AZELASTINE HYDROCHLORIDE- azelastine hydrochloride_spray, metered

Azelastine hydrochloride, a phthalazinone derivative, exhibits histamine H 1 in vitro 1 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. Absorption After intranasal administration, the systemic bioavailability of azelastine hydrochloride is approximately 40%. Maximum plasma concentrations (C max 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 Distribution Based on intravenous and oral administration, the steady-state volume of distribution is 14. In vitro 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 a 70 to 75% higher C max 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 coadministration of orally administered azelastine (4 mg twice daily) with erythromycin (500 mg three times daily for 7 days). In this study, coadministration of orally administered azelastine with erythromycin resulted in C max max 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%. No pharmacokinetic interaction was observed with coadministration of orally administered azelastine (4 mg twice daily) with ranitidine hydrochloride (150 mg twice daily). Oral coadministration of azelastine with ranitidine resulted in C max max Theophylline No significant pharmacokinetic interaction was observed with the coadministration of an oral 4 mg dose of azelastine hydrochloride twice daily and theophylline 300 mg or 400 mg twice daily.

Azelastine hydrochloride nasal spray is an H 1 1 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.

For intranasal use only ( 2. 3 Seasonal allergic rhinitis: circle Pediatric patients 5 to 11 years of age: 1 spray per nostril twice daily ( 2. 1 circle 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 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. 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. 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.

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. 1 To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 or FDA at 1-800-FDA-1088 or www. gov/medwatch. Use of azelastine hydrochloride nasal spray has been associated with somnolence [ see Warnings and Precautions ( 5. 1 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. 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. 6%) Headache 58 (14. 7%) Somnolence 45 (11. 4%) Nasal Burning 16 (4. 7%) Pharyngitis 15 (3. 8%) Paroxysmal Sneezing 12 (3. 1%) Dry Mouth 11 (2. 7%) Nausea 11 (2. 1%) Rhinitis 9 (2. 4%) Fatigue 9 (2. 4%) Dizziness 8 (2%) 5 (1. 4%) Epistaxis 8 (2%) 5 (1. 4%) Weight Increase 8 (2%) 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% and 0. 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% vs. 5%), cough (11. 3%), conjunctivitis (5. 8%), and asthma (4. 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. clinical trials. Cardiovascular: Dermatological: Digestive: Metabolic and Nutritional: Musculoskeletal: Neurological: Psychological: Respiratory: Special Senses: Urogenital: Whole Body: Vasomotor Rhinitis Adverse 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 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 hydrochloride nasal spray and vehicle placebo was 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 Spray N = 216 Vehicle Placebo N = 210 Bitter Taste 42 (19. 4%) Headache 17 (7. 6%) Dysesthesia 17 (7. 3%) Rhinitis 12 (5. 4%) Epistaxis 7 (3. 4%) Sinusitis 7 (3. 9%) Somnolence 7 (3. 2%) 2 (1%) Reactions observed infrequently (< 2% and exceeding placebo incidence) in patients who received azelastine hydrochloride nasal spray (2 sprays/nostril twice daily) in U. clinical trials in vasomotor rhinitis were similar to those observed in U. clinical trials in seasonal allergic rhinitis. In controlled trials involving nasal and oral azelastine hydrochloride formulations, there were infrequent occurrences of hepatic transaminase elevations. During the post approval use of azelastine hydrochloride 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: 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.

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 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. 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. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 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 2 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 2 2 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 2 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 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 use by lactating women (see Clinical Considerations) Clinical Considerations Monitoring for Adverse Reactions Breastfed infants of lactating women treated with azelastine hydrochloride should be monitored for possible signs of milk rejection related to the bitter taste of azelastine hydrochloride. The safety and effectiveness of azelastine hydrochloride nasal spray for the treatment of symptoms of seasonal allergic rhinitis have been established for patients 5 years and older [ see Adverse Reactions ( 6. 1 see Adverse Reactions ( 6. 2 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.

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

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.
NONCLINICAL TOXICOLOGY
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 a mg/m 2 2 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 a mg/m 2 2
CLINICAL STUDIES
Two Sprays Per Nostril Twice Daily The 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 a day for up to 4 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 a 0 to 5 categorical scale. Azelastine hydrochloride nasal spray two sprays per nostril twice daily demonstrated a 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 Placebo *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 a 0 to 5 categorical scale. Treatment N Baseline LS Mean (SD) Change from Baseline (SD) Treatment Difference P-value Trial 1: 12 Hour AM and PM Reflective MSC Azelastine Hydrochloride Nasal Spray 63 11. 01 Placebo Nasal Spray 60 10. 52) Trial 2: 12 Hour AM and PM Reflective MSC Azelastine Hydrochloride Nasal Spray 63 12. 01 Placebo Nasal Spray 63 12. 01) Trial 3: 12 Hour AM and PM Reflective MSC Azelastine Hydrochloride Nasal Spray 66 12. 04 Placebo Nasal Spray 66 11. 57) In dose-ranging trials, administration of azelastine hydrochloride nasal spray two sprays per nostril twice daily resulted in a statistically significant decrease in symptoms compared to saline placebo within 3 hours after initial dosing and persisted over the 12-hour dosing interval. One Spray Per Nostril Twice Daily The 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 a day for up to 2 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 a 0 to 3 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 Placebo *Total Nasal Symptom Score (TNSS): Average of individual symptoms of runny nose, sneezing, itchy nose, and nasal congestion as assessed by patients on a 0 to 3 categorical scale. Treatment N Baseline LS Mean (SD) Change from Baseline (SD) Treatment Difference P-value Trial 4: 12 Hour AM and PM Reflective TNSS Azelastine Hydrochloride Nasal Spray 138 16. 01 Placebo Nasal Spray 141 17. 29) Trial 5: 12 Hour AM and PM Reflective TNSS Azelastine Hydrochloride Nasal Spray 137 16. 02 Placebo Nasal Spray 136 16. 01) 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. 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 a day for up to 4 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 a significantly greater decrease in a symptom complex comprised of rhinorrhea, post nasal drip, nasal congestion, and sneezing compared to placebo.

Zydus Pharmaceuticals USA Inc.

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