AZELASTINE HYDROCHLORIDE spray, metered

Azelastine Hydrochloride by

Drug Labeling and Warnings

Azelastine Hydrochloride by is a Prescription medication manufactured, distributed, or labeled by Amneal Pharmaceuticals LLC, Amneal Pharmaceuticals, LLC. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

  • 1  INDICATIONS AND USAGE

    1.1 Allergic Rhinitis

    Azelastine HCl nasal spray, 0.15% is indicated for the relief of the symptoms of seasonal allergic rhinitis in patients 6 years of age and older and perennial allergic rhinitis in patients 6 years of age and older.

  • 2  DOSAGE AND ADMINISTRATION

    2.1 Seasonal Allergic Rhinitis

    Children 6 to 11 years of age: Azelastine HCl nasal spray, 0.15%, 1 spray per nostril twice daily.

    Adults and adolescents 12 years of age and older: Azelastine HCl nasal spray, 0.15%, 1 or 2 sprays per nostril twice daily. Azelastine HCl nasal spray, 0.15% may also be administered as 2 sprays per nostril once daily.

    2.2 Perennial Allergic Rhinitis

    Children 6 to 11 years of age: Azelastine HCl nasal spray, 0.15%, 1 spray per nostril twice daily.

    Adults and adolescents 12 years of age and older: Azelastine HCl nasal spray, 0.15%, 2 sprays per nostril twice daily.

    2.3 Important Administration Instructions

    Administer azelastine HCl nasal spray, 0.15% by the intranasal route only.

    Priming: Prime azelastine HCl nasal spray, 0.15% before initial use by releasing 6 sprays or until a fine mist appears. When azelastine HCl nasal spray, 0.15% has not been used for 3 or more days, reprime with 2 sprays or until a fine mist appears.

    Avoid spraying azelastine HCl nasal spray, 0.15% into the eyes.

  • 3  DOSAGE FORMS AND STRENGTHS

    Azelastine HCl nasal spray, 0.15% is a nasal spray solution available in one dosage strength:

    • Each spray of azelastine HCl nasal spray, 0.15% delivers a volume of 0.137 mL solution containing 205.5 mcg of azelastine HCl, USP.
  • 4  CONTRAINDICATIONS

    None.

  • 5  WARNINGS AND PRECAUTIONS

    5.1 Activities Requiring Mental Alertness

    In clinical trials, the occurrence of somnolence has been reported in some patients taking azelastine HCl nasal spray, 0.15% [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 HCl nasal spray, 0.15%. Concurrent use of azelastine HCl nasal spray, 0.15% 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 HCl nasal spray, 0.15% 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.

    Children 6 to 11 years of age

     

    In a 4 week clinical trial, 489 patients ages 6 to 11 years with perennial allergic rhinitis, with or without concomitant seasonal allergic rhinitis, were treated with either azelastine HCl nasal spray, 0.1%, azelastine HCl nasal spray, 0.15% or placebo, one spray per nostril twice daily. Overall, adverse events were similar in the azelastine HCl nasal spray, 0.15% group (24%), azelastine HCl nasal spray, 0.1% group (26%) and the placebo group (24%). Overall, less than 1% of the combined azelastine HCl nasal spray groups discontinued due to adverse events.

    Table 2 contains adverse reactions reported with frequencies greater than or equal to 2% and more frequently than placebo in children 6 to 11 years of age treated with azelastine HCl nasal spray, 0.1% OR azelastine HCl nasal spray, 0.15% in the controlled trial described above.

    Table 2. Adverse Reactions Reported in ≥2% Incidence in a Placebo-Controlled Trial of 4 Weeks’ Duration with Azelastine HCl Nasal Spray, 0.1% or Azelastine HCl Nasal Spray, 0.15% in Children 6 to 11 Years of Age with Perennial Allergic Rhinitis

    1 spray twice daily

    Azelastine HCl Nasal Spray, 0.1%

    (N=166)

    Azelastine HCl Nasal Spray, 0.15%

    (N=161)

    Vehicle Placebo

    (N=162)

    Epistaxis

    8 (5%)

    7 (4%)

    5 (3%)

    Nasal Discomfort

    1 (<1%)

    7 (4%)

    0 (0%)

    Dysgeusia

    4 (2%)

    6 (4%)

    1 (<1%)

    Upper respiratory infection

    4 (2%)

    4 (3%)

    3 (2%)

    Sneezing

    3 (2%)

    4 (3%)

    2 (1%)

    Children 6 months to 5 years

    In a 4 week clinical trial, 191 patients ages 6 months to 5 years with either seasonal and/or perennial allergic rhinitis were treated with either azelastine HCl nasal spray, 0.1% or azelastine HCl nasal spray, 0.15% one spray per nostril twice daily. The most frequently (≥2%) reported adverse reactions were pyrexia, cough, epistaxis, sneezing, dysgeusia, rhinalgia, upper respiratory infection, vomiting, otitis media, contact dermatitis, and oropharyngeal pain. Overall, adverse events were slightly higher in the azelastine HCl nasal spray, 0.15% group (28%) compared to azelastine HCl nasal spray, 0.1% group (21%). Focused nasal examinations were performed and showed no incidence of nasal mucosal ulceration at any time point during the study. No patients had reports of nasal septal perforation. Overall, less than 3% of the combined azelastine HCl nasal spray groups discontinued due to adverse events.

    Azelastine HCl nasal spray, 0.15%

    The safety data described below reflect exposure to azelastine HCl nasal spray, 0.15% in 2114 patients (6 months of age and older) with seasonal or perennial allergic rhinitis from 10 clinical trials of 2 weeks to 12 months duration. In 8 double-blind, placebo-controlled clinical trials of 2 to 4 weeks duration, 1703 patients (646 males and 1059 females) with seasonal or perennial allergic rhinitis were treated with azelastine HCl nasal spray, 0.15% one or two sprays per nostril once or twice daily. In the 12 month open-label, active-controlled clinical trial, 466 patients (156 males and 310 females) with perennial allergic rhinitis were treated with azelastine HCl nasal spray, 0.15% two sprays per nostril twice daily. Of these 466 patients, 152 had participated in the 4-week placebo-controlled perennial allergic rhinitis clinical trials. In a 4-week, double-blind, placebo-controlled clinical trial, 161 patients (87 males and 74 females) ages 6 to 11 years of age with perennial allergic rhinitis, with or without concomitant seasonal allergic rhinitis, were treated with azelastine HCl nasal spray, 0.15% one spray per nostril twice daily. In a 4-week clinical trial, 95 patients (59 males and 36 females) ages 6 months to 5 years of age with seasonal and/or perennial allergic rhinitis were treated with azelastine HCl nasal spray, 0.15% one spray per nostril twice daily. The racial distribution for the 10 clinical trials was 79% white, 14% black, 2% Asian, and 5% other.

    Adults and Adolescents 12 Years of Age and Older

    In the 7 placebo controlled clinical trials of 2 to 4 week duration, 2343 patients with seasonal allergic rhinitis and 540 patients with perennial allergic rhinitis were treated with two sprays per nostril of either azelastine HCl nasal spray, 0.15% or placebo once or twice daily. Overall, adverse reactions were more common in the azelastine HCl nasal spray, 0.15% treatment groups (16 to 31%) than in the placebo groups (11 to 24%). Overall, less than 2% of patients discontinued due to adverse reactions and withdrawal due to adverse reactions was similar among the treatment groups.

    Table 3 contains adverse reactions reported with frequencies greater than or equal to 2% and more frequently than placebo in patients treated with azelastine HCl nasal spray, 0.15% in the seasonal and perennial allergic rhinitis controlled clinical trials.

    Table 3. Adverse Reactions with ≥2% Incidence in Placebo-Controlled Trials of 2 to 4 Weeks’ Duration with Azelastine HCl Nasal Spray, 0.15% in Adult and Adolescent Patients With Seasonal or Perennial Allergic Rhinitis

    2 sprays twice daily

    2 sprays once daily

    Azelastine HCl Nasal Spray, 0.15% (N=523)

    Vehicle Placebo (N=523)

    Azelastine HCl Nasal Spray, 0.15% (N=1021)

    Vehicle Placebo (N=816)

    Bitter Taste

    31 (6%)

    5 (1%)

    38 (4%)

    2 (<1%)

    Nasal Discomfort

    18 (3%)

    12 (2%)

    37 (4%)

    7 (1%)

    Epistaxis

    5 (1%)

    7 (1%)

    21 (2%)

    14 (2%)

    Sneezing

    9 (2%)

    1 (<1%)

    14 (1%)

    0 (0%)

    In the above trials, somnolence was reported in <1% of patients treated with azelastine HCl nasal spray, 0.15% (11 of 1544) or vehicle placebo (1 of 1339).

    Long-Term (12 Month) Safety Trial

    In the 12 month, open-label, active-controlled, long-term safety trial, 466 patients (12 years of age and older) with perennial allergic rhinitis were treated with azelastine HCl nasal spray, 0.15% two sprays per nostril twice daily and 237 patients were treated with mometasone nasal spray two sprays per nostril once daily. The most frequently reported adverse reactions (>5%) with azelastine HCl nasal spray, 0.15% were bitter taste, headache, sinusitis, and epistaxis. Focused nasal examinations were performed and no nasal ulcerations or septal perforations were observed. In each treatment group, approximately 3% of patients had mild epistaxis. No patients had reports of severe epistaxis. Fifty-four patients (12%) treated with azelastine HCl nasal spray, 0.15% and 17 patients (7%) treated with mometasone nasal spray discontinued from the trial due to adverse events.

    6.2 Postmarketing Experience

    During the post approval use of azelastine HCl nasal spray, 0.15%, 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: abdominal pain, atrial fibrillation, blurred vision, chest pain, confusion, disturbance or loss of sense of smell and/or taste, dizziness, dyspnea, facial swelling, hypertension, involuntary muscle contractions, nasal burning, nausea, nervousness, palpitations, paresthesia, parosmia, pruritus, rash, sneezing, insomnia, sweet taste, tachycardia, and throat irritation.

    Additionally, the following adverse reactions have been identified during the post approval use of the Astelin brand of azelastine HCl 0.1% nasal spray (total daily dose 0.55 mg to 1.1 mg). 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 the following: anaphylactoid reaction, application site irritation, facial edema, paroxysmal sneezing, tolerance, urinary retention, and xerophthalmia.

  • 7  DRUG INTERACTIONS

    7.1 Central Nervous System Depressants

    Concurrent use of azelastine HCl nasal spray, 0.15% 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)].

    7.2 Erythromycin and Ketoconazole

    Interaction studies investigating the cardiac effects, as measured by the corrected QT interval (QTc), of concomitantly administered oral azelastine HCl and erythromycin or ketoconazole were conducted. Oral erythromycin (500 mg three times daily for 7 days) had no effect on azelastine pharmacokinetics or QTc based on analyses of serial electrocardiograms. Ketoconazole (200 mg twice daily for 7 days) interfered with the measurement of azelastine plasma concentrations on the analytic HPLC; however, no effects on QTc were observed [see Clinical Pharmacology (12.2) and (12.3)].

    7.3 Cimetidine

    Cimetidine (400 mg twice daily) increased the mean Cmax and AUC of orally administered azelastine HCl (4 mg twice daily) by approximately 65% [see Clinical Pharmacology (12.3)].

  • 8  USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy

    Pregnancy Category C: There are no adequate and well-controlled clinical trials in pregnant women. Azelastine HCl has been shown to cause developmental toxicity in mice, rats, and rabbits. Azelastine HCl nasal spray, 0.15% should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

    Teratogenic Effects: In mice, azelastine HCl 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 HCl 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 HCl 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 HCl 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 HCl is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when azelastine HCl nasal spray, 0.15% is administered to a nursing woman.

    8.4 Pediatric Use

    The safety and effectiveness of azelastine HCl nasal spray, 0.15% have been established for seasonal allergic rhinitis in pediatric patients 6 to 17 years of age and perennial allergic rhinitis in pediatric patients 6 to 17 years of age [see Clinical Studies (14)]. The safety and effectiveness of azelastine HCl nasal spray, 0.15% in pediatric patients below 6 years of age have not been established.

    8.5 Geriatric Use

    Clinical trials of azelastine HCl nasal spray, 0.15% did not include sufficient numbers of patients 65 years of age and older 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 HCl nasal spray, 0.15%. Acute overdosage by adults with this dosage form is unlikely to result in clinically significant adverse events, other than increased somnolence, since one 30 mL bottle of azelastine HCl nasal spray, 0.15% contains up to 45 mg of azelastine HCl. Clinical trials in adults with single doses of the oral formulation of azelastine HCl (up to 16 mg) have not resulted in increased incidence of serious adverse events. General supportive measures should be employed if overdosage occurs. There is no known antidote to azelastine HCl nasal spray, 0.15%. Oral ingestion of antihistamines has the potential to cause serious adverse effects in children. Accordingly, azelastine HCl nasal spray, 0.15% should be kept out of the reach of children.

  • 11  DESCRIPTION

    Azelastine HCl nasal spray, 0.15% is an antihistamine (H1 receptor antagonist) formulated as a metered-spray solution for intranasal administration.

    Azelastine HCl, USP occurs as a white, almost odorless, crystalline powder with a bitter taste. It has a molecular weight of 418.36. 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 5.0 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 C22H24ClN3OHCl with the following chemical structure:

    07996fed-figure-01

    Azelastine HCl nasal spray, 0.15% contains 0.15% azelastine HCl, USP in an isotonic aqueous solution containing benzalkonium chloride (125 mcg/mL), edetate disodium, hypromellose, purified water, sodium citrate, sorbitol solution and sucralose. Hydrochloric acid or sodium hydroxide may be added for adjustment of pH (pH 6.4).

    After priming [see Dosage and Administration (2.3)], each metered spray delivers a 0.137 mL mean volume containing 205.5 mcg of azelastine HCl, USP (equivalent to 187.6 mcg of azelastine base). The 30 mL (net weight 30 gm of solution) bottle provides 200 metered sprays.

  • 12  CLINICAL PHARMACOLOGY

    12.1 Mechanism of Action

    Azelastine HCl, a phthalazinone derivative, exhibits histamine H1-receptor antagonist activity in isolated tissues, animal models, and humans. Azelastine HCl nasal spray, 0.15% 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 Effects:

    In a placebo-controlled trial (95 patients with allergic rhinitis), there was no evidence of an effect of azelastine HCl 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 HCl and erythromycin or ketoconazole were conducted. Oral erythromycin had no effect on azelastine pharmacokinetics or QTc based on analysis of serial electrocardiograms. Ketoconazole interfered with the measurement of azelastine plasma levels; however, no effects on QTc were observed [see Drug Interactions (7.2)].

    12.3 Pharmacokinetics

    Absorption:

    After intranasal administration of 2 sprays per nostril (822 mcg total dose) of azelastine HCl nasal spray, 0.15%, the mean azelastine peak plasma concentration (Cmax) is 409 pg/mL, the mean extent of systemic exposure (AUC) is 9312 pghr/mL and the median time to reach Cmax (tmax) is 4 hours. The systemic bioavailability of azelastine HCl is approximately 40% after intranasal administration.

    Distribution:

    Based on intravenous and oral administration, the steady-state volume of distribution of azelastine 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 a single-dose, intranasal administration of azelastine HCl nasal spray, 0.15% (822 mcg total dose), the mean desmethylazelastine Cmax is 38 pg/mL, the AUC is 3824 pghr/mL and the median tmax is 24 hours. After intranasal dosing of azelastine to steady-state, plasma concentrations of desmethylazelastine range from 20 to 50% of azelastine concentrations.

    Elimination:

    Following intranasal administration of azelastine HCl nasal spray, 0.15%, the elimination half-life of azelastine is 25 hours while that of desmethylazelastine is 57 hours. Approximately 75% of an oral dose of radiolabeled azelastine HCl 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 healthy 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: Co-administration of orally administered azelastine (4 mg twice daily) with erythromycin (500 mg three times daily for 7 days) resulted in Cmax of 5.36 ± 2.6 ng/mL and AUC of 49.7 ± 24 ngh/mL for azelastine, whereas, administration of azelastine alone resulted in Cmax of 5.57 ± 2.7 ng/mL and AUC of 48.4 ± 24 ngh/mL for azelastine [see Drug Interactions (7.2)].

    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%. Co-administration of orally administered azelastine (4 mg twice daily) with ranitidine HCl (150 mg twice daily) resulted in Cmax of 8.89 ± 3.28 ng/mL and AUC of 88.22 ± 40.43 ngh/mL for azelastine, whereas, administration of azelastine alone resulted in Cmax of 7.83 ± 4.06 ng/mL and AUC of 80.09 ± 43.55 ngh/mL for azelastine [see Drug Interactions (7.3)].

     

    Theophylline: No significant pharmacokinetic interaction was observed with the co-administration of an oral 4 mg dose of azelastine HCl 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 HCl 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 HCl 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

    Azelastine HCl nasal spray, 0.15%

    The efficacy and safety of azelastine HCl nasal spray, 0.15% in seasonal allergic rhinitis was evaluated in five randomized, multicenter, double-blind, placebo-controlled clinical trials in 2499 adult and adolescent patients 12 years and older with symptoms of seasonal allergic rhinitis (Trials 2, 3, 4, 5, and 6). The population of the trials was 12 to 83 years of age (64% female, 36% male; 81% white, 12% black, <2% Asian, 5% other; 23% Hispanic, 77% non-Hispanic). Assessment of efficacy was based on the rTNSS, iTNSS as described above, and other supportive secondary efficacy variables. The primary efficacy endpoint was the mean change from baseline in rTNSS over 2 weeks.

    Two 2-week seasonal allergic rhinitis trials evaluated the efficacy of azelastine HCl nasal spray, 0.15% dosed at 2 sprays twice daily. The first trial (Trial 2) compared the efficacy of azelastine HCl nasal spray, 0.15% and azelastine HCl nasal spray, 0.1% to vehicle placebo. The other trial (Trial 3) compared the efficacy of azelastine HCl nasal spray, 0.15% and azelastine HCl nasal spray, 0.1% to vehicle placebo. In these two trials, azelastine HCl nasal spray, 0.15% demonstrated greater decreases in rTNSS than placebo and the differences were statistically significant (Table 4).

    Three 2-week seasonal allergic rhinitis trials evaluated the efficacy of azelastine HCl nasal spray, 0.15% dosed at 2 sprays once daily compared to the vehicle placebo. Trial 4 demonstrated a greater decrease in rTNSS than placebo and the difference was statistically significant (Table 4). Trial 5 and Trial 6 were conducted in patients with Texas mountain cedar allergy. In Trial 5 and Trial 6, azelastine HCl nasal spray, 0.15% demonstrated a greater decrease in rTNSS than placebo and the differences were statistically significant (Trials 5 and 6; Table 4). Instantaneous TNSS results for the once daily dosing regimen of azelastine HCl nasal spray, 0.15% are shown in Table 5. In Trials 5 and 6, azelastine HCl nasal spray, 0.15% demonstrated a greater decrease in iTNSS than placebo and the differences were statistically significant.

    Table 4. Mean Change from Baseline in Reflective TNSS over 2 Weeks* in Adults and Children ≥ 12 years with Seasonal Allergic Rhinitis

     

    Treatment (sprays per nostril)

    n

    Baseline LS Mean

    Change from Baseline

    Difference From Placebo

    LS Mean

    95% CI

    P value

    Trial 2

    Two sprays twice daily

    Azelastine HCl Nasal Spray, 0.15%

    153

    18.2

    -4.3

    -1.2

    -2.1, -0.3

    0.01

    Azelastine HCl Nasal Spray, 0.1%

    153

    17.9

    -3.9

    -0.9

    -1.8, 0.1

    0.07

    Vehicle Placebo

    153

    18.1

    -3

    Trial 3

    Two sprays twice daily

    Azelastine HCl Nasal Spray, 0.15%

    177

    17.7

    -5.1

    -3

    -3.9, -2.1

    <0.001

    Azelastine HCl Nasal Spray, 0.1%

    169

    18.2

    -4.2

    -2.1

    -3.0, -1.2

    <0.001

    Vehicle Placebo

    177

    17.7

    -2.1

    Trial 4

    Two sprays once daily

    Azelastine HCl Nasal Spray, 0.15%

    238

    17.4

    -3.4

    -1

    -1.7, -0.3

    0.008

    Vehicle Placebo

    242

    17.4

    -2.4

    Trial 5

    Two sprays once daily

    Azelastine HCl Nasal Spray, 0.15%

    266

    18.5

    -3.3

    -1.4

    -2.1, -0.8

    <0.001

    Vehicle Placebo

    266

    18

    -1.9

    Trial 6

    Two sprays once daily

    Azelastine HCl Nasal Spray, 0.15%

    251

    18.5

    -3.4

    -1.4

    -2.1, -0.7

    <0.001

    Vehicle Placebo

    254

    18.8

    -2

    *Sum of AM and PM rTNSS for each day (Maximum score=24) and averaged over the 14 day treatment period

    Table 5. Mean Change from Baseline AM Instantaneous TNSS over 2 Weeks* in Adults and Children ≥ 12 years with Seasonal Allergic Rhinitis

    Treatment

    (sprays per nostril once daily)

    n

    Baseline LS Mean

    Change from Baseline

    Difference From Placebo

    LS Mean

    95% CI

    P value

    Trial 4

    Two sprays once daily

    Azelastine HCl Nasal Spray, 0.15%

    238

    8.1

    -1.3

    -0.2

    -0.6, 0.1

    0.15

    Vehicle Placebo

    242

    8.3

    -1.1

    Trial 5

    Two sprays once daily

    Azelastine HCl Nasal Spray, 0.15%

    266

    8.7

    -1.4

    -0.7

    -1, -0.4

    <0.001

    Vehicle Placebo

    266

    8.3

    -0.7

    Trial 6

    Two sprays once daily

    Azelastine HCl Nasal Spray, 0.15%

    251

    8.9

    -1.4

    -0.6

    -0.9, -0.3

    <0.001

    Vehicle Placebo

    254

    8.9

    -0.8

    *AM iTNSS for each day (Maximum score=12) and averaged over the 14 day treatment period

    Azelastine HCl nasal spray, 0.15% at a dose of 1 spray twice daily was not studied. The azelastine HCl nasal spray, 0.15% 1 spray twice daily dosing regimen is supported by previous findings of efficacy for azelastine HCl nasal spray, 0.1% and a favorable comparison of azelastine HCl nasal spray, 0.15% to azelastine nasal spray 0.1% and azelastine HCl nasal spray 0.1% (Table 4).

    The efficacy and safety of azelastine HCl nasal spray, 0.15% in children 6 to 11 years of age with seasonal allergic rhinitis was evaluated in a clinical study that enrolled pediatric patients with perennial allergic rhinitis, with or without concomitant seasonal allergic rhinitis (described below in Section 14.2).

    14.2 Perennial Allergic Rhinitis

    Azelastine HCl nasal spray, 0.15%

    The efficacy and safety of azelastine HCl nasal spray, 0.15% in perennial allergic rhinitis was evaluated in one randomized, multicenter, double-blind, placebo-controlled clinical trial in 578 adult and adolescent patients 12 years and older with symptoms of perennial allergic rhinitis. The population of the trial was 12 to 84 years of age (68% female, 32% male; 85% white, 11% black, 1% Asian, 3% other; 17% Hispanic, 83% non-Hispanic).

    Assessment of efficacy was based on the 12-hour reflective total nasal symptom score (rTNSS) assessed daily in the morning and evening, the instantaneous total nasal symptom score (iTNSS), and other supportive secondary efficacy variables. The primary efficacy endpoint was the mean change from baseline rTNSS over 4 weeks. The one 4-week perennial allergic rhinitis trial evaluated the efficacy of azelastine HCl nasal spray, 0.15%, azelastine HCl nasal spray, 0.1%, and vehicle placebo dosed at 2 sprays per nostril twice daily. In this trial, azelastine HCl nasal spray, 0.15% demonstrated a greater decrease in rTNSS than placebo and the difference was statistically significant (Table 6).

    Table 6. Mean Change from Baseline in Reflective TNSS over 4 Weeks* in Adults and Children ≥12 years with Perennial Allergic Rhinitis

    Treatment (sprays per nostril twice daily)

    n

    Baseline LS Mean

    Change from Baseline

    Difference From Placebo

    LS Mean

    95% CI

    P value

    Two sprays twice daily

    Azelastine HCl Nasal Spray, 0.15%

    192

    15.8

    -4

    -0.9

    -1.7, -0.1

    0.03

    Azelastine HCl Nasal Spray, 0.1%

    194

    15.5

    -3.8

    -0.7

    -1.5, 0.1

    0.08

    Vehicle Placebo

    192

    14.7

    -3.1

    *Sum of AM and PM rTNSS for each day (Maximum score=24) and averaged over the 28 day treatment period

    The efficacy and safety of azelastine HCl nasal spray, 0.1% and azelastine HCl nasal spray, 0.15% in pediatric patients 6 to 11 years of age with perennial allergic rhinitis, with or without concomitant seasonal allergic rhinitis, was evaluated in a randomized, double-blind, placebo-controlled clinical trial in 486 patients. All patients received one spray per nostril twice daily. The study population was 58% males and 42% females; 78% white, 13% black, 3% Asian, and 6% other.

    Assessment of efficacy was based on the 12-hour reflective total nasal symptom score (rTNSS) assessed daily in the morning and evening. The primary efficacy endpoint was the mean change from baseline rTNSS over 4 weeks (Table 7). Both active treatments demonstrated statistically significant decreases in rTNSS compared to placebo. There was no statistically significant difference between the two active-treatment groups. There was also no difference in treatment effect between patients with perennial allergic rhinitis only compared to those with perennial allergic rhinitis and concomitant seasonal allergic rhinitis.

    Table 7. Mean Change from Baseline in Reflective TNSS over 4 Weeks* in Children 6 to 11 years with Perennial Allergic Rhinitis

     

    Treatment (sprays per nostril twice daily)

    n

    Baseline LS Mean

    Change from Baseline

    Difference From Placebo

    LS Mean

    95% CI

    P value

    One spray twice daily

    Azelastine HCl Nasal Spray, 0.15%

    159

    16.6

    -3.5

    -1

    -1.7, -0.3

    0.005

    Azelastine HCl Nasal Spray, 0.1%

    166

    16.4

    -3.4

    -0.9

    -1.6, -0.2

    0.015

    Vehicle Placebo

    161

    16.1

    -2.5

    *Sum of AM and PM rTNSS for each day (Maximum score=24) and averaged over the 28 day treatment period

    The efficacy of azelastine HCl nasal spray, 0.1% and azelastine HCl nasal spray, 0.15% in children 6 months to 5 years of age with allergic rhinitis was explored in a clinical study (described above in Section 14.1).

  • 16  HOW SUPPLIED/STORAGE AND HANDLING

    Azelastine HCl nasal spray, 0.15% is supplied as a 30 mL package (NDC: 65162-706-84) 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 white safety clip and a white or clear plastic dust cover. The net content of the bottle is 30 mL (net weight 30 gm of solution). The 30 mL bottle contains 45 mg (1.5 mg/mL) of azelastine HCl, USP. After priming [see Dosage and Administration (2.3)], each spray delivers a fine mist containing a mean volume of 0.137 mL solution containing 205.5 mcg of azelastine HCl, USP. The correct amount of medication in each spray cannot be assured before the initial priming and after 200 sprays for the 30 mL bottle have been used, even though the bottle is not completely empty. The bottle should be discarded after 200 sprays have been used.

    Azelastine HCl nasal spray, 0.15% should not be used after the expiration date “EXP” printed on the medicine label and carton.

    Storage

    Store upright at controlled room temperature 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Protect from freezing.

  • 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 HCl nasal spray, 0.15%. Caution patients against engaging in hazardous occupations requiring complete mental alertness and motor coordination such as driving or operating machinery after administration of azelastine HCl nasal spray, 0.15% [see Warnings and Precautions (5.1)].

    Concurrent Use of Alcohol and other Central Nervous System Depressants

    Avoid concurrent use of azelastine HCl nasal spray, 0.15% 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 HCl nasal spray, 0.15% may lead to adverse reactions, most common of which include pyrexia, dysgeusia, nasal discomfort, epistaxis, headache, sneezing, fatigue, somnolence, upper respiratory infection, cough, rhinalgia, vomiting, otitis media, contact dermatitis, and oropharyngeal pain [see Adverse Reactions (6.1)].

    Priming

    Instruct patients to prime the pump before initial use and when azelastine HCl nasal spray, 0.15% 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 HCl nasal spray, 0.15% into their eyes.

    Keep Out of Children’s Reach

    Instruct patients to keep azelastine HCl nasal spray, 0.15% out of the reach of children. If a child accidentally ingests azelastine HCl nasal spray, 0.15%, seek medical help or call a poison control center immediately.

    Distributed by:
    Amneal Pharmaceuticals LLC
    Bridgewater, NJ 08807

    Rev. 09-2017-00

  • PATIENT INFORMATION

     Azelastine (a-ZEL-uh-steen) HCl Nasal Spray, 0.15%

    Important: For use in your nose only.

    What is Azelastine HCl Nasal Spray, 0.15%?

    • Azelastine HCl nasal spray, 0.15% is a prescription medicine used to treat symptoms of seasonal allergic rhinitis in patients 6 years of age and older and year-round allergic rhinitis in people age 6 years and older.
    • Azelastine HCl nasal spray, 0.15% may help to reduce your nasal symptoms including stuffy nose, runny nose, itching and sneezing.

    It is not known if azelastine HCl nasal spray, 0.15% is safe and effective in children under 6 years of age.

    What should I tell my healthcare provider before using azelastine HCl nasal spray, 0.15%?

    Before using azelastine HCl nasal spray, 0.15%, tell your healthcare provider if you are:

    • allergic to any of the ingredients in azelastine HCl nasal spray, 0.15%. See the end of this leaflet for a complete list of ingredients in azelastine HCl nasal spray, 0.15%.
    • pregnant, or plan to become pregnant. It is not known if azelastine HCl nasal spray, 0.15% will harm your unborn baby.
    • breastfeeding, or plan to breastfeed. It is not known if azelastine HCl passes into your breast milk. You and your healthcare provider should decide if you will use azelastine HCl nasal spray, 0.15% if you plan to breastfeed.

    Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Azelastine HCl nasal spray, 0.15% and other medicines may affect each other, causing side effects.

    How should I use azelastine HCl nasal spray, 0.15%?

    • Read the Instructions for Use at the end of this leaflet for information about the right way to use azelastine HCl nasal spray, 0.15%.
    • An adult should help a young child use azelastine HCl nasal spray, 0.15%.
    • Spray azelastine HCl nasal spray, 0.15% in your nose only. Do not spray it into your eyes or mouth.
    • Use azelastine HCl nasal spray, 0.15% exactly as your healthcare provider tells you to use it.
    • Do not use more than your healthcare provider tells you.
    • Throw away your azelastine HCl nasal spray, 0.15% bottle after using 200 sprays. Even though the bottle may not be completely empty, you may not get the correct dose of medicine.
    • If you use too much or a child accidentally swallows azelastine HCl nasal spray, 0.15%, call your healthcare provider or go to the nearest hospital emergency room right away.

    What should I avoid while using azelastine HCl nasal spray, 0.15%?

    Azelastine HCl nasal spray, 0.15% can cause sleepiness:

    • Do not drive, operate machinery, or do other dangerous activities until you know how azelastine HCl nasal spray, 0.15% affects you.
    • Do not drink alcohol or take other medicines that may cause you to feel sleepy while using azelastine HCl nasal spray, 0.15%. It may make your sleepiness worse.

    What are the possible side effects of azelastine HCl nasal spray, 0.15%?

    The most common side effects of azelastine HCl nasal spray, 0.15% include:

    • fever
    • unusual taste
    • nose pain or discomfort
    • nosebleeds
    • headache
    • sneezing
    • fatigue
    • sleepiness
    • upper respiratory tract infections
    • cough
    • vomiting
    • middle ear infection
    • skin rash
    • sore throat

    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 HCl nasal spray, 0.15%. 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 HCl nasal spray, 0.15%?

    • Keep azelastine HCl nasal spray, 0.15% upright at 68°F to 77°F (20°C to 25°C).
    • Do not freeze azelastine HCl nasal spray, 0.15%.
    • Do not use azelastine HCl nasal spray, 0.15% after the expiration date “EXP” on the medicine label and box.

    Keep azelastine HCl nasal spray, 0.15% and all medicines out of reach of children.

    General information about the safe and effective use of azelastine HCl nasal spray, 0.15%.

    Medicines are sometimes prescribed for conditions other than those listed in a Patient Information leaflet. Do not use azelastine HCl nasal spray, 0.15% for a condition for which it was not prescribed. Do not give azelastine HCl nasal spray, 0.15% 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 HCl nasal spray, 0.15%. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about azelastine HCl nasal spray, 0.15% that is written for health professionals.

    For more information, go to www.amneal.com or call 1-877-835-5472.

    What are the ingredients in azelastine HCl nasal spray, 0.15%?

    Active ingredient: azelastine HCl, USP

    Inactive ingredients: benzalkonium chloride, edetate disodium, hypromellose, purified water, sodium citrate, sorbitol and sucralose.

    Hydrochloric acid or sodium hydroxide may be added for adjustment of pH (pH 6.4).

    *Trademarks are the property of their respective owners.

    Distributed by:
    Amneal Pharmaceuticals LLC
    Bridgewater, NJ 08807

    Rev. 09-2017-00

  • Instructions for Use


    Azelastine (a-ZEL-uh-steen) Hydrochloride Nasal Spray, 0.15%

    Important: For use in your nose only.

    For the correct dose of medicine:

    • Keep your head tilted downward when spraying into your nostril.
    • Change nostrils each time you use the spray.
    • Breathe gently and do not tip your head back after using the spray. This will keep the medicine from running down into your throat. You may get a bitter taste in your mouth.

    Figure A identifies the parts of your azelastine HCl nasal spray, 0.15% pump.

    Figure A 

    Figure A

    Before you use azelastine HCl nasal spray, 0.15% for the first time, you will need to prime the bottle.

    For use in young children: An adult should help a young child use azelastine HCl nasal spray, 0.15%. (See “Using your azelastine HCl nasal spray, 0.15%” Steps 1 through 8).

     

    Priming your azelastine HCl nasal spray, 0.15%

    Remove the dust cover over the tip of the bottle and the white safety clip just under the “shoulders” of the bottle (See Figure B).

    Figure B

    Figure B

    • Hold the bottle upright with 2 fingers on the shoulders of the spray pump unit and put your thumb on the bottom of the bottle. Press upward with your thumb and release for the pumping action. Repeat this until you see a fine mist (See Figure C).
    • To get a fine mist you must pump the spray fast and use firm pressure against the bottom of the bottle. If you see a stream of liquid, the pump is not working correctly and you may have nasal discomfort.
    • This should happen in 6 sprays or less.

    Now your pump is primed and ready to use.

    Figure C 

    Figure C

      • Do not use azelastine HCl nasal spray, 0.15% unless you see a fine mist after you do the priming sprays. If you do not see a fine mist, clean the tip of the spray nozzle. See the “Cleaning the Spray Tip of your Azelastine HCl Nasal Spray, 0.15%” section below.
      • If you do not use azelastine HCl nasal spray, 0.15% for 3 or more days, you will need to prime the pump with 2 sprays or until you see a fine mist.

      Using your azelastine HCl nasal spray, 0.15%

      For use in young children: An adult should help a young child use azelastine HCl nasal spray, 0.15%. (See Steps 1 through 8).

      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).

    Figure D 

    Figure D

    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).

    Figure E 

    Figure E

    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 HCl nasal spray, 0.15%. This will help to keep the medicine from going into your throat.

    Step 8.             When you finish using your azelastine HCl nasal spray, 0.15%, 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 HCl Nasal Spray, 0.15%

     

    • If the spray tip opening is clogged, do not use a pin or pointed object to unclog the tip. Unscrew the spray pump unit from the bottle by turning it to the left (counter-clockwise) (See Figure F).
    • Soak only the spray pump unit in warm water. Squirt the spray unit several times while holding it under water. Use the pumping action to clear the opening in the tip (See Figure G).

    Figure F 

    Figure F

    Figure G

    Figure G

     

    • Let the spray pump unit air dry. Make sure it is dry before you put it back onto the bottle.
    • Put the spray pump unit back into the open bottle and tighten it by turning clockwise (to the right).
    • To keep the medicine from leaking out, use firm pressure when you put the pump back onto the bottle.
    • After cleaning, follow the instructions for priming.

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

    Distributed by:
    Amneal Pharmaceuticals LLC
    Bridgewater, NJ 08807

    Rev. 09-2017-00

  • PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

    label

    carton
  • INGREDIENTS AND APPEARANCE
    AZELASTINE HYDROCHLORIDE 
    azelastine hydrochloride spray, metered
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 65162-706
    Route of AdministrationNASAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    AZELASTINE HYDROCHLORIDE (UNII: 0L591QR10I) (AZELASTINE - UNII:ZQI909440X) AZELASTINE HYDROCHLORIDE205.5 ug
    Inactive Ingredients
    Ingredient NameStrength
    BENZALKONIUM CHLORIDE (UNII: F5UM2KM3W7)  
    EDETATE DISODIUM (UNII: 7FLD91C86K)  
    HYPROMELLOSES (UNII: 3NXW29V3WO)  
    WATER (UNII: 059QF0KO0R)  
    SODIUM CITRATE (UNII: 1Q73Q2JULR)  
    SUCRALOSE (UNII: 96K6UQ3ZD4)  
    SORBITOL (UNII: 506T60A25R)  
    HYDROCHLORIC ACID (UNII: QTT17582CB)  
    SODIUM HYDROXIDE (UNII: 55X04QC32I)  
    Product Characteristics
    ColorWHITE (clear) Score    
    ShapeSize
    FlavorImprint Code
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 65162-706-84200 in 1 BOTTLE01/11/2018
    11 in 1 CARTON; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA20819901/11/2018
    Labeler - Amneal Pharmaceuticals LLC (123797875)
    Establishment
    NameAddressID/FEIBusiness Operations
    Amneal Pharmaceuticals, LLC963900878ANALYSIS(65162-706) , LABEL(65162-706) , MANUFACTURE(65162-706) , PACK(65162-706)
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