Azelastine

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 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 spray is an H1-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 )

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Azelastine hydrochloride, a phthalazinone derivative, exhibits histamine H1-receptor antagonist activity in isolated tissues, animal models, and humans. Azelastine hydrochloride nasal spray 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 H1-receptor antagonist activity. 12.2 Pharmacodynamics Cardiac Electrophysiology In a 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 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. These drugs had no effect on QTc based on analysis of serial electrocardiograms. At a dose approximately 8 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 (C max ) are achieved in 2­-3 hours. Azelastine hydrochloride administered intranasally at doses above two sprays per nostril twice daily for 29 days resulted in greater than proportional increases in C max 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 administratio

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 spray 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 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 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 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 4 sprays or until a fine mist appears. When azelastine hydrochloride nasal spray has not been used for 3 or more days, reprime with 2 sprays or until a fine mist appears. Avoid spraying azelastine hydrochloride nasal spray into the eyes.

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 Apotex CORP. at 1-800-706-5575 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 spray Two Sprays Per Nostril Twice Daily Adverse 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 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 spray 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 spray 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 Spray 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 hydrochloride nasal spray One Spray Per Nostril Twice Daily Adverse experience information for azelastine hydrochloride nasal spray 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 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 5 to 11 years of age were exposed to azelastine hydrochloride nasal spray 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 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 Daily The following reactions were observed infrequently (<2% and exceeding placebo incidence) in patients who received azelastine hydrochloride nasal spray 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

5 WARNINGS AND PRECAUTIONS Somnolence: Avoid engaging in hazardous occupations requiring complete mental alertness such as driving or operating machinery when taking azelastine hydrochloride nasal spray. ( 5.1 ) Alcohol 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 a 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 )] .

4 CONTRAINDICATIONS None. None ( 4 )

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.