DrugLib.com — Drug Information Portal

Rx drug information, pharmaceutical research, clinical trials, news, and more

Astepro (Azelastine Hydrochloride) - Description and Clinical Pharmacology

 
 



DESCRIPTION

ASTEPRO (azelastine hydrochloride) Nasal Spray 0.1%, 137 micrograms (mcg), is an antihistamine formulated as a metered-spray solution for intranasal administration. ASTEPRO (azelastine hydrochloride) Nasal Spray 0.15%, 205.5 micrograms (mcg), is formulated as a metered-spray solution for intranasal administration.

Azelastine hydrochloride occurs as a white, almost 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 glycerine. It has a melting point of about 225°C and the pH of a saturated solution is between 5.0 and 5.4. Its chemical name is (±)-1-(2H)-phthalazinone,4-[(4-chlorophenyl) methyl]-2-(hexahydro-1-methyl-1H-azepin-4-yl)-, monohydrochloride. Its molecular formula is C22H24ClN3O•HCl with the following chemical structure:

ASTEPRO Nasal Spray 0.1% contains 0.1% azelastine hydrochloride in an isotonic aqueous solution containing sorbitol, sucralose, hypromellose, sodium citrate, edetate disodium, benzalkonium chloride (125 mcg/mL), and purified water (pH 6.4).

After priming [see Dosage and Administration (2.3)], each metered spray delivers a 0.137 mL mean volume containing 137 mcg of azelastine hydrochloride (equivalent to 125 mcg of azelastine base). The 30-mL (net weight 30 gm of solution) bottle provides 200 metered sprays.

ASTEPRO Nasal Spray 0.15% contains 0.15% azelastine hydrochloride in an isotonic aqueous solution containing sorbitol, sucralose, hypromellose, sodium citrate, edetate disodium, benzalkonium chloride (125 mcg/mL), and purified water (pH 6.4).

After priming [see Dosage and Administration (2.3)], each metered spray delivers a 0.137 mL mean volume containing 205.5 mcg of azelastine hydrochloride (equivalent to 187.6 mcg of azelastine base). The 30-mL (net weight 30 gm of solution) bottle provides 200 metered sprays.

CLINICAL PHARMACOLOGY

Mechanism of Action

Azelastine hydrochloride, a phthalazinone derivative, exhibits histamine H1 -receptor antagonist activity in isolated tissues, animal models, and humans. ASTEPRO 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 (7.2)].

Pharmacokinetics

Absorption: After intranasal administration of 2 sprays per nostril (548 mcg total dose) of ASTEPRO 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 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 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 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 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 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 (7.2)].

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 (7.3)].

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.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

In 2-year carcinogenicity studies in rats and mice, azelastine hydrochloride did not show evidence of carcinogenicity at oral doses up to 30 mg/kg and 25 mg/kg, respectively. These doses were approximately 150 and 60 times the maximum recommended human daily intranasal dose [MRHDID] on a mg/m2 basis.

Azelastine hydrochloride showed no genotoxic effects in the Ames test, DNA repair test, mouse lymphoma forward mutation assay, mouse micronucleus test, or chromosomal aberration test in rat bone marrow.

Reproduction and fertility studies in rats showed no effects on male or female fertility at oral doses up to 30 mg/kg (approximately 150 times the MRHDID in adults on a mg/m2 basis). At 68.6 mg/kg (approximately 340 times the MRHDID on a mg/m2 basis), the duration of estrous cycles was prolonged and copulatory activity and the number of pregnancies were decreased. The numbers of corpora lutea and implantations were decreased; however, pre-implantation loss was not increased.

CLINICAL STUDIES

Seasonal Allergic Rhinitis

ASTEPRO Nasal Spray 0.1%

The efficacy and safety of ASTEPRO 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 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 4 (Trial 1).

The efficacy of ASTEPRO 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 Nasal Spray 0.15%

The efficacy and safety of ASTEPRO 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 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 Nasal Spray 0.15% and ASTEPRO Nasal Spray 0.1% to vehicle placebo. In these two trials, ASTEPRO Nasal Spray 0.15% demonstrated greater decreases in rTNSS than placebo and the differences were statistically significant (Table 4).

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

Table 4. Mean Change from Baseline in Reflective TNSS over 2 Weeks* in Adults and Children ≥ 12 years with Seasonal Allergic Rhinitis
*Sum of AM and PM rTNSS for each day (Maximum score=24) and averaged over the 14 day treatment period
  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
Vehicle Placebo 254 18.8 -2.0  
Table 5. Mean Change from Baseline AM Instantaneous TNSS over 2 Weeks* in Adults and Children ≥ 12 years with Seasonal Allergic Rhinitis
*AM iTNSS for each day (Maximum score=12) and averaged over the 14 day treatment period
  Treatment
(sprays per nostril once daily)
n Baseline
LS Mean
Change
from
Baseline
Difference From 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 -0.7 -1.0, -0.4 <0.001
Vehicle Placebo 266 8.3 -0.7  
Trial 6
Two sprays once daily ASTEPRO Nasal Spray 0.15% 251 8.9 -1.4 -0.6 -0.9, -0.3 <0.001
Vehicle Placebo 254 8.9 -0.8  

ASTEPRO Nasal Spray 0.15% at a dose of 1 spray twice daily was not studied. The ASTEPRO 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 Nasal Spray 0.15% to Astelin Nasal Spray and ASTEPRO Nasal Spray 0.1% (Table 4).

The efficacy and safety of ASTEPRO Nasal Spray 0.1% and 0.15% in children 6 to 11 years of age with seasonal allergic rhinitis was evaluated in a clinical study that enrolled pediatric patients with perennial allergic rhinitis, with or without concomitant seasonal allergic rhinitis (described below in Section 14.2).

Perennial Allergic Rhinitis

ASTEPRO Nasal Spray 0.1% and 0.15%

The efficacy and safety of ASTEPRO 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 4-week perennial allergic rhinitis trial evaluated the efficacy of ASTEPRO Nasal Spray 0.15%, ASTEPRO Nasal Spray 0.1%, and vehicle placebo dosed at 2 sprays per nostril twice daily. In this trial, ASTEPRO Nasal Spray 0.15% demonstrated a greater decrease in rTNSS than placebo and the difference was statistically significant (Table 6).

Table 6. Mean Change from Baseline in Reflective TNSS over 4 Weeks* In Adults and Children ≥ 12 years with Perennial Allergic Rhinitis
*Sum of AM and PM rTNSS for each day (Maximum score=24) and averaged over the 28 day treatment period
  Treatment
(sprays per nostril twice daily)
n Baseline
LS Mean
Change
from
Baseline
Difference 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  

The efficacy and safety of ASTEPRO Nasal Spray 0.1% and 0.15% in pediatric patients 6 to 11 years of age with perennial allergic rhinitis, with or without concomitant seasonal allergic rhinitis, was evaluated in a randomized, double-blind, placebo-controlled clinical trial in 486 patients. All patients received one spray per nostril twice daily. The study population was 58% males and 42% females; 78% white, 13% black, 3% Asian, and 6% other.

Assessment of efficacy was based on the 12-hour reflective total nasal symptom score (rTNSS) assessed daily in the morning and evening. The primary efficacy endpoint was the mean change from baseline rTNSS over 4 weeks (Table 7). Both active treatments demonstrated statistically significant decreases in rTNSS compared to placebo. There was no difference between the two active-treatment groups. There was also no difference in treatment effect between patients with perennial allergic rhinitis only compared to those with perennial allergic rhinitis and concomitant seasonal allergic rhinitis.

Table 7. Mean Change from Baseline in Reflective TNSS over 4 Weeks* In Children 6 to 11 years with Perennial Allergic Rhinitis
*Sum of AM and PM rTNSS for each day (Maximum score=24) and averaged over the 28 day treatment period
  Treatment
(sprays per nostril twice daily)
n Baseline
LS Mean
Change
from
Baseline
Difference From Placebo
LS
Mean
95% CI P value
One spray twice daily ASTEPRO Nasal Spray 0.15% 159 16.6 -3.5 -1.0 -1.7, -0.3 0.005
ASTEPRO Nasal Spray 0.1% 166 16.4 -3.4 -0.9 -1.6, -0.2 0.015
Vehicle Placebo 161 16.1 -2.5  

-- advertisement -- The American Red Cross
 
Home | About Us | Contact Us | Site usage policy | Privacy policy

All Rights reserved - Copyright DrugLib.com, 2006-2017