AZELASTINE HYDROCHLORIDE

Azelastine HCl nasal spray, 0.1%, 137 micrograms (mcg), is an antihistamine formulated as a metered-spray solution for intranasal administration. Azelastine HCl, 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, 0.1% contains 0.1% azelastine HCl, USP in an aqueous solution at pH 6.8 ± 0.3. It also contains benzalkonium chloride (125 mcg/mL), citric acid, dibasic sodium phosphate, edetate disodium, hypromellose, purified water (pH 6.8) and sodium chloride. After priming [see Dosage and Administration (2.3) ] , each metered spray delivers a 0.137 mL mean volume containing 137 mcg of azelastine HCl, USP (equivalent to 125 mcg of azelastine base). The bottle can deliver 200 metered sprays. 1

Azelastine hydrochloride (HCl) nasal spray, 0.1% is indicated for the treatment of the symptoms of seasonal allergic rhinitis in adults and pediatric patients 5 years and older, and for the treatment of the symptoms of vasomotor rhinitis in adults and adolescent patients 12 years and older. Azelastine HCl nasal spray, 0.1% is an H 1 -receptor antagonist indicated for the treatment of the symptoms of seasonal allergic rhinitis in adults and pediatric patients 5 years and older and for the treatment of the symptoms of vasomotor rhinitis in adults and adolescent patients 12 years and older. (1)

For intranasal use only. (2.3) Seasonal allergic rhinitis: Pediatric patients 5 to 11 years of age: 1 spray per nostril twice daily. (2.1) Adults and adolescents 12 years of age and older: 1 or 2 sprays per nostril twice daily. (2.1) Vasomotor rhinitis: 2 sprays per nostril twice daily in adults and adolescents 12 years of age and older. (2.2) Prime azelastine HCl nasal spray, 0.1% before initial use and when it has not been used for 3 or more days. (2.3) 2.1 Seasonal Allergic Rhinitis The recommended dosage of azelastine HCl nasal spray, 0.1% in adults and adolescent patients 12 years and older with seasonal allergic rhinitis is one or two sprays per nostril twice daily. The recommended dosage of azelastine HCl nasal spray, 0.1% in pediatric patients 5 years to 11 years of age is one spray per nostril twice daily. 2.2 Vasomotor Rhinitis The recommended dosage of azelastine HCl nasal spray, 0.1% in adults and adolescent patients 12 years and older with vasomotor rhinitis is two sprays per nostril twice daily. 2.3 Important Administration Instructions Administer azelastine HCl nasal spray, 0.1% by the intranasal route only. Priming: Prime azelastine HCl nasal spray, 0.1% before initial use by releasing 4 sprays or until a fine mist appears. When azelastine HCl nasal spray, 0.1% 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, 0.1% into the eyes.

None. None. (4)

Use of azelastine HCl nasal spray, 0.1% has been associated with somnolence [see Warnings and Precautions (5.1) ] . The most common adverse reactions (≥2% incidence) are: bitter taste, headache, somnolence, dysesthesia, rhinitis, nasal burning, pharyngitis, epistaxis, sinusitis, paroxysmal sneezing, nausea, dry mouth, fatigue, dizziness, and weight increase. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect rates observed in practice. Seasonal Allergic Rhinitis Azelastine HCl nasal spray, 0.1% Two Sprays Per Nostril Twice Daily Adverse experience information for azelastine HCl nasal spray, 0.1% is derived from six placebo- and active-controlled, 2-day to 8-week clinical trials which included 391 patients, 12 years of age and older, with seasonal allergic rhinitis who received azelastine HCl nasal spray, 0.1% at a dose of 2 sprays per nostril twice daily. In placebo-controlled efficacy trials, the incidence of discontinuation due to adverse reactions in patients receiving azelastine HCl nasal spray, 0.1% and vehicle placebo was 2.2% and 2.8%, respectively. Table 1 contains adverse reactions that were reported with frequencies ≥2% in the azelastine HCl nasal spray, 0.1% 2 sprays per nostril twice daily treatment group and more frequently than placebo. Table 1: Adverse Reactions Reported in ≥2% Incidence in Placebo-Controlled Trials in Patients with Seasonal Allergic Rhinitis [n (%)] Azelastine HCl Nasal Spray, 0.1% N = 391 Vehicle Placebo N = 353 Bitter Taste 77 (19.7%) 2 (0.6%) Headache 58 (14.8%) 45 (12.7%) Somnolence 45 (11.5%) 19 (5.4%) Nasal Burning 16 (4.1%) 6 (1.7%) Pharyngitis 15 (3.8%) 10 (2.8%) Paroxysmal Sneezing 12 (3.1%) 4 (1.1%) Dry Mouth 11 (2.8%) 6 (1.7%) Nausea 11 (2.8%) 4 (1.1%) Rhinitis 9 (2.3%) 5 (1.4%) Fatigue 9 (2.3%) 5 (1.4%) Dizziness 8 (2.0%) 5 (1.4%) Epistaxis 8 (2.0%) 5 (1.4%) Weight Increase 8 (2.0%) 0 (0.0%) Azelastine HCl Nasal Spray, 0.1% One Spray Per Nostril Twice Daily Adverse experience information for azelastine HCl nasal spray, 0.1% at a dose of one spray per nostril twice daily is derived from two placebo-controlled 2-week clinical studies which included 276 patients 12 years of age and older with seasonal allergic rhinitis. The incidence of discontinuation due to adverse reactions in patients receiving azelastine HCl nasal spray, 0.1% and vehicle placebo was 0.0% and 0.8%, respectively. Bitter taste was reported in 8.3% of patients compared to none in the placebo group. Somnolence was reported in 0.4% of patients compared to none in the placebo group. A total of 176 patients 5 to 11 years of age were exposed to azelastine HCl nasal spray, 0.1% at a dose of 1 spray each nostril twice daily in 3 placebo-controlled studies. In these studies, adverse reactions that occurred more frequently in patients treated with azelastine HCl nasal spray, 0.1% than with placebo, and that were not represented in the adult adverse reactions table above include rhinitis/cold symptoms (17.0% vs. 9.5%), cough (11.4% vs. 8.3%), conjunctivitis (5.1% vs. 1.8%), and asthma (4.5% vs. 4.1%). Adverse Reactions <2% in azelastine HCl nasal spray, 0.1% One or Two Sprays Per Nostril Twice Daily The following reactions were observed infrequently (<2% and exceeding placebo incidence) in patients who received azelastine HCl nasal spray, 0.1% dosed at 1 or 2 sprays per nostril twice daily in U.S. clinical trials. Cardiovascular: flushing, hypertension, tachycardia. Dermatological: contact dermatitis, eczema, hair and follicle infection, furunculosis, skin laceration. Digestive: constipation, gastroenteritis, glossitis, ulcerative stomatitis, vomiting, increased SGPT, aphthous stomatitis, diarrhea, toothache. Metabolic and Nutritional: increased appetite. Musculoskeletal: myalgia, temporomandibular dislocation, rheumatoid arthritis. Neurological: hyperkinesia, hypoesthesia, vertigo. Psychological: anxiety, depersonalization, depression, nervousness, sleep disorder, thinking abnormal. Respiratory: bronchospasm, coughing, throat burning, laryngitis, bronchitis, dry throat, nocturnal dyspnea, nasopharyngitis, nasal congestion, pharyngolaryngeal pain, sinusitis, nasal dryness, paranasal sinus hypersecretion, post nasal drip. Special Senses: conjunctivitis, eye abnormality, eye pain, watery eyes, taste loss. Urogenital: albuminuria, amenorrhea, breast pain, hematuria, increased urinary frequency. Whole Body: allergic reaction, back pain, herpes simplex, viral infection, malaise, pain in extremities, abdominal pain, pyrexia. Vasomotor Rhinitis Adverse experience information for azelastine HCl nasal spray, 0.1% is derived from two placebo-controlled clinical studies which included 216 patients 12 years and older with vasomotor rhinitis who received azelastine HCl nasal spray, 0.1% at a dose of 2 sprays per nostril twice daily for up to 28 days. The incidence of discontinuation due to adverse reactions in patients receiving azelastine HCl nasal spray, 0.1% and vehicle placebo was 2.8% and 2.9%, respectively. The following adverse reactions were reported with frequencies ≥ 2% in the azelastine HCl nasal spray, 0.1% treatment group and more frequently than placebo. Table 2: Adverse Reactions Reported in ≥2% Incidence in Placebo-Controlled Trials in Patients with Vasomotor Rhinitis [n (%)] Azelastine HCl Nasal Spray, 0.1% N = 216 Vehicle Placebo N = 210 Bitter Taste 42 (19.4%) 5 (2.4%) Headache 17 (7.9%) 16 (7.6%) Dysesthesia 17 (7.9%) 7 (3.3%) Rhinitis 12 (5.6%) 5 (2.4%) Epistaxis 7 (3.2%) 5 (2.4%) Sinusitis 7 (3.2%) 4 (1.9%) Somnolence 7 (3.2%) 2 (1.0%) Reactions observed infrequently (<2% and exceeding placebo incidence) in patients who received azelastine HCl nasal spray, 0.1% (2 sprays/nostril twice daily) in U.S. clinical trials in vasomotor rhinitis were similar to those observed in U.S. clinical trials in seasonal allergic rhinitis. In controlled trials involving nasal and oral azelastine HCl formulations, there were infrequent occurrences of hepatic transaminase elevations. 6.2 Postmarketing Experience During the post approval use of azelastine HCl nasal spray, 0.1%, the following adverse reactions have been identified. Because these reactions are reported voluntarily from 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: 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.

7.1 Central Nervous System Depressants Concurrent use of azelastine HCl nasal spray, 0.1% with alcohol or other central nervous system depressants should be avoided because reductions in alertness and impairment of central nervous system performance may occur [see Warnings and Precautions (5.1) ] .