Azela

Dosage Forms And Strengths

Azelastine HCl Nasal Solution (Nasal Spray), 0.15% is a nasal spray solution. Each spray of Azelastine HCl Nasal Solution (Nasal Spray), 0.15% delivers a volume of 0.137 mL solution containing 205.5 mcg of azelastine hydrochloride.

Storage And Handling

Azelastine HCl Nasal Solution (Nasal Spray), 0.15% is supplied as a 30-mL package (NDC 45802-026- 83) delivering 200 metered sprays in a high-density polyethylene (HDPE) bottle fitted with a metereddose spray pump unit. The spray pump unit consists of a nasal spray pump fitted with a violet safety clip and a violet 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 hydrochloride. After priming , each spray delivers a fine mist containing a mean volume of 0.137 mL solution containing 205.5 mcg of azelastine hydrochloride. 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 Solution (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° - 25°C (68° - 77°F). Protect from freezing.

Manufactured by Perrigo Yeruham 80500, Israel. Revised: Apr 2014

Allergic Rhinitis

Azelastine HCl Nasal Solution (Nasal Spray), 0.15% is indicated for the relief of the symptoms of seasonal and perennial allergic rhinitis in patients 12 years of age and older.

Pediatric use information for patients ages 6 to 11 years of age for treatment of allergic rhinitis, including seasonal and perennial allergic rhinitis is approved for Meda Pharmaceuticals’ azelastine hydrochloride nasal spray product. However, due to Meda Pharmaceuticals’ marketing exclusivity rights, this drug product is not labeled with that pediatric information.

Seasonal Allergic Rhinitis

In adults and adolescents 12 years of age and older, the recommended dose of Azelastine HCl Nasal Solution (Nasal Spray), 0.15% is 1 or 2 sprays per nostril twice daily. Azelastine HCl Nasal Solution (Nasal Spray), 0.15% may also be administered as 2 sprays per nostril once daily.

Pediatric use information for patients ages 6 to 11 years of age for treatment of allergic rhinitis, including seasonal and perennial allergic rhinitis is approved for Meda Pharmaceuticals’ azelastine hydrochloride nasal spray product. However, due to Meda Pharmaceuticals’ marketing exclusivity rights, this drug product is not labeled with that pediatric information.

Perennial Allergic Rhinitis

In adults and adolescents 12 years of age and older, the recommended dose of Azelastine HCl Nasal Solution (Nasal Spray), 0.15% is 2 sprays per nostril twice daily.

Pediatric use information for patients ages 6 to 11 years of age for treatment of allergic rhinitis, including seasonal and perennial allergic rhinitis is approved for Meda Pharmaceuticals’ azelastine hydrochloride nasal spray product. However, due to Meda Pharmaceuticals’ marketing exclusivity rights, this drug product is not labeled with that pediatric information.

Important Administration Instructions

Administer Azelastine HCl Nasal Solution (Nasal Spray), 0.15% by the intranasal route only.

Priming

Prime Azelastine HCl Nasal Solution (Nasal Spray), 0.15% before initial use by releasing 6 sprays or until a fine mist appears. When Azelastine HCl Nasal Solution (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 Solution (Nasal Spray), 0.15% into the eyes.

None.

WARNINGS

Included as part of the "PRECAUTIONS" Section

PRECAUTIONS

Activities Requiring Mental Alertness

In clinical trials, the occurrence of somnolence has been reported in some patients taking azelastine HCl nasal solution (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 HCl Nasal Solution (Nasal Spray), 0.15%. Concurrent use of Azelastine HCl Nasal Solution (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

Patient Counseling Information

See FDA-approved patient labeling (PATIENT INFORMATION).

Activities Requiring Mental Alertness

Somnolence has been reported in some patients taking azelastine HCl nasal solution (nasal spray). Patients should be cautioned against engaging in hazardous occupations requiring complete mental alertness and motor coordination such as driving or operating machinery after administration of Azelastine HCl Nasal Solution (Nasal Spray), 0.15%.

Concurrent Use Of Alcohol And Other Central Nervous System Depressants

Concurrent use of Azelastine HCl Nasal Solution (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.

Common Adverse Reactions

Patients should be informed that the treatment with Azelastine HCl Nasal Solution (Nasal Spray), 0.15% may lead to adverse reactions, most common of which include bitter taste, nasal discomfort, epistaxis, headache, sneezing, fatigue, and somnolence.

Pediatric use information for patients ages 6 to 11 years of age for treatment of allergic rhinitis, including seasonal and perennial allergic rhinitis is approved for Meda Pharmaceuticals’ azelastine hydrochloride nasal spray product. However, due to Meda Pharmaceuticals’ marketing exclusivity rights, this drug product is not labeled with that pediatric information.

Priming

Patients should be instructed to prime the pump before initial use and when Azelastine HCl Nasal Solution (Nasal Spray), 0.15% has not been used for 3 or more days.

Keep Spray Out Of Eyes

Patients should be instructed to avoid spraying Azelastine HCl Nasal Solution (Nasal Spray), 0.15% into their eyes.

Keep Out Of Children’s Reach

Patients should be instructed to keep Azelastine HCl Nasal Solution (Nasal Spray), 0.15% out of the reach of children. If a child accidentally ingests Azelastine HCl Nasal Solution (Nasal Spray), 0.15%, seek medical help or call a poison control center immediately.

Nonclinical Toxicology

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.

Use In Specific Populations

Pregnancy

Pregnancy Category C

There are no adequate and well-controlled clinical trials in pregnant women. Azelastine hydrochloride has been shown to cause developmental toxicity in mice, rats, and rabbits. Azelastine HCl nasal solution (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 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).

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 HCl Nasal Solution (Nasal Spray), 0.15% is administered to a nursing woman.

Pediatric Use

The safety and effectiveness of azelastine HCl nasal solution (nasal spray) in pediatric patients 6 to 17 years of age have been established. The safety and effectiveness of azelastine HCl nasal solution (nasal spray) in pediatric patients below 6 years of age have not been established.

Pediatric use information for patients ages 6 to 11 years of age for treatment of allergic rhinitis, including seasonal and perennial allergic rhinitis is approved for Meda Pharmaceuticals’ azelastine hydrochloride nasal spray product. However, due to Meda Pharmaceuticals’ marketing exclusivity rights, this drug product is not labeled with that pediatric information.

Geriatric Use

Clinical trials of azelastine HCl nasal solution (nasal spray) 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.

SIDE EFFECTS

Use of azelastine HCl nasal solution (nasal spray) has been associated with somnolence.

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.

AzelastineHCl Nasal Solution (Nasal Spray), 0.1%

The safety data described below reflect exposure to azelastine HCl nasal solution (nasal spray), 0.1% in 713 patients 12 years of age and older from 2 clinical trials of 2 weeks to 12 months duration. In a 2- week, double-blind, placebo-controlled, and active-controlled (azelastine HCl nasal solution (nasal spray) without sweetener; azelastine hydrochloride) clinical trial, 285 patients (115 males and 170 females) 12 years of age and older with seasonal allergic rhinitis were treated with azelastine HCl nasal solution (nasal spray), 0.1% one or two sprays per nostril daily. In the 12 month open-label, activecontrolled (azelastine HCl nasal solution (nasal spray) without sweetener) clinical trial, 428 patients (207 males and 221 females) 12 years of age and older with perennial allergic rhinitis and/or nonallergic rhinitis were treated with azelastine HCl nasal solution (nasal spray), 0.1% two sprays per nostril twice daily. The racial and ethnic distribution for the 2 clinical trials was 82% white, 8% black, 6% Hispanic, 3% Asian, and <1% other.

Adults and Adolescents 12 Years of Age and Older

In the two week clinical trial, 835 patients 12 years of age and older with seasonal allergic rhinitis were treated with one of six treatments: one spray per nostril of either azelastine HCl nasal solution (nasal spray), 0.1%, azelastine HCl nasal solution (nasal spray) without sweetener or placebo twice daily; or 2 sprays per nostril of azelastine HCl nasal solution (nasal spray), 0.1%, azelastine HCl nasal solution (nasal spray) without sweetener, or placebo twice daily. Overall, adverse reactions were more common in the azelastine HCl nasal solution (nasal spray), 0.1% treatment groups (21-28%) than in the placebo groups (16-20%). Overall, less than 1% of patients discontinued due to adverse reactions and withdrawal due to adverse reactions was similar among the treatment groups.

Table 1 contains adverse reactions reported with frequencies greater than or equal to 2% and more frequently than placebo in patients treated with azelastine HCl nasal solution (nasal spray), 0.1% in the controlled clinical trial described above.

Table 1: Adverse Reactions in ≥2% Incidence in a Placebo-Controlled Trail of 2 Weeks' Duration with Azelastine HCl Nasal Solution (Nasap Spray), 0.1% in Adult and Adolescent Patients with Seasonal Allergic Rhinitis

Long-Term (12 Month) Safety Trial

In the 12 month, open-label, active-controlled, long-term safety trial, 862 patients 12 years of age and older with perennial allergic and/or nonallergic rhinitis were treated with azelastine HCl nasal solution (nasal spray), 0.1% two sprays per nostril twice daily or azelastine HCl nasal solution (nasal spray) without sweetener two sprays per nostril twice daily. The most frequently reported adverse reactions were headache, bitter taste, epistaxis, and nasopharyngitis and were generally similar between treatment groups. Focused nasal examinations were performed and showed that the incidence of nasal mucosal ulceration in each treatment group was approximately 1% at baseline and approximately 1.5% throughout the 12 month treatment period. In each treatment group, 5-7% of patients had mild epistaxis. No patients had reports nasal septal perforation or severe epistaxis. Twenty-two patients (5%) treated with azelastine HCl nasal solution (nasal spray), 0.1% and 17 patients (4%) treated with azelastine HCl nasal solution (nasal spray) without sweetener discontinued from the trial due to adverse events.

AzelastineHCl Nasal Solution (Nasal Spray), 0.15%

The safety data described below reflect exposure to azelastine HCl nasal solution (nasal spray), 0.15% in 1858 patients (12 years of age and older) with seasonal or perennial allergic rhinitis from 8 clinical trials of 2 weeks to 12 months duration. In 7 double-blind, placebo-controlled clinical trials of 2 to 4 weeks duration, 1544 patients (560 males and 984 females) with seasonal or perennial allergic rhinitis were treated with azelastine HCl nasal solution (nasal spray), 0.15% 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 solution (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. The racial distribution for the 8 clinical trials was 80% white, 13% 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 solution (nasal spray), 0.15% or placebo once or twice daily. Overall, adverse reactions were more common in the azelastine HCl nasal solution (nasal spray), 0.15% treatment groups (16-31%) than in the placebo groups (11-24%). Overall, less than 2% of patients discontinued due to adverse reactions and withdrawal due to adverse reactions was similar among the treatment groups.

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

Table 2: Adverse Reactions with ≥2% Incidence in a Placebo-Controlled Trail of 2 to 4 Weeks' Duration with Azelastine HCl Nasal Solution (Nasap Spray), 0.15% in Adult and Adolescent Patients With Seasonal or Perennial Allergic Rhinitis

In the above trials, somnolence was reported in <1% of patients treated with azelastine HCl nasal solution (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 solution (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 solution (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 solution (nasal spray), 0.15% and 17 patients (7%) treated with mometasone nasal spray discontinued from the trial due to adverse events.

Pediatric use information for patients ages 6 to 11 years of age for treatment of allergic rhinitis, including seasonal and perennial allergic rhinitis is approved for Meda Pharmaceuticals’ azelastine hydrochloride nasal spray product. However, due to Meda Pharmaceuticals’ marketing exclusivity rights, this drug product is not labeled with that pediatric information.

Postmarketing Experience

During the post approval use of azelastine HCl nasal solution (nasal spray), 0.1% and 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, nasal burning, nausea, sweet taste, and throat irritation.

Additionally, the following adverse reactions have been identified during the post approval use of the azelastine HCl nasal solution (nasal spray) without sweetener brand of azelastine hydrochloride 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, atrial fibrillation, blurred vision, chest pain, confusion, dizziness, dyspnea, facial edema, hypertension, involuntary muscle contractions, nervousness, palpitations, paresthesia, parosmia, paroxysmal sneezing, pruritus, rash, disturbance or loss of sense of smell and/or taste, tachycardia, tolerance, urinary retention, and xerophthalmia.

DRUG INTERACTIONS

Central Nervous System Depressants

Concurrent use of Azelastine HCl Nasal Solution (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.

Erythromycin And Ketoconazole

Interaction studies investigating the cardiac effects, as measured by the corrected QT interval (QTc), of concomitantly administered oral azelastine hydrochloride 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.

Cimetidine

Cimetidine (400 mg twice daily) increased the mean Cmax and AUC of orally administered azelastine hydrochloride (4 mg twice daily) by approximately 65%.

Pregnancy Category C

There are no adequate and well-controlled clinical trials in pregnant women. Azelastine hydrochloride has been shown to cause developmental toxicity in mice, rats, and rabbits. Azelastine HCl nasal solution (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 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).

Use of azelastine HCl nasal solution (nasal spray) has been associated with somnolence.

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.

AzelastineHCl Nasal Solution (Nasal Spray), 0.1%

The safety data described below reflect exposure to azelastine HCl nasal solution (nasal spray), 0.1% in 713 patients 12 years of age and older from 2 clinical trials of 2 weeks to 12 months duration. In a 2- week, double-blind, placebo-controlled, and active-controlled (azelastine HCl nasal solution (nasal spray) without sweetener; azelastine hydrochloride) clinical trial, 285 patients (115 males and 170 females) 12 years of age and older with seasonal allergic rhinitis were treated with azelastine HCl nasal solution (nasal spray), 0.1% one or two sprays per nostril daily. In the 12 month open-label, activecontrolled (azelastine HCl nasal solution (nasal spray) without sweetener) clinical trial, 428 patients (207 males and 221 females) 12 years of age and older with perennial allergic rhinitis and/or nonallergic rhinitis were treated with azelastine HCl nasal solution (nasal spray), 0.1% two sprays per nostril twice daily. The racial and ethnic distribution for the 2 clinical trials was 82% white, 8% black, 6% Hispanic, 3% Asian, and <1% other.

Adults and Adolescents 12 Years of Age and Older

In the two week clinical trial, 835 patients 12 years of age and older with seasonal allergic rhinitis were treated with one of six treatments: one spray per nostril of either azelastine HCl nasal solution (nasal spray), 0.1%, azelastine HCl nasal solution (nasal spray) without sweetener or placebo twice daily; or 2 sprays per nostril of azelastine HCl nasal solution (nasal spray), 0.1%, azelastine HCl nasal solution (nasal spray) without sweetener, or placebo twice daily. Overall, adverse reactions were more common in the azelastine HCl nasal solution (nasal spray), 0.1% treatment groups (21-28%) than in the placebo groups (16-20%). Overall, less than 1% of patients discontinued due to adverse reactions and withdrawal due to adverse reactions was similar among the treatment groups.

Table 1 contains adverse reactions reported with frequencies greater than or equal to 2% and more frequently than placebo in patients treated with azelastine HCl nasal solution (nasal spray), 0.1% in the controlled clinical trial described above.

Table 1: Adverse Reactions in ≥2% Incidence in a Placebo-Controlled Trail of 2 Weeks' Duration with Azelastine HCl Nasal Solution (Nasap Spray), 0.1% in Adult and Adolescent Patients with Seasonal Allergic Rhinitis

Long-Term (12 Month) Safety Trial

In the 12 month, open-label, active-controlled, long-term safety trial, 862 patients 12 years of age and older with perennial allergic and/or nonallergic rhinitis were treated with azelastine HCl nasal solution (nasal spray), 0.1% two sprays per nostril twice daily or azelastine HCl nasal solution (nasal spray) without sweetener two sprays per nostril twice daily. The most frequently reported adverse reactions were headache, bitter taste, epistaxis, and nasopharyngitis and were generally similar between treatment groups. Focused nasal examinations were performed and showed that the incidence of nasal mucosal ulceration in each treatment group was approximately 1% at baseline and approximately 1.5% throughout the 12 month treatment period. In each treatment group, 5-7% of patients had mild epistaxis. No patients had reports nasal septal perforation or severe epistaxis. Twenty-two patients (5%) treated with azelastine HCl nasal solution (nasal spray), 0.1% and 17 patients (4%) treated with azelastine HCl nasal solution (nasal spray) without sweetener discontinued from the trial due to adverse events.

AzelastineHCl Nasal Solution (Nasal Spray), 0.15%

The safety data described below reflect exposure to azelastine HCl nasal solution (nasal spray), 0.15% in 1858 patients (12 years of age and older) with seasonal or perennial allergic rhinitis from 8 clinical trials of 2 weeks to 12 months duration. In 7 double-blind, placebo-controlled clinical trials of 2 to 4 weeks duration, 1544 patients (560 males and 984 females) with seasonal or perennial allergic rhinitis were treated with azelastine HCl nasal solution (nasal spray), 0.15% 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 solution (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. The racial distribution for the 8 clinical trials was 80% white, 13% 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 solution (nasal spray), 0.15% or placebo once or twice daily. Overall, adverse reactions were more common in the azelastine HCl nasal solution (nasal spray), 0.15% treatment groups (16-31%) than in the placebo groups (11-24%). Overall, less than 2% of patients discontinued due to adverse reactions and withdrawal due to adverse reactions was similar among the treatment groups.

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

Table 2: Adverse Reactions with ≥2% Incidence in a Placebo-Controlled Trail of 2 to 4 Weeks' Duration with Azelastine HCl Nasal Solution (Nasap Spray), 0.15% in Adult and Adolescent Patients With Seasonal or Perennial Allergic Rhinitis

In the above trials, somnolence was reported in <1% of patients treated with azelastine HCl nasal solution (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 solution (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 solution (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 solution (nasal spray), 0.15% and 17 patients (7%) treated with mometasone nasal spray discontinued from the trial due to adverse events.

Pediatric use information for patients ages 6 to 11 years of age for treatment of allergic rhinitis, including seasonal and perennial allergic rhinitis is approved for Meda Pharmaceuticals’ azelastine hydrochloride nasal spray product. However, due to Meda Pharmaceuticals’ marketing exclusivity rights, this drug product is not labeled with that pediatric information.

Postmarketing Experience

During the post approval use of azelastine HCl nasal solution (nasal spray), 0.1% and 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, nasal burning, nausea, sweet taste, and throat irritation.

Additionally, the following adverse reactions have been identified during the post approval use of the azelastine HCl nasal solution (nasal spray) without sweetener brand of azelastine hydrochloride 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, atrial fibrillation, blurred vision, chest pain, confusion, dizziness, dyspnea, facial edema, hypertension, involuntary muscle contractions, nervousness, palpitations, paresthesia, parosmia, paroxysmal sneezing, pruritus, rash, disturbance or loss of sense of smell and/or taste, tachycardia, tolerance, urinary retention, and xerophthalmia.

There have been no reported overdosages with azelastine HCl nasal solution (nasal spray). 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 Solution (Nasal Spray), 0.15% contains up to 45 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 events. General supportive measures should be employed if overdosage occurs. There is no known antidote to azelastine HCl nasal solution (nasal spray). Oral ingestion of antihistamines has the potential to cause serious adverse effects in children. Accordingly, Azelastine HCl Nasal Solution (Nasal Spray), 0.15% should be kept out of the reach of children.

Cardiac Effects

In a placebo-controlled trial (95 patients 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. 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.

Absorption

After intranasal administration of 2 sprays per nostril (548 mcg total dose) of azelastine HCl nasal solution (nasal spray), 0.1%, the mean azelastine peak plasma concentration (Cmax) is 200 pg/mL, the mean extent of systemic exposure (AUC) is 5122 pg•hr/mL and the median time to reach Cmax (tmax is 3 hours. After intranasal administration of 2 sprays per nostril (822 mcg total dose) of azelastine HCl nasal solution (nasal spray), 0.15%, the mean azelastine peak plasma concentration (Cmax) is 409 pg/mL, the mean extent of systemic exposure (AUC) is 9312 pg•hr/mL and the median time to reach Cmax (tmax ) is 4 hours. The systemic bioavailability of azelastine hydrochloride 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 solution (nasal spray), 0.1% (548 mcg total dose), the mean desmethylazelastine Cmax is 23 pg/mL, the AUC is 2131 pg•hr/mL and the median tmax is 24 hours. After a single-dose, intranasal administration of azelastine HCl nasal solution (nasal spray), 0.15% (822 mcg total dose), the mean desmethylazelastine Cmax is 38 pg/mL, the AUC is 3824 pg•hr/mL and the median tmax is 24 hours. After intranasal dosing of azelastine to steady-state, plasma concentrations of desmethylazelastine range from 20-50% of azelastine concentrations.

Elimination

Following intranasal administration of azelastine HCl nasal solution (nasal spray), 0.1%, the elimination half-life of azelastine is 22 hours while that of desmethylazelastine is 52 hours. Following intranasal administration of azelastine HCl nasal solution (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 hydrochloride was excreted in the feces with less than 10% as unchanged azelastine.