Astepro

The safety data described below reflect exposure to ASTEPRO 0.1% in 975 patients 6 months of age and older from 4 clinical trials of 2 weeks to 12 months duration. In a 2-week, double-blind, placebo-controlled, and active-controlled (Astelin^® Nasal Spray; azelastine hydrochloride) clinical trial, 285 patients (115 males and 170 females) 12 years of age and older with seasonal allergic rhinitis were treated with ASTEPRO 0.1% one or two sprays per nostril daily. In the 12 month open-label, active-controlled (Astelin Nasal Spray) clinical trial, 428 patients (207 males and 221 females) 12 years of age and older with perennial allergic rhinitis and/or nonallergic rhinitis were treated with ASTEPRO 0.1% two sprays per nostril twice daily. In a 4-week, double-blind, placebo-controlled clinical trial, 166 patients (101 males and 65 females) ages 6 to 11 years of age with perennial allergic rhinitis, with or without concomitant seasonal allergic rhinitis, were treated with ASTEPRO 0.1% one spray per nostril twice daily. In a 4-week clinical trial, 96 patients (51 males and 45 females) ages 6 months to 5 years of age with seasonal and/or perennial allergic rhinitis were treated with ASTEPRO 0.1% one spray per nostril twice daily. The racial and ethnic distribution for the 4 clinical trials was 80% white, 11% black, 8% Hispanic, 3% Asian, and 2% other.

In the 12 month, open-label, active-controlled, long-term safety trial, 862 patients 12 years of age and older with perennial allergic and/or nonallergic rhinitis were treated with ASTEPRO 0.1% two sprays per nostril twice daily or Astelin Nasal Spray two sprays per nostril twice daily. The most frequently reported adverse reactions were headache, bitter taste, epistaxis, and nasopharyngitis and were generally similar between treatment groups. Focused nasal examinations were performed and showed that the incidence of nasal mucosal ulceration in each treatment group was approximately 1% at baseline and approximately 1.5% throughout the 12 month treatment period. In each treatment group, 5-7% of patients had mild epistaxis. No patients had reports of nasal septal perforation or severe epistaxis. Twenty-two patients (5%) treated with ASTEPRO 0.1% and 17 patients (4%) treated with Astelin Nasal Spray discontinued from the trial due to adverse events.

The safety data described below reflect exposure to ASTEPRO 0.15% in 2114 patients (6 months of age and older) with seasonal or perennial allergic rhinitis from 10 clinical trials of 2 weeks to 12 months duration. In 8 double-blind, placebo-controlled clinical trials of 2 to 4 weeks duration, 1703 patients (646 males and 1059 females) with seasonal or perennial allergic rhinitis were treated with ASTEPRO 0.15% one or two sprays per nostril once or twice daily. In the 12 month open-label, active-controlled clinical trial, 466 patients (156 males and 310 females) with perennial allergic rhinitis were treated with ASTEPRO 0.15% two sprays per nostril twice daily. Of these 466 patients, 152 had participated in the 4-week placebo-controlled perennial allergic rhinitis clinical trials. In a 4-week, double-blind, placebo-controlled clinical trial, 161 patients (87 males and 74 females) ages 6 to 11 years of age with perennial allergic rhinitis, with or without concomitant seasonal allergic rhinitis, were treated with ASTEPRO 0.15% one spray per nostril twice daily. In a 4-week clinical trial, 95 patients (59 males and 36 females) ages 6 months to 5 years of age with seasonal and/or perennial allergic rhinitis were treated with ASTEPRO 0.15% one spray per nostril twice daily. The racial distribution for the 10 clinical trials was 79% white, 14% black, 2% Asian, and 5% other.

In the 12 month, open-label, active-controlled, long-term safety trial, 466 patients (12 years of age and older) with perennial allergic rhinitis were treated with ASTEPRO 0.15% two sprays per nostril twice daily and 237 patients were treated with mometasone nasal spray two sprays per nostril once daily. The most frequently reported adverse reactions (>5%) with ASTEPRO 0.15% were bitter taste, headache, sinusitis, and epistaxis. Focused nasal examinations were performed and no nasal ulcerations or septal perforations were observed. In each treatment group, approximately 3% of patients had mild epistaxis. No patients had reports of severe epistaxis. Fifty-four patients (12%) treated with ASTEPRO 0.15% and 17 patients (7%) treated with mometasone nasal spray discontinued from the trial due to adverse events.

Limited data from postmarketing experience over decades of use with ASTEPRO in pregnant women have not identified any drug associated risks of miscarriage, birth defects, or other adverse maternal or fetal outcomes. In animal reproduction studies, there was no evidence of fetal harm at oral doses approximately 4 times the clinical daily dose. Oral administration of azelastine hydrochloride to pregnant mice, rats, and rabbits, during the period of organogenesis, produced developmental toxicity that included structural abnormalities, decreased embryo-fetal survival, and decreased fetal body weights at doses 180 times and higher than the maximum recommended human daily intranasal dose (MRHDID) of 1.644 mg. However, the relevance of these findings in animals to pregnant women was considered questionable based upon the high animal to human dose multiple.

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

There are no data on the presence of azelastine hydrochloride in human milk, the effects on the breastfed infant, or the effects on milk production following use of azelastine hydrochloride. Because many drugs are excreted in human milk, caution should be exercised when ASTEPRO is administered to a nursing woman.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ASTEPRO and any potential adverse effects on the breastfed infant from ASTEPRO or from the underlying maternal condition.

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) ].

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

Based on intravenous and oral administration, the steady-state volume of distribution of azelstine 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 a single-dose, intranasal administration of ASTEPRO 0.1% (548 mcg total dose), the mean desmethylazelastine C_max is 23 pg/mL, the AUC is 2131 pg•hr/mL and the median t_max is 24 hours. After a single-dose, intranasal administration of ASTEPRO 0.15% (822 mcg total dose), the mean desmethylazelastine C_max is 38 pg/mL, the AUC is 3824 pg•hr/mL and the median t_max is 24 hours. After intranasal dosing of azelastine to steady-state, plasma concentrations of desmethylazelastine range from 20-50% of azelastine concentrations.

Following intranasal administration of ASTEPRO 0.1%, the elimination half-life of azelastine is 22 hours while that of desmethylazelastine is 52 hours. Following intranasal administration of ASTEPRO 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.

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 C_max 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.

The efficacy and safety of ASTEPRO 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 0.1%, Astelin (azelastine hydrochloride) Nasal Spray or vehicle placebo twice daily; or 2 sprays per nostril of ASTEPRO 0.1%, Astelin 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 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 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 demonstrated a greater decrease from baseline in the summed AM and PM rTNSS compared with placebo and the difference was statistically significant.

The efficacy of ASTEPRO 0.1% and ASTEPRO 0.15% in children 6 months to 5 years of age with allergic rhinitis was explored in a 4 week, randomized, open-label safety trial in 191 patients. While the primary objective was to determine the safety of ASTEPRO in this age group, the study included an exploratory efficacy assessment of daily overall allergy symptom scores. Efficacy in children 6 months to 5 years of age was supported by a numerical decrease in the overall allergy symptom score in both treatment groups. There was no statistically significant difference between the two treatment groups.

The efficacy and safety of ASTEPRO 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 0.15% and Astelin (azelastine hydrochloride) Nasal Spray to vehicle placebo. The other trial (Trial 3) compared the efficacy of ASTEPRO 0.15% and ASTEPRO 0.1% to vehicle placebo. In these two trials, ASTEPRO 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 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 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 0.15% are shown in Table 5. In Trials 5 and 6, ASTEPRO 0.15% demonstrated a greater decrease in iTNSS than placebo and the differences were statistically significant.

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

The efficacy and safety of ASTEPRO 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).

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

The efficacy and safety of ASTEPRO 0.1% and ASTEPRO 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 statistically significant 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.

The efficacy of ASTEPRO 0.1% and ASTEPRO 0.15% in children 6 months to 5 years of age with allergic rhinitis was explored in a clinical study (described above in Section 14.1).