Azelastine Hydrochloride

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# Overview
Azelastine Hydrochloride is an anti-asthmatic agent that is FDA approved for the treatment of allergic rhinitis.   Common adverse reactions include bitter taste, nasal discomfort, epistaxis, headache, sneezing, fatigue, somnolence, and upper respiratory infection.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)

### Allergic Rhinitis
- ASTEPRO Nasal Spray 0.1% and 0.15% is indicated for the relief of the symptoms of seasonal and perennial allergic rhinitis in patients 6 years of age and older.
- Dosing information:
- Seasonal Allergic Rhinitis
- In adults and adolescents 12 years of age and older, the recommended dose of ASTEPRO Nasal Spray 0.1% and 0.15% is 1 or 2 sprays per nostril twice daily. ASTEPRO Nasal Spray 0.15% may also be administered as 2 sprays per nostril once daily.
- Perennial Allergic Rhinitis
- In adults and adolescents 12 years of age and older, the recommended dose of ASTEPRO Nasal Spray 0.15% is 2 sprays per nostril twice daily.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Azelastine Hydrochloride in adult patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Azelastine Hydrochloride in adult patients.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)

### Allergic Rhinitis
- ASTEPRO Nasal Spray 0.1% and 0.15% is indicated for the relief of the symptoms of seasonal and perennial allergic rhinitis in patients 6 years of age and older.
- Dosing information:
- Seasonal Allergic Rhinitis
- In children 6 to 11 years of age, the recommended dose of ASTEPRO Nasal Spray 0.1% and 0.15% is 1 spray per nostril twice daily.
- Perennial Allergic Rhinitis
- In children 6 to 11 years of age, the recommended dose of ASTEPRO Nasal Spray 0.1% and 0.15% is 1 spray per nostril twice daily.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Azelastine Hydrochloride in pediatric patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Azelastine Hydrochloride in pediatric patients.

# Contraindications
None.

# Warnings
Activities Requiring Mental Alertness
- In clinical trials, the occurrence of somnolence has been reported in some patients taking ASTEPRO 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 ASTEPRO Nasal Spray. Concurrent use of ASTEPRO 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.

# Adverse Reactions

## 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.
ASTEPRO Nasal Spray 0.1%
- The safety data described below reflect exposure to ASTEPRO Nasal Spray 0.1% in 879 patients 6 years of age and older from 3 clinical trials of 2 weeks to 12 months duration. In a 2-week, double-blind, placebo-controlled, and active-controlled (Astelin Nasal Spray; azelastine hydrochloride) clinical trial, 285 patients (115 males and 170 females) 12 years of age and older with seasonal allergic rhinitis were treated with ASTEPRO Nasal Spray 0.1% one or two sprays per nostril daily. In the 12 month open-label, active-controlled (Astelin Nasal Spray) 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 ASTEPRO Nasal Spray 0.1% two sprays per nostril twice daily. In a 4-week, double-blind, placebo-controlled clinical trial, 166 patients (101 males and 65 females) ages 6 to 11 years of age with perennial allergic rhinitis, with or without concomitant seasonal allergic rhinitis, were treated with ASTEPRO Nasal Spray 0.1% one spray per nostril twice daily. The racial and ethnic distribution for the 3 clinical trials was 81% white, 9% black, 5% Hispanic, 3% Asian, and 2% 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 ASTEPRO Nasal Spray 0.1%, Astelin Nasal Spray or placebo twice daily; or 2 sprays per nostril of ASTEPRO Nasal Spray 0.1%, Astelin Nasal Spray, or placebo twice daily. Overall, adverse reactions were more common in the ASTEPRO 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 ASTEPRO Nasal Spray 0.1% in the controlled clinical trial described above.
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 ASTEPRO Nasal Spray 0.1% two sprays per nostril twice daily or Astelin Nasal Spray 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 of nasal septal perforation or severe epistaxis. Twenty-two patients (5%) treated with ASTEPRO Nasal Spray 0.1% and 17 patients (4%) treated with Astelin Nasal Spray discontinued from the trial due to adverse events.
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 ASTEPRO Nasal Spray 0.1%, ASTEPRO Nasal Spray 0.15% or placebo one spray per nostril twice daily. Overall, adverse events were similar in the ASTEPRO Nasal Spray 0.15% group (24%), ASTEPRO Nasal Spray 0.1% group (26%) and the placebo group (24%). Overall, less than 1% of the combined ASTEPRO 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 ASTEPRO Nasal Spray 0.1% or 0.15% in the controlled trial described above.
ASTEPRO Nasal Spray 0.15%
- The safety data described below reflect exposure to ASTEPRO Nasal Spray 0.15% in 2019 patients (6 years of age and older) with seasonal or perennial allergic rhinitis from 9 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 ASTEPRO 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 ASTEPRO 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 ASTEPRO Nasal Spray 0.15% one spray per nostril twice daily. The racial distribution for the 9 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 ASTEPRO Nasal Spray 0.15% or placebo once or twice daily. Overall, adverse reactions were more common in the ASTEPRO 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 3 contains adverse reactions reported with frequencies greater than or equal to 2% and more frequently than placebo in patients treated with ASTEPRO Nasal Spray 0.15% in the seasonal and perennial allergic rhinitis controlled clinical trials.
- In the above trials, somnolence was reported in <1% of patients treated with ASTEPRO 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 ASTEPRO 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 ASTEPRO 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 ASTEPRO Nasal Spray 0.15% and 17 patients (7%) treated with mometasone nasal spray discontinued from the trial due to adverse events.
Children 6 to 11 years of age
- See summary under ASTEPRO Nasal Spray 0.1%

## Postmarketing Experience
- During the post approval use of ASTEPRO 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 Astelin 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 ASTEPRO 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.
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%.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): C
- 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. ASTEPRO 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).
Pregnancy Category (AUS): 
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Azelastine Hydrochloride in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Azelastine Hydrochloride during labor and delivery.

### 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 ASTEPRO Nasal Spray is administered to a nursing woman.

### Pediatric Use
- The safety and effectiveness of ASTEPRO Nasal Spray in pediatric patients 6 to 17 years of age have been established. The safety and effectiveness of ASTEPRO Nasal Spray in pediatric patients below 6 years of age have not been established.

### Geriatic Use
- Clinical trials of ASTEPRO 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.

### Gender
There is no FDA guidance on the use of Azelastine Hydrochloride with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Azelastine Hydrochloride with respect to specific racial populations.

### Renal Impairment
There is no FDA guidance on the use of Azelastine Hydrochloride in patients with renal impairment.

### Hepatic Impairment
There is no FDA guidance on the use of Azelastine Hydrochloride in patients with hepatic impairment.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Azelastine Hydrochloride in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Azelastine Hydrochloride in patients who are immunocompromised.

# Administration and Monitoring

### Administration
Seasonal Allergic Rhinitis
- In children 6 to 11 years of age, the recommended dose of ASTEPRO Nasal Spray 0.1% and 0.15% is 1 spray per nostril twice daily.
- In adults and adolescents 12 years of age and older, the recommended dose of ASTEPRO Nasal Spray 0.1% and 0.15% is 1 or 2 sprays per nostril twice daily. ASTEPRO Nasal Spray 0.15% may also be administered as 2 sprays per nostril once daily.
Perennial Allergic Rhinitis
- In children 6 to 11 years of age, the recommended dose of ASTEPRO Nasal Spray 0.1% and 0.15% is 1 spray per nostril twice daily.
- In adults and adolescents 12 years of age and older, the recommended dose of ASTEPRO Nasal Spray 0.15% is 2 sprays per nostril twice daily.
Important Administration Instructions
- Administer ASTEPRO Nasal Spray by the intranasal route only.
- Priming: Prime ASTEPRO Nasal Spray before initial use by releasing 6 sprays or until a fine mist appears. When ASTEPRO Nasal Spray has not been used for 3 or more days, reprime with 2 sprays or until a fine mist appears. Avoid spraying ASTEPRO Nasal Spray into the eyes.
DOSAGE FORMS AND STRENGTHS
- ASTEPRO Nasal Spray is a nasal spray solution. Each spray of ASTEPRO Nasal Spray 0.1% delivers a volume of 0.137 mL solution containing 137 mcg of azelastine hydrochloride. Each spray of ASTEPRO Nasal Spray 0.15% delivers a volume of 0.137 mL solution containing 205.5 mcg of azelastine hydrochloride.

### Monitoring
There is limited information regarding Azelastine Hydrochloride Monitoring in the drug label.

# IV Compatibility
There is limited information regarding the compatibility of Azelastine Hydrochloride and IV administrations.

# Overdosage
- There have been no reported overdosages with ASTEPRO 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 ASTEPRO Nasal Spray 0.1% contains up to 30 mg of azelastine hydrochloride and one 30-mL bottle of ASTEPRO 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 ASTEPRO Nasal Spray. Oral ingestion of antihistamines has the potential to cause serious adverse effects in children. Accordingly, ASTEPRO Nasal Spray should be kept out of the reach of children.

# Pharmacology

## Mechanism of Action
- Azelastine hydrochloride, a phthalazinone derivative, exhibits histamine H1 -receptor antagonist activity in isolated tissues, animal models, and humans. ASTEPRO 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.

## Structure
- ASTEPRO (azelastine hydrochloride) Nasal Spray 0.1%, 137 micrograms (mcg), is an antihistamine formulated as a metered-spray solution for intranasal administration. ASTEPRO (azelastine hydrochloride) Nasal Spray 0.15%, 205.5 micrograms (mcg), is 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 225C and the pH of a saturated solution is between 5.0 and 5.4. Its chemical name is ()-1-(2H)-phthalazinone,4--2-(hexahydro-1-methyl-1H-azepin-4-yl)-, monohydrochloride. Its molecular formula is C22H24ClN3OHCl with the following chemical structure:
- ASTEPRO Nasal Spray 0.1% contains 0.1% azelastine hydrochloride in an isotonic aqueous solution containing sorbitol, sucralose, hypromellose, sodium citrate, edetate disodium, benzalkonium chloride (125 mcg/mL), and purified water (pH 6.4).
- 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 30-mL (net weight 30 gm of solution) bottle provides 200 metered sprays.
- ASTEPRO Nasal Spray 0.15% contains 0.15% azelastine hydrochloride in an isotonic aqueous solution containing sorbitol, sucralose, hypromellose, sodium citrate, edetate disodium, benzalkonium chloride (125 mcg/mL), and purified water (pH 6.4).
- After priming , each metered spray delivers a 0.137 mL mean volume containing 205.5 mcg of azelastine hydrochloride (equivalent to 187.6 mcg of azelastine base). The 30-mL (net weight 30 gm of solution) bottle provides 200 metered sprays.

## Pharmacodynamics
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.

## Pharmacokinetics
- Absorption: After intranasal administration of 2 sprays per nostril (548 mcg total dose) of ASTEPRO Nasal Spray 0.1%, the mean azelastine peak plasma concentration (Cmax) is 200 pg/mL, the mean extent of systemic exposure (AUC) is 5122 pghr/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 ASTEPRO 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 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 ASTEPRO Nasal Spray 0.1% (548 mcg total dose), the mean desmethylazelastine Cmax is 23 pg/mL, the AUC is 2131 pghr/mL and the median tmax is 24 hours. After a single-dose, intranasal administration of ASTEPRO 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 20-50% of azelastine concentrations.
- Elimination: Following intranasal administration of ASTEPRO Nasal Spray 0.1%, the elimination half-life of azelastine is 22 hours while that of desmethylazelastine is 52 hours. Following intranasal administration of ASTEPRO 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.
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 70-75% 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.
- 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 hydrochloride (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.
- 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.

## 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  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.

# Clinical Studies
ASTEPRO Nasal Spray 0.1%
- The efficacy and safety of ASTEPRO Nasal Spray 0.1% was evaluated in a 2-week, randomized, multicenter, double-blind, placebo-controlled clinical trial including 834 adult and adolescent patients 12 years of age and older with symptoms of seasonal allergic rhinitis. The population was 12 to 83 years of age (60% female, 40% male; 69% white, 16% black, 12% Hispanic, 2% Asian, 1% other).
- Patients were randomized to one of six treatment groups: 1 spray per nostril of either ASTEPRO Nasal Spray 0.1%, Astelin (azelastine hydrochloride) Nasal Spray or vehicle placebo twice daily; or 2 sprays per nostril of ASTEPRO Nasal Spray 0.1%, Astelin (azelastine hydrochloride) Nasal Spray or vehicle placebo twice daily.
- Assessment of efficacy was based on the 12-hour reflective total nasal symptom score (rTNSS) assessed daily in the morning and evening, in addition to the instantaneous total nasal symptom score (iTNSS) and other supportive secondary efficacy variables. TNSS is calculated as the sum of the patients scoring of the four individual nasal symptoms (rhinorrhea, nasal congestion, sneezing, and nasal itching) on a 0 to 3 categorical severity scale (0 = absent, 1 = mild, 2 = moderate, 3 = severe). The rTNSS required patients to record symptom severity over the previous 12 hours. For the primary efficacy endpoint, the mean change from baseline rTNSS, morning (AM) and evening (PM) rTNSS scores were summed for each day (maximum score of 24) and then averaged over the 2 weeks. The iTNSS, recorded immediately prior to the next dose, were assessed as an indication of whether the effect was maintained over the dosing interval.
- In this trial, ASTEPRO Nasal Spray 0.1% two sprays twice a day demonstrated a greater decrease in rTNSS and iTNSS than placebo and the difference was statistically significant. The trial results are presented in Table 4 (Trial 1).
- The efficacy of ASTEPRO Nasal Spray 0.1% one spray per nostril twice daily for seasonal allergic rhinitis is supported by two, 2-week, placebo-controlled clinical trials with Astelin (azelastine hydrochloride) Nasal Spray in 413 patients with seasonal allergic rhinitis. In these trials, efficacy was assessed using the TNSS (described above). Astelin Nasal Spray demonstrated a greater decrease from baseline in the summed AM and PM rTNSS compared with placebo and the difference was statistically significant.
ASTEPRO Nasal Spray 0.15%
- The efficacy and safety of ASTEPRO 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 ASTEPRO Nasal Spray 0.15% dosed at 2 sprays twice daily. The first trial (Trial 2) compared the efficacy of ASTEPRO Nasal Spray 0.15% and Astelin (azelastine hydrochloride) Nasal Spray to vehicle placebo. The other trial (Trial 3) compared the efficacy of ASTEPRO Nasal Spray 0.15% and ASTEPRO Nasal Spray 0.1% to vehicle placebo. In these two trials, ASTEPRO 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 ASTEPRO 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, ASTEPRO 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 ASTEPRO Nasal Spray 0.15% are shown in Table 5. In Trials 5 and 6, ASTEPRO Nasal Spray 0.15% demonstrated a greater decrease in iTNSS than placebo and the differences were statistically significant.
ASTEPRO Nasal Spray 0.15% at a dose of 1 spray twice daily was not studied. The ASTEPRO Nasal Spray 0.15% 1 spray twice daily dosing regimen is supported by previous findings of efficacy for Astelin (azelastine hydrochloride) Nasal Spray and a favorable comparison of ASTEPRO Nasal Spray 0.15% to Astelin Nasal Spray and ASTEPRO Nasal Spray 0.1% (Table 4).
The efficacy and safety of ASTEPRO Nasal Spray 0.1% and 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.

# How Supplied
- ASTEPRO (azelastine hydrochloride) Nasal Spray 0.1% is supplied as a 30-mL package 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 blue safety clip and a blue plastic dust cover. The net content of the bottle is 30 mL (net weight 30 gm of solution). Each bottle contains 30 mg (1 mg/mL) of azelastine hydrochloride. After priming , each spray delivers a fine mist containing a mean volume of 0.137 mL solution containing 137 mcg of azelastine hydrochloride. The correct amount of medication in each spray cannot be assured before the initial priming and after 200 sprays have been used, even though the bottle is not completely empty. The bottle should be discarded after 200 sprays have been used.
- ASTEPRO (azelastine hydrochloride) Nasal Spray 0.15% is supplied as a 30-mL package (NDC 0037-0243-30) 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 blue safety clip and a blue 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.
- ASTEPRO Nasal Spray should not be used after the expiration date EXP printed on the medicine label and carton.

## Storage
- Store upright at controlled room temperature 20 - 25C (68 - 77F). Protect from freezing.

# Images

## Drug Images

## Package and Label Display Panel

# 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 ASTEPRO 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 ASTEPRO Nasal Spray.
Concurrent Use of Alcohol and other Central Nervous System Depressants
- Concurrent use of ASTEPRO 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'
Common Adverse Reactions
- Patients should be informed that the treatment with ASTEPRO Nasal Spray may lead to adverse reactions, most common of which include bitter taste, nasal discomfort, epistaxis, headache, sneezing, fatigue, somnolence, and respiratory infection.
Priming
- Patients should be instructed to prime the pump before initial use and when ASTEPRO Nasal Spray has not been used for 3 or more days.
Keep Spray Out of Eyes
- Patients should be instructed to avoid spraying ASTEPRO Nasal Spray into their eyes.
Keep Out of Childrens Reach
- Patients should be instructed to keep ASTEPRO Nasal Spray out of the reach of children. If a child accidentally ingests ASTEPRO Nasal Spray, seek medical help or call a poison control center immediately.

# Precautions with Alcohol
- 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

# Brand Names
Astelin,
Astelin Ready-Spray,
Optivar,
Astepro

# Look-Alike Drug Names
There is limited information regarding Azelastine Hydrochloride Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price