ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. Use of azelastine HCl nasal spray, 0.1% has been associated with somnolence [see Warnings and Precautions (5.1)]. The most common adverse reactions (>=2% incidence) are: bitter taste, headache, somnolence, dysesthesia, rhinitis, nasal burning, pharyngitis, epistaxis, sinusitis, paroxysmal sneezing, nausea, dry mouth, fatigue, dizziness, and weight increase. (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. Seasonal Allergic Rhinitis Azelastine HCl nasal spray, 0.1% Two Sprays Per Nostril Twice Daily Adverse experience information for azelastine HCl nasal spray, 0.1% is derived from six placebo- and active-controlled, 2-day to 8-week clinical trials which included 391 patients, 12 years of age and older, with seasonal allergic rhinitis who received azelastine HCl nasal spray, 0.1% at dose of sprays per nostril twice daily. In placebo-controlled efficacy trials, the incidence of discontinuation due to adverse reactions in patients receiving azelastine HCl nasal spray, 0.1% and vehicle placebo was 2.2% and 2.8%, respectively. Table contains adverse reactions that were reported with frequencies >=2% in the azelastine HCl nasal spray, 0.1% sprays per nostril twice daily treatment group and more frequently than placebo.Table 1: Adverse Reactions Reported in >=2% Incidence in Placebo-Controlled Trials in Patients with Seasonal Allergic Rhinitis [n (%)]Azelastine HCl Nasal Spray, 0.1% = 391Vehicle Placebo = 353Bitter Taste 77 (19.7%)2 (0.6%)Headache 58 (14.8%)45 (12.7%)Somnolence 45 (11.5%)19 (5.4%)Nasal Burning 16 (4.1%)6 (1.7%)Pharyngitis 15 (3.8%)10 (2.8%)Paroxysmal Sneezing 12 (3.1%)4 (1.1%)Dry Mouth 11 (2.8%)6 (1.7%)Nausea 11 (2.8%)4 (1.1%)Rhinitis (2.3%)5 (1.4%)Fatigue (2.3%)5 (1.4%)Dizziness (2.0%)5 (1.4%)Epistaxis (2.0%)5 (1.4%)Weight Increase (2.0%)0 (0.0%)Azelastine HCl Nasal Spray, 0.1% One Spray Per Nostril Twice Daily Adverse experience information for azelastine HCl nasal spray, 0.1% at dose of one spray per nostril twice daily is derived from two placebo-controlled 2-week clinical studies which included 276 patients 12 years of age and older with seasonal allergic rhinitis. The incidence of discontinuation due to adverse reactions in patients receiving azelastine HCl nasal spray, 0.1% and vehicle placebo was 0.0% and 0.8%, respectively. Bitter taste was reported in 8.3% of patients compared to none in the placebo group. Somnolence was reported in 0.4% of patients compared to none in the placebo group. total of 176 patients to 11 years of age were exposed to azelastine HCl nasal spray, 0.1% at dose of spray each nostril twice daily in placebo-controlled studies. In these studies, adverse reactions that occurred more frequently in patients treated with azelastine HCl nasal spray, 0.1% than with placebo, and that were not represented in the adult adverse reactions table above include rhinitis/cold symptoms (17.0% vs. 9.5%), cough (11.4% vs. 8.3%), conjunctivitis (5.1% vs. 1.8%), and asthma (4.5% vs. 4.1%). Adverse Reactions <2% in azelastine HCl nasal spray, 0.1% One or Two Sprays Per Nostril Twice Daily The following reactions were observed infrequently (<2% and exceeding placebo incidence) in patients who received azelastine HCl nasal spray, 0.1% dosed at or sprays per nostril twice daily in U.S. clinical trials. Cardiovascular: flushing, hypertension, tachycardia. Dermatological: contact dermatitis, eczema, hair and follicle infection, furunculosis, skin laceration. Digestive: constipation, gastroenteritis, glossitis, ulcerative stomatitis, vomiting, increased SGPT, aphthous stomatitis, diarrhea, toothache. Metabolic and Nutritional: increased appetite. Musculoskeletal: myalgia, temporomandibular dislocation, rheumatoid arthritis. Neurological: hyperkinesia, hypoesthesia, vertigo. Psychological: anxiety, depersonalization, depression, nervousness, sleep disorder, thinking abnormal. Respiratory: bronchospasm, coughing, throat burning, laryngitis, bronchitis, dry throat, nocturnal dyspnea, nasopharyngitis, nasal congestion, pharyngolaryngeal pain, sinusitis, nasal dryness, paranasal sinus hypersecretion, post nasal drip. Special Senses: conjunctivitis, eye abnormality, eye pain, watery eyes, taste loss. Urogenital: albuminuria, amenorrhea, breast pain, hematuria, increased urinary frequency.Whole Body: allergic reaction, back pain, herpes simplex, viral infection, malaise, pain in extremities, abdominal pain, pyrexia. Vasomotor Rhinitis Adverse experience information for azelastine HCl nasal spray, 0.1% is derived from two placebo-controlled clinical studies which included 216 patients 12 years and older with vasomotor rhinitis who received azelastine HCl nasal spray, 0.1% at dose of sprays per nostril twice daily for up to 28 days. The incidence of discontinuation due to adverse reactions in patients receiving azelastine HCl nasal spray, 0.1% and vehicle placebo was 2.8% and 2.9%, respectively. The following adverse reactions were reported with frequencies >= 2% in the azelastine HCl nasal spray, 0.1% treatment group and more frequently than placebo.Table 2: Adverse Reactions Reported in >=2% Incidence in Placebo-Controlled Trials in Patients with Vasomotor Rhinitis [n (%)]Azelastine HCl Nasal Spray, 0.1% = 216Vehicle Placebo = 210Bitter Taste 42 (19.4%)5 (2.4%)Headache 17 (7.9%)16 (7.6%)Dysesthesia 17 (7.9%)7 (3.3%)Rhinitis 12 (5.6%)5 (2.4%)Epistaxis (3.2%)5 (2.4%)Sinusitis (3.2%)4 (1.9%)Somnolence (3.2%)2 (1.0%)Reactions observed infrequently (<2% and exceeding placebo incidence) in patients who received azelastine HCl nasal spray, 0.1% (2 sprays/nostril twice daily) in U.S. clinical trials in vasomotor rhinitis were similar to those observed in U.S. clinical trials in seasonal allergic rhinitis. In controlled trials involving nasal and oral azelastine HCl formulations, there were infrequent occurrences of hepatic transaminase elevations. 6.2 Postmarketing Experience. During the post approval use of azelastine HCl nasal spray, 0.1%, 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: anaphylaxis, application site irritation, atrial fibrillation, chest pain, confusion, dyspnea, facial edema, involuntary muscle contractions, nasal sores, palpitations, paresthesia, parosmia, pruritus, rash, disturbance or loss of sense of smell and/or taste, tolerance, urinary retention, vision abnormal and xerophthalmia.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Two-year carcinogenicity studies in Crl:CD(SD)BR rats and NMRI mice were conducted to assess the carcinogenic potential of azelastine HCl. No evidence of tumorigenicity was observed in rats at doses up to 30 mg/kg (approximately 270 and 240 times the MRHDID for adults and children, respectively, on mg/m2 basis). No evidence for tumorigenicity was observed in mice at doses up to 25 mg/kg (approximately 110 and 100 times the MRHDID for adults and children, respectively, on mg/m2 basis). Azelastine HCl 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. There were no effects on male or female fertility and reproductive performance in male and female rats at oral doses up to 30 mg/kg (approximately 270 times the MRHDID in adults on mg/m2 basis). At 68.6 mg/kg (approximately 610 times the MRHDID on mg/m2 basis), the duration of estrous cycles was prolonged and copulatory activity and the number of pregnancies were decreased. The numbers of corpora lutea and implantations were decreased; however, pre-implantation loss was not increased.

CLINICAL 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, 0.1% 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 Electrophysiology: In placebo-controlled study (95 subjects with allergic rhinitis), there was no evidence of an effect of azelastine HCl nasal spray, 0.1% (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. These drugs had no effect on QTc based on analysis of serial electrocardiograms. At dose approximately times the maximum recommended dose, azelastine HCl does not prolong the QTc interval to any clinically relevant extent. 12.3 Pharmacokinetics. Absorption: After intranasal administration, the systemic bioavailability of azelastine HCl is approximately 40%. Maximum plasma concentrations (Cmax) are achieved in to hours. Azelastine HCl administered intranasally at doses above two sprays per nostril twice daily for 29 days resulted in greater than proportional increases in Cmax and area under the curve (AUC) for azelastine. Distribution: Based on intravenous and oral administration, the steady-state volume of distribution 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 intranasal dosing of azelastine HCl to steady-state, plasma concentrations of desmethylazelastine range from 20% to 50% of azelastine concentrations. Limited data indicate that the metabolite profile is similar when azelastine HCl is administered via the intranasal or oral route. Elimination: Based on intravenous and oral administration, the elimination half-life and plasma clearance are 22 hours and 0.5 L/h/kg, respectively. Approximately 75% of an oral dose of radiolabeled azelastine HCl 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 70% to 75% higher Cmax and AUC compared to normal 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: No significant pharmacokinetic interaction was observed with the co-administration of orally administered azelastine (4 mg twice daily) with erythromycin (500 mg three times daily for days). In this study, co-administration of orally administered azelastine with erythromycin 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. 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%. No pharmacokinetic interaction was observed with co-administration of orally administered azelastine (4 mg twice daily) with ranitidine hydrochloride (150 mg twice daily). Oral co-administration of azelastine with ranitidine resulted in Cmax of 8.89 +-3.28 ng/mL and AUC of 88.22 +- 40.43 ngoh/mL for azelastine, whereas, azelastine when administered alone resulted in Cmax of 7.83 +- 4.06 ng/mL and AUC of 80.09 +- 43.55 ngoh/mL for azelastine. 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. Two Sprays Per Nostril Twice Daily The efficacy and safety of azelastine HCl nasal spray, 0.1% were evaluated in three placebo-controlled clinical trials of azelastine HCl nasal spray, 0.1% including 322 patients with seasonal allergic rhinitis who received two sprays per nostril twice day for up to weeks. These trials included 55 pediatric patients ages 12 to 16 years. Assessment of efficacy was based on the 12-hour reflective Total Symptom Complex (TSC) and Major Symptom Complex (MSC). The MSC was calculated as the average of individual symptoms of nose blows, sneezes, runny nose/sniffles, itchy nose, and watery eyes as assessed by patients on 0 to categorical scale. Azelastine HCl nasal spray, 0.1% two sprays per nostril twice daily demonstrated greater decrease in the MSC than placebo (Table 3).Table 3: Mean Change from Baseline in Reflective MSC in Adults and Adolescents >=12 Years with Seasonal Allergic Rhinitis Treated with Azelastine HCl Nasal Spray, 0.1% Two Sprays Per Nostril Twice Daily Versus PlaceboTreatmentNBaseline LS Mean (SD)Change from Baseline (SD)Treatment DifferenceP-valueTrial 1: 12 Hour AM and PM Reflective MSCAzelastine HCl Nasal Spray, 0.1% 6311.48 (4.13)-3.05 (3.51)1.98<0.01Placebo Nasal Spray 6010.84 (4.53)-1.07 (3.52)Trial 2: 12 Hour AM and PM Reflective MSCAzelastine HCl Nasal Spray, 0.1% 6312.50 (4.5)-4.10 (3.46)2.03<0.01Placebo Nasal Spray 6312.18 (4.64)-2.07 (4.01)Trial 3: 12 Hour AM and PM Reflective MSCAzelastine HCl Nasal Spray, 0.1% 6612.04 (4.03)-3.31 (3.74)1.350.04Placebo Nasal Spray 6611.66 (3.96)-1.96 (3.57) Major Symptom Complex (MSC): Average of individual symptoms of nose blows, sneezes, runny nose/sniffles, itchy nose, and watery eyes as assessed by patients on 0 to categorical scale.In dose-ranging trials, administration of azelastine HCl nasal spray, 0.1% two sprays per nostril twice daily resulted in statistically significant decrease in symptoms compared to saline placebo within hours after initial dosing and persisted over the 12-hour dosing interval. One Spray Per Nostril Twice Daily The efficacy and safety of azelastine HCl nasal spray, 0.1% were evaluated in two placebo-controlled clinical trials of azelastine HCl nasal spray, 0.1% including 275 patients with seasonal allergic rhinitis who received one spray per nostril twice day for up to weeks. Assessment of efficacy was based on the 12-hour reflective Total Nasal Symptom Score [rTNSS]. rTNSS is calculated as the sum of the patients scoring of four individual nasal symptoms (runny nose, sneezing, itchy nose, and nasal congestion) as assessed by patients on 0 to categorical scale. The primary efficacy endpoint was the change from Baseline to Day 14 in rTNSS. The mean change from baseline in rTNSS was greater in patients receiving azelastine HCl nasal spray, 0.1% one spray per nostril twice daily than those receiving placebo (Table 4).Table 4: Mean Change from Baseline in Reflective TNSS in Adults and Adolescents >=12 years with Seasonal Allergic Rhinitis Treated with Azelastine HCl Nasal Spray, 0.1% One Spray Per Nostril Twice Daily Versus PlaceboTreatmentNBaseline LS Mean (SD)Change from Baseline (SD)Treatment DifferenceP-valueTrial 4: 12 Hour AM and PM Reflective TNSSAzelastine HCl Nasal Spray, 0.1% 13816.34 (4.22)-2.69 (4.79)1.380.01Placebo Nasal Spray 14117.21 (4.32)-1.31 (4.29)Trial 5: 12 Hour AM and PM Reflective TNSS Azelastine HCl Nasal Spray, 0.1% 13716.62 (4.20)-3.68 (4.16)1.180.02Placebo Nasal Spray 13616.84 (4.77)-2.50 (4.01) Total Nasal Symptom Score (TNSS): Average of individual symptoms of runny nose, sneezing, itchy nose, and nasal congestion as assessed by patients on 0 to categorical scale. Two-week studies comparing the efficacy (and safety) of azelastine HCl nasal spray, 0.1% two sprays per nostril twice daily versus one spray per nostril twice daily were not conducted. 14.2 Vasomotor Rhinitis. The efficacy and safety of azelastine HCl nasal spray, 0.1% were evaluated in two placebo-controlled clinical trials of azelastine HCl nasal spray, 0.1% including 216 patients with vasomotor rhinitis who received two sprays per nostril twice day for up to weeks. These patients had vasomotor rhinitis for at least one year, negative skin tests to indoor and outdoor aeroallergens, negative nasal smears for eosinophils, and negative sinus X-rays. Azelastine HCl nasal spray, 0.1% demonstrated significantly greater decrease in symptom complex comprised of rhinorrhea, post nasal drip, nasal congestion, and sneezing compared to placebo.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. None. None. (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Azelastine HCl nasal spray, 0.1%, 137 micrograms (mcg), is an antihistamine formulated as metered-spray solution for intranasal administration. Azelastine HCl, USP occurs as white, almost odorless, crystalline powder with bitter taste. It has molecular weight of 418.37. It is sparingly soluble in water, methanol, and propylene glycol and slightly soluble in ethanol, octanol, and glycerine. It has melting point of about 225C and the pH of saturated solution is between 5.0 and 5.4. Its chemical name is (+-)-1-(2H)-phthalazinone,4-[(4-chlorophenyl) methyl]-2-(hexahydro-1-methyl-1H-azepin-4-yl)-, monohydrochloride. Its molecular formula is C22H24ClN3OoHCl with the following chemical structure:Azelastine HCl nasal spray, 0.1% contains 0.1% azelastine HCl, USP in an aqueous solution at pH 6.8 +- 0.3. It also contains benzalkonium chloride (125 mcg/mL), citric acid, dibasic sodium phosphate, edetate disodium, hypromellose, purified water (pH 6.8) and sodium chloride. After priming [see Dosage and Administration (2.3)], each metered spray delivers 0.137 mL mean volume containing 137 mcg of azelastine HCl, USP (equivalent to 125 mcg of azelastine base). The bottle can deliver 200 metered sprays. 1.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. For intranasal use only. (2.3) Seasonal allergic rhinitis: Pediatric patients to 11 years of age: spray per nostril twice daily. (2.1) Adults and adolescents 12 years of age and older: or sprays per nostril twice daily. (2.1) Vasomotor rhinitis: sprays per nostril twice daily in adults and adolescents 12 years of age and older. (2.2) Prime azelastine HCl nasal spray, 0.1% 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: Pediatric patients to 11 years of age: spray per nostril twice daily. (2.1) Adults and adolescents 12 years of age and older: or sprays per nostril twice daily. (2.1) Pediatric patients to 11 years of age: spray per nostril twice daily. (2.1) Adults and adolescents 12 years of age and older: or sprays per nostril twice daily. (2.1) Vasomotor rhinitis: sprays per nostril twice daily in adults and adolescents 12 years of age and older. (2.2) Prime azelastine HCl nasal spray, 0.1% before initial use and when it has not been used for or more days. (2.3) 2.1 Seasonal Allergic Rhinitis. The recommended dosage of azelastine HCl nasal spray, 0.1% in adults and adolescent patients 12 years and older with seasonal allergic rhinitis is one or two sprays per nostril twice daily. The recommended dosage of azelastine HCl nasal spray, 0.1% in pediatric patients years to 11 years of age is one spray per nostril twice daily. 2.2 Vasomotor Rhinitis. The recommended dosage of azelastine HCl nasal spray, 0.1% in adults and adolescent patients 12 years and older with vasomotor rhinitis is two sprays per nostril twice daily. 2.3 Important Administration Instructions. Administer azelastine HCl nasal spray, 0.1% by the intranasal route only. Priming: Prime azelastine HCl nasal spray, 0.1% before initial use by releasing sprays or until fine mist appears. When azelastine HCl nasal spray, 0.1% has not been used for or more days, reprime with sprays or until fine mist appears. Avoid spraying azelastine HCl nasal spray, 0.1% into the eyes.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Azelastine HCl nasal spray, 0.1% is nasal spray solution. Each spray of azelastine HCl nasal spray, 0.1% delivers volume of 0.137 mL solution containing 137 mcg of azelastine HCl, USP. Azelastine HCl nasal spray, 0.1%: 137 mcg of azelastine HCl, USP in each 0.137 mL spray. (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. 7.1 Central Nervous System Depressants. Concurrent use of azelastine HCl nasal spray, 0.1% 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)].

GERIATRIC USE SECTION.

8.5 Geriatric Use. Clinical trials of azelastine HCl nasal spray, 0.1% did not include sufficient numbers of patients aged 65 and over 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.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. Product: 50090-3833NDC: 50090-3833-0 30 mL in BOTTLE, SPRAY 1 in CARTON.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Azelastine hydrochloride (HCl) nasal spray, 0.1% is indicated for the treatment of the symptoms of seasonal allergic rhinitis in adults and pediatric patients years and older, and for the treatment of the symptoms of vasomotor rhinitis in adults and adolescent patients 12 years and older. Azelastine HCl nasal spray, 0.1% is an H1-receptor antagonist indicated for the treatment of the symptoms of seasonal allergic rhinitis in adults and pediatric patients years and older and for the treatment of the symptoms of vasomotor rhinitis in adults and adolescent patients 12 years and older. (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. See FDA-approved patient labeling (Patient Information and Instructions for Use). Activities Requiring Mental Alertness Somnolence has been reported in some patients taking azelastine HCl nasal spray, 0.1%. 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, 0.1% [see Warnings and Precautions (5.1)]. Concurrent Use of Alcohol and other Central Nervous System Depressants Instruct patients to avoid concurrent use of azelastine HCl nasal spray, 0.1% 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, 0.1% may lead to adverse reactions, which include bitter taste, headache, somnolence, dysesthesia, rhinitis, nasal burning, pharyngitis, epistaxis, sinusitis, paroxysmal sneezing, nausea, dry mouth, fatigue, dizziness, and weight increase [see Adverse Reactions (6.1)]. Priming Instruct patients to prime the pump before initial use and when azelastine HCl nasal spray, 0.1% has not been used for or more days [see Dosage and Administration (2.3)]. Keep Spray Out of Eyes Instruct patients to avoid spraying azelastine HCl nasal spray, 0.1% into their eyes. Keep Out of Childrens Reach Instruct patients to keep azelastine HCl nasal spray, 0.1% out of the reach of children. If child accidentally ingests azelastine HCl nasal spray, 0.1%, seek medical help or call poison control center immediately. Distributed by: Amneal Pharmaceuticals LLC Bridgewater, NJ 08807Rev. 10-2018-02.

INSTRUCTIONS FOR USE SECTION.

Instructions for Use Azelastine Hydrochloride (ay ze las teen hye droe klor ide) Nasal Spray, 0.1% 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, 0.1% pumpBefore you use azelastine HCl nasal spray, 0.1% for the first time, you will need to prime the bottle. Priming your azelastine HCl nasal spray, 0.1% Remove the dust cover over the tip of the pump and the white safety clip just under the shoulders of the pump (See Figure B).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. Now your pump is primed and ready to use.Do not use azelastine HCl nasal spray, 0.1% 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 azelastine HCl nasal spray, 0.1% section below. If you do not use azelastine HCl nasal spray, 0.1% 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, 0.1% 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).Step 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).Step 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, 0.1%. This will help to keep the medicine from going into your throat. Step 8. When you finish using your azelastine HCl nasal spray, 0.1%, 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, 0.1% 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. 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. 10-2018-02. 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. 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, 0.1% 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 azelastine HCl nasal spray, 0.1% section below. If you do not use azelastine HCl nasal spray, 0.1% 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, 0.1% 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. A. Figure B. Figure C. Figure D. Figure E. Figure and G.

MECHANISM OF ACTION SECTION.

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, 0.1% 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.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Two-year carcinogenicity studies in Crl:CD(SD)BR rats and NMRI mice were conducted to assess the carcinogenic potential of azelastine HCl. No evidence of tumorigenicity was observed in rats at doses up to 30 mg/kg (approximately 270 and 240 times the MRHDID for adults and children, respectively, on mg/m2 basis). No evidence for tumorigenicity was observed in mice at doses up to 25 mg/kg (approximately 110 and 100 times the MRHDID for adults and children, respectively, on mg/m2 basis). Azelastine HCl 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. There were no effects on male or female fertility and reproductive performance in male and female rats at oral doses up to 30 mg/kg (approximately 270 times the MRHDID in adults on mg/m2 basis). At 68.6 mg/kg (approximately 610 times the MRHDID on 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.

NURSING MOTHERS SECTION.

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. Breastfed infants should be monitored for signs of milk rejection during azelastine HCl use by lactating women (see Clinical Considerations).The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for azelastine HCl nasal spray, 0.1% and any potential adverse effects on the breastfed infant from azelastine HCl nasal spray, 0.1% or from the underlying maternal condition. Clinical Considerations Monitoring for Adverse Reactions Breastfed infants of lactating women treated with azelastine HCl nasal spray, 0.1% should be monitored for possible signs of milk rejection related to the bitter taste of azelastine HCl.

OVERDOSAGE SECTION.

10 OVERDOSAGE. There have been no reported overdosages with azelastine HCl nasal spray, 0.1%. Acute overdosage by adults with this dosage form is unlikely to result in clinically significant adverse reactions, other than increased somnolence, since one bottle of azelastine HCl nasal spray, 0.1% contains 30 mg of azelastine(HCl). Clinical trials in adults with single doses of the oral formulation of azelastine (HCl) (up to 16 mg) have not resulted in increased incidence of serious adverse reactions. General supportive measures should be employed if overdosage occurs. There is no known antidote to azelastine HCl nasal spray, 0.1%. Oral ingestion of antihistamines has the potential to cause serious adverse effects in young children. Accordingly, azelastine HCl nasal spray, 0.1% should be kept out of the reach of children.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

Azelastine. Label Image.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of azelastine HCl nasal spray, 0.1% for the treatment of symptoms of seasonal allergic rhinitis have been established for patients years and older [see Adverse Reactions (6.1) and Clinical Studies (14.1)]. The safety and effectiveness of azelastine HCl nasal spray, 0.1% for the treatment of vasomotor rhinitis have been established for patients 12 years and older [see Adverse Reactions (6.1) and Clinical Studies (14.2)]. The safety and effectiveness of azelastine HCl nasal spray, 0.1% in pediatric patients below the age of years with seasonal allergic rhinitis and in pediatric patients below the age of 12 years with vasomotor rhinitis have not been established.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Cardiac Electrophysiology: In placebo-controlled study (95 subjects with allergic rhinitis), there was no evidence of an effect of azelastine HCl nasal spray, 0.1% (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. These drugs had no effect on QTc based on analysis of serial electrocardiograms. At dose approximately times the maximum recommended dose, azelastine HCl does not prolong the QTc interval to any clinically relevant extent.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Absorption: After intranasal administration, the systemic bioavailability of azelastine HCl is approximately 40%. Maximum plasma concentrations (Cmax) are achieved in to hours. Azelastine HCl administered intranasally at doses above two sprays per nostril twice daily for 29 days resulted in greater than proportional increases in Cmax and area under the curve (AUC) for azelastine. Distribution: Based on intravenous and oral administration, the steady-state volume of distribution 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 intranasal dosing of azelastine HCl to steady-state, plasma concentrations of desmethylazelastine range from 20% to 50% of azelastine concentrations. Limited data indicate that the metabolite profile is similar when azelastine HCl is administered via the intranasal or oral route. Elimination: Based on intravenous and oral administration, the elimination half-life and plasma clearance are 22 hours and 0.5 L/h/kg, respectively. Approximately 75% of an oral dose of radiolabeled azelastine HCl 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 70% to 75% higher Cmax and AUC compared to normal 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: No significant pharmacokinetic interaction was observed with the co-administration of orally administered azelastine (4 mg twice daily) with erythromycin (500 mg three times daily for days). In this study, co-administration of orally administered azelastine with erythromycin 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. 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%. No pharmacokinetic interaction was observed with co-administration of orally administered azelastine (4 mg twice daily) with ranitidine hydrochloride (150 mg twice daily). Oral co-administration of azelastine with ranitidine resulted in Cmax of 8.89 +-3.28 ng/mL and AUC of 88.22 +- 40.43 ngoh/mL for azelastine, whereas, azelastine when administered alone resulted in Cmax of 7.83 +- 4.06 ng/mL and AUC of 80.09 +- 43.55 ngoh/mL for azelastine. 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.

PREGNANCY SECTION.

8.1 Pregnancy. Risk Summary Limited data from post-marketing experience over decades of use with azelastine HCl nasal spray, 0.1% 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 270 times and higher than the maximum recommended human daily intranasal dose (MRHDID) of 1.096 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. Data Animal Data In 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 300 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 15 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 270 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 610 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 20 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 530 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 270 times the MRHDID (on mg/m2 basis at maternal dose of 30 mg/kg/day).

SPL PATIENT PACKAGE INSERT SECTION.

PATIENT INFORMATION. Azelastine Hydrochloride (ay ze las teen hye droe klor ide) Nasal Spray, 0.1% Important: For use in your nose only. What is azelastine HCl nasal spray, 0.1% Azelastine HCl nasal spray, 0.1% is prescription medicine used to treat symptoms of seasonal allergic rhinitis in people age and older and vasomotor rhinitis in people age 12 and older. Azelastine HCl nasal spray, 0.1% may help to reduce your nasal symptoms including stuffy nose, runny nose, itching and sneezing. It is not known if azelastine HCl nasal spray, 0.1% is safe and effective in children with seasonal allergic rhinitis under years of age or in children with vasomotor rhinitis under 12 years of age. What should tell my healthcare provider before using azelastine HCl nasal spray, 0.1% Before using azelastine HCl nasal spray, 0.1%, tell your healthcare provider if you are: allergic to any of the ingredients in azelastine HCl nasal spray, 0.1%. See the end of this leaflet for complete list of ingredients in azelastine HCl nasal spray, 0.1%. pregnant, or plan to become pregnant. 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, 0.1% 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, 0.1% and other medicines may affect each other, causing side effects. How should use azelastine HCl nasal spray, 0.1% Read the Instructions for Use at the end of this leaflet for information about the right way to use azelastine HCl nasal spray, 0.1%. Spray azelastine HCl nasal spray, 0.1% in your nose only. Do not spray it into your eyes or mouth. Use azelastine HCl nasal spray, 0.1% 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, 0.1% 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, 0.1%, call your healthcare provider or go to the nearest hospital emergency room right away. What should avoid while using azelastine HCl nasal spray, 0.1% Azelastine HCl nasal spray, 0.1% can cause sleepiness: Do not drive, operate machinery, or do other dangerous activities until you know how azelastine HCl nasal spray, 0.1% affects you. Do not drink alcohol or take other medicines that may cause you to feel sleepy while using azelastine HCl nasal spray, 0.1%. It may make your sleepiness worse. What are the possible side effects of azelastine HCl nasal spray, 0.1% The most common side effects of azelastine HCl nasal spray, 0.1% include: unusual bitter taste headache sleepiness nose burning, pain or discomfort runny nose scratchy or sore throat nosebleeds inflammation or swelling of the sinuses sneezing nausea dry mouth fatigue dizziness weight increase 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, 0.1%. 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, 0.1% Keep azelastine HCl nasal spray, 0.1% upright at 68 to 77F (20 to 25C). Do not freeze azelastine HCl nasal spray, 0.1%. Do not use azelastine HCl nasal spray, 0.1% after the expiration date EXP on the medicine label and box. Keep azelastine HCl nasal spray, 0.1% and all medicines out of reach of children. General information about the safe and effective use of azelastine HCl nasal spray, 0.1%. Medicines are sometimes prescribed for conditions other than those listed in Patient Information leaflet. Do not use azelastine HCl nasal spray, 0.1% for condition for which it was not prescribed. Do not give azelastine HCl nasal spray, 0.1% 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, 0.1%. 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, 0.1% that is written for health professionals. For more information call 1-877-835-5472. What are the ingredients in azelastine HCl nasal spray, 0.1% Active ingredient: Azelastine HCl, USPInactive ingredients: Benzalkonium chloride, citric acid, dibasic sodium phosphate, edetate disodium, hypromellose, purified water (pH 6.8) and sodium chloride. Trademarks are the property of their respective owners.Distributed by: Amneal Pharmaceuticals LLC Bridgewater, NJ 08807Rev. 10-2018-02. Azelastine HCl nasal spray, 0.1% is prescription medicine used to treat symptoms of seasonal allergic rhinitis in people age and older and vasomotor rhinitis in people age 12 and older. Azelastine HCl nasal spray, 0.1% 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, 0.1%. See the end of this leaflet for complete list of ingredients in azelastine HCl nasal spray, 0.1%. pregnant, or plan to become pregnant. 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, 0.1% 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, 0.1%. Spray azelastine HCl nasal spray, 0.1% in your nose only. Do not spray it into your eyes or mouth. Use azelastine HCl nasal spray, 0.1% 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, 0.1% 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, 0.1%, call your healthcare provider or go to the nearest hospital emergency room right away. Do not drive, operate machinery, or do other dangerous activities until you know how azelastine HCl nasal spray, 0.1% affects you. Do not drink alcohol or take other medicines that may cause you to feel sleepy while using azelastine HCl nasal spray, 0.1%. It may make your sleepiness worse. unusual bitter taste headache sleepiness nose burning, pain or discomfort runny nose scratchy or sore throat nosebleeds inflammation or swelling of the sinuses sneezing nausea dry mouth fatigue dizziness weight increase Keep azelastine HCl nasal spray, 0.1% upright at 68 to 77F (20 to 25C). Do not freeze azelastine HCl nasal spray, 0.1%. Do not use azelastine HCl nasal spray, 0.1% after the expiration date EXP on the medicine label and box.

SPL UNCLASSIFIED SECTION.

2.1 Seasonal Allergic Rhinitis. The recommended dosage of azelastine HCl nasal spray, 0.1% in adults and adolescent patients 12 years and older with seasonal allergic rhinitis is one or two sprays per nostril twice daily. The recommended dosage of azelastine HCl nasal spray, 0.1% in pediatric patients years to 11 years of age is one spray per nostril twice daily.

USER SAFETY WARNINGS SECTION.

8USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk Summary Limited data from post-marketing experience over decades of use with azelastine HCl nasal spray, 0.1% 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 270 times and higher than the maximum recommended human daily intranasal dose (MRHDID) of 1.096 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. Data Animal Data In 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 300 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 15 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 270 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 610 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 20 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 530 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 270 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. Breastfed infants should be monitored for signs of milk rejection during azelastine HCl use by lactating women (see Clinical Considerations).The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for azelastine HCl nasal spray, 0.1% and any potential adverse effects on the breastfed infant from azelastine HCl nasal spray, 0.1% or from the underlying maternal condition. Clinical Considerations Monitoring for Adverse Reactions Breastfed infants of lactating women treated with azelastine HCl nasal spray, 0.1% should be monitored for possible signs of milk rejection related to the bitter taste of azelastine HCl.. 8.4 Pediatric Use. The safety and effectiveness of azelastine HCl nasal spray, 0.1% for the treatment of symptoms of seasonal allergic rhinitis have been established for patients years and older [see Adverse Reactions (6.1) and Clinical Studies (14.1)]. The safety and effectiveness of azelastine HCl nasal spray, 0.1% for the treatment of vasomotor rhinitis have been established for patients 12 years and older [see Adverse Reactions (6.1) and Clinical Studies (14.2)]. The safety and effectiveness of azelastine HCl nasal spray, 0.1% in pediatric patients below the age of years with seasonal allergic rhinitis and in pediatric patients below the age of 12 years with vasomotor rhinitis have not been established. 8.5 Geriatric Use. Clinical trials of azelastine HCl nasal spray, 0.1% did not include sufficient numbers of patients aged 65 and over 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.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Somnolence: Avoid engaging in hazardous occupations requiring complete mental alertness such as driving or operating machinery when taking azelastine HCl nasal spray, 0.1%. (5.1) Alcohol and other central nervous system (CNS) depressants: Avoid concurrent use with azelastine HCl nasal spray, 0.1% because further decreased alertness and impairment of CNS performance may occur. (5.1) Somnolence: Avoid engaging in hazardous occupations requiring complete mental alertness such as driving or operating machinery when taking azelastine HCl nasal spray, 0.1%. (5.1) Alcohol and other central nervous system (CNS) depressants: Avoid concurrent use with azelastine HCl nasal spray, 0.1% because further decreased alertness and impairment of CNS performance may occur. (5.1) 5.1 Somnolence in Activities Requiring Mental Alertness. In clinical trials, the occurrence of somnolence has been reported in some patients taking azelastine HCl nasal spray, 0.1% [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 motor vehicle after administration of azelastine HCl nasal spray, 0.1%. Concurrent use of azelastine HCl nasal spray, 0.1% 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)].