AZELASTINE HYDROCHLORIDE

1 INDICATIONS AND USAGE Azelastine hydrochloride nasal solution (nasal spray), 0.1% (137 mcg per spray) 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 hydrochloride nasal solution (nasal spray) 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 )

Purpose Antihistamine

2 DOSAGE AND ADMINISTRATION 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 hydrochloride nasal solution 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 hydrochloride nasal solution 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 solution 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 hydrochloride nasal solution 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 solution by the intranasal route only. Priming: Prime azelastine hydrochloride nasal solution before initial use by releasing 4 sprays or until a fine mist appears. When azelastine hydrochloride nasal solution has not been used for 3 or more days, reprime with 2 sprays or until a fine mist appears. Avoid spraying azelastine hydrochloride nasal solution into the eyes.

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

4 CONTRAINDICATIONS None. None. ( 4 )

Do not use if you have if you have ever had an allergic reaction to this product or any of its ingredients

Ask a doctor before use if you ■ have had recent nose ulcers or nose surgery ■ have had a nose injury that has not healed

Stop use and ask a doctor if ■ an allergic reaction, such as a skin rash, to this product occurs ■ you have severe or frequent nosebleeds

6 ADVERSE REACTIONS Use of azelastine hydrochloride nasal solution 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 Sun Pharmaceutical Industries, Inc. at 1-800-818-4555 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 Hydrochloride Nasal Solution Two Sprays Per Nostril Twice Daily Adverse experience information for azelastine hydrochloride nasal solution 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 solution 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 hydrochloride nasal solution and vehicle placebo was 2.2% and 2.8%, respectively. Table 1 contains adverse reactions that were reported with frequencies ≥2% in the azelastine hydrochloride nasal solution 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 Hydrochloride Nasal Solution 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%) 5 (1.4%) Epistaxis 8 (2%) 5 (1.4%) Weight Increase 8 (2%) 0 (0%) Azelastine Hydrochloride Nasal Solution One Spray Per Nostril Twice Daily Adverse experience information for azelastine hydrochloride nasal solution 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 hydrochloride nasal solution and vehicle placebo was 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 hydrochloride nasal solution 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 hydrochloride nasal solution than with placebo, and that were not represented in the adult adverse reactions table above include rhinitis/cold symptoms (17% 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 Solution One or Two Sprays Per Nostril Twice Daily The following reactions were observed infrequently (<2% and exceeding placebo incidence) in patients who received azelastine hydrochloride nasal solution 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 lacer …

7 DRUG INTERACTIONS 7.1 Central Nervous System Depressants Concurrent use of azelastine hydrochloride nasal solution 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 ) ].

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Limited data from postmarketing experience over decades of use with azelastine hydrochloride nasal solution 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 5 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 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 300 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 15 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 270 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 610 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 20 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 530 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 5 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 270 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. Breastfed infants should be monitored for signs of milk rejection during azelastine hydrochloride nasal solution use by lactating women (see Clinical Considerations). The develo …

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 hydrochloride nasal solution 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.

11 DESCRIPTION Azelastine Hydrochloride Nasal Solution (Nasal Spray), 0.1% (137 mcg per spray), is an antihistamine formulated as a metered-spray solution for intranasal administration. Azelastine hydrochloride 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 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 hydrochloride nasal solution contains 0.1% azelastine hydrochloride in an aqueous solution at pH 6.8 ± 0.3. It also contains benzalkonium chloride 50% solution (250 mcg/mL), edetate disodium, hypromellose, citric acid anhydrous, dibasic sodium phosphate, sodium chloride, and water for injection. After priming [ see Dosage and Administration (2.3) ], each metered spray delivers a 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. chemicalstructure

Drug Facts Active ingredient (in each spray) Azelastine hydrochloride USP 205.5 mcg (equivalent to 187.6 mcg azelastine)

10 OVERDOSAGE There have been no reported overdosages with azelastine hydrochloride nasal solution. 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 solution 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 solution. Oral ingestion of antihistamines has the potential to cause serious adverse effects in young children. Accordingly, azelastine hydrochloride nasal solution should be kept out of the reach of children.

16 HOW SUPPLIED/STORAGE AND HANDLING Azelastine hydrochloride nasal solution (Nasal Spray), 0.1% (137 mcg per spray) is supplied as a 30 mL package (NDC 47335-779-91) 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 blue safety clip and a blue 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 a fine mist containing a 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 solution (nasal spray) should not be used after the expiration date "Exp" printed on the medicine label and carton. Storage: Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F) [see USP Controlled Room Temperature]. Protect from freezing.