Azelastine hcl nasal

6 ADVERSE REACTIONS Use of azelastine HCl nasal spray has been associated with somnolence [ see Warnings and Precautions (5.1) ]. The most common adverse reactions (≥2% incidence) are: pyrexia, dysgeusia, nasal discomfort, epistaxis, headache, sneezing, fatigue, somnolence, upper respiratory infection, cough, rhinalgia, vomiting, otitis media, contact dermatitis, and oropharyngeal pain (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Perrigo at 1-866-634-9120 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 a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect rates observed in practice. Children 6 to 11 years of age In a 4 week clinical trial, 489 patients ages 6 to 11 years with perennial allergic rhinitis, with or without concomitant seasonal allergic rhinitis, were treated with either azelastine HCl nasal spray, 0.1%, azelastine HCl nasal spray, 0.15% or placebo, one spray per nostril twice daily. Overall, adverse events were similar in the azelastine HCl nasal spray, 0.15% group (24%), azelastine HCl nasal spray, 0.1% group (26%) and the placebo group (24%). Overall, less than 1% of the combined azelastine HCl nasal spray groups discontinued due to adverse events. Table 2 contains adverse reactions reported with frequencies greater than or equal to 2% and more frequently than placebo in children 6 to 11 years of age treated with azelastine HCl nasal spray, 0.1% or azelastine HCl nasal spray, 0.15% in the controlled trial described above. Table 2. Adverse Reactions Reported in ≥2% Incidence in a Placebo-Controlled Trial of 4 Weeks’ Duration with azelastine HCl nasal spray, 0.1% or azelastine HCl nasal spray, 0.15% in Children 6 to 11 Years of Age with Perennial Allergic Rhinitis 1 spray twice daily Azelastine HCl nasal spray, 0.1% (N=166) Azelastine HCl nasal spray, 0.15% (N=161) Vehicle Placebo (N=162) Epistaxis 8 (5%) 7 (4%) 5 (3%) Nasal Discomfort 1 (<1%) 7 (4%) 0 (0%) Dysgeusia 4 (2%) 6 (4%) 1 (<1%) Upper respiratory infection 4 (2%) 4 (3%) 3 (2%) Sneezing 3 (2%) 4 (3%) 2 (1%) Children 6 months to 5 years In a 4 week clinical trial, 191 patients ages 6 months to 5 years with either seasonal and/or perennial allergic rhinitis were treated with either azelastine HCl nasal spray, 0.1% or azelastine HCl nasal spray, 0.15% one spray per nostril twice daily. The most frequently (≥2%) reported adverse reactions were pyrexia, cough, epistaxis, sneezing, dysgeusia, rhinalgia, upper respiratory infection, vomiting, otitis media, contact dermatitis, and oropharyngeal pain. Overall, adverse events were slightly higher in the azelastine HCl nasal spray, 0.15% group (28%) compared to azelastine HCl nasal spray, 0.1% group (21%). Focused nasal examinations were performed and showed no incidence of nasal mucosal ulceration at any time point during the study. No patients had reports of nasal septal perforation. Overall, less than 3% of the combined azelastine HCl nasal spray groups discontinued due to adverse events. Azelastine HCl nasal spray, 0.15% The safety data described below reflect exposure to azelastine HCl nasal spray, 0.15% in 2114 patients (6 months of age and older) with seasonal or perennial allergic rhinitis from 10 clinical trials of 2 weeks to 12 months duration. In 8 double-blind, placebo-controlled clinical trials of 2 to 4 weeks duration, 1703 patients (646 males and 1059 females) with seasonal or perennial allergic rhinitis were treated with azelastine HCl nasal spray, 0.15% one or two sprays per nostril once or twice daily. In the 12 month open-label, active-controlled clinical trial, 466 patients (156 males and 310 females) with perennial allergic rhinitis were treated with azelastine HCl nasal spray, 0.15% two sprays per nostril twice daily. Of these 466 patients, 152 had participated in the 4-week placebo-controlled perennial allergic rhinitis clinical trials. In a 4-week, double-blind, placebo-controlled clinical trial, 161 patients (87 males and 74 females) ages 6 to 11 years of age with perennial allergic rhinitis, with or without concomitant seasonal allergic rhinitis, were treated with azelastine HCl nasal spray, 0.15% one spray per nostril twice daily. In a 4-week clinical trial, 95 patients (59 males and 36 females) ages 6 months to 5 years of age with seasonal and/or perennial allergic rhinitis were treated with azelastine HCl nasal spray, 0.15% one spray per nostril twice daily. The racial distribution for the 10 clinical trials was 79% white, 14% black, 2% Asian, and 5% other. Adults and Adolescents 12 Years of Age and Older In the 7 placebo controlled clinical trials of 2 to 4 week duration, 2343 patients with seasonal allergic rhinitis and 540 patients with perennial allergic rhinitis were treated with two sprays per nostril of either azelastine HCl nasal spray, 0.15% or placebo once or twice daily. Overall, adverse reactions were more common in the azelastine HCl nasal spray, 0.15% treatment groups (16-31%) than in the placebo groups (11-24%). Overall, less than 2% of patients discontinued due to adverse reactions and withdrawal due to adverse reactions was similar among the treatment groups. Table 3 contains adverse reactions reported with frequencies greater than or equal to 2% and more frequently than placebo in patients treated with azelastine HCl nasal spray, 0.15% in the seasonal and perennial allergic rhinitis controlled clinical trials. Table 3. Adverse Reactions with ≥ 2% Incidence in Placebo-Controlled Trials of 2 to 4 Weeks’ Duration with azelastine HCl nasal spray, 0.15% in Adult and Adolescent Patients With Seasonal or Perennial Allergic Rhinitis 2 sprays twice daily 2 sprays once daily Azelastine HCl nasal spray, 0.15% (N=523) Vehicle Placebo (N=523) Azelastine HCl nasal spray, 0.15% (N=1021) Vehicle Placebo (N=816) Bitter Taste 31 (6%) 5 (1%) 38 (4%) 2 (<1%) Nasal Discomfort 18 (3%) 12 (2%) 37 (4%) 7 (1%) Epistaxis 5 (1%) 7 (1%) 21 (2%) 14 (2%) Sneezing 9 (2%) 1 (<1%) 14 (1%) 0 (0%) In the above trials, somnolence was reported in <1% of patients treated with azelastine HCl nasal spray, 0.15% (11 of 1544) or vehicle placebo (1 of 1339). Long-Term (12 Month) Safety Trial: In the 12 month, open-label, active-controlled, long-term safety trial, 466 patients (12 years of age and older) with perennial allergic rhinitis were treated with azelastine HCl nasal spray, 0.15% two sprays per nostril twice daily and 237 patients were treated with mometasone nasal spray two sprays per nostril once daily. The most frequently reported adverse reactions (>5%) with azelastine HCl nasal spray, 0.15% were bitter taste, headache, sinusitis, and epistaxis. Focused nasal examinations were performed and no nasal ulcerations or septal perforations were observed. In each treatment group, approximately 3% of patients had mild epistaxis. No patients had reports of severe epistaxis. Fifty-four patients (12%) treated with azelastine HCl nasal spray, 0.15% and 17 patients (7%) treated with mometasone nasal spray discontinued from the trial due to adverse events. 6.2 Postmarketing Experience During the post approval use of azelastine HCl nasal spray, the following adverse reactions have been identified. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse reactions reported include: abdominal pain, atrial fibrillation, blurred vision, chest pain, confusion, disturbance or loss of sense of smell and/or taste, dizziness, dyspnea, facial swelling, hypertension, involuntary muscle contractions, nasal burning, nausea, nervousness, palpitations, paresthesia, parosmia, pruritus, rash, sneezing, insomnia, sweet taste, tachycardia, and throat irritation. Additionally, the following adverse reactions have been identified during the post approval use of the azelastine HCl nasal spray without sweetener brand of azelastine hydrochloride 0.1% nasal spray (total daily dose 0.55 mg to 1.1 mg). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse reactions reported include the following: anaphylactoid reaction, application site irritation, facial edema, paroxysmal sneezing, tolerance, urinary retention, and xerophthalmia.

4 CONTRAINDICATIONS None. None

11 DESCRIPTION Azelastine HCl nasal spray, 0.15% is an antihistamine (H 1 receptor antagonist) formulated as a metered-spray solution for intranasal administration. Azelastine hydrochloride, USP occurs as a white, almost odorless, crystalline powder with a bitter taste. It has a 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 a melting point of about 225°C and the pH of a 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 C 22 H 24 ClN 3 O•HCl with the following chemical structure: Azelastine HCl nasal spray, 0.15% contains 0.15% azelastine hydrochloride, USP in an isotonic aqueous solution containing sorbitol, sucralose, hypromellose, sodium citrate, edetate disodium, benzalkonium chloride (125 mcg/mL), and purified water (pH 6.4). After priming [ see Dosage and Administration (2.3) ], each metered spray delivers a 0.137 mL mean volume containing 205.5 mcg of azelastine hydrochloride, USP (equivalent to 187.6 mcg of azelastine base). The 30-mL (net weight 30 gm of solution) bottle provides 200 metered sprays. azelastine-hcl-chemical-structure.jpg

2 DOSAGE AND ADMINISTRATION • For intranasal use only (2.3). • Seasonal allergic rhinitis: ▪ 6 to 11 years: azelastine HCl nasal spray, 0.15%: 1 spray per nostril twice daily (2.1) ▪ Adults and adolescents 12 years of age and older: o azelastine HCl nasal spray, 0.15%: 1 or 2 sprays per nostril twice daily (2.1), or o azelastine HCl nasal spray, 0.15%: 2 sprays per nostril once daily (2.1) • Perennial allergic rhinitis: ▪ 6 to 11 years : azelastine HCl nasal spray, 0.15%: 1 spray per nostril twice daily (2.2) ▪ Adults and adolescents 12 years of age and older : azelastine HCl nasal spray, 0.15%: 2 sprays per nostril twice daily (2.2) • Prime azelastine HCl nasal spray, 0.15% before initial use and when it has not been used for 3 or more days. (2.3) 2.1 Seasonal Allergic Rhinitis Children 6 to 11 years of age: azelastine HCl nasal spray, 0.15%, 1 spray per nostril twice daily. Adults and adolescents 12 years of age and older: azelastine HCl nasal spray, 0.15%, 1 or 2 sprays per nostril twice daily. Azelastine HCl nasal spray, 0.15% may also be administered as 2 sprays per nostril once daily. 2.2 Perennial Allergic Rhinitis Children 6 to 11 years of age: azelastine HCl nasal spray, 0.15%, 1 spray per nostril twice daily. Adults and adolescents 12 years of age and older: azelastine HCl nasal spray, 0.15%, 2 sprays per nostril twice daily. 2.3 Important Administration Instructions Administer azelastine HCl nasal spray, 0.15% by the intranasal route only. Priming: Prime azelastine HCl nasal spray, 0.15% before initial use by releasing 6 sprays or until a fine mist appears. When azelastine HCl nasal spray, 0.15% has not been used for 3 or more days, reprime with 2 sprays or until a fine mist appears. Avoid spraying azelastine HCl nasal spray, 0.15% into the eyes.

1 INDICATIONS AND USAGE Azelastine HCl nasal spray, 0.15% is an H 1 -receptor antagonist indicated for the relief of the symptoms of: • Seasonal allergic rhinitis in patients 6 years of age and older. (1.1) • Perennial allergic rhinitis in patients 6 years of age and older. (1.1) 1.1 Allergic Rhinitis Azelastine HCl nasal spray, 0.15% is indicated for the relief of the symptoms of seasonal allergic rhinitis in patients 6 years of age and older and perennial allergic rhinitis in patients 6 years of age and older.

10 OVERDOSAGE There have been no reported overdosages with azelastine HCl nasal spray. Acute overdosage by adults with this dosage form is unlikely to result in clinically significant adverse events, other than increased somnolence, since one 30-mL bottle of azelastine HCl nasal spray, 0.15% contains up to 45 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 events. General supportive measures should be employed if overdosage occurs. There is no known antidote to azelastine HCl nasal spray. Oral ingestion of antihistamines has the potential to cause serious adverse effects in children. Accordingly, azelastine HCl nasal spray, 0.15% should be kept out of the reach of children.

7 DRUG INTERACTIONS 7.1 Central Nervous System Depressants Concurrent use of azelastine HCl nasal spray, 0.15% with alcohol or other central nervous system depressants should be avoided because reductions in alertness and impairment of central nervous system performance may occur [ see Warnings and Precautions (5.1) ]. 7.2 Erythromycin and Ketoconazole Interaction studies investigating the cardiac effects, as measured by the corrected QT interval (QTc), of concomitantly administered oral azelastine hydrochloride and erythromycin or ketoconazole were conducted. Oral erythromycin (500 mg three times daily for 7 days) had no effect on azelastine pharmacokinetics or QTc based on analyses of serial electrocardiograms. Ketoconazole (200 mg twice daily for 7 days) interfered with the measurement of azelastine plasma concentrations on the analytic HPLC; however, no effects on QTc were observed [ see Clinical Pharmacology (12.2) and (12.3) ]. 7.3 Cimetidine Cimetidine (400 mg twice daily) increased the mean C max and AUC of orally administered azelastine hydrochloride (4 mg twice daily) by approximately 65% [ see Clinical Pharmacology (12.3) ].

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Azelastine hydrochloride, a phthalazinone derivative, exhibits histamine H 1 -receptor antagonist activity in isolated tissues, animal models, and humans. Azelastine HCl nasal spray, 0.15% is administered as a racemic mixture with no difference in pharmacologic activity noted between the enantiomers in in vitro studies. The major metabolite, desmethylazelastine, also possesses H 1 -receptor antagonist activity. 12.2 Pharmacodynamics Cardiac Effects: In a placebo-controlled trial (95 patients with allergic rhinitis), there was no evidence of an effect of azelastine hydrochloride nasal spray (2 sprays per nostril twice daily for 56 days) on cardiac repolarization as represented by the corrected QT interval (QTc) of the electrocardiogram. Following multiple dose oral administration of azelastine 4 mg or 8 mg twice daily, the mean change in QTc was 7.2 msec and 3.6 msec, respectively. Interaction studies investigating the cardiac repolarization effects of concomitantly administered oral azelastine hydrochloride and erythromycin or ketoconazole were conducted. Oral erythromycin had no effect on azelastine pharmacokinetics or QTc based on analysis of serial electrocardiograms. Ketoconazole interfered with the measurement of azelastine plasma levels; however, no effects on QTc were observed [ see Drug Interactions (7.2) ]. 12.3 Pharmacokinetics Absorption: After intranasal administration of 2 sprays per nostril (822 mcg total dose) of azelastine HCl nasal spray, 0.15%, the mean azelastine peak plasma concentration (C max ) is 409 pg/mL, the mean extent of systemic exposure (AUC) is 9312 pg•hr/mL and the median time to reach C max (t max ) is 4 hours. The systemic bioavailability of azelastine hydrochloride is approximately 40% after intranasal administration. Distribution: Based on intravenous and oral administration, the steady-state volume of distribution of azelastine is 14.5 L/kg. In vitro studies with human plasma indicate that the plasma protein binding of azelastine and its metabolite, desmethylazelastine, are approximately 88% and 97%, respectively. Metabolism: Azelastine is oxidatively metabolized to the principal active metabolite, desmethylazelastine, by the cytochrome P450 enzyme system. The specific P450 isoforms responsible for the biotransformation of azelastine have not been identified. After a single-dose, intranasal administration of azelastine HCl nasal spray, 0.15% (822 mcg total dose), the mean desmethylazelastine C max is 38 pg/mL, the AUC is 3824 pg•hr/mL and the median t max is 24 hours. After intranasal dosing of azelastine to steady-state, plasma concentrations of desmethylazelastine range from 20-50% of azelastine concentrations. Elimination: Following intranasal administration of azelastine HCl nasal spray, 0.15%, the elimination half-life of azelastine is 25 hours while that of desmethylazelastine is 57 hours. Approximately 75% of an oral dose of radiolabeled azelastine hydrochloride was excreted in the feces with less than 10% as unchanged azelastine. Special Populations: Hepatic Impairment: Following oral administration, pharmacokinetic parameters were not influenced by hepatic impairment. Renal Impairment: Based on oral, single-dose studies, renal insufficiency (creatinine clearance <50 mL/min) resulted in a 70-75% higher C max and AUC compared to healthy subjects. Time to maximum concentration was unchanged. Age: Following oral administration, pharmacokinetic parameters were not influenced by age. Gender: Following oral administration, pharmacokinetic parameters were not influenced by gender. Race: The effect of race has not been evaluated. Drug-Drug Interactions: Erythromycin: Co-administration of orally administered azelastine (4 mg twice daily) with erythromycin (500 mg three times daily for 7 days) resulted in C max of 5.36 ± 2.6 ng/mL and AUC of 49.7 ± 24 ng•h/mL for azelastine, whereas, administration of azelastine alone resulted in C max of 5.57 ± 2.7 ng/mL and AUC of 48.4 ± 24 ng•h/mL for azelastine [ see Drug Interactions (7.2) ]. Cimetidine and Ranitidine: In a multiple-dose, steady-state drug interaction trial in healthy subjects, cimetidine (400 mg twice daily) increased orally administered mean azelastine (4 mg twice daily) concentrations by approximately 65%. Co-administration of orally administered azelastine (4 mg twice daily) with ranitidine hydrochloride (150 mg twice daily) resulted in C max of 8.89 ±3.28 ng/mL and AUC of 88.22 ± 40.43 ng•h/mL for azelastine, whereas, administration of azelastine alone resulted in C max of 7.83 ± 4.06 ng/mL and AUC of 80.09 ± 43.55 ng•h/mL for azelastine [ see Drug Interactions (7.3) ]. Theophylline: No significant pharmacokinetic interaction was observed with the co-administration of an oral 4 mg dose of azelastine hydrochloride twice daily and theophylline 300 mg or 400 mg twice daily.

12.1 Mechanism of Action Azelastine hydrochloride, a phthalazinone derivative, exhibits histamine H 1 -receptor antagonist activity in isolated tissues, animal models, and humans. Azelastine HCl nasal spray, 0.15% is administered as a racemic mixture with no difference in pharmacologic activity noted between the enantiomers in in vitro studies. The major metabolite, desmethylazelastine, also possesses H 1 -receptor antagonist activity.

12.2 Pharmacodynamics Cardiac Effects: In a placebo-controlled trial (95 patients with allergic rhinitis), there was no evidence of an effect of azelastine hydrochloride nasal spray (2 sprays per nostril twice daily for 56 days) on cardiac repolarization as represented by the corrected QT interval (QTc) of the electrocardiogram. Following multiple dose oral administration of azelastine 4 mg or 8 mg twice daily, the mean change in QTc was 7.2 msec and 3.6 msec, respectively. Interaction studies investigating the cardiac repolarization effects of concomitantly administered oral azelastine hydrochloride and erythromycin or ketoconazole were conducted. Oral erythromycin had no effect on azelastine pharmacokinetics or QTc based on analysis of serial electrocardiograms. Ketoconazole interfered with the measurement of azelastine plasma levels; however, no effects on QTc were observed [ see Drug Interactions (7.2) ].

12.3 Pharmacokinetics Absorption: After intranasal administration of 2 sprays per nostril (822 mcg total dose) of azelastine HCl nasal spray, 0.15%, the mean azelastine peak plasma concentration (C max ) is 409 pg/mL, the mean extent of systemic exposure (AUC) is 9312 pg•hr/mL and the median time to reach C max (t max ) is 4 hours. The systemic bioavailability of azelastine hydrochloride is approximately 40% after intranasal administration. Distribution: Based on intravenous and oral administration, the steady-state volume of distribution of azelastine is 14.5 L/kg. In vitro studies with human plasma indicate that the plasma protein binding of azelastine and its metabolite, desmethylazelastine, are approximately 88% and 97%, respectively. Metabolism: Azelastine is oxidatively metabolized to the principal active metabolite, desmethylazelastine, by the cytochrome P450 enzyme system. The specific P450 isoforms responsible for the biotransformation of azelastine have not been identified. After a single-dose, intranasal administration of azelastine HCl nasal spray, 0.15% (822 mcg total dose), the mean desmethylazelastine C max is 38 pg/mL, the AUC is 3824 pg•hr/mL and the median t max is 24 hours. After intranasal dosing of azelastine to steady-state, plasma concentrations of desmethylazelastine range from 20-50% of azelastine concentrations. Elimination: Following intranasal administration of azelastine HCl nasal spray, 0.15%, the elimination half-life of azelastine is 25 hours while that of desmethylazelastine is 57 hours. Approximately 75% of an oral dose of radiolabeled azelastine hydrochloride was excreted in the feces with less than 10% as unchanged azelastine. Special Populations: Hepatic Impairment: Following oral administration, pharmacokinetic parameters were not influenced by hepatic impairment. Renal Impairment: Based on oral, single-dose studies, renal insufficiency (creatinine clearance <50 mL/min) resulted in a 70-75% higher C max and AUC compared to healthy subjects. Time to maximum concentration was unchanged. Age: Following oral administration, pharmacokinetic parameters were not influenced by age. Gender: Following oral administration, pharmacokinetic parameters were not influenced by gender. Race: The effect of race has not been evaluated. Drug-Drug Interactions: Erythromycin: Co-administration of orally administered azelastine (4 mg twice daily) with erythromycin (500 mg three times daily for 7 days) resulted in C max of 5.36 ± 2.6 ng/mL and AUC of 49.7 ± 24 ng•h/mL for azelastine, whereas, administration of azelastine alone resulted in C max of 5.57 ± 2.7 ng/mL and AUC of 48.4 ± 24 ng•h/mL for azelastine [ see Drug Interactions (7.2) ]. Cimetidine and Ranitidine: In a multiple-dose, steady-state drug interaction trial in healthy subjects, cimetidine (400 mg twice daily) increased orally administered mean azelastine (4 mg twice daily) concentrations by approximately 65%. Co-administration of orally administered azelastine (4 mg twice daily) with ranitidine hydrochloride (150 mg twice daily) resulted in C max of 8.89 ±3.28 ng/mL and AUC of 88.22 ± 40.43 ng•h/mL for azelastine, whereas, administration of azelastine alone resulted in C max of 7.83 ± 4.06 ng/mL and AUC of 80.09 ± 43.55 ng•h/mL for azelastine [ see Drug Interactions (7.3) ]. Theophylline: No significant pharmacokinetic interaction was observed with the co-administration of an oral 4 mg dose of azelastine hydrochloride twice daily and theophylline 300 mg or 400 mg twice daily.

20211210

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3 DOSAGE FORMS AND STRENGTHS Azelastine HCl nasal spray, 0.15% is a nasal spray solution available in one dosage strength: • Each spray of azelastine HCl nasal spray, 0.15% delivers a volume of 0.137 mL solution containing 205.5 mcg of azelastine hydrochloride, USP. Nasal spray solution available in one dosage strength: • Azelastine HCl nasal spray, 0.15%: 205.5 mcg of azelastine hydrochloride, USP in each 0.137 mL spray (3).

azelastine hcl nasal Azelastine HCl AZELASTINE HYDROCHLORIDE AZELASTINE SORBITOL SUCRALOSE HYPROMELLOSE, UNSPECIFIED SODIUM CITRATE, UNSPECIFIED FORM EDETATE DISODIUM BENZALKONIUM CHLORIDE WATER

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 180 and 160 times the MRHDID for adults and children, respectively, on a mg/m 2 basis). No evidence for tumorigenicity was observed in mice at doses up to 25 mg/kg (approximately 75 and 65 times the MRHDID for adults and children, respectively, on a mg/m 2 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 180 times the MRHDID in adults on a mg/m 2 basis). At 68.6 mg/kg (approximately 410 times the MRHDID on a mg/m 2 basis), the duration of estrous cycles was prolonged and copulatory activity and the number of pregnancies were decreased. The numbers of corpora lutea and implantations were decreased; however, pre-implantation loss was not increased.

13 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 180 and 160 times the MRHDID for adults and children, respectively, on a mg/m 2 basis). No evidence for tumorigenicity was observed in mice at doses up to 25 mg/kg (approximately 75 and 65 times the MRHDID for adults and children, respectively, on a mg/m 2 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 180 times the MRHDID in adults on a mg/m 2 basis). At 68.6 mg/kg (approximately 410 times the MRHDID on a mg/m 2 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.

ANDA202743

Azelastine hcl nasal

Azelastine HCl

45802-026

HUMAN PRESCRIPTION DRUG

NASAL

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL - CARTON Rx Only NDC 45802-026-83 Azelastine HCl Nasal Spray, 0.15% 205.5 mcg per spray FOR INTRANASAL USE ONLY DO NOT SPRAY IN EYES 30 mL The following image is a placeholder representing the product identifier that is either affixed or imprinted on the drug package label during the packaging operation. carton serialization-template.jpg

Made in Israel Manufactured by Perrigo Yeruham, Israel Distributed By Perrigo® Allegan, MI 49010 • www.perrigorx.com Rev 11-20 9H400 RC J6

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. Caution patients against engaging in hazardous occupations requiring complete mental alertness and motor coordination such as driving or operating machinery after administration of azelastine HCl nasal spray, 0.15% [ see Warnings and Precautions (5.1) ]. Concurrent Use of Alcohol and other Central Nervous System Depressants Avoid concurrent use of azelastine HCl nasal spray, 0.15% with alcohol or other central nervous system depressants because additional reductions in alertness and additional impairment of central nervous system performance may occur [ see Warnings and Precautions (5.1) ]. Common Adverse Reactions Inform patients that the treatment with azelastine HCl nasal spray, 0.15% may lead to adverse reactions, most common of which include pyrexia, dysgeusia, nasal discomfort, epistaxis, headache, sneezing, fatigue, somnolence, upper respiratory infection, cough, rhinalgia, vomiting, otitis media, contact dermatitis, and oropharyngeal pain. [ see Adverse Reactions (6.1) ]. Priming Instruct patients to prime the pump before initial use and when azelastine HCl nasal spray, 0.15% has not been used for 3 or more days [ see Dosage and Administration (2.3) ]. Keep Spray Out of Eyes Instruct patients to avoid spraying azelastine HCl nasal spray, 0.15% into their eyes. Keep Out of Children’s Reach Instruct patients to keep azelastine HCl nasal spray, 0.15% out of the reach of children. If a child accidentally ingests azelastine HCl nasal spray, 0.15% seek medical help or call a poison control center immediately.

14 CLINICAL STUDIES 14.1 Seasonal Allergic Rhinitis Azelastine HCl nasal spray, 0.15% The efficacy and safety of azelastine HCl nasal spray, 0.15% in seasonal allergic rhinitis was evaluated in five randomized, multicenter, double-blind, placebo-controlled clinical trials in 2499 adult and adolescent patients 12 years and older with symptoms of seasonal allergic rhinitis (Trials 2, 3, 4, 5, and 6). The population of the trials was 12 to 83 years of age (64% female, 36% male; 81% white, 12% black, <2% Asian, 5% other; 23% Hispanic, 77% non-Hispanic). Assessment of efficacy was based on the rTNSS, iTNSS as described above, and other supportive secondary efficacy variables. The primary efficacy endpoint was the mean change from baseline in rTNSS over 2 weeks. Two 2-week seasonal allergic rhinitis trials evaluated the efficacy of azelastine HCl nasal spray, 0.15% dosed at 2 sprays twice daily. The first trial (Trial 2) compared the efficacy of azelastine HCl nasal spray, 0.15% and azelastine HCl nasal spray without sweetener to vehicle placebo. The other trial (Trial 3) compared the efficacy of azelastine HCl nasal spray, 0.15% and azelastine HCl nasal spray, 0.1% to vehicle placebo. In these two trials, azelastine HCl nasal spray, 0.15% demonstrated greater decreases in rTNSS than placebo and the differences were statistically significant (Table 4). Three 2-week seasonal allergic rhinitis trials evaluated the efficacy of azelastine HCl nasal spray, 0.15% dosed at 2 sprays once daily compared to the vehicle placebo. Trial 4 demonstrated a greater decrease in rTNSS than placebo and the difference was statistically significant (Table 4). Trial 5 and Trial 6 were conducted in patients with Texas mountain cedar allergy. In Trial 5 and Trial 6, azelastine HCl nasal spray, 0.15% demonstrated a greater decrease in rTNSS than placebo and the differences were statistically significant (Trials 5 and 6; Table 4). Instantaneous TNSS results for the once daily dosing regimen of azelastine HCl nasal spray, 0.15% are shown in Table 5. In Trials 5 and 6, azelastine HCl nasal spray, 0.15% demonstrated a greater decrease in iTNSS than placebo and the differences were statistically significant. Table 4. Mean Change from Baseline in Reflective TNSS over 2 Weeks* in Adults and Children ≥ 12 years with Seasonal Allergic Rhinitis Treatment (sprays per nostril) n Baseline LS Mean Change from Baseline Difference From Placebo LS Mean 95% CI P value Trial 2 Two sprays twice daily Azelastine HCl nasal spray, 0.15% 153 18.2 -4.3 -1.2 -2.1, -0.3 0.01 Azelastine HCl nasal spray without sweetener 153 17.9 -3.9 -0.9 -1.8, 0.1 0.07 Vehicle Placebo 153 18.1 -3.0 Trial 3 Two sprays twice daily Azelastine HCl nasal spray, 0.15% 177 17.7 -5.1 -3.0 -3.9, -2.1 <0.001 Azelastine HCl nasal spray, 0.1% 169 18.2 -4.2 -2.1 -3.0, -1.2 <0.001 Vehicle Placebo 177 17.7 -2.1 Trial 4 Two sprays once daily Azelastine HCl nasal spray, 0.15% 238 17.4 -3.4 -1.0 -1.7, -0.3 0.008 Vehicle Placebo 242 17.4 -2.4 Trial 5 Two sprays once daily Azelastine HCl nasal spray, 0.15% 266 18.5 -3.3 -1.4 -2.1, -0.8 <0.001 Vehicle Placebo 266 18.0 -1.9 Trial 6 Two sprays once daily Azelastine HCl nasal spray, 0.15% 251 18.5 -3.4 -1.4 -2.1, -0.7 <0.001 Vehicle Placebo 254 18.8 -2.0 *Sum of AM and PM rTNSS for each day (Maximum score=24) and averaged over the 14 day treatment period Table 5. Mean Change from Baseline AM Instantaneous TNSS over 2 Weeks* in Adults and Children ≥ 12 years with Seasonal Allergic Rhinitis Treatment (sprays per nostril once daily) n Baseline LS Mean Change from Baseline Difference From Placebo LS Mean 95% CI P value Trial 4 Two sprays once daily Azelastine HCl nasal spray, 0.15% 238 8.1 -1.3 -0.2 -0.6, 0.1 0.15 Vehicle Placebo 242 8.3 -1.1 Trial 5 Two sprays once daily Azelastine HCl nasal spray, 0.15% 266 8.7 -1.4 -0.7 -1.0, -0.4 <0.001 Vehicle Placebo 266 8.3 -0.7 Trial 6 Two sprays once daily Azelastine HCl nasal spray, 0.15% 251 8.9 -1.4 -0.6 -0.9, -0.3 <0.001 Vehicle Placebo 254 8.9 -0.8 *AM iTNSS for each day (Maximum score=12) and averaged over the 14 day treatment period Azelastine HCl nasal spray, 0.15% at a dose of 1 spray twice daily was not studied. The azelastine HCl nasal spray, 0.15% 1 spray twice daily dosing regimen is supported by previous findings of efficacy for azelastine HCl nasal spray without sweetener and a favorable comparison of azelastine HCl nasal spray, 0.15% to azelastine HCl nasal spray without sweetener and azelastine HCl nasal spray, 0.1% (Table 4). The efficacy and safety of azelastine HCl nasal spray, 0.15% in children 6 to 11 years of age with seasonal allergic rhinitis was evaluated in a clinical study that enrolled pediatric patients with perennial allergic rhinitis, with or without concomitant seasonal allergic rhinitis (described below in Section 14.2). 14.2 Perennial Allergic Rhinitis Azelastine HCl nasal spray, 0.15% The efficacy and safety of azelastine HCl nasal spray, 0.15% in perennial allergic rhinitis was evaluated in one randomized, multicenter, double-blind, placebo-controlled clinical trial in 578 adult and adolescent patients 12 years and older with symptoms of perennial allergic rhinitis. The population of the trial was 12 to 84 years of age (68% female, 32% male; 85% white, 11% black, 1% Asian, 3% other; 17% Hispanic, 83% non-Hispanic). Assessment of efficacy was based on the 12-hour reflective total nasal symptom score (rTNSS) assessed daily in the morning and evening, the instantaneous total nasal symptom score (iTNSS), and other supportive secondary efficacy variables. The primary efficacy endpoint was the mean change from baseline rTNSS over 4 weeks. The one 4-week perennial allergic rhinitis trial evaluated the efficacy of azelastine HCl nasal spray, 0.15%, azelastine HCl nasal spray, 0.1%, and vehicle placebo dosed at 2 sprays per nostril twice daily. In this trial, azelastine HCl nasal spray, 0.15% demonstrated a greater decrease in rTNSS than placebo and the difference was statistically significant (Table 6). Table 6. Mean Change from Baseline in Reflective TNSS over 4 Weeks* in Adults and Children ≥ 12 years with Perennial Allergic Rhinitis Treatment (sprays per nostril twice daily) n Baseline LS Mean Change from Baseline Difference From Placebo LS Mean 95% CI P value Two sprays twice daily Azelastine HCl nasal spray, 0.15% 192 15.8 -4.0 -0.9 -1.7, -0.1 0.03 Azelastine HCl nasal spray, 0.1% 194 15.5 -3.8 -0.7 -1.5, 0.1 0.08 Vehicle Placebo 192 14.7 -3.1 *Sum of AM and PM rTNSS for each day (Maximum score=24) and averaged over the 28 day treatment period The efficacy and safety of azelastine HCl nasal spray, 0.1% and azelastine HCl nasal spray, 0.15% in pediatric patients 6 to 11 years of age with perennial allergic rhinitis, with or without concomitant seasonal allergic rhinitis, was evaluated in a randomized, double-blind, placebo-controlled clinical trial in 486 patients. All patients received one spray per nostril twice daily. The study population was 58% males and 42% females; 78% white, 13% black, 3% Asian, and 6% other. Assessment of efficacy was based on the 12-hour reflective total nasal symptom score (rTNSS) assessed daily in the morning and evening. The primary efficacy endpoint was the mean change from baseline rTNSS over 4 weeks (Table 7). Both active treatments demonstrated statistically significant decreases in rTNSS compared to placebo. There was no statistically significant difference between the two active-treatment groups. There was also no difference in treatment effect between patients with perennial allergic rhinitis only compared to those with perennial allergic rhinitis and concomitant seasonal allergic rhinitis. Table 7. Mean Change from Baseline in Reflective TNSS over 4 Weeks* in Children 6 to 11 years with Perennial Allergic Rhinitis Treatment (sprays per nostril twice daily) n Baseline LS Mean Change from Baseline Difference From Placebo LS Mean 95% CI P value One spray twice daily Azelastine HCl nasal spray, 0.15% 159 16.6 -3.5 -1.0 -1.7, -0.3 0.005 Azelastine HCl nasal spray, 0.1% 166 16.4 -3.4 -0.9 -1.6, -0.2 0.015 Vehicle Placebo 161 16.1 -2.5 *Sum of AM and PM rTNSS for each day (Maximum score=24) and averaged over the 28 day treatment period The efficacy of azelastine HCl nasal spray, 0.1% and azelastine HCl nasal spray, 0.15% in children 6 months to 5 years of age with allergic rhinitis was explored in a clinical study (described above in Section 14.1).

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

8.4 Pediatric Use The safety and effectiveness of azelastine HCl nasal spray, 0.15% have been established for seasonal allergic rhinitis in pediatric patients 6 to 17 years of age and perennial allergic rhinitis in pediatric patients 6 to 17 years of age [ see Clinical Studies (14) ]. The safety and effectiveness of azelastine HCl nasal spray, 0.15% in pediatric patients below 6 years of age have not been established.

8.1 Pregnancy Risk Summary Limited data from postmarketing experience over decades of use with azelastine hydrochloride in pregnant women have not identified any drug associated risks of miscarriage, birth defects, or other adverse maternal or fetal outcomes. In animal reproduction studies, there was no evidence of fetal harm at oral doses approximately 4 times the clinical daily dose. Oral administration of azelastine hydrochloride to pregnant mice, rats, and rabbits, during the period of organogenesis, produced developmental toxicity that included structural abnormalities, decreased embryo-fetal survival, and decreased fetal body weights at doses 180 times and higher than the maximum recommended human daily intranasal dose (MRHDID) of 1.644 mg. However, the relevance of these findings in animals to pregnant women was considered questionable based upon the high animal to human dose multiple. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data In 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 200 times the maximum recommended human daily intranasal dose (MRHDID) in adults (on a mg/m 2 basis at a 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 9 times the MRHDID in adults (on a mg/m 2 basis at a maternal oral dose of 3 mg/kg/day). In an embryo-fetal development study in pregnant rats dosed during the period of organogenesis from gestation days 7 to 17, azelastine hydrochloride caused structural abnormalities (oligo-and brachydactylia), delayed ossification, and skeletal variations, in the absence of maternal toxicity, at approximately 180 times the MRHDID in adults (on a mg/m 2 basis at a maternal oral dose of 30 mg/kg/day). Azelastine hydrochloride caused embryo-fetal death and decreased fetal weight and severe maternal toxicity at approximately 410 times the MRHDID (on a mg/m 2 basis at a maternal oral dose of 68.6 mg/kg/day). Neither fetal nor maternal effects occurred at approximately 10 times the MRHDID (on a mg/m 2 basis at a maternal oral dose of 2 mg/kg/day). In an embryo-fetal development study in pregnant rabbits dosed during the period of organogenesis from gestation days 6 to 18, azelastine hydrochloride caused abortion, delayed ossification and decreased fetal weight and severe maternal toxicity at approximately 360 times the MRHDID in adults (on a mg/m 2 basis at a maternal oral dose of 30 mg/kg/day). Neither fetal nor maternal effects occurred at approximately 4 times the MRHDID (on a mg/m 2 basis at a maternal oral dose of 0.3 mg/kg/day). In a 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 180 times the MRHDID (on mg/m 2 basis at a maternal dose of 30 mg/kg/day.)

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Limited data from postmarketing experience over decades of use with azelastine hydrochloride in pregnant women have not identified any drug associated risks of miscarriage, birth defects, or other adverse maternal or fetal outcomes. In animal reproduction studies, there was no evidence of fetal harm at oral doses approximately 4 times the clinical daily dose. Oral administration of azelastine hydrochloride to pregnant mice, rats, and rabbits, during the period of organogenesis, produced developmental toxicity that included structural abnormalities, decreased embryo-fetal survival, and decreased fetal body weights at doses 180 times and higher than the maximum recommended human daily intranasal dose (MRHDID) of 1.644 mg. However, the relevance of these findings in animals to pregnant women was considered questionable based upon the high animal to human dose multiple. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data In 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 200 times the maximum recommended human daily intranasal dose (MRHDID) in adults (on a mg/m 2 basis at a 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 9 times the MRHDID in adults (on a mg/m 2 basis at a maternal oral dose of 3 mg/kg/day). In an embryo-fetal development study in pregnant rats dosed during the period of organogenesis from gestation days 7 to 17, azelastine hydrochloride caused structural abnormalities (oligo-and brachydactylia), delayed ossification, and skeletal variations, in the absence of maternal toxicity, at approximately 180 times the MRHDID in adults (on a mg/m 2 basis at a maternal oral dose of 30 mg/kg/day). Azelastine hydrochloride caused embryo-fetal death and decreased fetal weight and severe maternal toxicity at approximately 410 times the MRHDID (on a mg/m 2 basis at a maternal oral dose of 68.6 mg/kg/day). Neither fetal nor maternal effects occurred at approximately 10 times the MRHDID (on a mg/m 2 basis at a maternal oral dose of 2 mg/kg/day). In an embryo-fetal development study in pregnant rabbits dosed during the period of organogenesis from gestation days 6 to 18, azelastine hydrochloride caused abortion, delayed ossification and decreased fetal weight and severe maternal toxicity at approximately 360 times the MRHDID in adults (on a mg/m 2 basis at a maternal oral dose of 30 mg/kg/day). Neither fetal nor maternal effects occurred at approximately 4 times the MRHDID (on a mg/m 2 basis at a maternal oral dose of 0.3 mg/kg/day). In a 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 180 times the MRHDID (on mg/m 2 basis at a 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 following use of azelastine hydrochloride. Because many drugs are excreted in human milk, caution should be exercised when azelastine HCl nasal spray, 0.15% is administered to a nursing woman. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for azelastine HCl nasal spray, 0.15% and any potential adverse effects on the breastfed infant from azelastine HCl nasal spray, 0.15% or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of azelastine HCl nasal spray, 0.15% have been established for seasonal allergic rhinitis in pediatric patients 6 to 17 years of age and perennial allergic rhinitis in pediatric patients 6 to 17 years of age [ see Clinical Studies (14) ]. The safety and effectiveness of azelastine HCl nasal spray, 0.15% in pediatric patients below 6 years of age have not been established. 8.5 Geriatric Use Clinical trials of azelastine HCl nasal spray did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

16 HOW SUPPLIED/STORAGE AND HANDLING Azelastine HCl nasal spray, 0.15% is supplied as a 30-mL package (NDC 45802- 026 -83) delivering 200 metered sprays in a high-density polyethylene (HDPE) bottle fitted with a metered-dose spray pump unit. The spray pump unit consists of a nasal spray pump fitted with a violet safety clip and a violet plastic dust cover. The net content of the bottle is 30 mL (net weight 30 gm of solution). The 30-mL bottle contains 45 mg (1.5 mg/mL) of azelastine hydrochloride, USP. After priming [ see Dosage and Administration (2.3) ], each spray delivers a fine mist containing a mean volume of 0.137 mL solution containing 205.5 mcg of azelastine hydrochloride, USP. The correct amount of medication in each spray cannot be assured before the initial priming and after 200 sprays for the 30-mL bottle have been used, even though the bottle is not completely empty. The bottle should be discarded after 200 sprays have been used. Azelastine HCl nasal spray, 0.15% should not be used after the expiration date “EXP” printed on the medicine label and carton. Storage: Store upright at controlled room temperature 20° to 25°C (68° to 77°F). Protect from freezing.

Important: For use in your nose only.