DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS 7.1 Central Nervous System Depressants Concurrent use of azelastine hydrochloride nasal spray with alcohol or other central nervous system depressants should be avoided because reductions in alertness and impairment of central nervous system performance may occur [see Warnings and Precautions (5.1)].

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION oFor intranasal use only. (2.3)oSeasonal 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)oVasomotor rhinitis: sprays per nostril twice daily in adults and adolescents 12 years of age and older. (2.2)oPrime azelastine hydrochloride nasal spray before initial use and when it has not been used for or more days. (2.3). oFor intranasal use only. (2.3). oSeasonal 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). oVasomotor rhinitis: sprays per nostril twice daily in adults and adolescents 12 years of age and older. (2.2). oPrime azelastine hydrochloride nasal spray 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 hydrochloride nasal spray 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 hydrochloride nasal spray 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 hydrochloride nasal spray 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 hydrochloride nasal spray by the intranasal route only.Priming: Prime azelastine hydrochloride nasal spray before initial use by releasing sprays or until fine mist appears. When azelastine hydrochloride nasal spray has not been used for or more days, reprime with sprays or until fine mist appears. Avoid spraying azelastine hydrochloride nasal spray into the eyes.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS Use of azelastine hydrochloride nasal spray 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 Hi-Tech Pharmacal Co., Inc. at 1-800-262-9010 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 Hydrochloride Nasal Spray Two Sprays Per Nostril Twice DailyAdverse experience information for azelastine hydrochloride nasal spray 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 hydrochloride nasal spray 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 hydrochloride nasal spray and vehicle placebo was 2.2% and 2.8%, respectively.Table contains adverse reactions that were reported with frequencies >=2% in the azelastine hydrochloride nasal spray 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 Hydrochloride Nasal SprayN 391Vehicle Placebo = 353Bitter Taste77 (19.7%)2 (0.6%)Headache58 (14.8%)45 (12.7%)Somnolence45 (11.5%)19 (5.4%)Nasal Burning16 (4.1%)6 (1.7%)Pharyngitis15 (3.8%)10 (2.8%)Paroxysmal Sneezing12 (3.1%)4 (1.1%)Dry Mouth11 (2.8%)6 (1.7%)Nausea11 (2.8%)4 (1.1%)Rhinitis9 (2.3%)5 (1.4%)Fatigue9 (2.3%)5 (1.4%)Dizziness8 (2.0%)5 (1.4%)Epistaxis8 (2.0%)5 (1.4%)Weight Increase8 (2.0%)0 (0.0%) Azelastine Hydrochloride Nasal Spray One Spray Per Nostril Twice DailyAdverse experience information for azelastine hydrochloride nasal spray 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 hydrochloride nasal spray 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.A total of 176 patients to 11 years of age were exposed to azelastine hydrochloride nasal spray 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 hydrochloride nasal spray 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 Hydrochloride Nasal Spray One or Two Sprays Per Nostril Twice DailyThe following reactions were observed infrequently (<2% and exceeding placebo incidence) in patients who received azelastine hydrochloride nasal spray 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 RhinitisAdverse experience information for azelastine hydrochloride nasal spray is derived from two placebo-controlled clinical studies which included 216 patients 12 years and older with vasomotor rhinitis who received azelastine hydrochloride nasal spray 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 hydrochloride nasal spray and vehicle placebo was 2.8% and 2.9%, respectively.The following adverse reactions were reported with frequencies >= 2% in the azelastine hydrochloride nasal spray 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 Hydrochloride Nasal SprayN 216Vehicle Placebo = 210Bitter Taste42 (19.4%)5 (2.4%)Headache17 (7.9%)16 (7.6%)Dysesthesia17 (7.9%)7 (3.3%)Rhinitis12 (5.6%)5 (2.4%)Epistaxis7 (3.2%)5 (2.4%)Sinusitis7 (3.2%)4 (1.9%)Somnolence7 (3.2%)2 (1.0%)Reactions observed infrequently (<2% and exceeding placebo incidence) in patients who received azelastine hydrochloride nasal spray (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 hydrochloride formulations, there were infrequent occurrences of hepatic transaminase elevations.. Azelastine Hydrochloride Nasal Spray Two Sprays Per Nostril Twice Daily. Azelastine Hydrochloride Nasal Spray One Spray Per Nostril Twice Daily. Adverse Reactions <2% in Azelastine Hydrochloride Nasal Spray One or Two Sprays Per Nostril Twice Daily. 6.2 Postmarketing Experience During the post approval use of azelastine hydrochloride nasal spray, 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 hydrochloride. No evidence of tumorigenicity was observed in rats at doses up to 30 mg/kg day (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 hydrochloride showed no genotoxic effects in the Ames test, DNA repair test, mouse lymphoma forward mutation assay, mouse micronucleus test, or chromosomal aberration test in rat bone marrow.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 hydrochloride, phthalazinone derivative, exhibits histamine H1-receptor antagonist activity in isolated tissues, animal models, and humans. Azelastine hydrochloride nasal spray 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 hydrochloride nasal spray (2 sprays per nostril twice daily for 56 days) on cardiac repolarization as represented by the corrected QT interval (QTc) of the electrocardiogram. Following multiple dose oral administration of azelastine 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 hydrochloride 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 hydrochloride does not prolong the QTc interval to any clinically relevant extent.. 12.3 Pharmacokinetics Absorption: After intranasal administration, the systemic bioavailability of azelastine hydrochloride is approximately 40%. Maximum plasma concentrations (Cmax) are achieved in to hours.Azelastine hydrochloride 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 hydrochloride 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 hydrochloride 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 hydrochloride was excreted in the feces with less than 10% as unchanged azelastine.Special Populations:Hepatic Impairment: Following oral administration, pharmacokinetic parameters were not influenced by hepatic impairment.Renal Impairment: Based on oral, single-dose studies, renal insufficiency (creatinine clearance <50 mL/min) resulted in 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 hydrochloride 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 DailyThe efficacy and safety of azelastine hydrochloride nasal spray were evaluated in three placebo-controlled clinical trials of azelastine hydrochloride nasal spray 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 hydrochloride nasal spray 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 Hydrochloride Nasal Spray 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 Hydrochloride Nasal SprayPlacebo Nasal Spray636011.48 (4.13)10.84 (4.53)-3.05 (3.51)-1.07 (3.52)1.98<0.01Trial 2: 12 Hour AM and PM Reflective MSCAzelastine Hydrochloride Nasal SprayPlacebo Nasal Spray636312.50 (4.5)12.18 (4.64)-4.10 (3.46)-2.07 (4.01)2.03<0.01Trial 3: 12 Hour AM and PM Reflective MSCAzelastine Hydrochloride Nasal SprayPlacebo Nasal Spray666612.04 (4.03)11.66 (3.96)-3.31 (3.74)-1.96 (3.57)1.350.04 Major Symptom Comlex (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 hydrochloride nasal spray 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 DailyThe efficacy and safety of azelastine hydrochloride nasal spray were evaluated in two placebo-controlled clinical trials of azelastine hydrochloride nasal spray 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 hydrochloride nasal spray 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 Hydrochloride Nasal Spray 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 Hydrochloride Nasal SprayPlacebo Nasal Spray13814116.34 (4.22)17.21 (4.32)-2.69 (4.79)-1.31 (4.29)1.380.01Trial 5: 12 Hour AM and PM Reflective TNSSAzelastine Hydrochloride Nasal SprayPlacebo Nasal Spray13713616.62 (4.20)16.84 (4.77)-3.68 (4.16)-2.50 (4.01)1.180.02 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 hydrochloride nasal spray 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 hydrochloride nasal spray were evaluated in two placebo-controlled clinical trials of azelastine hydrochloride nasal spray 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 hydrochloride nasal spray 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 Hydrochloride Nasal Spray, 137 micrograms (mcg), is an antihistamine formulated as metered-spray solution for intranasal administration. Azelastine hydrochloride 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 Hydrochloride Nasal Spray contains 0.1% azelastine hydrochloride 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, sodium chloride, and purified water.After priming [see Dosage and Administration (2.3) ], each metered spray delivers 0.137 mL mean volume containing 137 mcg of azelastine hydrochloride (equivalent to 125 mcg of azelastine base). The bottle can deliver 200 metered sprays.. Chemical Structure.

DOSAGE FORMS & STRENGTHS SECTION.

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

GERIATRIC USE SECTION.

8.5 Geriatric Use Clinical trials of azelastine hydrochloride nasal spray 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 Azelastine Hydrochloride Nasal Spray, 137 mcg is supplied as 30-mL package (NDC 50383-738-30) delivering 200 metered sprays in high-density polyethylene (HDPE) bottle fitted with metered-dose spray pump unit. The spray pump unit consists of nasal spray pump fitted with white safety clip and clear plastic dust cover. The net content of the bottle is 30 mL (net weight 30 gm of solution). Each bottle contains 30 mg (1 mg/mL) of azelastine hydrochloride. After priming [see Dosage and Administration (2.3) ], each spray delivers fine mist containing mean volume of 0.137 mL solution containing 137 mcg of azelastine hydrochloride. The correct amount of medication in each spray cannot be assured before the initial priming and after 200 sprays have been used, even though the bottle is not completely empty. The bottle should be discarded after 200 sprays have been used. Azelastine Hydrochloride Nasal Spray should not be used after the expiration date EXP printed on the medicine label and carton.Storage: Store at controlled room temperature 20-25C (68-77F). Protect from freezing.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE Azelastine hydrochloride nasal spray 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 hydrochloride nasal spray 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 AlertnessSomnolence has been reported in some patients taking azelastine hydrochloride nasal spray. Caution patients against engaging in hazardous occupations requiring complete mental alertness and motor coordination such as driving or operating machinery after administration of azelastine hydrochloride nasal spray [see Warnings and Precautions (5.1) ].Concurrent Use of Alcohol and other Central Nervous System DepressantsInstruct patients to avoid concurrent use of azelastine hydrochloride nasal spray 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 ReactionsInform patients that the treatment with azelastine hydrochloride nasal spray 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) ].PrimingInstruct patients to prime the pump before initial use and when azelastine hydrochloride nasal spray has not been used for or more days [see Dosage and Administration (2.3) ].Keep Spray Out of EyesInstruct patients to avoid spraying azelastine hydrochloride nasal spray into their eyes.Keep Out of Childrens ReachInstruct patients to keep azelastine hydrochloride nasal spray out of the reach of children. If child accidentally ingests azelastine hydrochloride nasal spray, seek medical help or call poison control center immediately.Rx onlyManufactured byHi-Tech Pharmacal Co., Inc.Amityville, NY 11701Rev.738:00 10/18PATIENT INFORMATIONAzelastine HydrochlorideNasal Spray(a zel as teen)Important: For use in your nose only.What is Azelastine Hydrochloride Nasal SprayoAzelastine Hydrochloride Nasal Spray 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.oAzelastine Hydrochloride Nasal Spray may help to reduce your nasal symptoms including stuffy nose, runny nose, itching and sneezing.It is not known if Azelastine Hydrochloride Nasal Spray 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 Hydrochloride Nasal SprayBefore using Azelastine Hydrochloride Nasal Spray, tell your healthcare provider if you are:oallergic to any of the ingredients in Azelastine Hydrochloride Nasal Spray. See the end of this leaflet for complete list of ingredients in Azelastine Hydrochloride Nasal Spray.opregnant, or plan to become pregnant. obreastfeeding, or plan to breastfeed. It is not known if Azelastine Hydrochloride Nasal Spray passes into your breast milk. You and your healthcare provider should decide if you will use Azelastine Hydrochloride Nasal Spray 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 Hydrochloride Nasal Spray and other medicines may affect each other, causing side effects.How should use Azelastine Hydrochloride Nasal SprayoRead the Instructions for Use at the end of this leaflet for information about the right way to use Azelastine Hydrochloride Nasal Spray.oSpray Azelastine Hydrochloride Nasal Spray in your nose only. Do not spray it into your eyes or mouth.oUse Azelastine Hydrochloride Nasal Spray exactly as your healthcare provider tells you to use it.oDo not use more than your healthcare provider tells you.oThrow away your Azelastine Hydrochloride Nasal Spray bottle after using 200 sprays. Even though the bottle may not be completely empty, you may not get the correct dose of medicine.oIf you use too much or child accidentally swallows Azelastine Hydrochloride Nasal Spray, call your healthcare provider or go to the nearest hospital emergency room right away.What should avoid while using Azelastine Hydrochloride Nasal SprayAzelastine Hydrochloride Nasal Spray can cause sleepiness:oDo not drive, operate machinery, or do other dangerous activities until you know how Azelastine Hydrochloride Nasal Spray affects you.oDo not drink alcohol or take other medicines that may cause you to feel sleepy while using Azelastine Hydrochloride Nasal Spray. It may make your sleepiness worse.What are the possible side effects of Azelastine Hydrochloride Nasal SprayThe most common side effects of Azelastine Hydrochloride Nasal Spray include:ounusual bitter tasteoheadacheosleepinessonose burning, pain or discomfortorunny noseoscratchy or sore throatonosebleedsoinflammation or swelling of the sinusesosneezingonauseaodry mouthofatigueodizzinessoweight increaseTell 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 Hydrochloride Nasal Spray. 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 Hydrochloride Nasal SprayoKeep Azelastine Hydrochloride Nasal Spray upright at 68F to 77F (20C to 25C).oDo not freeze Azelastine Hydrochloride Nasal Spray.oDo not use Azelastine Hydrochloride Nasal Spray after the expiration date EXP on the medicine label and box.Keep Azelastine Hydrochloride Nasal Spray and all medicines out of reach of children.General information about the safe and effective use of Azelastine Hydrochloride Nasal Spray.Medicines are sometimes prescribed for conditions other than those listed in Patient Information leaflet. Do not use Azelastine Hydrochloride Nasal Spray for condition for which it was not prescribed. Do not give Azelastine Hydrochloride Nasal Spray 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 Hydrochloride Nasal Spray. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about Azelastine Hydrochloride Nasal Spray that is written for health professionals.For more information call 1-800-262-9010.What are the ingredients in Azelastine Hydrochloride Nasal SprayActive ingredient: azelastine hydrochlorideInactive ingredients: benzalkonium chloride, citric acid, dibasic sodium phosphate, edetate disodium, hypromellose, sodium chloride, and purified water.Manufactured byHi-Tech Pharmacal Co., Inc.Amityville, NY 11701Rev.738:00 10/18Instructions for UseAzelastine HydrochlorideNasal Spray(a zel as teen)Important: For use in your nose only.For the correct dose of medicine:oKeep your head tilted downward when spraying into your nostril.oChange nostrils each time you use the spray.oBreathe 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 Hydrochloride Nasal Spray pumpBefore you use Azelastine Hydrochloride Nasal Spray for the first time, you will need to prime the bottle.Priming your Azelastine Hydrochloride Nasal SprayRemove the clear 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 andoput 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).oTo 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.oThis should happen in sprays or less.Now your pump is primed and ready to use.oDo not use Azelastine Hydrochloride Nasal Spray 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 Hydrochloride section below.oIf you do not use Azelastine Hydrochloride Nasal Spray for or more days, you will need to prime the pump with sprays or until you see fine mist.Using your Azelastine Hydrochloride Nasal SprayStep 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 Hydrochloride Nasal Spray. This will help to keep the medicine from going into your throat.Step 8. When you finish using your Azelastine Hydrochloride Nasal Spray, 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 Hydrochloride Nasal SprayoIf 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).oSoak 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).oLet the spray pump unit air dry. Make sure it is dry before you put it back onto the bottle.oPut the spray pump unit back into the open bottle and tighten it by turning clockwise (to the right).oTo keep the medicine from leaking out, use firm pressure when you put the pump back onto the bottle.oAfter cleaning, follow the instructions for priming.This Patient Information and Instructions for Use has been approved by the U.S. Food and Drug Administration.Manufactured byHi-Tech Pharmacal Co., Inc.Amityville, NY 11701Rev.738:00 10/18. oAzelastine Hydrochloride Nasal Spray 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.. oAzelastine Hydrochloride Nasal Spray may help to reduce your nasal symptoms including stuffy nose, runny nose, itching and sneezing.. oallergic to any of the ingredients in Azelastine Hydrochloride Nasal Spray. See the end of this leaflet for complete list of ingredients in Azelastine Hydrochloride Nasal Spray.. opregnant, or plan to become pregnant. obreastfeeding, or plan to breastfeed. It is not known if Azelastine Hydrochloride Nasal Spray passes into your breast milk. You and your healthcare provider should decide if you will use Azelastine Hydrochloride Nasal Spray if you plan to breastfeed.. oRead the Instructions for Use at the end of this leaflet for information about the right way to use Azelastine Hydrochloride Nasal Spray.. oSpray Azelastine Hydrochloride Nasal Spray in your nose only. Do not spray it into your eyes or mouth.. oUse Azelastine Hydrochloride Nasal Spray exactly as your healthcare provider tells you to use it.. oDo not use more than your healthcare provider tells you.. oThrow away your Azelastine Hydrochloride Nasal Spray bottle after using 200 sprays. Even though the bottle may not be completely empty, you may not get the correct dose of medicine.. oIf you use too much or child accidentally swallows Azelastine Hydrochloride Nasal Spray, call your healthcare provider or go to the nearest hospital emergency room right away.. oDo not drive, operate machinery, or do other dangerous activities until you know how Azelastine Hydrochloride Nasal Spray affects you.. oDo not drink alcohol or take other medicines that may cause you to feel sleepy while using Azelastine Hydrochloride Nasal Spray. It may make your sleepiness worse.. ounusual bitter taste. oheadache. osleepiness. onose burning, pain or discomfort. orunny nose. oscratchy or sore throat. onosebleeds. oinflammation or swelling of the sinuses. osneezing. onausea. odry mouth. ofatigue. odizziness. oweight increase. oKeep Azelastine Hydrochloride Nasal Spray upright at 68F to 77F (20C to 25C).. oDo not freeze Azelastine Hydrochloride Nasal Spray.. oDo not use Azelastine Hydrochloride Nasal Spray after the expiration date EXP on the medicine label and box.. oKeep your head tilted downward when spraying into your nostril.. oChange nostrils each time you use the spray.. oBreathe 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.. oput 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).. oTo 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.. oThis should happen in sprays or less.. oDo not use Azelastine Hydrochloride Nasal Spray 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 Hydrochloride section below.. oIf you do not use Azelastine Hydrochloride Nasal Spray for or more days, you will need to prime the pump with sprays or until you see fine mist.. oIf 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).. oSoak 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).. oLet the spray pump unit air dry. Make sure it is dry before you put it back onto the bottle.. oPut the spray pump unit back into the open bottle and tighten it by turning clockwise (to the right).. oTo keep the medicine from leaking out, use firm pressure when you put the pump back onto the bottle.. oAfter cleaning, follow the instructions for priming.. Figure A. Figure B. Figure C. Figure D. Figure E. Figures & G.

LACTATION SECTION.

8.2 Lactation Risk Summary There are no data on the presence of azelastine hydrochloride in human milk, the effects on the breastfed infant, or the effects on milk production. Breastfed infants should be monitored for signs of milk rejection during azelastine hydrochloride nasal spray 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 hydrochloride nasal spray and any potential adverse effects on the breastfed infant from azelastine hydrochloride nasal spray or from the underlying maternal condition.Clinical ConsiderationsMonitoring for Adverse ReactionsBreastfed infants of lactating women treated with azelastine hydrochloride nasal spray should be monitored for possible signs of milk rejection related to the bitter taste of azelastine hydrochloride.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action Azelastine hydrochloride, phthalazinone derivative, exhibits histamine H1-receptor antagonist activity in isolated tissues, animal models, and humans. Azelastine hydrochloride nasal spray 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 hydrochloride. No evidence of tumorigenicity was observed in rats at doses up to 30 mg/kg day (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 hydrochloride showed no genotoxic effects in the Ames test, DNA repair test, mouse lymphoma forward mutation assay, mouse micronucleus test, or chromosomal aberration test in rat bone marrow.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.

OVERDOSAGE SECTION.

10 OVERDOSAGE There have been no reported overdosages with azelastine hydrochloride nasal spray. 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 hydrochloride nasal spray contains 30 mg of azelastine hydrochloride. Clinical trials in adults with single doses of the oral formulation of azelastine hydrochloride (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 hydrochloride nasal spray. Oral ingestion of antihistamines has the potential to cause serious adverse effects in young children. Accordingly, azelastine hydrochloride nasal spray should be kept out of the reach of children.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL AKORNNDC 50383-738-30200 Metered SpraysAzelastine Hydrochloride Nasal Spray, 0.1% (137 mcg per spray)Antihistamine Nasal SprayRx OnlyFOR INTRANASAL USE ONLYDO NOT SPRAY IN EYESEach spray delivers 0.137 mL (137 mcg azelastine hydrochloride).Patient: See the enclosed Instructions for Use30 mL. Carton.

PEDIATRIC USE SECTION.

8.4 Pediatric Use The safety and effectiveness of azelastine hydrochloride nasal spray 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 hydrochloride nasal spray 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 hydrochloride nasal spray 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 hydrochloride nasal spray (2 sprays per nostril twice daily for 56 days) on cardiac repolarization as represented by the corrected QT interval (QTc) of the electrocardiogram. Following multiple dose oral administration of azelastine 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 hydrochloride 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 hydrochloride 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 hydrochloride is approximately 40%. Maximum plasma concentrations (Cmax) are achieved in to hours.Azelastine hydrochloride 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 hydrochloride 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 hydrochloride 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 hydrochloride was excreted in the feces with less than 10% as unchanged azelastine.Special Populations:Hepatic Impairment: Following oral administration, pharmacokinetic parameters were not influenced by hepatic impairment.Renal Impairment: Based on oral, single-dose studies, renal insufficiency (creatinine clearance <50 mL/min) resulted in 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 hydrochloride twice daily and theophylline 300 mg or 400 mg twice daily.

PREGNANCY SECTION.

8.1 Pregnancy Risk Summary Limited data from postmarketing experience over decades of use with azelastine hydrochloride nasal spray 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 hydrochloride to pregnant mice, rats, and rabbits, during the period of organogenesis, produced developmental toxicity that included structural abnormalities, decreased embryo-fetal survival, and decreased fetal body weights at doses 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 to 4% and 15 to 20%, respectively.DataAnimal DataIn an embryo-fetal development study in mice dosed during the period of organogenesis, azelastine hydrochloride 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 hydrochloride 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 hydrochloride 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 hydrochloride 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 hydrochloride 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 UNCLASSIFIED SECTION.

2.1 Seasonal Allergic Rhinitis The recommended dosage of azelastine hydrochloride nasal spray 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 hydrochloride nasal spray in pediatric patients years to 11 years of age is one spray per nostril twice daily.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Limited data from postmarketing experience over decades of use with azelastine hydrochloride nasal spray 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 hydrochloride to pregnant mice, rats, and rabbits, during the period of organogenesis, produced developmental toxicity that included structural abnormalities, decreased embryo-fetal survival, and decreased fetal body weights at doses 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 to 4% and 15 to 20%, respectively.DataAnimal DataIn an embryo-fetal development study in mice dosed during the period of organogenesis, azelastine hydrochloride 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 hydrochloride 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 hydrochloride 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 hydrochloride 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 hydrochloride 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 hydrochloride 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 hydrochloride nasal spray 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 hydrochloride nasal spray and any potential adverse effects on the breastfed infant from azelastine hydrochloride nasal spray or from the underlying maternal condition.Clinical ConsiderationsMonitoring for Adverse ReactionsBreastfed infants of lactating women treated with azelastine hydrochloride nasal spray should be monitored for possible signs of milk rejection related to the bitter taste of azelastine hydrochloride.. 8.4 Pediatric Use The safety and effectiveness of azelastine hydrochloride nasal spray 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 hydrochloride nasal spray 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 hydrochloride nasal spray 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 hydrochloride nasal spray 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 oSomnolence: Avoid engaging in hazardous occupations requiring complete mental alertness such as driving or operating machinery when taking azelastine hydrochloride nasal spray. (5.1)oAlcohol and other central nervous system (CNS) depressants: Avoid concurrent use with azelastine hydrochloride nasal spray because further decreased alertness and impairment of CNS performance may occur. (5.1). oSomnolence: Avoid engaging in hazardous occupations requiring complete mental alertness such as driving or operating machinery when taking azelastine hydrochloride nasal spray. (5.1). oAlcohol and other central nervous system (CNS) depressants: Avoid concurrent use with azelastine hydrochloride nasal spray 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 hydrochloride nasal spray [see Adverse Reactions (6.1) ]. Patients should be cautioned against engaging in hazardous occupations requiring complete mental alertness and motor coordination such as operating machinery or driving motor vehicle after administration of azelastine hydrochloride nasal spray. Concurrent use of azelastine hydrochloride nasal spray with alcohol or other central nervous system depressants should be avoided because additional reductions in alertness and additional impairment of central nervous system performance may occur [see Drug Interactions (7.1) ].