AZELASTINE HYDROCHLORIDE- azelastine hydrochloride spray, metered 
Apotex Corp.

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HIGHLIGHTS OF PRESCRIBING INFORMATION


These highlights do not include all the information needed to use AZELASTINE hydrochloride safely and effectively. See full prescribing information for AZELASTINE hydrochloride.


AZELASTINE hydrochloride nasal spray
Initial U.S. Approval: 1996

INDICATIONS AND USAGE

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)

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)

DOSAGE FORMS AND STRENGTHS

Azelastine hydrochloride nasal spray: 137 mcg of azelastine hydrochloride in each 0.137 mL spray. (3)

CONTRAINDICATIONS

None (4)

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)

ADVERSE REACTIONS

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

USE IN SPECIFIC POPULATIONS

Pregnancy: Based on animal data, may cause fetal harm (8.1)

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 12/2014

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Seasonal Allergic Rhinitis

2.2 Vasomotor Rhinitis

2.3 Important Administration Instructions

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Somnolence in Activities Requiring Mental Alertness

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 Central Nervous System Depressants

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

14.1 Seasonal Allergic Rhinitis

14.2 Vasomotor Rhinitis

16 HOW SUPPLIED\STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

*
Sections or subsections omitted from the full prescribing information are not listed.

FULL PRESCRIBING INFORMATION

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.

2 DOSAGE AND ADMINISTRATION

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.

3 DOSAGE FORMS AND STRENGTHS

Azelastine hydrochloride nasal spray is a nasal spray solution. Each spray of azelastine hydrochloride nasal spray delivers a volume of 0.137 mL solution containing 137 mcg of azelastine hydrochloride.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

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)].

6 ADVERSE REACTIONS

Use of azelastine hydrochloride nasal spray has been associated with somnolence [see Warnings and Precautions (5.1)].

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 Taste77 (19.7%)2 (0.6%)
Headache58 (14.8%)45 (12.7%)
Somnolence45 (11.5%)19 (5.4%)
Nasal Burning16 (4.1%)6 (1.7%)
Pharyngitis15 (3.8%)10 (2.8%)
Paroxysmal Sneezing12 (3.1%)4 (1.1%)
Dry Mouth11 (2.8%)6 (1.7%)
Nausea11 (2.8%)4 (1.1%)
Rhinitis9 (2.3%)5 (1.4%)
Fatigue9 (2.3%)5 (1.4%)
Dizziness8 (2.0%)5 (1.4%)
Epistaxis8 (2.0%)5 (1.4%)
Weight Increase8 (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 Taste42 (19.4%)5 (2.4%)
Headache17 (7.9%)16 (7.6%)
Dysesthesia17 (7.9%)7 (3.3%)
Rhinitis12 (5.6%)5 (2.4%)
Epistaxis7 (3.2%)5 (2.4%)
Sinusitis7 (3.2%)4 (1.9%)
Somnolence7 (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.


6.2 Postmarketing 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.

7 DRUG INTERACTIONS

7.1 Central Nervous System Depressants

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)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C
There are no adequate and well-controlled clinical studies in pregnant women. Azelastine hydrochloride has been shown to cause developmental toxicity in mice, rats, and rabbits. Azelastine hydrochloride nasal spray should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Teratogenic Effects
In mice, azelastine hydrochloride caused embryo-fetal death, malformations (cleft palate; short or absent tail; fused, absent or branched ribs), delayed ossification, and decreased fetal weight at approximately 170 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 body weight). Neither fetal nor maternal effects occurred in mice at approximately 7 times the MRHDID in adults (on a mg/m2 basis at a maternal oral dose of 3 mg/kg/day).

In rats, azelastine hydrochloride caused malformations (oligo- and brachydactylia), delayed ossification and skeletal variations, in the absence of maternal toxicity, at approximately 150 times the MRHDID in adults (on a mg/m2 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 340 times the MRHDID (on a mg/m2 basis at a maternal oral dose of 68.6 mg/kg/day). Neither fetal nor maternal effects occurred at approximately 15 times the MRHDID (on a mg/m2 basis at a maternal oral dose of 2 mg/kg/day).

In rabbits, azelastine hydrochloride caused abortion, delayed ossification and decreased fetal weight and severe maternal toxicity at approximately 300 times the MRHDID in adults (on a mg/m2 basis at a maternal oral dose of 30 mg/kg/day). Neither fetal nor maternal effects occurred at approximately 3 times the MRHDID (on a mg/m2 basis at a maternal oral dose of 0.3 mg/kg/day).

8.3 Nursing Mothers

It is not known whether azelastine hydrochloride is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when azelastine hydrochloride nasal spray is administered to a nursing woman.

8.4 Pediatric 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 [see Adverse Reactions (6.1) and Clinical Studies (14.1)]. The safety and effectiveness of azelastine hydrochloride nasal spray for the treatment of vasomotor rhinitis have been established for patients 12 years and older [see Adverse Reactions (6.1) and Clinical Studies (14.2)]. 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.

8.5 Geriatric 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.

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.

11 DESCRIPTION

Azelastine hydrochloride nasal solution 0.1% (nasal spray), 137 micrograms (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 225ºC 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 C22H24ClN3O•HCl with the following chemical structure:

Structure.jpg

Azelastine hydrochloride nasal solution contains 0.1% azelastine hydrochloride 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 and sodium chloride.

After priming, 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.

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 (Cmax) 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 Cmax 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 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 Cmax and AUC compared to normal subjects. Time to maximum concentration was unchanged.

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 co­-administration of orally administered azelastine (4 mg twice daily) with erythromycin (500 mg three times daily for 7 days). In this study, co-administration of orally administered azelastine with erythromycin resulted in Cmax of 5.36 ± 2.6 ng/mL and AUC of 49.7 ± 24 ng•h/mL for azelastine, whereas, administration of azelastine alone resulted in Cmax of 5.57 ± 2.7 ng/mL and AUC of 48.4 ± 24 ng•h/mL for azelastine.

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 co-administration of orally administered azelastine (4 mg twice daily) with ranitidine hydrochloride (150 mg twice daily). Oral co-administration of azelastine with ranitidine resulted in Cmax of 8.89 ±3.28 ng/mL and AUC of 88.22 ± 40.43 ng•h/mL for azelastine, whereas, azelastine when administered alone resulted in Cmax of 7.83 ± 4.06 ng/mL and AUC of 80.09 ± 43.55 ng•h/mL for azelastine.

Theophylline
No significant pharmacokinetic interaction was observed with the co­-administration of an oral 4 mg dose of azelastine hydrochloride twice daily and theophylline 300 mg or 400 mg twice daily.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In 2-year carcinogenicity studies in rats and mice, azelastine hydrochloride did not show evidence of carcinogenicity at oral doses up to 30 mg/kg and 25 mg/kg, respectively. These doses were approximately 150 and 60 times the maximum recommended human daily intranasal dose [MRHDID] on a mg/m2 basis.

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.

Reproduction and fertility studies in rats showed no effects on male or female fertility at oral doses up to 30 mg/kg (approximately 150 times the MRHDID in adults on a mg/m2 basis). At 68.6 mg/kg (approximately 340 times the MRHDID on a mg/m2 basis), the duration of estrous cycles was prolonged and copulatory activity and the number of pregnancies were decreased. The numbers of corpora lutea and implantations were decreased; however, pre-implantation loss was not increased.

14 CLINICAL STUDIES

14.1 Seasonal Allergic Rhinitis

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

TreatmentNBaseline LS Mean (SD)Change from Baseline (SD)Treatment DifferenceP-value
Trial 1: 12 Hour AM and PM Reflective MSC
Azelastine
hydrochloride Nasal
Spray
6311.48 (4.13)-3.05 (3.51)1.98<0.01
Placebo Nasal Spray6010.84 (4.53)-1.07 (3.52)
Trial 2: 12 Hour AM and PM Reflective MSC
Azelastine hydrochloride
Nasal Spray
6312.50 (4.5)-4.10 (3.46)2.03<0.01
Placebo Nasal Spray6312.18 (4.64)-2.07 (4.01)
Trial 3: 12 Hour AM and PM Reflective MSC
Azelastine hydrochloride
Nasal Spray
6612.04 (4.03)-3.31 (3.74)1.350.04
Placebo Nasal Spray6611.66 (3.96)-1.96 (3.57)

*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.

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

TreatmentNBaseline LS Mean (SD)Change from Baseline (SD)Treatment DifferenceP-value
Trial 4: 12 Hour AM and PM Reflective TNSS
Azelastine hydrochloride
Nasal Spray
13816.34 (4.22)-2.69 (4.79)1.380.01
Placebo Nasal Spray14117.21 (4.32)-1.31 (4.29)
Trial 5: 12 Hour AM and PM Reflective TNSS
Azelastine hydrochloride
Nasal Spray
13716.62 (4.20)-3.68 (4.16)1.180.02
Placebo Nasal Spray13616.84 (4.77)-2.50 (4.01)

* 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.

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.

14.2 Vasomotor Rhinitis

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.

16 HOW SUPPLIED\STORAGE AND HANDLING

Azelastine hydrochloride nasal solution 0.1% (nasal spray), 137 mcg/spray, (NDC 60505-0833-5) is supplied as a package containing 200 metered sprays in a high-density polyethylene (HDPE) bottle fitted with a metered-dose spray pump unit. A leaflet of patient instructions is also provided. The spray pump unit consists of a nasal spray pump fitted with a safety clip and a plastic dust cover.

The Azelastine hydrochloride nasal solution 0.1% (nasal spray), 137 mcg/spray, bottle contains 30 mg (1 mg/mL) of azelastine hydrochloride. The bottle can deliver 200 metered sprays. Each spray delivers a mean of 0.137 mL solution containing 137 mcg of azelastine hydrochloride.

Storage

Store upright at 20º to 25ºC (68º to 77ºF) [See USP Controlled Room Temperature]. Protect from freezing.

Keep bottle tightly closed and away from children.

17 PATIENT COUNSELING INFORMATION

See FDA-approved patient labeling (Patient Information and Instructions for Use).

Activities Requiring Mental Alertness
Somnolence has been reported in some patients taking azelastine hydrochloride Nasal Spray. Caution patients against engaging in hazardous occupations requiring complete mental alertness and motor coordination such as driving or operating machinery after administration of azelastine hydrochloride nasal spray [see Warnings and Precautions (5.1)].

Concurrent Use of Alcohol and other Central Nervous System Depressants
Instruct patients to avoid concurrent use of azelastine hydrochloride nasal spray with alcohol or other central nervous system depressants because additional reductions in alertness and additional impairment of central nervous system performance may occur [see Warnings and Precautions (5.1)].

Common Adverse Reactions
Inform patients that the treatment with azelastine hydrochloride nasal spray may lead to adverse reactions, which include bitter taste, headache, somnolence, dysesthesia, rhinitis, nasal burning, pharyngitis, epistaxis, sinusitis, paroxysmal sneezing, nausea, dry mouth, fatigue, dizziness, and weight increase [see Adverse Reactions (6.1)].

Priming
Instruct patients to prime the pump before initial use and when azelastine hydrochloride nasal spray has not been used for 3 or more days [see Dosage and Administration (2.3)].

Keep Spray Out of Eyes
Instruct patients to avoid spraying azelastine hydrochloride nasal spray into their eyes.

Keep Out of Children’s Reach
Instruct patients to keep azelastine hydrochloride nasal spray out of the reach of children. If a child accidentally ingests azelastine hydrochloride nasal spray, seek medical help or call a poison control center immediately.

APOTEX INC.
AZELASTINE HYDROCHLORIDE NASAL SPRAY
137 mcg

Manufactured byManufactured for
Apotex Inc.Apotex Corp.
Toronto, Ontario Weston, FL
Canada M9L 1T9 33326

December 2014

PATIENT INFORMATION
Azelastine hydrochloride
(a-ZEL-as-teen)
Nasal Spray

Important: For use in your nose only.

What is azelastine hydrochloride nasal spray?

It is not known if azelastine hydrochloride nasal spray is safe and effective in children with seasonal allergic rhinitis under 5 years of age or in children with vasomotor rhinitis under 12 years of age.

What should I tell my healthcare provider before using azelastine hydrochloride nasal spray? Before using azelastine hydrochloride nasal spray, tell your healthcare provider if you are:

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Azelastine hydrochloride nasal spray and other medicines may affect each other, causing side effects.

How should I use azelastine hydrochloride nasal spray?

What should I avoid while using azelastine hydrochloride nasal spray? Azelastine hydrochloride nasal spray can cause sleepiness:

What are the possible side effects of azelastine hydrochloride nasal spray?

The most common side effects of azelastine hydrochloride nasal spray include:

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all of the possible side effects of azelastine hydrochloride nasal spray. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1­ 800-FDA-1088.

How should I store azelastine hydrochloride nasal spray?

Keep azelastine hydrochloride nasal spray and all medicines out of reach of children. General information about the safe and effective use of azelastine hydrochloride nasal spray.

Medicines are sometimes prescribed for conditions other than those listed in a Patient Information leaflet. Do not use azelastine hydrochloride nasal spray for a condition for which it was not prescribed. Do not give azelastine hydrochloride nasal spray to other people, even if they have the same symptoms that you have. It may harm them.

This Patient Information leaflet summarizes the most important information about azelastine hydrochloride nasal spray. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about azelastine hydrochloride nasal spray that is written for health professionals.

For more information call 1-800-706-5575.

What are the ingredients in azelastine hydrochloride nasal spray?
Active ingredient: azelastine hydrochloride

Inactive ingredients: benzalkonium chloride (125 mcg/mL), citric acid, dibasic sodium phosphate, edetate disodium, hypromellose, purified water and sodium chloride.


Instructions for Use
Azelastine hydrochloride
[a-ZEL-as-teen] 
Nasal Spray

Important: For use in your nose only.

For the correct dose of medicine:

Figure A identifies the parts of your azelastine hydrochloride nasal spray pump

FigureA.jpg

Before you use azelastine hydrochloride nasal spray for the first time, you will need to prime the bottle. Priming your azelastine hydrochloride nasal spray

Remove the plastic dust cover over the tip of the pump and the safety clip just under the "shoulders" of the pump (See Figure B).

FigureB.jpg

Hold the bottle upright with 2 fingers on the shoulders of the spray pump unit and

Now your pump is primed and ready to use.

FigureC.jpg

Using your azelastine hydrochloride nasal spray

Step 1. Blow your nose to clear your nostrils.

Step 2. Keep your head tilted downward toward your toes.

Step 3. Place the spray tip about ¼ inch to ½ inch into 1 nostril. Hold bottle upright and aim the spray tip toward the back of your nose (See Figure D).

FigureD.jpg

Step 4. Close your other nostril with a finger. Press the pump 1 time and sniff gently at the same time, keeping your head tilted forward and down (See Figure E).

FigureE.jpg

Step 5. Repeat Step 3 and Step 4 in your other nostril.

Step 6. If your healthcare provider tells you to use 2 sprays in each nostril, repeat Steps 2 through 4 above for the second spray in each nostril.

Step 7. Breathe in gently, and do not tilt your head back after using azelastine hydrochloride nasal spray. This will help to keep the medicine from going into your throat.

Step 8. When you finish using your azelastine hydrochloride nasal spray, wipe the spray tip with a clean tissue or cloth. Put the safety clip and dust cover back on the bottle.

Cleaning the Spray Tip of your Azelastine Hydrochloride Nasal Spray

FigureF-and-G.jpg

This Patient Information and Instructions for Use has been approved by the U.S. Food and Drug Administration.

APOTEX INC.
AZELASTINE HYDROCHLORIDE NASAL SPRAY
137 mcg

Manufactured byManufactured for
Apotex Inc.Apotex Corp.
Toronto, OntarioWeston, FL
Canada M9L 1T933326

December 2014

PRINCIPAL DISPLAY PANEL - BOTTLE LABEL

APOTEX CORP. NDC 60505-0833-5

AZELASTINE HYDROCHLORIDE NASAL SOLUTION 0.1% (NASAL SOLUTION),

137 mcg/spray

Rx only

30 mL

137mcg-bottle-label

AZELASTINE HYDROCHLORIDE 
azelastine hydrochloride spray, metered
Product Information
Product TypeHUMAN PRESCRIPTION DRUG LABELItem Code (Source)NDC:60505-0833
Route of AdministrationNASALDEA Schedule    
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
AZELASTINE HYDROCHLORIDE (AZELASTINE) AZELASTINE HYDROCHLORIDE137 ug
Inactive Ingredients
Ingredient NameStrength
BENZALKONIUM CHLORIDE 
EDETATE DISODIUM 
HYPROMELLOSES 
CITRIC ACID MONOHYDRATE 
SODIUM PHOSPHATE, DIBASIC 
SODIUM CHLORIDE 
WATER 
Packaging
#Item CodePackage DescriptionMarketing Start DateMarketing End Date
1NDC:60505-0833-51 in 1 CARTON
1200 in 1 BOTTLE, SPRAY; Combination Product Type = C112160
Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
ANDAANDA07795403/01/2010
Labeler - Apotex Corp. (845263701)

Revised: 12/2014
Document Id: 226c2cff-8c4f-06dc-9ab9-dff9b669d3cd
Set id: 4f58c203-f649-a18e-aaf3-70b0797652f4
Version: 4
Effective Time: 20141230
 
Apotex Corp.