1.1 Allergic Rhinitis

Azelastine hydrochloride nasal solution (nasal spray), 0.15% is indicated for the relief of the symptoms of seasonal and perennial allergic rhinitis in patients 12 years of age and older.

2.1 Seasonal Allergic Rhinitis

The recommended dose of azelastine hydrochloride nasal solution (nasal spray), 0.15% is 1 or 2 sprays per nostril twice daily for seasonal allergic rhinitis. Azelastine hydrochloride nasal solution (nasal spray), 0.15% may also be administered as 2 sprays per nostril once daily.

2.2 Perennial Allergic Rhinitis

The recommended dose of azelastine hydrochloride nasal solution (nasal spray), 0.15% for perennial allergic rhinitis is 2 sprays per nostril twice daily.

2.3 Important Administration Instructions

Administer azelastine hydrochloride nasal solution (nasal spray) by the intranasal route only.

Priming: Prime azelastine hydrochloride nasal solution (nasal spray) before initial use by releasing 6 sprays or until a fine mist appears. When azelastine hydrochloride nasal solution (nasal spray) has not been used for 3 or more days, reprime with 2 sprays or until a fine mist appears. Avoid spraying azelastine hydrochloride nasal solution (nasal spray) into the eyes.

5.1 Activities Requiring Mental Alertness

In clinical trials, the occurrence of somnolence has been reported in some patients taking azelastine hydrochloride nasal solution (nasal spray) [see Adverse Reactions (6.1)]. Patients should be cautioned against engaging in hazardous occupations requiring complete mental alertness and motor coordination such as operating machinery or driving a motor vehicle after administration of azelastine hydrochloride nasal solution (nasal spray). Concurrent use of azelastine hydrochloride nasal solution (nasal spray) with alcohol or other central nervous system depressants should be avoided because additional reductions in alertness and additional impairment of central nervous system performance may occur [see Drug Interactions (7.1)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect rates observed in practice.

Azelastine hydrochloride nasal solution (nasal spray), 0.1% 
The safety data described below reflect exposure to azelastine hydrochloride nasal solution (nasal spray), 0.1% with sweetener in 713 patients 12 years of age and older from 2 clinical trials of 2 weeks to 12 months duration. In a 2-week, double-blind, placebo-controlled, and active-controlled (azelastine hydrochloride nasal solution (nasal spray) without sweetener; azelastine hydrochloride) clinical trial, 285 patients (115 males and 170 females) 12 years of age and older with seasonal allergic rhinitis were treated with azelastine hydrochloride nasal solution (nasal spray), 0.1% with sweetener one or two sprays per nostril daily. In the 12 month open-label, active-controlled (azelastine hydrochloride nasal solution (nasal spray) without sweetener) 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 azelastine hydrochloride nasal solution (nasal spray), 0.1% with sweetener two sprays per nostril twice daily. The racial and ethnic distribution for the 2 clinical trials was 82% white, 8% black, 6% Hispanic, 3% Asian, and <1% other.

Adults and Adolescents 12 Years of Age and Older
In the two week clinical trial, 835 patients 12 years of age and older with seasonal allergic rhinitis were treated with one of six treatments: one spray per nostril of either azelastine hydrochloride nasal solution (nasal spray), 0.1% with sweetener, azelastine hydrochloride nasal solution (nasal spray) without sweetener or placebo twice daily; or 2 sprays per nostril of azelastine hydrochloride nasal solution (nasal spray), 0.1% with sweetener, azelastine hydrochloride nasal solution (nasal spray) without sweetener, or placebo twice daily. Overall, adverse reactions were more common in the azelastine hydrochloride nasal solution (nasal spray), 0.1% with sweetener treatment groups (21-28%) than in the placebo groups (16-20%). Overall, less than 1% of patients discontinued due to adverse reactions and withdrawal due to adverse reactions was similar among the treatment groups.

Table 1 contains adverse reactions reported with frequencies greater than or equal to 2% and more frequently than placebo in patients treated with azelastine hydrochloride nasal solution (nasal spray), 0.1% with sweetener in the controlled clinical trial described above.

Table 1. Adverse Reactions Reported in ≥2% Incidence in a Placebo-Controlled Trial of 2 Weeks’ Duration with Azelastine Hydrochloride Nasal Solution (Nasal Spray), 0.1% in Adult and Adolescent Patients with Seasonal Allergic Rhinitis

Long-Term (12 Month) Safety Trial:
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 azelastine hydrochloride nasal solution (nasal spray), 0.1% with sweetener two sprays per nostril twice daily or azelastine hydrochloride nasal solution (nasal spray) without sweetener 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 azelastine hydrochloride nasal solution (nasal spray), 0.1% with sweetener and 17 patients (4%) treated with azelastine hydrochloride nasal solution (nasal spray) without sweetener discontinued from the trial due to adverse events.

Azelastine hydrochloride nasal solution (nasal spray), 0.15% 
The safety data described below reflect exposure to azelastine hydrochloride nasal solution (nasal spray), 0.15% in 1858 patients (12 years of age and older) with seasonal or perennial allergic rhinitis from 8 clinical trials of 2 weeks to 12 months duration. In 7 double-blind, placebo-controlled clinical trials of 2 to 4 weeks duration, 1544 patients (560 males and 984 females) with seasonal or perennial allergic rhinitis were treated with azelastine hydrochloride nasal solution (nasal spray), 0.15% 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 azelastine hydrochloride nasal solution (nasal spray), 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. The racial distribution for the 8 clinical trials was 80% white, 13% black, 2% Asian, and 5% other.

Adults and Adolescents 12 Years of Age and Older
In the 7 placebo controlled clinical trials of 2 to 4 week duration, 2343 patients with seasonal allergic rhinitis and 540 patients with perennial allergic rhinitis were treated with two sprays per nostril of either azelastine hydrochloride nasal solution (nasal spray), 0.15% or placebo once or twice daily. Overall, adverse reactions were more common in the azelastine hydrochloride nasal solution (nasal spray), 0.15% treatment groups (16-31%) than in the placebo groups (11-24%). Overall, less than 2% of patients discontinued due to adverse reactions and withdrawal due to adverse reactions was similar among the treatment groups.

Table 2 contains adverse reactions reported with frequencies greater than or equal to 2% and more frequently than placebo in patients treated with azelastine hydrochloride nasal solution (nasal spray), 0.15% in the seasonal and perennial allergic rhinitis controlled clinical trials.

In the above trials, somnolence was reported in <1% of patients treated with azelastine hydrochloride nasal solution (nasal spray), 0.15% (11 of 1544) or vehicle placebo (1 of 1339).

Long-Term (12 Month) Safety Trial:
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 azelastine hydrochloride nasal solution (nasal spray), 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 azelastine hydrochloride nasal solution (nasal spray), 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 azelastine hydrochloride nasal solution (nasal spray), 0.15% and 17 patients (7%) treated with mometasone nasal spray discontinued from the trial due to adverse events.

6.2 Postmarketing Experience

During the post approval use of azelastine hydrochloride nasal solution (nasal spray), 0.1% and 0.15%, the following adverse reactions have been identified. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse reactions reported include: abdominal pain, nasal burning, nausea, sweet taste, and throat irritation.

Additionally, the following adverse reactions have been identified during the post approval use of azelastine hydrochloride nasal solution (nasal spray) without sweetener, 0.1% (total daily dose 0.55 mg to 1.1 mg). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse reactions reported include the following: anaphylactoid reaction, application site irritation, atrial fibrillation, blurred vision, chest pain, confusion, dizziness, dyspnea, facial edema, hypertension, involuntary muscle contractions, nervousness, palpitations, paresthesia, parosmia, paroxysmal sneezing, pruritus, rash, disturbance or loss of sense of smell and/or taste, tachycardia, tolerance, urinary retention, and xerophthalmia.

7.1 Central Nervous System Depressants

Concurrent use of azelastine hydrochloride nasal solution (nasal spray) with alcohol or other central nervous system depressants should be avoided because reductions in alertness and impairment of central nervous system performance may occur [see Warnings and Precautions (5.1)].

7.2 Erythromycin and Ketoconazole

Interaction studies investigating the cardiac effects, as measured by the corrected QT interval (QTc), of concomitantly administered oral azelastine hydrochloride and erythromycin or ketoconazole were conducted. Oral erythromycin (500 mg three times daily for 7 days) had no effect on azelastine pharmacokinetics or QTc based on analyses of serial electrocardiograms. Ketoconazole (200 mg twice daily for 7 days) interfered with the measurement of azelastine plasma concentrations on the analytic HPLC; however, no effects on QTc were observed [see Clinical Pharmacology (12.2) and (12.3)].

7.3 Cimetidine

Cimetidine (400 mg twice daily) increased the mean Cmax and AUC of orally administered azelastine hydrochloride (4 mg twice daily) by approximately 65% [see Clinical Pharmacology (12.3)].

8.1 Pregnancy

Pregnancy Category C:

There are no adequate and well-controlled clinical trials in pregnant women. Azelastine hydrochloride has been shown to cause developmental toxicity in mice, rats, and rabbits. Azelastine hydrochloride nasal solution (nasal spray) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Teratogenic Effects:

In mice, azelastine hydrochloride caused embryo-fetal death, malformations (cleft palate; short or absent tail; fused, absent or branched ribs), delayed ossification, and decreased fetal weight at an oral dose approximately 170 times the maximum recommended human daily intranasal dose (MRHDID) in adults on a mg/m2 basis. This dose also caused maternal toxicity as evidenced by decreased body weight. Neither fetal nor maternal effects occurred at a dose that was approximately 7 times the MRHDID.

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

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

8.3 Nursing Mothers

It is not known whether azelastine hydrochloride is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when azelastine hydrochloride nasal solution (nasal spray) is administered to a nursing woman.

8.4 Pediatric Use

Safety and effectiveness of azelastine hydrochloride nasal solution (nasal spray) in pediatric patients below the age of 12 years have not been established.

8.5 Geriatric Use

Clinical trials of azelastine hydrochloride nasal solution (nasal spray) did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

12.1 Mechanism of Action

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

12.2 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)].

12.3 Pharmacokinetics

Absorption:

After intranasal administration of 2 sprays per nostril (548 mcg total dose) of azelastine hydrochloride nasal solution (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 azelastine hydrochloride nasal solution (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 azelastine hydrochloride nasal solution (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 azelastine hydrochloride nasal solution (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 azelastine hydrochloride nasal solution (nasal spray), 0.1%, the elimination half-life of azelastine is 22 hours while that of desmethylazelastine is 52 hours.Following intranasal administration of azelastine hydrochloride nasal solution (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.

13.1 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.

13.2 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).

14.1 Seasonal Allergic Rhinitis

Azelastine hydrochloride nasal solution (nasal spray), 0.1%

The efficacy and safety of azelastine hydrochloride nasal solution (nasal spray), 0.1% with sweetener 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 azelastine hydrochloride nasal solution (nasal spray), 0.1% with sweetener, azelastine hydrochloride nasal solution (nasal spray) without sweetener or vehicle placebo twice daily; or 2 sprays per nostril of azelastine hydrochloride nasal solution (nasal spray), 0.1% with sweetener, azelastine hydrochloride nasal solution (nasal spray) without sweetener 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, azelastine hydrochloride nasal solution (nasal spray), 0.1% with sweetener 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 azelastine hydrochloride nasal solution (nasal spray), 0.1% with sweetener one spray per nostril twice daily for seasonal allergic rhinitis is supported by two, 2-week, placebo-controlled clinical trials with azelastine hydrochloride nasal solution (nasal spray) without sweetener in 413 patients with seasonal allergic rhinitis. In these trials, efficacy was assessed using the TNSS (described above). Azelastine hydrochloride nasal solution (nasal spray) without sweetener demonstrated a greater decrease from baseline in the summed AM and PM rTNSS compared with placebo and the difference was statistically significant.

Azelastine hydrochloride nasal solution (nasal spray), 0.15%

The efficacy and safety of azelastine hydrochloride nasal solution (nasal spray), 0.15% with sweetener 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 azelastine hydrochloride nasal solution (nasal spray), 0.15% with sweetener dosed at 2 sprays twice daily. The first trial (Trial 2) compared the efficacy of azelastine hydrochloride nasal solution (nasal spray), 0.15% with sweetener and azelastine hydrochloride nasal solution (nasal spray) without sweetener to vehicle placebo. The other trial (Trial 3) compared the efficacy of azelastine hydrochloride nasal solution (nasal spray), 0.15% with sweetener and azelastine hydrochloride nasal solution (nasal spray), 0.1% with sweetener to vehicle placebo. In these two trials, azelastine hydrochloride nasal solution (nasal spray), 0.15% with sweetener 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 azelastine hydrochloride nasal solution (nasal spray), 0.15% with sweetener 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, azelastine hydrochloride nasal solution (nasal spray), 0.15% with sweetener 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 azelastine hydrochloride nasal solution (nasal spray), 0.15% with sweetener are shown in Table 4. In Trials 5 and 6, azelastine hydrochloride nasal solution (nasal spray), 0.15% with sweetener demonstrated a greater decrease in iTNSS than placebo and the differences were statistically significant.

Azelastine hydrochloride nasal solution (nasal spray), 0.15% with sweetener at a dose of 1 spray twice daily was not studied. The azelastine hydrochloride nasal solution (nasal spray), 0.15% with sweetener 1 spray twice daily dosing regimen is supported by previous findings of efficacy for azelastine hydrochloride nasal solution (nasal spray) without sweetener and a favorable comparison of azelastine hydrochloride nasal solution (nasal spray), 0.15% with sweetener to azelastine hydrochloride nasal solution (nasal spray), 0.1% without sweetener and azelastine hydrochloride nasal solution (nasal spray), 0.1% with sweetener (Table 3).

14.2 Perennial Allergic Rhinitis

Azelastine hydrochloride nasal solution (nasal spray), 0.15%

The efficacy and safety of azelastine hydrochloride nasal solution (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 azelastine hydrochloride nasal solution (nasal spray), 0.15%, azelastine hydrochloride nasal solution (nasal spray), 0.1%, and vehicle placebo dosed at 2 sprays per nostril twice daily. In this trial, azelastine hydrochloride nasal solution (nasal spray), 0.15% demonstrated a greater decrease in rTNSS than placebo and the difference was statistically significant (Table 5).

Storage:
Store upright at 20° to 25°C (68° to 77°F) [see USP controlled room temperature]. Protect from freezing.

17.1 Activities Requiring Mental Alertness

Somnolence has been reported in some patients taking azelastine hydrochloride nasal solution (nasal spray). Patients should be cautioned against engaging in hazardous occupations requiring complete mental alertness and motor coordination such as driving or operating machinery after administration of azelastine hydrochloride nasal solution (nasal spray) [see Warnings and Precautions (5.1)].

17.2 Concurrent Use of Alcohol and other Central Nervous System Depressants

Concurrent use of azelastine hydrochloride nasal solution (nasal spray) with alcohol or other central nervous system depressants should be avoided because additional reductions in alertness and additional impairment of central nervous system performance may occur [see Warnings and Precautions (5.1)].

17.3 Common Adverse Reactions

Patients should be informed that the treatment with azelastine hydrochloride nasal solution (nasal spray) may lead to adverse reactions, which include bitter taste, nasal discomfort, epistaxis, headache, fatigue, somnolence, and sneezing [see Adverse Reactions (6.1)].

17.4 Priming

Patients should be instructed to prime the pump before initial use and when azelastine hydrochloride nasal solution (nasal spray) has not been used for 3 or more days [see Dosage and Administration (2.3)].

17.5 Keep Spray Out of Eyes

Patients should be instructed to avoid spraying azelastine hydrochloride nasal solution (nasal spray) into their eyes.

17.6 Keep Out of Children’s Reach

Patients should be instructed to keep azelastine hydrochloride nasal solution (nasal spray) out of the reach of children. If a child accidentally ingests azelastine hydrochloride nasal solution (nasal spray), seek medical help or call a poison control center immediately.

288606

May 2011