Azelastine Hydrochloride

Azelastine Hydrochloride
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Deepika Beereddy, MBBS [2]

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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.

• DOSAGE

• 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.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-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
• 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.

Non–Guideline-Supported Use

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

Contraindications

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

Warnings

There is limited information regarding Azelastine Hydrochloride Warnings' in the drug label.

Adverse Reactions

Clinical Trials Experience

There is limited information regarding Azelastine Hydrochloride Clinical Trials Experience in the drug label.

Postmarketing Experience

There is limited information regarding Azelastine Hydrochloride Postmarketing Experience in the drug label.

Drug Interactions

There is limited information regarding Azelastine Hydrochloride Drug Interactions in the drug label.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): There is no FDA guidance on usage of Azelastine Hydrochloride in women who are pregnant.
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

There is no FDA guidance on the use of Azelastine Hydrochloride in women who are nursing.

Pediatric Use

There is no FDA guidance on the use of Azelastine Hydrochloride in pediatric settings.

Geriatic Use

There is no FDA guidance on the use of Azelastine Hydrochloride in geriatric settings.

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

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

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 is limited information regarding Azelastine Hydrochloride overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

Pharmacology

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

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

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

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 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 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 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 ASTEPRO 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 ASTEPRO 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 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 ng•h/mL for azelastine, whereas, administration of azelastine alone resulted in Cmax of 5.57 ± 2.7 ng/mL and AUC of 48.4 ± 24 ng•h/mL for azelastine.

• Cimetidine and Ranitidine: In a multiple-dose, steady-state drug interaction trial in healthy subjects, cimetidine (400 mg twice daily) increased orally administered mean azelastine (4 mg twice daily) concentrations by approximately 65%. 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 ng•h/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 ng•h/mL for azelastine.

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

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.

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

There is limited information regarding Azelastine Hydrochloride How Supplied in the drug label.

Storage

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

Images

Drug Images

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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 Children’s 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

Alcohol-Azelastine Hydrochloride interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

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

References

The contents of this FDA label are provided by the National Library of Medicine.