A Comprehensive Monograph on Azelastine (DB00972)

Executive Summary

Azelastine is a second-generation, phthalazinone-derivative antihistamine distinguished by a uniquely comprehensive pharmacological profile that extends beyond simple histamine receptor blockade.[1] Its primary clinical utility stems from a multi-modal mechanism of action that includes potent and selective histamine H1-receptor antagonism, stabilization of mast cells to prevent mediator release, and broad anti-inflammatory effects.[1] These properties make it a highly effective agent for the management of allergic rhinitis (seasonal and perennial), non-allergic vasomotor rhinitis, and allergic conjunctivitis, for which it is available in intranasal and ophthalmic formulations.[1] A key clinical advantage of Azelastine is its rapid onset of action, with intranasal formulations providing symptom relief within 15 minutes, a significant improvement over most oral antihistamines.[1]

The drug is generally well-tolerated, with the most common adverse effects being a transient bitter taste and the potential for somnolence. A critical safety consideration is the warning against concurrent use with alcohol or other central nervous system (CNS) depressants due to the risk of additive impairment.[3] Azelastine's long history of clinical use, beginning with its initial U.S. Food and Drug Administration (FDA) approval in 1996, culminated in the landmark prescription-to-over-the-counter (Rx-to-OTC) switch of its 0.15% nasal spray formulation in 2021, a testament to its robust safety and efficacy record.[2]

Beyond its established indications, Azelastine is the subject of compelling emerging research. Preclinical and early clinical studies have identified its potential as a broad-spectrum antiviral agent, showing activity against SARS-CoV-2 and other common respiratory viruses.[12] Furthermore, preliminary in vitro data suggest novel anti-cancer properties, opening new avenues for future therapeutic investigation. In conclusion, Azelastine stands as a versatile and effective therapeutic agent whose unique pharmacological properties and rapid action offer distinct advantages in the management of allergic and non-allergic nasal and ocular symptoms, with a promising future for expanded applications.

Section 1: Molecular Profile and Synthesis

This section establishes the fundamental chemical and physical identity of Azelastine, providing the foundational knowledge required to understand its pharmacological behavior.

1.1 Identification and Nomenclature

Azelastine is a small molecule drug uniquely identified in pharmacological and chemical databases by its DrugBank ID, DB00972, and its Chemical Abstracts Service (CAS) Registry Number, 58581-89-8.[1] The hydrochloride salt, which is the form used in most pharmaceutical preparations, has a distinct CAS Number of 79307-93-0.[17]

The systematic chemical name for Azelastine, according to the International Union of Pure and Applied Chemistry (IUPAC), is 4-(p-Chlorobenzyl)-2-(hexahydro-1-methyl-1H-azepin-4-yl)-1-(2H)-phthalazinone.[1] It is further defined by the Chemical Entities of Biological Interest (ChEBI) database as a phthalazine compound with specific oxo, 1-methylazepan-4-yl, and 4-chlorobenzyl substituents.[15]

Azelastine is known by numerous synonyms and international names, which facilitates its identification across diverse scientific literature and global markets. These include its international nonproprietary names (INN) in various languages such as Azelastina (Spanish), Azélastine (French), and Azelastinum (Latin).[1] It is also referenced by developmental codes like A-5610 and database-specific identifiers such as FDA UNII ZQI909440X and ChEMBL ID CHEMBL639.[2]

1.2 Physicochemical Properties

The molecular formula for the Azelastine base is C22​H24​ClN3​O, corresponding to an average molecular weight of 381.898 g/mol and a precise monoisotopic mass of 381.160790112 Da.[1] Its hydrochloride salt has the formula

C22​H25​Cl2​N3​O and a molar mass of 418.36 g/mol.[17]

Physically, Azelastine hydrochloride presents as a white to off-white, nearly odorless crystalline powder characterized by a distinct bitter taste.[15] It is sparingly soluble in water, methanol, and propylene glycol, and demonstrates slight solubility in solvents such as chloroform, dimethyl sulfoxide (DMSO), and ethanol.[15] The compound is stable under recommended storage conditions, typically between 2°C and 8°C.[15] The melting point for the base is reported as 111-115°C, while the hydrochloride salt has a significantly higher melting point of approximately 225°C.[15] Other estimated physicochemical parameters include a boiling point of 533.9°C and a pKa of 9.82.[15]

Table 1: Key Identifiers and Physicochemical Properties of Azelastine

Property	Value
DrugBank ID	DB00972
CAS Number	58581-89-8 (Base); 79307-93-0 (HCl Salt)
IUPAC Name	4-(p-Chlorobenzyl)-2-(hexahydro-1-methyl-1H-azepin-4-yl)-1-(2H)-phthalazinone
Molecular Formula	C22​H24​ClN3​O (Base); C22​H25​Cl2​N3​O (HCl Salt)
Average Molecular Weight	381.9 g/mol (Base); 418.4 g/mol (HCl Salt)
Appearance	White crystalline powder
Melting Point	~225°C (HCl Salt)
Solubility	Sparingly soluble in water, methanol
Drug Class	Histamine H1 Antagonist; Second-generation Antihistamine

1.3 Chemical Structure and Stereochemistry

Structurally, Azelastine is classified as a phthalazinone derivative.[1] Its chemical architecture is built upon a phthalazinone core, which is substituted at the 4-position with a 4-chlorobenzyl group and at the 2-position with a hexahydro-1-methyl-1H-azepin-4-yl group.[1]

Azelastine possesses a chiral center, and the drug is manufactured and administered as a racemic mixture of its two enantiomers. Importantly, extensive in vitro pharmacological studies have demonstrated no significant difference in activity between the individual enantiomers.[18] This lack of stereospecific activity simplifies its clinical pharmacology and obviates the need for complex and costly chiral separation during the manufacturing process.

1.4 Synthesis and Manufacturing Pathways

The chemical synthesis of Azelastine hydrochloride is a multi-step process that has been refined to optimize yield and purity, as detailed in patent literature.[21] A common and efficient synthetic route begins with N-Methylhexahydroazepin-4-one hydrochloride as the starting material.[22]

The key transformations in the synthesis include:

1. Acylhydrazone Formation: The initial step involves the reaction of N-Methylhexahydroazepin-4-one hydrochloride with benzoyl hydrazine to form an acylhydrazone intermediate.[21]
2. Reduction: The acylhydrazone is then subjected to a reduction reaction, typically employing a reducing agent such as potassium borohydride, to yield a reduced product.[22]
3. Acidolysis: The subsequent step is an acidolysis of the reduced intermediate, which prepares the molecule for the final condensation.[21]
4. Condensation and Salification: The final crucial step is the condensation of the acidolysis product with 2-(p-chlorobenzoyl) benzoic acid. This reaction forms the core structure of Azelastine. The resulting free base is then treated with hydrochloric acid in a salification step to produce the stable and pharmaceutically preferred Azelastine hydrochloride salt.[21]

Process optimization strategies described in patent filings focus on controlling molar ratios of reactants, maintaining specific reaction temperatures, and utilizing aqueous solvent systems during crystallization and recrystallization. These refinements are designed to effectively remove inorganic impurities and have been reported to achieve final product yields of over 95% with an HPLC purity exceeding 99.95%.[21]

Section 2: Comprehensive Pharmacological Profile

This section dissects the complex pharmacology of Azelastine, moving beyond a simple classification to explore the multiple mechanisms that underpin its clinical efficacy.

2.1 Mechanism of Action: A Multi-Modal Approach

Azelastine's clinical effectiveness is rooted in a multi-modal mechanism of action that is more complex than that of many other antihistamines. It operates through a combination of direct receptor antagonism, mast cell stabilization, and broad anti-inflammatory activity.

2.1.1 Primary Activity: Histamine H1-Receptor Antagonism

The principal pharmacological action of Azelastine is as a potent, selective, and competitive antagonist of the histamine H1-receptor.[1] It exhibits a much lower affinity for H2-receptors, ensuring its targeted effect on allergic pathways.[1] By competitively binding to H1-receptors on effector cells located in the respiratory tract, blood vessels, and sensory nerves, Azelastine directly blocks the actions of histamine.[17] This blockade prevents the downstream signaling that leads to the classic symptoms of an allergic reaction, including vasodilation (contributing to congestion), increased capillary permeability (causing runny nose and watery eyes), smooth muscle contraction, and sensory nerve stimulation (causing itching and sneezing).[6]

2.1.2 Secondary Mechanisms: Mast Cell Stabilization and Anti-inflammatory Effects

Beyond its primary function, Azelastine possesses significant secondary mechanisms that contribute to its therapeutic efficacy. It exhibits mast cell-stabilizing properties, which inhibit the degranulation process and prevent the initial release of histamine and other pre-formed inflammatory mediators from mast cells upon allergen exposure.[1] This action effectively preempts the allergic cascade before it can fully develop.

Furthermore, Azelastine demonstrates broad anti-inflammatory effects by inhibiting the synthesis and/or release of a wide array of pro-inflammatory molecules. These include newly synthesized lipid mediators like leukotrienes and platelet-activating factor (PAF), as well as cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6).[1] At a cellular level, it has been shown to reduce the migration of inflammatory cells into nasal tissue and downregulate the expression of intercellular adhesion molecule-1 (ICAM-1), a protein crucial for inflammatory cell recruitment.[4] An additional beneficial effect is its ability to increase the motility of bronchial epithelial cilia, which enhances mucociliary transport and helps clear secretions from the airways.[24]

This "triple action" profile—H1-antagonism, mast cell stabilization, and anti-inflammatory activity—provides a clear pharmacological basis for Azelastine's robust clinical performance. While standard second-generation antihistamines primarily block H1-receptors, Azelastine's additional mechanisms allow it to target the allergic response more comprehensively. This explains its superior efficacy in alleviating nasal congestion, a complex inflammatory symptom not solely driven by histamine, compared to many oral antihistamines.[7] It also provides the rationale for its approved indication in treating vasomotor rhinitis, a non-allergic condition characterized by neurogenic inflammation and mast cell degranulation where histamine is not the only mediator involved.[1] Consequently, Azelastine functions not just as an antihistamine, but as a broad-spectrum topical anti-inflammatory agent for the nasal mucosa, positioning it as a more complete treatment for rhinitis than single-mechanism drugs.

2.2 Pharmacodynamics: Onset, Duration, and Clinical Effects

A defining pharmacodynamic feature of Azelastine is its remarkably rapid onset of action, which is a key clinical differentiator. When administered as an intranasal spray, patients often experience symptom relief within 15 minutes.[1] The ophthalmic solution is even faster, with effects observed in as little as 3 minutes.[1] This speed is significantly greater than that of most oral antihistamines, which typically require 60 minutes or more to take effect.[29]

The therapeutic effects of Azelastine are also long-lasting. A single dose typically provides symptom relief for at least 12 hours, and some formulations offer up to 24 hours of control.[6] This sustained duration of action supports a convenient once or twice-daily dosing schedule, enhancing patient adherence.

2.3 Pharmacokinetics: A Detailed Analysis

2.3.1 Absorption and Bioavailability

Following intranasal administration, Azelastine is systemically absorbed with a bioavailability of approximately 40%.[1] Peak plasma concentrations (

Cmax​) are typically reached within 2 to 3 hours post-dose.[1] In contrast, systemic absorption following ocular administration is relatively low.[17] Studies have shown that at doses exceeding the recommended maximum, there are greater-than-proportional increases in both

Cmax​ and the area under the curve (AUC), suggesting that the drug's absorption or clearance may become saturated at high concentrations, leading to non-linear pharmacokinetics.[1]

2.3.2 Distribution and Protein Binding

Azelastine exhibits extensive distribution into body tissues, as indicated by its large steady-state volume of distribution (Vd​) of 14.5 L/kg.[19] Both the parent drug and its primary active metabolite, desmethylazelastine, are highly bound to plasma proteins, with binding percentages of approximately 88% and 97%, respectively.[19]

2.3.3 Metabolism: Cytochrome P450 Pathway and the Role of Desmethylazelastine

Azelastine undergoes extensive oxidative metabolism in the liver, primarily mediated by the cytochrome P450 (CYP) enzyme system.[19] While the specific P450 isoforms responsible for its biotransformation have not been definitively identified, this metabolic pathway is crucial to its clearance.[19]

The principal metabolite formed is desmethylazelastine, which is itself pharmacologically active and possesses significant H1-receptor antagonist activity.[4] At steady-state, the plasma concentrations of desmethylazelastine are substantial, ranging from 20% to 50% of the parent Azelastine concentrations, thereby contributing meaningfully to the overall therapeutic effect.[19]

2.3.4 Elimination and Half-Life

The primary route of elimination for Azelastine and its metabolites is through the feces. Following an oral radiolabeled dose, approximately 75% of the radioactivity was recovered in the feces, with less than 10% being excreted as unchanged parent drug.[1] This indicates that the drug is cleared predominantly through metabolism and/or biliary excretion.

Azelastine has a long elimination half-life (t1/2​) of approximately 22 hours.[1] The active metabolite, desmethylazelastine, has an even more prolonged half-life of 54 hours.[1] This extended presence of a pharmacologically active substance in the circulation is clinically significant. A half-life of over two days for desmethylazelastine ensures that a consistent level of H1-receptor blockade is maintained between doses, preventing breakthrough symptoms and contributing to the stable, long-lasting symptom control observed with once or twice-daily dosing. It also implies that the drug's pharmacological effects may persist for several days after discontinuation. The total plasma clearance of Azelastine is 0.5 L/h/kg.[1]

2.3.5 Pharmacokinetics in Special Populations

Studies have evaluated the pharmacokinetics of Azelastine in various populations. Following oral administration, pharmacokinetic parameters were not found to be significantly influenced by age, gender, or hepatic impairment.[19] However, in subjects with renal insufficiency (creatinine clearance <50 mL/min), the

Cmax​ and AUC were 70-75% higher compared to subjects with normal renal function, suggesting that accumulation may occur and that caution or dose adjustment may be warranted in this population.[19]

Table 2: Summary of Pharmacokinetic Parameters

Parameter	Azelastine	Desmethylazelastine (Metabolite)
Bioavailability (Intranasal)	~40%	N/A
Time to Peak Plasma Conc. (Tmax​)	2-3 hours	N/A
Volume of Distribution (Vd​)	14.5 L/kg	N/A
Plasma Protein Binding	~88%	~97%
Elimination Half-life (t1/2​)	~22 hours	~54 hours
Primary Route of Elimination	Fecal (~75%)	N/A

Section 3: Clinical Efficacy and Therapeutic Applications

This section translates the pharmacological properties of Azelastine into its real-world clinical use, supported by evidence from regulatory approvals and extensive clinical trials.

3.1 Approved Indications and Formulations

3.1.1 Allergic Rhinitis (Seasonal and Perennial)

Intranasal Azelastine is a cornerstone therapy for the symptomatic treatment of both seasonal allergic rhinitis (SAR) and perennial allergic rhinitis (PAR).[1] Its approvals span a wide range of age groups, with prescription formulations indicated for children as young as 6 months for PAR and 2 years for SAR.[1] The over-the-counter (OTC) formulation is approved for use in individuals aged 6 years and older.[1]

3.1.2 Vasomotor Rhinitis

A key feature that distinguishes Azelastine from many other antihistamines is its approved indication for the symptomatic treatment of vasomotor (non-allergic) rhinitis in patients aged 12 years and older.[1] This approval reflects its efficacy in conditions where inflammation is not driven by IgE-mediated allergic reactions.

3.1.3 Allergic Conjunctivitis

In its ophthalmic formulation, Azelastine is indicated for the treatment of ocular itching associated with allergic conjunctivitis, providing targeted relief for eye-related allergy symptoms.[1]

3.1.4 Available Formulations

Azelastine is available in several formulations to target specific sites of allergic inflammation:

• Nasal Sprays: Marketed as a metered-dose spray solution in two primary strengths: 0.1%, delivering 137 mcg per actuation, and a higher-concentration 0.15% formulation, delivering 205.5 mcg per actuation.[5]
• Ophthalmic Solution: Formulated as sterile eye drops for direct application to the conjunctiva.[1]

3.2 Dosing, Administration, and Combination Therapies

Dosing regimens for intranasal Azelastine are tailored to the patient's age and the specific indication. For adults with SAR, a typical dose is one or two sprays in each nostril, administered either once or twice daily. Pediatric dosing is generally lower, for example, one spray per nostril twice daily for children.[5]

Proper administration technique is crucial for maximizing efficacy and minimizing local side effects. Patients are instructed to prime the pump before initial use, tilt their head forward while spraying to direct the medication toward the back of the nose, and avoid sniffing too deeply. This technique helps reduce the likelihood of experiencing the drug's characteristic bitter taste.[5]

Azelastine is also a component of a highly effective fixed-dose combination therapy. Marketed under the brand name Dymista™, this nasal spray combines Azelastine with the intranasal corticosteroid (INCS) fluticasone propionate.[1] Indicated for SAR in patients 6 years of age and older, this combination has been shown in clinical trials to provide more comprehensive symptom relief than either agent used as monotherapy.[1]

3.3 Analysis of Clinical Trial Evidence

Azelastine's efficacy and safety have been established through a robust clinical development program, including numerous trials from Phase 1 to Phase 4.[41]

• Allergic Rhinitis (SAR & PAR): Large-scale, randomized, double-blind, placebo-controlled trials have consistently demonstrated the efficacy of Azelastine. A pivotal trial for the 0.15% formulation in PAR (NCT00712920) showed a statistically significant improvement in the 12-hour reflective Total Nasal Symptom Score (rTNSS) compared to placebo, with a particularly strong effect on rhinorrhea (runny nose).[27] Post-marketing (Phase 4) studies have confirmed the safety of both 0.1% and 0.15% formulations in pediatric populations as young as 6 months (NCT01880840).[42] Allergen challenge chamber studies have been used to precisely characterize its rapid onset of action (NCT04652245, NCT03004131).[44]
• Vasomotor Rhinitis: A Phase 4 study (NCT00979615) was conducted to compare the safety and efficacy of Azelastine with another intranasal antihistamine, olopatadine, specifically in the vasomotor rhinitis population.[45]
• Combination Therapy: The development of Dymista was supported by dedicated pharmacokinetic studies (NCT01194622, NCT01190852) to ensure the bioequivalence of the fixed-dose combination relative to its individual components.[43] A large Phase 3 trial (NCT00740792) definitively established that the azelastine/fluticasone combination was superior to placebo and to each of the monotherapy arms in treating SAR.[47]

3.4 Comparative Efficacy Analysis

3.4.1 Versus Oral Antihistamines

Direct comparative studies have highlighted key advantages of intranasal Azelastine over commonly used oral antihistamines.

• Onset of Action: In a head-to-head crossover study using an environmental exposure unit, Azelastine nasal spray demonstrated a statistically significant onset of action at 15 minutes. This was markedly faster than oral cetirizine (60 minutes) and oral loratadine (75 minutes), positioning Azelastine as a preferred option for patients seeking rapid symptom relief.[29]
• Overall Efficacy: In the same study, patient-rated overall efficacy for Azelastine was comparable to cetirizine and statistically superior to loratadine.[29] This is corroborated by user-reported data, where Azelastine nasal consistently receives higher average satisfaction ratings than oral loratadine and cetirizine.[48]
• Efficacy in Non-Responders: A significant finding from clinical research is Azelastine's efficacy in patients who have failed previous therapy with oral antihistamines. A multicenter, double-blind trial specifically enrolled SAR patients who remained symptomatic after a week of treatment with fexofenadine. In this population, Azelastine monotherapy provided statistically significant symptom improvement compared to placebo, establishing its value as an effective alternative or second-line treatment.[50]

3.4.2 Versus Intranasal Corticosteroids (INCS)

When compared to INCS, the standard of care for persistent allergic rhinitis, Azelastine offers a different therapeutic profile.

• Onset of Action: Azelastine's primary advantage is its much faster onset of action, providing relief in minutes, whereas INCS can take hours or even days to achieve their maximal effect.[7]
• Efficacy: While INCS are highly effective, particularly for nasal congestion, studies have shown Azelastine to have at least comparable efficacy to fluticasone propionate and, in some cases, superior efficacy to mometasone furoate.[7]
• Synergistic Combination: The most compelling evidence lies in combination therapy. The fixed-dose combination of Azelastine and fluticasone propionate (Dymista) consistently demonstrates greater efficacy in controlling nasal symptoms than either agent used alone. This synergy provides a powerful therapeutic option for patients with moderate-to-severe AR or those who are inadequately controlled on monotherapy.[4]

Table 3: FDA-Approved Indications and Dosing Regimens by Age and Formulation

Formulation	Indication	Approved Age Range	Recommended Dosage
Astelin® (0.1%)	Seasonal Allergic Rhinitis (SAR)	5 to 11 years	1 spray per nostril twice daily
Astelin® (0.1%)	Seasonal Allergic Rhinitis (SAR)	≥12 years	1 or 2 sprays per nostril twice daily
Astelin® (0.1%)	Vasomotor Rhinitis (VMR)	≥12 years	2 sprays per nostril twice daily
Astepro® (0.1%)	Perennial Allergic Rhinitis (PAR)	6 months to 5 years	1 spray per nostril twice daily
Astepro® (0.1%)	Seasonal Allergic Rhinitis (SAR)	2 to 5 years	1 spray per nostril twice daily
Astepro® Allergy (0.15%)	SAR / PAR	6 to 11 years	1 spray per nostril twice daily
Astepro® Allergy (0.15%)	SAR / PAR	≥12 years	1-2 sprays/nostril twice daily OR 2 sprays/nostril once daily
Dymista® (Azelastine/Fluticasone)	Seasonal Allergic Rhinitis (SAR)	≥6 years	1 spray per nostril twice daily

Section 4: Safety, Tolerability, and Risk Management

This section provides a comprehensive assessment of Azelastine's safety profile, focusing on common adverse effects, critical warnings, and the extensive potential for drug-drug interactions.

4.1 Profile of Adverse Drug Reactions

Azelastine is generally well-tolerated, but is associated with a distinct profile of adverse drug reactions (ADRs).

• Most Common ADRs: The most frequently reported side effects across numerous clinical trials and post-marketing surveillance are a bitter taste (dysgeusia), headache, somnolence (drowsiness), and local nasal irritation, such as a burning sensation.[3]
• Incidence Rates: The incidence of these effects can vary by formulation. The bitter taste was particularly prominent with the original Astelin (0.1%) formulation, reported by up to 20% of users.[55] This issue was addressed in the newer Astepro formulations, which include taste-masking agents like sucralose, reducing the incidence of dysgeusia to approximately 4-6%.[3] Somnolence is reported in a significant minority of patients, with rates around 12-16% in some user-reported datasets, though controlled trials have sometimes reported rates closer to placebo (~2%).[3]
• Other Reported Side Effects: A broader range of less common side effects has been documented. These include epistaxis (nosebleeds), pharyngitis (sore throat), paroxysmal sneezing, nausea, dry mouth, fatigue, and dizziness.[8] Infrequently (<2% incidence), reactions affecting various organ systems have been reported, including cardiovascular (tachycardia), dermatological (contact dermatitis), psychological (anxiety, depression), and respiratory (cough, bronchospasm) events.[9]

4.2 Warnings, Precautions, and Contraindications

The labeling for Azelastine includes several important warnings and precautions to ensure its safe use.

• Primary Warning: Somnolence and CNS Depression: The most significant safety concern is the potential for somnolence and impairment of mental alertness. All product labeling carries a prominent warning cautioning patients against engaging in hazardous occupations that require complete mental alertness and motor coordination, such as driving a motor vehicle or operating machinery, after administration.[9]
• Interaction with CNS Depressants: Concurrent use of Azelastine with alcohol or other CNS depressant medications (e.g., sedatives, tranquilizers, opioids, muscle relaxants) must be avoided. This combination can lead to additive reductions in alertness and further impairment of CNS performance, increasing the risk of accidents.[9]
• Contraindications: The only absolute contraindications identified are hypersensitivity to Azelastine or any of its components and the co-administration of potent sedative-hypnotics like sodium oxybate, where the pharmacodynamic synergism can lead to profound and dangerous CNS depression.[25]
• Use in Pregnancy and Lactation: Azelastine is classified as Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women, and animal reproduction studies have shown adverse effects on the fetus.[3] Therefore, it should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.[8] It is not known for certain if Azelastine passes into human breast milk, but it is a possibility, so caution is advised for nursing mothers.[8]

While classified as a second-generation antihistamine—a group generally known for reduced sedative effects due to limited penetration of the blood-brain barrier (BBB)—Azelastine carries a notable risk of CNS depression. This distinction arises from its pharmacokinetic profile. The systemic bioavailability of intranasal Azelastine is substantial, at approximately 40%.[3] This means a significant portion of the administered dose enters the bloodstream and is distributed throughout the body. Consequently, enough Azelastine and its active metabolite can cross the BBB to induce clinically relevant somnolence in a subset of patients. This inherent risk is amplified to a dangerous level when combined with other CNS depressants, making the warning against co-administration with substances like alcohol a critical risk management point for clinicians and a crucial counseling topic for patients.

4.3 Comprehensive Review of Drug-Drug Interactions

Azelastine has a significant number of potential drug-drug interactions, primarily centered on its CNS depressant effects and its metabolism.

• Major Interactions: There are 3 identified major interactions, which are with sedative-hypnotics such as sodium oxybate. These combinations are contraindicated due to the high risk of synergistic and life-threatening CNS depression.[58]
• Moderate Interactions (Pharmacodynamic): The largest category, comprising over 200 moderate interactions, involves other drugs with CNS depressant properties. This includes a wide range of medication classes: opioids, benzodiazepines, barbiturates, muscle relaxants, tricyclic antidepressants, and other sedating antihistamines. The interaction is pharmacodynamic in nature, resulting in an additive effect that can cause excessive sleepiness, dizziness, and impaired cognitive and motor function.[25]
• Metabolic Interactions (Pharmacokinetic): As Azelastine is metabolized by the CYP450 system, there is potential for pharmacokinetic interactions.
• CYP Inhibition: Cimetidine, a non-specific CYP inhibitor, was shown in a clinical study to increase mean Azelastine concentrations by approximately 65%, suggesting that co-administration with potent CYP inhibitors should be done with caution.[5]
• CYP3A4 Pathway: While the specific isoforms are not fully identified, some data suggest a role for CYP3A4. Azelastine may increase the levels of certain CYP3A4 substrates.[58] However, clinical studies with the potent CYP3A4 inhibitor erythromycin and the H2-antagonist ranitidine did not show a significant pharmacokinetic interaction, indicating that the metabolic pathway may be complex or involve multiple enzymes, making it less susceptible to inhibition by single-pathway inhibitors.[19]

Section 5: Regulatory and Commercial Landscape

This section traces the regulatory journey and market presence of Azelastine, highlighting key milestones that have shaped its clinical use and accessibility.

5.1 Regulatory Approval History: A Timeline (FDA and EMA)

Azelastine has a long and well-documented regulatory history in the United States, marked by a series of approvals for new formulations, expanded indications, and different patient populations.

• November 1, 1996: The U.S. FDA granted initial approval to Azelastine under the brand name Astelin (NDA 020114). This first approval was for the treatment of seasonal allergic rhinitis (SAR) in patients aged 12 years and older.[2]
• October 15, 2008: To address the significant issue of the drug's bitter taste, a new formulation containing a sweetening agent was developed. This product, Astepro 0.10% (NDA 022203), was approved by the FDA.[36]
• September 2, 2009: A higher-strength 0.15% formulation of Astepro was approved, offering the convenience of a once-daily dosing option for SAR.[60]
• May 1, 2012: The FDA approved Dymista (NDA 202236), a fixed-dose combination nasal spray containing Azelastine and the corticosteroid fluticasone propionate, for the treatment of SAR.[39]
• 2013-2015: The indications for Astepro were progressively expanded to younger pediatric populations. Approvals were granted for SAR and perennial allergic rhinitis (PAR) down to the age of 6 years in 2013, and further extended in 2015 to include SAR in children aged 2-6 years and PAR in children aged 6 months to less than 6 years.[36]

In Europe, while Azelastine monotherapy is widely available [15], the European Medicines Agency (EMA) regulatory documentation focuses heavily on the combination product with fluticasone (Dymista). A paediatric investigation plan (PIP) for this combination was formally agreed upon on April 6, 2011, to guide its development for use in children.[62] The product has since been registered in numerous EU member states through decentralized procedures, such as in the Netherlands in 2014.[64] The EMA continues to monitor its safety through periodic safety update reports (PSURs).[65]

5.2 The Rx-to-OTC Switch: Rationale and Impact

A pivotal event in Azelastine's history occurred on June 17, 2021, when the FDA approved the 0.15% strength of Azelastine hydrochloride nasal spray, now branded as Astepro Allergy, for over-the-counter (OTC) sale. This approval covers the treatment of SAR and PAR in adults and children aged 6 years and older.[10]

This decision was a first-in-class Rx-to-OTC switch, making Azelastine the first and only antihistamine nasal spray available directly to consumers in the U.S..[10] The approval was designated as a "partial switch" because the 0.1% strength and the indications for younger pediatric populations (6 months to <6 years) remain available by prescription only. This reflects a nuanced, risk-based regulatory approach that reserves medical oversight for the most vulnerable patient groups.[10]

The Rx-to-OTC switch represents the culmination of Azelastine's product lifecycle and serves as a powerful validation of its long-term safety and efficacy profile. The FDA's switch process requires an extensive body of evidence demonstrating that a medication can be used safely and effectively by the general public for self-medication without the direct supervision of a healthcare provider.[10] The approval of Astepro Allergy signifies that after reviewing 25 years of clinical trial data and post-marketing surveillance, the FDA concluded that for patients aged 6 and older, the benefits of increased access outweighed the manageable risks of somnolence and bitter taste. This decision has fundamentally altered Azelastine's place in the allergy treatment landscape, transforming it from a prescription product into a mainstream consumer health option that competes directly with oral OTC antihistamines and intranasal steroids.

5.3 Global Formulations and Brand Names

Azelastine is marketed globally under a variety of brand names.

• United States: The most common brand names are Astelin, Astepro (prescription), Astepro Allergy (OTC), Optivar (ophthalmic solution), and Dymista (combination product with fluticasone).[1]
• International Markets: In Europe and other regions, it is known by names such as Allergodil, Lastin, Afluon, and Rhino1ast.[7]

Section 6: Emerging Research and Future Directions

This forward-looking section explores the investigational uses of Azelastine beyond its established indications, highlighting its potential for drug repurposing in novel therapeutic areas.

6.1 Investigational Antiviral Properties

Recent research has unveiled a promising new application for Azelastine as a potential broad-spectrum antiviral agent. This line of inquiry began with computational drug repurposing models that identified Azelastine as a candidate for inhibiting SARS-CoV-2 infection.[12]

Subsequent in vitro laboratory studies have validated this prediction. Azelastine was shown to effectively reduce the virus-induced cytopathic effect and lower viral RNA copy numbers in infected cell cultures (Vero E6 cells) with a half-maximal effective concentration (EC50​) in the low micromolar range (2.2–6.5 µM). Crucially, this antiviral potency was maintained across major SARS-CoV-2 variants of concern, including Alpha, Beta, Delta, and Omicron (BA.1).[12] The effect was also demonstrated in more clinically relevant models using reconstituted human nasal tissue.[12] This preclinical work led to a Phase 2 clinical study, which provided the first human evidence that an azelastine-containing nasal spray could significantly accelerate viral clearance from the nasopharynx of SARS-CoV-2 positive individuals.[12]

Further investigation has expanded these findings, revealing that Azelastine's antiviral activity is not limited to coronaviruses. It also inhibits the replication of other common respiratory pathogens, including seasonal human coronavirus 229E, Respiratory Syncytial Virus (RSV), and Influenza A (H1N1).[14]

This emerging body of evidence for broad-spectrum antiviral activity suggests a potential paradigm shift in the utility of Azelastine. Its existing formulation as a nasal spray delivers the drug directly to the nasal mucosa, the primary site of initial colonization and replication for most respiratory viruses. This localized delivery, combined with its well-established safety profile and OTC availability in some regions, makes it an attractive candidate for rapid deployment as a non-specific prophylactic or early treatment measure. The mechanism is likely independent of its antihistamine effects and may target a host-cell pathway or a viral process common to multiple pathogens. If these findings are confirmed in larger, more definitive clinical trials, Azelastine could be repurposed from a symptomatic allergy treatment into a vital public health tool for reducing viral load, limiting disease progression, and potentially decreasing community transmission of respiratory infections.

6.2 Preclinical Evidence for Anti-Cancer Activity

In another distinct area of research, preliminary preclinical studies have uncovered novel anti-cancer properties of Azelastine. In vitro experiments using human cervical cancer (HeLa) cells demonstrated that Azelastine exerts multidirectional anti-cancer effects at concentrations between 45–90 µM.[13]

The observed mechanisms included the induction of apoptosis (programmed cell death) through the activation of caspases 3 and 7, the promotion of DNA damage, and the arrest of the cell cycle in the S phase. Furthermore, Azelastine was found to induce mitotic catastrophe, a form of cell death resulting from aberrant mitosis. These cytotoxic and anti-proliferative effects highlight a previously unknown biological activity of the molecule.[13] While these findings are at a very early, preclinical stage, they suggest that the pharmacological profile of Azelastine may be more complex than previously understood and could warrant further investigation for potential applications in oncology, possibly as an adjunct in combination therapy regimens.

6.3 Novel Combination Therapies and Off-Label Considerations

Research continues to explore ways to optimize the use of Azelastine in its primary field of rhinitis treatment. Beyond the successful combination with fluticasone, studies are investigating combinations with other intranasal corticosteroids, such as mometasone and budesonide. These alternatives may offer different benefit-to-risk profiles or prove more effective for specific patient subgroups.[70]

The concept of triple-agent therapy is also being explored. One clinical study evaluated a combination of azelastine, the corticosteroid triamcinolone, and the vasoconstrictor oxymetazoline. Patients rated this triple combination as superior for the relief of sinus pressure, suggesting a role for such multi-mechanism approaches in treating complex sinonasal symptoms.[70] Additionally, clinical evidence has shown that Azelastine is effective in managing mixed rhinitis—a condition where patients exhibit both allergic and non-allergic triggers—which can often be challenging to treat with single-agent therapies.[7]

Conclusion and Expert Recommendations

Azelastine is a well-established second-generation antihistamine whose clinical value is significantly enhanced by a unique multi-modal pharmacology, encompassing mast cell stabilization and broad anti-inflammatory effects. This complex mechanism of action underpins its proven efficacy in treating not only allergic rhinitis and conjunctivitis but also non-allergic vasomotor rhinitis.

Its primary clinical advantage is its rapid onset of action, which provides a clear therapeutic benefit over slower-acting oral antihistamines and intranasal corticosteroids for patients requiring acute symptom control. The drug possesses a favorable long-term safety profile, a fact underscored by the successful Rx-to-OTC switch of its 0.15% nasal spray formulation. However, the risk of somnolence and the absolute necessity of avoiding co-administration with other CNS depressants, including alcohol, remain the most critical risk management and patient counseling points for all formulations.

The future outlook for Azelastine is exceptionally promising. The most compelling new direction lies in the clinical validation of its broad-spectrum antiviral properties. If confirmed in large-scale trials, Azelastine nasal spray could be repurposed as a crucial, readily accessible public health tool for the prophylaxis and early treatment of a wide range of respiratory viral infections.

Based on the comprehensive evidence, the following recommendations are made:

1. Clinical Practice: Azelastine nasal spray should be considered a first-line therapeutic option for patients with allergic or vasomotor rhinitis who prioritize or require rapid relief of their symptoms. The fixed-dose combination with fluticasone propionate (Dymista™) represents a superior choice for patients with moderate-to-severe symptoms or those who are inadequately controlled on monotherapy.
2. Patient Counseling: Healthcare providers must emphasize the potential for somnolence and strongly advise patients to avoid alcohol and other CNS depressants while using Azelastine. Proper administration technique should also be taught to minimize the common side effect of bitter taste.
3. Future Research: The potential antiviral application of Azelastine warrants high-priority, large-scale clinical investigation to confirm its efficacy in preventing and treating respiratory viral infections in a real-world setting. Further exploration of novel combination therapies and its preliminary anti-cancer signals may also yield new and valuable therapeutic applications.

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