride nasal spray) Nasal Spray 0.15% dosed at 2 sprays twice daily. The first trial (Trial 2) compared the efficacy of ASTEPRO Nasal Spray 0.15% and Astelin (azelastine hydrochloride) Nasal Spray to vehicle placebo. The other trial (Trial 3) compared the efficacy of ASTEPRO (azelastine hydrochloride nasal spray) Nasal Spray 0.15% and ASTEPRO (azelastine hydrochloride nasal spray) Nasal Spray 0.1% to vehicle placebo. In these two trials, ASTEPRO (azelastine hydrochloride nasal spray) Nasal Spray 0.15% demonstrated greater decreases in rTNSS than placebo and the differences were statistically significant (Table 3).

Three 2-week seasonal allergic rhinitis trials evaluated the efficacy of ASTEPRO (azelastine hydrochloride nasal spray) Nasal Spray 0.15% dosed at 2 sprays once daily compared to the vehicle placebo. Trial 4 demonstrated a greater decrease in rTNSS than placebo and the difference was statistically significant (Table 3). Trial 5 and Trial 6 were conducted in patients with Texas mountain cedar allergy. In Trial 5 and Trial 6, ASTEPRO (azelastine hydrochloride nasal spray) Nasal Spray 0.15% demonstrated a greater decrease in rTNSS than placebo and the differences were statistically significant (Trials 5 and 6; Table 3). Instantaneous TNSS results for the once daily dosing regimen of ASTEPRO (azelastine hydrochloride nasal spray) Nasal Spray 0.15% are shown in Table 4. In Trials 5 and 6, ASTEPRO (azelastine hydrochloride nasal spray) Nasal Spray 0.15% demonstrated a greater decrease in iTNSS than placebo and the differences were statistically significant.

Table 3: Mean Change from Baseline in Reflective TNSS over 2 Weeks* in Adults and Children ≥ 12 years with Seasonal Allergic Rhinitis

  Treatment (sprays per nostril) n Baseline LS Mean Change from Baseline Difference From Placebo
LS Mean 95% CI P value
Trial 1
Two sprays twice daily ASTEPRO Nasal Spray 0.1% 146 18.0 -5.0 -2.2 -3.2,-1.2 < 0.001
Astelin Nasal Spray 137 18.2 -4.2 -1.4 -2.4,-0.4 0.01
Vehicle Placebo 138 18.2 -2.8      
One spray twice daily ASTEPRO Nasal Spray 0.1% 139 18.2 -4.2 -0.7 -1.7, 0.3 0.18
Astelin Nasal Spray 137 18.1 -4.0 -0.4 -1.5, 0.6 0.41
Vehicle Placebo 137 18.0 -3.5      
Trial 2
Two sprays twice daily ASTEPRO Nasal Spray 0.15% 153 18.2 -4.3 -1.2 -2.1, -0.3 0.01
Astelin Nasal Spray 153 17.9 -3.9 -0.9 -1.8, 0.1 0.07
Vehicle Placebo 153 18.1 -3.0      
Trial 3
Two sprays twice daily ASTEPRO Nasal Spray 0.15% 177 17.7 -5.1 -3.0 -3.9, -2.1 < 0.001
ASTEPRO Nasal Spray 0.1% 169 18.2 -4.2 -2.1 -3.0, -1.2 < 0.001
Vehicle Placebo 177 17.7 -2.1      
Trial 4
Two sprays once daily ASTEPRO Nasal Spray 0.15% 238 17.4 -3.4 -1.0 -1.7, -0.3 0.008
Vehicle Placebo 242 17.4 -2.4      
Trial 5
Two sprays once daily ASTEPRO Nasal Spray 0.15% 266 18.5 -3.3 -1.4 -2.1, -0.8 < 0.001
Vehicle Placebo 266 18.0 -1.9      
Trial 6
Two sprays once daily ASTEPRO Nasal Spray 0.15% 251 18.5 -3.4 -1.4 -2.1, -0.7 < 0.001
*Sum of AM and PM rTNSS for each day (Maximum score=24) and averaged over the 14 day treatment period

Table 4: Mean Change from Baseline AM Instantaneous TNSS over 2 Weeks* in Adults and Children ≥ 12 years with Seasonal Allergic Rhinitis

  Treatment (sprays per nostril once daily) n Baseline LS Mean Change from Baseline Diffe renceFrom Placebo
LS Mean 95% CI P value
Trial 4
Two sprays once daily ASTEPRO Nasal Spray 0.15% 238 8.1 -1.3 -0.2 -0.6, 0.1 0.15
Vehicle Placebo 242 8.3 -1.1      
Trial 5
Two sprays once daily ASTEPRO Nasal Spray 0.15% 266 8.7 -1.4   -1.0, -0.4 < 0.001
Vehicle Placebo 266 8.3 -0.7 -0.7    
Trial 6
Two sprays once daily ASTEPRO Nasal Spray 0.15% 251 8.9 -1.4   -0.9, -0.3 < 0.001
Vehicle Placebo 254 8.9 -0.8 -0.6    
*AM iTNSS for each day (Maximum score=12) and averaged over the 14 day treatment period

ASTEPRO (azelastine hydrochloride nasal spray) Nasal Spray 0.15% at a dose of 1 spray twice daily was not studied. The ASTEPRO (azelastine hydrochloride nasal spray) Nasal Spray 0.15% 1 spray twice daily dosing regimen is supported by previous findings of efficacy for Astelin (azelastine hydrochloride) Nasal Spray and a favorable comparison of ASTEPRO (azelastine hydrochloride nasal spray) Nasal Spray 0.15% to Astelin Nasal Spray and ASTEPRO (azelastine hydrochloride nasal spray) Nasal Spray 0.1% (Table 3).

Perennial Allergic Rhinitis

ASTEPRO (azelastine hydrochloride nasal spray) Nasal Spray 0.15%

The efficacy and safety of ASTEPRO (azelastine hydrochloride nasal spray) Nasal Spray 0.15% in perennial allergic rhinitis was evaluated in one randomized, multicenter, double-blind, placebo-controlled clinical trial in 578 adult and adolescent patients 12 years and older with symptoms of perennial allergic rhinitis. The population of the trial was 12 to 84 years of age (68% female, 32% male; 85% white, 11% black, 1% Asian, 3% other; 17% Hispanic, 83% non-Hispanic).

Assessment of efficacy was based on the 12-hour reflective total nasal symptom score (rTNSS) assessed daily in the morning and evening, the instantaneous total nasal symptom score (iTNSS), and other supportive secondary efficacy variables. The primary efficacy endpoint was the mean change from baseline rTNSS over 4 weeks. The one 4­week perennial allergic rhinitis trial evaluated the efficacy of ASTEPRO (azelastine hydrochloride nasal spray) Nasal Spray 0.15%, ASTEPRO (azelastine hydrochloride nasal spray) Nasal Spray 0.1%, and vehicle placebo dosed at 2 sprays per nostril twice daily. In this trial, ASTEPRO (azelastine hydrochloride nasal spray) Nasal Spray 0.15% demonstrated a greater decrease in rTNSS than placebo and the difference was statistically significant (Table 5).

Table 5: Mean Change from Baseline in Reflective TNSS over 4 Weeks* In Adults and Children ≥ 12 years with Perennial Allergic Rhinitis

  Treatment (sprays per nostril twice daily) n Baseline LS Mean Change from Baseline Differ ence From Placebo
LS Mean 95% CI P value
Two sprays twice daily ASTEPRO Nasal Spray 0.15% 192 15.8 -4.0 -0.9 -1.7, -0.1 0.03
ASTEPRO Nasal Spray 0.1% 194 15.5 -3.8 -0.7 -1.5, 0.1 0.08
Vehicle Placebo 192 14.7 -3.1      
*Sum of AM and PM rTNSS for each day (Maximum score=24) and averaged over the 28 day treatment period

Last reviewed on RxList: 3/10/2011
This monograph has been modified to include the generic and brand name in many instances.

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