Azelastine

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.

For intranasal use only Seasonal allergic rhinitis: Pediatric patients 5 to 11 years of age: 1 spray per nostril twice daily Adults and adolescents 12 years of age and older: 1 or 2 sprays per nostril twice daily Vasomotor rhinitis: 2 sprays per nostril twice daily in adults and adolescents 12 years of age and older Prime azelastine hydrochloride nasal spray before initial use and when it has not been used for 3 or more days

2.1Seasonal 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.

2.2Vasomotor 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.

2.3Important 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.

Somnolence: Avoid engaging in hazardous occupations requiring complete mental alertness such as driving or operating machinery when taking azelastine hydrochloride nasal spray. 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.

5.1Somnolence in Activities Requiring Mental Alertness

In clinical trials, the occurrence of somnolence has been reported in some patients taking azelastine hydrochloride nasal spray . 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 .

None. None

8 USE IN SPECIFIC POPULATIONS

8.1Pregnancy Risk Summary Limited

data from postmarketing experience over decades of use with azelastine hydrochloride nasal spray 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/m2 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/m2 basis at a maternal dose of 30 mg/kg/day).

8.2Lactation 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 . The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for azelastine hydrochloride and any potential adverse effects on the breastfed infant from azelastine hydrochloride or from the underlying maternal condition. 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.

8.4Pediatric Use 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 . The safety and effectiveness of azelastine hydrochloride nasal spray for the treatment of vasomotor rhinitis have been established for patients 12 years and older . The safety and effectiveness of azelastine hydrochloride nasal spray in pediatric patients below the age of 5 years with seasonal allergic rhinitis and in pediatric patients below the age of 12 years with vasomotor rhinitis have not been established.

8.5Geriatric Use 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.

Use of azelastine hydrochloride nasal spray has been associated with somnolence . 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. 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

6.1Clinical 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, ulcerative stomatitis, vomiting, increased SGPT, aphthous stomatitis, diarrhea, toothache. Metabolic and Nutritional Increased appetite.

Musculoskeletal Myalgia, temporomandibular dislocation, rheumatoid arthritis. Neurological Hyperkinesias, 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 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 2.8% and 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%) 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 hydrochloride nasal spray (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 hydrochloride formulations, there were infrequent occurrences of hepatic transaminase elevations.

6.2Postmarketing Experience 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.