ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS The following clinically significant adverse reaction is described elsewhere in the labeling:Somnolence [see Warnings and Precautions (5.1)] Somnolence [see Warnings and Precautions (5.1)] The most common adverse reactions (>=2% incidence) are: pyrexia, dysgeusia, nasal discomfort, epistaxis, headache, sneezing, fatigue, somnolence, upper respiratory infection, cough, rhinalgia, vomiting, otitis media, contact dermatitis, and oropharyngeal pain (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect rates observed in practice.Children to 11 Years of Age In 4-week clinical trial, 489 patients ages to 11 years with perennial allergic rhinitis, with or without concomitant seasonal allergic rhinitis, were treated with either azelastine HCl nasal spray, 0.1%, azelastine HCl nasal spray, 0.15% or placebo, one spray per nostril twice daily. Overall, adverse events were similar in the azelastine HCl nasal spray, 0.15% group (24%), azelastine HCl nasal spray, 0.1% group (26%) and the placebo group (24%). Overall, less than 1% of the combined azelastine HCl nasal spray groups discontinued due to adverse events. Table contains adverse reactions reported with frequencies greater than or equal to 2% and more frequently than placebo in children to 11 years of age treated with azelastine HCl nasal spray, 0.1% or azelastine HCl nasal spray, 0.15% in the controlled trial described above.Table 2. Adverse Reactions Reported in >=2% Incidence in Placebo-Controlled Trial of Weeks Duration with Azelastine HCl Nasal Spray, 0.1% or Azelastine HCl Nasal Spray, 0.15% in Children to 11 Years of Age with Perennial Allergic Rhinitis1 spray twice dailyAzelastine HCl Nasal Spray, 0.1% (N=166)Azelastine HCl Nasal Spray, 0.15% (N=161)Vehicle Placebo (N=162)Epistaxis (5%)7 (4%)5 (3%)Nasal Discomfort (<1%)7 (4%)0 (0%)Dysgeusia (2%)6 (4%)1 (<1%)Upper Respiratory Infection (2%)4 (3%)3 (2%)Sneezing (2%)4 (3%)2 (1%)Children Months to Years In 4-week clinical trial, 191 patients ages months to years with either seasonal and/or perennial allergic rhinitis were treated with either azelastine HCl nasal spray, 0.1% or azelastine HCl nasal spray, 0.15% one spray per nostril twice daily. The most frequently (>=2%) reported adverse reactions were pyrexia, cough, epistaxis, sneezing, dysgeusia, rhinalgia, upper respiratory infection, vomiting, otitis media, contact dermatitis, and oropharyngeal pain. Overall, adverse events were slightly higher in the azelastine HCl nasal spray, 0.15% group (28%) compared to azelastine HCl nasal spray, 0.1% group (21%). Focused nasal examinations were performed and showed no incidence of nasal mucosal ulceration at any time point during the study. No patients had reports of nasal septal perforation. Overall, less than 3% of the combined azelastine HCl nasal spray groups discontinued due to adverse events. Azelastine HCl Nasal Spray, 0.15% The safety data described below reflect exposure to azelastine HCl nasal spray, 0.15% in 2114 patients (6 months of age and older) with seasonal or perennial allergic rhinitis from 10 clinical trials of weeks to 12 months duration. In double-blind, placebo-controlled clinical trials of to weeks duration, 1703 patients (646 males and 1059 females) with seasonal or perennial allergic rhinitis were treated with azelastine HCl nasal spray, 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 azelastine HCl 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. In 4-week, double-blind, placebo-controlled clinical trial, 161 patients (87 males and 74 females) ages to 11 years of age with perennial allergic rhinitis, with or without concomitant seasonal allergic rhinitis, were treated with azelastine HCl nasal spray, 0.15% one spray per nostril twice daily. In 4-week clinical trial, 95 patients (59 males and 36 females) ages months to years of age with seasonal and/or perennial allergic rhinitis were treated with azelastine HCl nasal spray, 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. Adults and Adolescents 12 Years of Age and OlderIn the placebo controlled clinical trials of to 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 HCl nasal spray, 0.15% or placebo once or twice daily. Overall, adverse reactions were more common in the azelastine HCl nasal spray, 0.15% treatment groups (16 to 31%) than in the placebo groups (11 to 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 contains adverse reactions reported with frequencies greater than or equal to 2% and more frequently than placebo in patients treated with azelastine HCl nasal spray, 0.15% in the seasonal and perennial allergic rhinitis controlled clinical trials. Table 3. Adverse Reactions with >=2% Incidence in Placebo-Controlled Trials of to Weeks Duration with Azelastine HCl Nasal Spray, 0.15% in Adult and Adolescent Patients with Seasonal or Perennial Allergic Rhinitis2 sprays twice daily2 sprays once dailyAzelastine HCl Nasal Spray, 0.15% (N=523)Vehicle Placebo (N=523)Azelastine HCl Nasal Spray, 0.15% (N=1021)Vehicle Placebo (N=816)Bitter Taste 31 (6%)5 (1%)38 (4%)2 (<1%)Nasal Discomfort 18 (3%)12 (2%)37 (4%)7 (1%)Epistaxis (1%)7 (1%)21 (2%)14 (2%)Sneezing (2%)1 (<1%)14 (1%)0 (0%)In the above trials, somnolence was reported in <1% of patients treated with azelastine HCl 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 HCl 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 HCl 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 HCl nasal spray, 0.15% and 17 patients (7%) treated with mometasone nasal spray discontinued from the trial due to adverse events. 6.2 Post-marketing Experience. During the post approval use of azelastine HCl nasal spray, 0.15%, the following adverse reactions have been identified. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. Adverse reactions reported include: abdominal pain, atrial fibrillation, blurred vision, chest pain, confusion, disturbance or loss of sense of smell and/or taste, dizziness, dyspnea, facial swelling, hypertension, involuntary muscle contractions, nasal burning, nausea, nervousness, palpitations, paresthesia, parosmia, pruritus, rash, sneezing, insomnia, sweet taste, tachycardia, and throat irritation.Additionally, the following adverse reactions have been identified during the post approval use of the Astelin brand of azelastine HCl 0.1% nasal spray (total daily dose 0.55 mg to 1.1 mg). Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. Adverse reactions reported include the following: anaphylactoid reaction, application site irritation, facial edema, paroxysmal sneezing, tolerance, urinary retention, and xerophthalmia.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action. Azelastine HCl, phthalazinone derivative, exhibits histamine H1-receptor antagonist activity in isolated tissues, animal models, and humans. Azelastine HCl nasal spray, 0.15% is administered as 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 EffectsIn placebo-controlled trial (95 patients with allergic rhinitis), there was no evidence of an effect of azelastine HCl 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 mg or 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 HCl 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. AbsorptionAfter intranasal administration of sprays per nostril (822 mcg total dose) of azelastine HCl nasal spray, 0.15%, the mean azelastine peak plasma concentration (Cmax) is 409 pg/mL, the mean extent of systemic exposure (AUC) is 9312 pgohr/mL and the median time to reach Cmax (tmax) is hours. The systemic bioavailability of azelastine HCl is approximately 40% after intranasal administration. DistributionBased 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.EliminationFollowing intranasal administration of azelastine HCl 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 HCl was excreted in the feces with less than 10% as unchanged azelastine. MetabolismAzelastine 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 single-dose, intranasal administration of azelastine HCl nasal spray, 0.15% (822 mcg total dose), the mean desmethylazelastine Cmax is 38 pg/mL, the AUC is 3824 pgohr/mL and the median tmax is 24 hours. After intranasal dosing of azelastine to steady-state, plasma concentrations of desmethylazelastine range from 20 to 50% of azelastine concentrations.Special PopulationsPatients with Hepatic Impairment: Following oral administration, pharmacokinetic parameters were not influenced by hepatic impairment.Patients with Renal Impairment: Based on oral, single-dose studies, renal insufficiency (creatinine clearance <50 mL/min) resulted in 70 to 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. Male and Female Patients: Following oral administration, pharmacokinetic parameters were not influenced by gender. Race: The effect of race has not been evaluated. Drug Interaction Studies Erythromycin: Co-administration of orally administered azelastine (4 mg twice daily) with erythromycin (500 mg three times daily for days) resulted in Cmax of 5.36 +- 2.6 ng/mL and AUC of 49.7 +- 24 ngoh/mL for azelastine, whereas, administration of azelastine alone resulted in Cmax of 5.57 +- 2.7 ng/mL and AUC of 48.4 +- 24 ngoh/mL for azelastine [see Drug Interactions (7.2)]. Cimetidine and Ranitidine: In 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 HCl (150 mg twice daily) resulted in Cmax of 8.89 +- 3.28 ng/mL and AUC of 88.22 +- 40.43 ngoh/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 ngoh/mL for azelastine [see Drug Interactions (7.3)]. Theophylline: No significant pharmacokinetic interaction was observed with the co-administration of an oral mg dose of azelastine HCl twice daily and theophylline 300 mg or 400 mg twice daily.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES 14.1 Seasonal Allergic Rhinitis. Azelastine HCl Nasal Spray, 0.15% The efficacy and safety of azelastine HCl 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 weeks. Two 2-week seasonal allergic rhinitis trials evaluated the efficacy of azelastine HCl nasal spray, 0.15% dosed at sprays twice daily. The first trial (Trial 2) compared the efficacy of azelastine HCl nasal spray, 0.15% and azelastine HCl nasal spray, 0.1% to vehicle placebo. The other trial (Trial 3) compared the efficacy of azelastine HCl nasal spray, 0.15% and azelastine HCl nasal spray, 0.1% to vehicle placebo. In these two trials, azelastine HCl 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 azelastine HCl nasal spray, 0.15% dosed at sprays once daily compared to the vehicle placebo. Trial demonstrated greater decrease in rTNSS than placebo and the difference was statistically significant (Table 4). Trial and Trial were conducted in patients with Texas mountain cedar allergy. In Trial and Trial 6, azelastine HCl nasal spray, 0.15% demonstrated greater decrease in rTNSS than placebo and the differences were statistically significant (Trials and 6; Table 4). Instantaneous TNSS results for the once daily dosing regimen of azelastine HCl nasal spray, 0.15% are shown in Table 5. In Trials and 6, azelastine HCl nasal spray, 0.15% demonstrated greater decrease in iTNSS than placebo and the differences were statistically significant. Table 4. Mean Change from Baseline in Reflective TNSS over Weeks in Adults and Children >= 12 years with Seasonal Allergic RhinitisTreatment (sprays per nostril)nBaseline LS MeanChange from BaselineDifference From PlaceboLS Mean95% CIP valueTrial 2Two sprays twice dailyAzelastine HCl Nasal Spray, 0.15% 15318.2-4.3-1.2-2.1, -0.30.01Azelastine HCl Nasal Spray, 0.1% 15317.9-3.9-0.9-1.8, 0.10.07Vehicle Placebo 15318.1-3Trial 3Two sprays twice dailyAzelastine HCl Nasal Spray, 0.15% 17717.7-5.1-3-3.9, -2.1<0.001Azelastine HCl Nasal Spray, 0.1% 16918.2-4.2-2.1-3.0, -1.2<0.001Vehicle Placebo 17717.7-2.1Trial 4Two sprays once daily Azelastine HCl Nasal Spray, 0.15% 23817.4-3.4-1-1.7, -0.30.008Vehicle Placebo 24217.4-2.4Trial 5Two sprays once dailyAzelastine HCl Nasal Spray, 0.15% 26618.5-3.3-1.4-2.1, -0.8<0.001Vehicle Placebo 26618-1.9Trial 6Two sprays once daily Azelastine HCl Nasal Spray, 0.15% 25118.5-3.4-1.4-2.1, -0.7<0.001Vehicle Placebo 25418.8-2Sum of AM and PM rTNSS for each day (Maximum score=24) and averaged over the 14 day treatment periodTable 5. Mean Change from Baseline AM Instantaneous TNS over Weeks in Adults and Children >= 12 years with Seasonal Allergic RhinitisTreatment(sprays per nostril once daily)nBaseline LS MeanChange from BaselineDifference From PlaceboLS Mean95% CIP valueTrial 4Two sprays once dailyAzelastine HCl Nasal Spray, 0.15%2388.1-1.3-0.2-0.6, 0.10.15Vehicle Placebo2428.3-1.1Trial 5Two sprays once dailyAzelastine HCl Nasal Spray, 0.15%2668.7-1.4-0.7-1, -0.4<0.001Vehicle Placebo2668.3-0.7Trial 6Two sprays once dailyAzelastine HCl Nasal Spray, 0.15%2518.9-1.4-0.6-0.9, -0.3<0.001Vehicle Placebo2548.9-0.8AM iTNSS for each day (Maximum score=12) and averaged over the 14 day treatment periodAzelastine HCl nasal spray, 0.15% at dose of spray twice daily was not studied. The azelastine HCl nasal spray, 0.15% spray twice daily dosing regimen is supported by previous findings of efficacy for azelastine HCl nasal spray, 0.1% and favorable comparison of azelastine HCl nasal spray, 0.15% to azelastine nasal spray 0.1% and azelastine HCl nasal spray 0.1% (Table 4).The efficacy and safety of azelastine HCl nasal spray, 0.15% in children to 11 years of age with seasonal allergic rhinitis was evaluated in clinical study that enrolled pediatric patients with perennial allergic rhinitis, with or without concomitant seasonal allergic rhinitis (described below in Section 14.2). 14.2 Perennial Allergic Rhinitis. Azelastine HCl Nasal Spray, 0.15% The efficacy and safety of azelastine HCl nasal spray, 0.15% in pediatric patients to 11 years of age with perennial allergic rhinitis, with or without concomitant seasonal allergic rhinitis, was evaluated in randomized, double-blind, placebo-controlled clinical trial in 486 patients. All patients received one spray per nostril twice daily. The study population 58% male 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 instantaneous total nasal symptom score (iTNSS), and other supportive secondary efficacy variables. The primary efficacy endpoint was the mean change from baseline rTNSS over weeks. The one 4-week perennial allergic rhinitis trial evaluated the efficacy of azelastine HCl nasal spray, 0.15%, azelastine HCl nasal spray, 0.1%, and vehicle placebo dosed at sprays per nostril twice daily. In this trial, azelastine HCl nasal spray, 0.15% demonstrated greater decrease in rTNSS than placebo and the difference was statistically significant (Table 6). Table 6. Mean Change from Baseline in Reflective TNSS over Weeks in Adults and Children >=12 years with Perennial Allergic RhinitisTreatment (sprays per nostril twice daily)nBaseline LS MeanChange from BaselineDifference From PlaceboLS Mean95% CIP valueTwo sprays twice dailyAzelastine HCl Nasal Spray, 0.15%19215.8-4-0.9-1.7, -0.10.03Azelastine HCl Nasal Spray, 0.1%19415.5-3.8-0.7-1.5, 0.10.08Vehicle Placebo19214.7-3.1Sum of AM and PM rTNSS for each day (Maximum score=24) and averaged over the 28 day treatment period The efficacy and safety of azelastine HCl nasal spray, 0.1% and azelastine HCl nasal spray, 0.15% in pediatric patients to 11 years of age with perennial allergic rhinitis, with or without concomitant seasonal allergic rhinitis, was evaluated in 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 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. Table 7. Mean Change from Baseline in Reflective TNSS over Weeks in Children to 11 years with Perennial Allergic RhinitisTreatment (sprays per nostril twice daily)nBaseline LS MeanChange from BaselineDifference From PlaceboLS Mean95% CIP valueOne spray twice daily Azelastine HCl Nasal Spray, 0.15% 15916.6-3.5-1-1.7, -0.30.005Azelastine HCl Nasal Spray, 0.1% 16616.4-3.4-0.9-1.6, -0.20.015Vehicle Placebo 16116.1-2.5Sum of AM and PM rTNSS for each day (Maximum score=24) and averaged over the 28 day treatment period The efficacy of azelastine HCl nasal spray, 0.1% and azelastine HCl nasal spray, 0.15% in children months to years of age with allergic rhinitis was explored in clinical study (described above in Section 14.1).

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION . For intranasal use only (2.3). Seasonal allergic rhinitis:6 to 11 years: Azelastine HCl nasal spray, 0.15%: spray per nostril twice daily (2.1) Adults and adolescents 12 years of age and older:Azelastine HCl nasal spray, 0.15%: or sprays per nostril twice daily (2.1), orAzelastine HCl nasal spray, 0.15%: sprays per nostril once daily (2.1) Perennial allergic rhinitis:6 to 11 years: Azelastine HCl nasal spray, 0.15%: spray per nostril twice daily (2.2) Adults and adolescents 12 years of age and older: Azelastine HCl nasal spray, 0.15%: sprays per nostril twice daily (2.2) Prime azelastine HCl nasal spray, 0.15% before initial use and when it has not been used for or more days. (2.3) For intranasal use only (2.3). Seasonal allergic rhinitis:6 to 11 years: Azelastine HCl nasal spray, 0.15%: spray per nostril twice daily (2.1) Adults and adolescents 12 years of age and older:Azelastine HCl nasal spray, 0.15%: or sprays per nostril twice daily (2.1), orAzelastine HCl nasal spray, 0.15%: sprays per nostril once daily (2.1) 6 to 11 years: Azelastine HCl nasal spray, 0.15%: spray per nostril twice daily (2.1) Adults and adolescents 12 years of age and older:Azelastine HCl nasal spray, 0.15%: or sprays per nostril twice daily (2.1), orAzelastine HCl nasal spray, 0.15%: sprays per nostril once daily (2.1) Azelastine HCl nasal spray, 0.15%: or sprays per nostril twice daily (2.1), or. Azelastine HCl nasal spray, 0.15%: sprays per nostril once daily (2.1) Perennial allergic rhinitis:6 to 11 years: Azelastine HCl nasal spray, 0.15%: spray per nostril twice daily (2.2) Adults and adolescents 12 years of age and older: Azelastine HCl nasal spray, 0.15%: sprays per nostril twice daily (2.2) Prime azelastine HCl nasal spray, 0.15% before initial use and when it has not been used for or more days. (2.3) 6 to 11 years: Azelastine HCl nasal spray, 0.15%: spray per nostril twice daily (2.2) Adults and adolescents 12 years of age and older: Azelastine HCl nasal spray, 0.15%: sprays per nostril twice daily (2.2) Prime azelastine HCl nasal spray, 0.15% before initial use and when it has not been used for or more days. (2.3) 2.1 Recommended DosageforSeasonal Allergic Rhinitis. Children to 11 years of age: Azelastine HCl nasal spray, 0.15%, spray per nostril twice daily. Adults and adolescents 12 years of age and older: Azelastine HCl nasal spray, 0.15%, or sprays per nostril twice daily. Azelastine HCl nasal spray, 0.15% may also be administered as sprays per nostril once daily. 2.2 Recommended DosageforPerennial Allergic Rhinitis. Children to 11 years of age: Azelastine HCl nasal spray, 0.15%, spray per nostril twice daily. Adults and adolescents 12 years of age and older: Azelastine HCl nasal spray, 0.15%, sprays per nostril twice daily. 2.3 Important Administration Instructions. Administer azelastine HCl nasal spray, 0.15% by the intranasal route only.Avoid spraying azelastine HCl nasal spray, 0.15% into the eyes.Priming or re-priming Prime azelastine HCl nasal spray, 0.15% before initial use by releasing sprays or until fine mist appears. When azelastine HCl nasal spray, 0.15% has not been used for or more days, re-prime with sprays or until fine mist appears.. Administer azelastine HCl nasal spray, 0.15% by the intranasal route only.. Avoid spraying azelastine HCl nasal spray, 0.15% into the eyes.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information and Instructions for Use). SomnolenceSomnolence has been reported in some patients taking azelastine HCl nasal spray, 0.15%. Caution patients against engaging in hazardous occupations requiring complete mental alertness and motor coordination such as driving or operating machinery after administration of azelastine HCl nasal spray, 0.15% [see Warnings and Precautions (5.1)]. Concurrent Use of Alcohol and other Central Nervous System Depressants Avoid concurrent use of azelastine HCl nasal spray, 0.15% with alcohol or other central nervous system depressants because additional reductions in alertness and additional impairment of central nervous system performance may occur [see Warnings and Precautions (5.1)].Common Adverse Reactions Inform patients that the treatment with azelastine HCl nasal spray, 0.15% may lead to adverse reactions, most common of which include pyrexia, dysgeusia, nasal discomfort, epistaxis, headache, sneezing, fatigue, somnolence, upper respiratory infection, cough, rhinalgia, vomiting, otitis media, contact dermatitis, and oropharyngeal pain [see Adverse Reactions (6.1)]. Priming Instruct patients to prime the pump before initial use and when azelastine HCl nasal spray, 0.15% has not been used for or more days [see Dosage and Administration (2.3)]. Keep Spray Out of EyesInstruct patients to avoid spraying azelastine HCl nasal spray, 0.15% into their eyes. Keep Out of Childrens ReachInstruct patients to keep azelastine HCl nasal spray, 0.15% out of the reach of children. If child accidentally ingests azelastine HCl nasal spray, 0.15%, seek medical help or call poison control center immediately. Distributed by: Amneal Pharmaceuticals LLC Bridgewater, NJ 08807 Rev. 07-2021-01.

INSTRUCTIONS FOR USE SECTION.

Instructions for Use. Azelastine (ay ze las teen) Hydrochloride Nasal Spray, 0.15%Important: For use in your nose only. For the correct dose of medicine: Keep your head tilted downward when spraying into your nostril. Change nostrils each time you use the spray. Breathe gently and do not tip your head back after using the spray. This will keep the medicine from running down into your throat. You may get bitter taste in your mouth. Figure identifies the parts of your azelastine HCl nasal spray, 0.15% pump. Figure ABefore you use azelastine HCl nasal spray, 0.15% for the first time, you will need to prime the bottle.For use in young children: An adult should help young child use azelastine HCl nasal spray, 0.15%. (See Using your azelastine HCl nasal spray, 0.15% Steps through 8). Priming your azelastine HCl nasal spray, 0.15%Remove the dust cover over the tip of the bottle and the white safety clip just under the shoulders of the bottle (See Figure B).Figure BHold the bottle upright with fingers on the shoulders of the spray pump unit and put your thumb on the bottom of the bottle. Press upward with your thumb and release for the pumping action. Repeat this until you see fine mist (See Figure C). To get fine mist you must pump the spray fast and use firm pressure against the bottom of the bottle. If you see stream of liquid, the pump is not working correctly and you may have nasal discomfort. This should happen in sprays or less. Now your pump is primed and ready to use. Figure CDo not use azelastine HCl nasal spray, 0.15% unless you see fine mist after you do the priming sprays. If you do not see fine mist, clean the tip of the spray nozzle. See the Cleaning the Spray Tip of your zelastine HCl Nasal Spray, 0.15% section below. If you do not use azelastine HCl nasal spray, 0.15% for or more days, you will need to prime the pump with sprays or until you see fine mist. Using your azelastine HCl nasal spray, 0.15%For use in young children: An adult should help young child use azelastine HCl nasal spray, 0.15%. (See Steps through 8). Step 1. Blow your nose to clear your nostrils. Step 2. Keep your head tilted downward toward your toes. Step 3. Place the spray tip about 1/4 inch to 1/2 inch into nostril. Hold bottle upright and aim the spray tip toward the back of your nose (See Figure D). Figure DStep 4. Close your other nostril with finger. Press the pump time and sniff gently at the same time, keeping your head tilted forward and down (See Figure E). Figure EStep 5. Repeat Step and Step in your other nostril. Step 6. If your healthcare provider tells you to use sprays in each nostril, repeat Steps through above for the second spray in each nostril. Step 7. Breathe in gently, and do not tilt your head back after using azelastine HCl nasal spray, 0.15%. This will help to keep the medicine from going into your throat. Step 8. When you finish using your azelastine HCl nasal spray, 0.15%, wipe the spray tip with clean tissue or cloth. Put the safety clip and dust cover back on the bottle. Cleaning the Spray Tip of your Azelastine HCl Nasal Spray, 0.15% If the spray tip opening is clogged, do not use pin or pointed object to unclog the tip. Unscrew the spray pump unit from the bottle by turning it to the left (counter-clockwise) (See Figure F). Soak only the spray pump unit in warm water. Squirt the spray unit several times while holding it under water. Use the pumping action to clear the opening in the tip (See Figure G). Figure FFigure Let the spray pump unit air dry. Make sure it is dry before you put it back onto the bottle. Put the spray pump unit back into the open bottle and tighten it by turning clockwise (to the right). To keep the medicine from leaking out, use firm pressure when you put the pump back onto the bottle. After cleaning, follow the instructions for priming. This Patient Information and Instructions for Use has been approved by the U.S. Food and Drug Administration. Distributed by: Amneal Pharmaceuticals LLC Bridgewater, NJ 08807Rev. 07-2021-01. Keep your head tilted downward when spraying into your nostril. Change nostrils each time you use the spray. Breathe gently and do not tip your head back after using the spray. This will keep the medicine from running down into your throat. You may get bitter taste in your mouth. Hold the bottle upright with fingers on the shoulders of the spray pump unit and put your thumb on the bottom of the bottle. Press upward with your thumb and release for the pumping action. Repeat this until you see fine mist (See Figure C). To get fine mist you must pump the spray fast and use firm pressure against the bottom of the bottle. If you see stream of liquid, the pump is not working correctly and you may have nasal discomfort. This should happen in sprays or less. Do not use azelastine HCl nasal spray, 0.15% unless you see fine mist after you do the priming sprays. If you do not see fine mist, clean the tip of the spray nozzle. See the Cleaning the Spray Tip of your zelastine HCl Nasal Spray, 0.15% section below. If you do not use azelastine HCl nasal spray, 0.15% for or more days, you will need to prime the pump with sprays or until you see fine mist. If the spray tip opening is clogged, do not use pin or pointed object to unclog the tip. Unscrew the spray pump unit from the bottle by turning it to the left (counter-clockwise) (See Figure F). Soak only the spray pump unit in warm water. Squirt the spray unit several times while holding it under water. Use the pumping action to clear the opening in the tip (See Figure G). Let the spray pump unit air dry. Make sure it is dry before you put it back onto the bottle. Put the spray pump unit back into the open bottle and tighten it by turning clockwise (to the right). To keep the medicine from leaking out, use firm pressure when you put the pump back onto the bottle. After cleaning, follow the instructions for priming. Figure A. Figure B. Figure C. Figure D. Figure E. Figure F. Figure G.

SPL PATIENT PACKAGE INSERT SECTION.

PATIENT INFORMATION Azelastine (ay ze las teen) HCl Nasal Spray, 0.15% Important: For use in your nose only. What is Azelastine HCl Nasal Spray, 0.15% Azelastine HCl nasal spray, 0.15% is prescription medicine used to treat symptoms of seasonal allergic rhinitis in people years of age and older and year-round allergic rhinitis in people years of age. Azelastine HCl nasal spray, 0.15% may help to reduce your nasal symptoms including stuffy nose, runny nose, itching and sneezing. It is not known if azelastine HCl nasal spray, 0.15% is safe and effective in children under years of age. What should tell my healthcare provider before using azelastine HCl nasal spray, 0.15%Before using azelastine HCl nasal spray, 0.15%, tell your healthcare provider about all of your medical conditions, including if you are:allergic to any of the ingredients in azelastine HCl nasal spray, 0.15%. See the end of this leaflet for complete list of ingredients in azelastine HCl nasal spray, 0.15%. pregnant, or plan to become pregnant. It is not known if azelastine HCl nasal spray, 0.15% will harm your unborn baby. breastfeeding, or plan to breastfeed. It is not known if azelastine HCl passes into your breast milk. You and your healthcare provider should decide if you will use azelastine HCl nasal spray, 0.15% if you plan to breastfeed. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Azelastine HCl nasal spray, 0.15% and other medicines may affect each other, causing side effects. How should use azelastine HCl nasal spray, 0.15% Read the Instructions for Use at the end of this leaflet for information about the right way to use azelastine HCl nasal spray, 0.15%. An adult should help young child use azelastine HCl nasal spray, 0.15%. Spray azelastine HCl nasal spray, 0.15% in your nose only. Do not spray it into your eyes or mouth. Use azelastine HCl nasal spray, 0.15% exactly as your healthcare provider tells you to use it. Do not use more than your healthcare provider tells you. Throw away your azelastine HCl nasal spray, 0.15% bottle after using 200 sprays. Even though the bottle may not be completely empty, you may not get the correct dose of medicine. If you use too much or child accidentally swallows azelastine HCl nasal spray, 0.15%, call your healthcare provider or go to the nearest hospital emergency room right away. What should avoid while using azelastine HCl nasal spray, 0.15%Azelastine HCl nasal spray, 0.15% can cause sleepiness:Do not drive, operate machinery, or do other dangerous activities until you know how azelastine HCl nasal spray, 0.15% affects you. Do not drink alcohol or take other medicines that may cause you to feel sleepy while using azelastine HCl nasal spray, 0.15%. It may make your sleepiness worse.What are the possible side effects of azelastine HCl nasal spray, 0.15%The most common side effects of azelastine HCl nasal spray, 0.15% include: fever unusual taste nose pain or discomfort nosebleeds headache sneezing fatigue upper respiratory tract infections cough vomiting middle ear infection skin rash sore throat Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all of the possible side effects of azelastine HCl nasal spray, 0.15%. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should store azelastine HCl nasal spray, 0.15%Store azelastine HCl nasal spray, 0.15% upright at room temperature between 68F to 77F (20C to 25C). Do not freeze azelastine HCl nasal spray, 0.15%. Do not use azelastine HCl nasal spray, 0.15% after the expiration date EXP on the medicine label and carton. Keep azelastine HCl nasal spray, 0.15% and all medicines out of reach of children.General information about the safe and effective use of azelastine HCl nasal spray, 0.15%.Medicines are sometimes prescribed for conditions other than those listed in Patient Information leaflet. Do not use azelastine HCl nasal spray, 0.15% for condition for which it was not prescribed. Do not give azelastine HCl nasal spray, 0.15% to other people, even if they have the same symptoms that you have. It may harm them. This Patient Information leaflet summarizes the most important information about azelastine HCl nasal spray, 0.15%. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about azelastine HCl nasal spray, 0.15% that is written for health professionals. For more information, go to www.amneal.com or call 1-877-835-5472. What are the ingredients in azelastine HCl nasal spray, 0.15%Active ingredient: azelastine HCl, USP Inactive ingredients: benzalkonium chloride, edetate disodium, hypromellose, purified water, sodium citrate, sorbitol and sucralose. Hydrochloric acid or sodium hydroxide may be added for adjustment of pH (pH 6.4). Trademarks are the property of their respective owners. Distributed by:Amneal Pharmaceuticals LLCBridgewater, NJ 08807 Rev. 07-2021-01. Azelastine HCl nasal spray, 0.15% is prescription medicine used to treat symptoms of seasonal allergic rhinitis in people years of age and older and year-round allergic rhinitis in people years of age. Azelastine HCl nasal spray, 0.15% may help to reduce your nasal symptoms including stuffy nose, runny nose, itching and sneezing. allergic to any of the ingredients in azelastine HCl nasal spray, 0.15%. See the end of this leaflet for complete list of ingredients in azelastine HCl nasal spray, 0.15%. pregnant, or plan to become pregnant. It is not known if azelastine HCl nasal spray, 0.15% will harm your unborn baby. breastfeeding, or plan to breastfeed. It is not known if azelastine HCl passes into your breast milk. You and your healthcare provider should decide if you will use azelastine HCl nasal spray, 0.15% if you plan to breastfeed. Read the Instructions for Use at the end of this leaflet for information about the right way to use azelastine HCl nasal spray, 0.15%. An adult should help young child use azelastine HCl nasal spray, 0.15%. Spray azelastine HCl nasal spray, 0.15% in your nose only. Do not spray it into your eyes or mouth. Use azelastine HCl nasal spray, 0.15% exactly as your healthcare provider tells you to use it. Do not use more than your healthcare provider tells you. Throw away your azelastine HCl nasal spray, 0.15% bottle after using 200 sprays. Even though the bottle may not be completely empty, you may not get the correct dose of medicine. Do not drive, operate machinery, or do other dangerous activities until you know how azelastine HCl nasal spray, 0.15% affects you. Do not drink alcohol or take other medicines that may cause you to feel sleepy while using azelastine HCl nasal spray, 0.15%. It may make your sleepiness worse.. fever unusual taste nose pain or discomfort nosebleeds headache sneezing fatigue upper respiratory tract infections cough vomiting middle ear infection skin rash sore throat Store azelastine HCl nasal spray, 0.15% upright at room temperature between 68F to 77F (20C to 25C). Do not freeze azelastine HCl nasal spray, 0.15%. Do not use azelastine HCl nasal spray, 0.15% after the expiration date EXP on the medicine label and carton.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS . 8.1 Pregnancy. Risk SummaryLimited data from post-marketing experience over decades of use with azelastine HCl 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 times the clinical daily dose. Oral administration of azelastine HCl 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 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% to 4% and 15% to 20%, respectively. DataAnimal DataIn an embryo-fetal development study in mice dosed during the period of organogenesis, azelastine HCl caused embryo-fetal death, structural abnormalities (cleft palate; short or absent tail; fused, absent or branched ribs), delayed ossification, and decreased fetal weight at approximately 200 times the maximum recommended human daily intranasal dose (MRHDID) in adults (on mg/m2 basis at maternal oral dose of 68.6 mg/kg/day), which also caused maternal toxicity as evidenced by decreased maternal body weight. Neither fetal nor maternal effects occurred in mice at approximately times the MRHDID in adults (on mg/m2 basis at maternal oral dose of mg/kg/day).In an embryo-fetal development study in pregnant rats dosed during the period of organogenesis from gestation days to 17, azelastine HCl caused structural abnormalities (oligo- and brachydactylia), delayed ossification and skeletal variations, in the absence of maternal toxicity, at approximately 180 times the MRHDID in adults (on mg/m2 basis at maternal oral dose of 30 mg/kg/day). Azelastine HCl caused embryo-fetal death and decreased fetal weight and severe maternal toxicity at approximately 410 times the MRHDID (on mg/m2 basis at maternal oral dose of 68.6 mg/kg/day). Neither fetal nor maternal effects occurred at approximately 10 times the MRHDID (on mg/m2 basis at maternal oral dose of mg/kg/day). In an embryo-fetal development study in pregnant rabbits dosed during the period of organogenesis from gestation days to 18, azelastine HCl caused abortion, delayed ossification and decreased fetal weight and severe maternal toxicity at approximately 360 times the MRHDID in adults (on mg/m2 basis at maternal oral dose of 30 mg/kg/day). Neither fetal nor maternal effects occurred at approximately times the MRHDID (on mg/m2 basis at maternal oral dose of 0.3 mg/kg/day). In prenatal and postnatal development study in pregnant rats dosed from late in the gestation period and through the lactation period from gestation day 17 through lactation day 21, azelastine HCl produced no adverse developmental effects on pups at maternal doses up to approximately 180 times the MRHDID (on mg/m2 basis at maternal dose of 30 mg/kg/day). 8.2 Lactation. Risk Summary There are no data on the presence of azelastine HCl 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 azelastine HCl nasal spray, 0.15% is administered to nursing woman. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for azelastine HCl and any potential adverse effects on the breastfed infant from azelastine HCl or from the underlying maternal condition. 8.4 Pediatric Use. The safety and effectiveness of azelastine HCl nasal spray, 0.15% have been established for seasonal allergic rhinitis in pediatric patients to 17 years of age and perennial allergic rhinitis in pediatric patients to 17 years of age [see Clinical Studies (14)]. The safety and effectiveness of azelastine HCl nasal spray, 0.15% in pediatric patients below years of age have not been established. 8.5 Geriatric Use. Clinical trials of azelastine HCl nasal spray, 0.15% 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.