Azelastine Hydrochloride

Introduction Overview

Generic Name

azelastine hydrochloride

Brand Name

Astelin, Astepro, Astepro Allergy

Dosage Form

nasal spray, metered-dose solution

Drug Class

nasal antihistamines and decongestants

Pharmacokinetics

Absorption

Azelastine hydrochloride, when administered intranasally via nasal spray, exhibits systemic bioavailability of approximately 40%. Peak plasma concentrations (Cmax) are typically reached within 2 to 3 hours post-dose. Studies demonstrate that dosing above two sprays per nostril twice daily results in greater than dose-proportional increases in systemic exposure as measured by Cmax and area under the plasma concentration-time curve (AUC), indicating nonlinear pharmacokinetics at higher doses.

Distribution

The volume of distribution at steady-state is estimated to be 14.5 L/kg based on intravenous and oral administration studies, indicating extensive tissue distribution. Azelastine shows high plasma protein binding, with approximately 88% bound to plasma proteins, while its major active metabolite, desmethylazelastine, exhibits even higher protein binding at about 97%. This extensive binding affects its pharmacokinetic behavior and tissue penetration.

Metabolism

Azelastine undergoes oxidative metabolism primarily via the cytochrome P450 enzyme system to form desmethylazelastine, its principal active metabolite. The exact isoforms responsible for this metabolism have not been fully characterized. Plasma concentrations of desmethylazelastine range from 20% to 50% of those of azelastine following intranasal administration at steady-state. The metabolite profile is similar irrespective of administration route (intranasal or oral).

Elimination

The elimination half-life of azelastine is approximately 22 hours, with a plasma clearance of about 0.5 L/h/kg from combined intravenous and oral data. Approximately 75% of an oral dose is excreted via feces, with less than 10% as unchanged drug. Renal elimination of unchanged drug is minimal. Pharmacokinetic parameters are generally unaffected by hepatic impairment but show increased exposure in renal impairment, with renal insufficiency (creatinine clearance <50 mL/min) associated with 70-75% higher Cmax and AUC values compared to normal subjects. Age and gender do not significantly alter pharmacokinetics.

Dosage Forms

Adults

For seasonal allergic rhinitis, adults and adolescents ≥12 years should administer 1 or 2 sprays per nostril twice daily via intranasal route. For vasomotor rhinitis, the recommended dose is 2 sprays per nostril twice daily in adults and adolescents 12 years and older. Each spray delivers 137 mcg azelastine hydrochloride.

Adolescents

Adolescents 12 years and older follow adult dosing as above. Pediatric patients 5 to 11 years with seasonal allergic rhinitis should use 1 spray per nostril twice daily. Safety and efficacy not established in children under 5 years for allergic rhinitis and under 12 years for vasomotor rhinitis.

Special Populations

In patients with hepatic impairment, pharmacokinetics are not significantly altered, so no dose adjustment is typically necessary. Renal impairment leads to increased systemic exposure; clinical monitoring is advised. Elderly patients may require cautious dose titration due to possible decreased hepatic, renal, or cardiac function. Azelastine hydrochloride nasal spray has not been studied or recommended for use in pediatric patients younger than 5 years for allergic rhinitis or younger than 12 years for vasomotor rhinitis.

Mechanism Of Action

Azelastine hydrochloride is a selective histamine H1-receptor antagonist that exhibits its pharmacologic effects primarily through competitive inhibition of histamine at H1 receptors in nasal mucosa and other tissues. The drug exists as a racemic mixture of enantiomers that exhibit equivalent pharmacologic activity in vitro. By binding to H1 receptors, azelastine prevents histamine-induced smooth muscle contraction, increased vascular permeability, and sensory nerve activation, thus reducing nasal symptoms such as sneezing, itching, rhinorrhea, and nasal congestion characteristic of allergic and vasomotor rhinitis.

Azelastine also demonstrates additional anti-inflammatory properties, such as the inhibition of leukotriene production and reduced expression of inflammatory cytokines, contributing to its effectiveness in mitigating allergic responses. The active metabolite desmethylazelastine retains H1-antagonist activity, potentially prolonging and enhancing therapeutic effects.

At the cellular level, azelastine stabilizes mast cells and basophils, inhibiting mediator release, and interferes with eosinophil chemotaxis and activation, further attenuating allergic inflammatory processes. This dual action on histamine receptors and inflammatory pathways distinguishes azelastine from other antihistamines.

Clinically, azelastine's topical nasal administration allows localized action with reduced systemic effects compared to oral antihistamines, providing rapid relief within hours of dosing. Unlike systemic antihistamines with sedative properties, azelastine's nasal formulation limits central nervous system exposure, though somnolence may still occur in some patients. This pharmacodynamic profile supports azelastine's use in allergic rhinitis and vasomotor rhinitis symptom management.

Pharmacological Actions

Selective histamine H1-receptor antagonist activity, blocking histamine-mediated allergic responses.
Inhibition of mast cell and basophil degranulation, reducing release of inflammatory mediators.
Anti-inflammatory effects including inhibition of leukotriene synthesis and cytokine expression.
Reduction in nasal mucosal edema, sneezing, itching, and rhinorrhea.
Active metabolite desmethylazelastine possesses similar H1 antagonistic effects.
Rapid onset of action with localized effect via intranasal administration.
Minimal systemic absorption at therapeutic doses, reducing systemic side effects.
No significant effect on cardiac repolarization at therapeutic doses.

Therapeutic Clinical Uses

Treatment of symptoms of seasonal allergic rhinitis in adults and pediatric patients 5 years and older.
Management of symptoms of vasomotor rhinitis in adults and adolescents 12 years and older.
Relief of nasal congestion, sneezing, itching, and rhinorrhea associated with allergic conditions.
Used as a topical nasal antihistamine to minimize systemic adverse effects compared to oral agents.
Alternative treatment option for patients intolerant or unresponsive to oral antihistamines or intranasal corticosteroids.
Symptomatic relief of non-allergic rhinitis characterized by nasal hyperreactivity and congestion.

Side Or Adverse Effects

Bitter taste, reported in approximately 8% to 20% of patients depending on dose.
Headache occurring in up to 15% of users.
Somnolence reported in approximately 0.4% to 11.5% of patients, caution advised.
Nasal burning, irritation, or discomfort.
Pharyngitis and sore throat.
Epistaxis (nosebleeds) occurring in about 2% of patients.
Paroxysmal sneezing episodes.
Dry mouth and nausea.
Fatigue and dizziness in some patients.
Weight increase reported in rare cases.
Rare adverse effects: allergic reactions including anaphylaxis, nasal sores, and disturbances in taste or smell.
Postmarketing reports include chest pain, atrial fibrillation, confusion, and ocular symptoms such as xerophthalmia.
Rarely, dermatological reactions such as contact dermatitis or eczema.
Infrequent reports of bronchospasm, cough, and throat irritation.

Precautions

Avoid use when engaging in hazardous activities requiring full mental alertness due to possible somnolence.
Avoid concurrent use with alcohol or other central nervous system depressants to prevent additive sedation.
Prime the nasal spray before initial use and if unused for 3 or more days to ensure proper dosing.
Avoid spraying into eyes to prevent irritation.
Use caution in patients with a history of sensitivity to azelastine or formulation ingredients.
Monitor for signs of allergic reaction or local nasal irritation during use.
Breastfeeding mothers should be cautious and monitor infants for signs of milk rejection due to bitter taste.
Caution in renal impairment due to increased systemic exposure.
Start elderly patients at lower doses due to possible altered pharmacokinetics and co-morbidities.
Avoid overuse beyond recommended dosing to reduce risk of adverse effects.

Warnings

Potential for somnolence; patients should avoid driving or operating machinery if affected.
Avoid use concomitantly with alcohol or CNS depressants due to increased CNS depression risk.
No contraindications identified, but use caution in patients with known hypersensitivity.
Pregnancy Category: No identified human risk but animal studies showed fetal effects at very high doses; use only if benefits justify risks.
Do not use in children under 5 years for allergic rhinitis or under 12 years for vasomotor rhinitis due to lack of safety data.
Monitor for nasal irritation or epistaxis with prolonged use.
Proper disposal after 200 sprays to maintain dosing accuracy and avoid contamination.
Store at controlled room temperature and protect from freezing for stability.

Contraindications

No known contraindications to azelastine hydrochloride nasal spray use.

Drug Interactions

Concomitant use with alcohol or other central nervous system depressants may enhance sedation and impair cognitive and motor functions.
Co-administration with cimetidine increases azelastine plasma concentrations by approximately 65%, warranting clinical monitoring.
No significant pharmacokinetic interactions with erythromycin, ranitidine, or theophylline have been observed.
Potential additive CNS depressant effects with other sedative medications should be considered.
No reported interactions affecting cardiac QT interval at therapeutic doses.
Limited data on interactions with other antihistamines; concurrent use generally not recommended.
No significant interaction observed with commonly used nasal decongestants or corticosteroids.

Preparations Of The Drug

Azelastine hydrochloride nasal spray solution 0.1%, delivering 137 mcg azelastine hydrochloride per 0.137 mL spray.
Metered-dose nasal spray bottle containing 200 sprays per bottle.
Formulated with benzalkonium chloride as a preservative and excipients such as citric acid, sodium phosphate, edetate disodium, hypromellose, purified water, and sodium chloride.
Comes with a nasal spray pump unit fitted with a safety clip and plastic dust cover.
Available in high-density polyethylene (HDPE) bottle, stored upright at room temperature.
Dispensed as a prescription-only medication.