Azelastine

Azelastine, first granted approval in 1996, is a histamine H1-receptor antagonist used to treat allergic and vasomotor rhinitis, as well as allergic conjunctivitis. [1] Owing to the broad spectrum of anti-inflammatory and anti-allergic activity, Azelastine can alleviate sneezing, nasal itching, runny nose, nasal congestion, and other symptoms.[2-4]

Pharmacological Class: Antihistamine [1]

Azelastine is indicated to treat symptoms of:

• Vasomotor rhinitis in adults and adolescent patients ≥12 years
• Seasonal allergic rhinitis in pediatrics and adult patients ≥5 years [5]
• Itchy eyes associated with allergic conjunctivitis [1]

The phthalazine derivative Azelastine is principally a selective antagonist of histamine H1-receptors, with a reduced affinity for H2-receptors, and is used for symptomatic management of allergies. Histamine H1-receptors are present on glandular cells, smooth muscle cells, and nerve terminals. The immunoglobulin E-receptor (IgE-receptor) cross-linking on mast cells causes histamine to be produced following allergen exposure in persons with sensitization. Histamine binds to H1-receptors and triggers allergic symptoms (for example: congestion, sneezing, and itching).

Azelastine seems to influence other mediators of allergy symptomatology even though its key mechanism of action is assumed to be via H1-receptor antagonism. Azelastine has been reported to have mast cell-stabilizing activity that restricts release of interleukin-6, tryptase, histamine, and tumor necrosis factor (TNF)-alpha from mast cells. Furthermore, it lowers mediators of mast cell degranulation like leukotrienes in nasal lavage of people suffering from rhinitis. By suppressing phospholipase A2 and leukotriene C4 synthase, it prevents them from being produced and released by eosinophils. [1]

• For intranasal use
• Seasonal allergic rhinitis:

(a) Children between the ages of 5 and 11 years: Twice daily, one spray per nostril

(b) Adults and adolescents ≥12 years: 1 or 2 sprays twice a day per nostril

• Adolescents and adults ≥12 years should apply 2 sprays per nostril twice a day for vasomotor rhinitis
• Before the first usage and when it has not been used for three days or longer, Azelastine nasal spray should be primed [5]

Absorption

Following intranasal use, Azelastine hydrochloride has a systemic bioavailability of around 40% and reaches maximum concentration (Cmax) in 2-3 hours. In both Cmax and area under the curve (AUC), greater than proportional rise were seen when provided at dosages above the maximum dose suggested.

Volume of distribution

Azelastine's steady-state volume of distribution following intravenous and oral dosing is 14.5 L/kg.

Protein binding

Azelastine and desmethylazelastine had plasma protein binding of around 88% and 97%, respectively, according to in-vitro tests on human plasma.

Metabolism

The cytochrome P450 (CYP) enzyme system converts Azelastine hydrochloride into its primary and biologically active metabolite, desmethylazelastine. Although Azelastine labels mention that the specific CYP enzyme implicated has not been determined, it has been recommended that CYP3A4, CYP2D6, and CYP1A2 are principally responsible for the N-demethylation of Azelastine.

Route of elimination

Approximately 75% of radiolabeled Azelastine hydrochloride taken orally was eliminated in the stool, leaving fewer than 10% of the drug unaltered.

Half-life

Azelastine showed elimination half-life of 22 hours based on intravenous and oral dosing. Desmethylazelastine, its main active metabolite, exhibits elimination half-life of 54 hours.

Clearance

It showed a plasma clearance of 0.5 L/h/kg based on intravenous and oral dosing. [1]

None [5]

Central Nervous System Depressants: Depressants for central nervous system or alcohol should not be used concurrently with Azelastine. This is because these interactions may reduce alertness and influence central nervous system functioning. [5]

The most commonly noted side effects are:

• Bitter taste
• Weight gain
• Dizziness
• Fatigue
• Dry mouth
• Nausea paroxysmal
• Sneezing
• Dysesthesia
• Rhinitis
• Nasal burning
• Pharyngitis
• Epistaxis
• Sinusitis
• Headache
• Somnolence [5]

• Somnolence: Getting engaged in risky activities (like driving or operating a machinery) that demand total mental attention should be avoided while using Azelastine
• Pregnancy: Azelastine should be used with caution in pregnant women as it may cause fetal harm [5]

Efficacy, Safety and Tolerability of Azelastine in patients with allergic rhinitis

In a meta-analysis of randomized controlled studies headed by Lee TA et al, Azelastine nasal spray was shown to be more effective than placebo in treating allergic rhinitis in terms of total symptom score. [6] Another study explored efficacy of Azelastine for treating symptoms of seasonal allergic rhinitis. Patients with seasonal allergic rhinitis participated in a 14-day, placebo-controlled, randomized, double-blind research. When compared to placebo, once-daily administration of Azelastine 0.15% nasal spray reduced a variety of nasal and ocular symptoms. [7]  

Azelastine nasal spray is an effective monotherapy for people who still experience symptoms after receiving fexofenadine, and it should be taken into consideration in the initial management of patients with moderate-to-severe seasonal allergic rhinitis, according to a multicenter, randomized, double-blind, placebo-controlled, 2-week study. [8]

Another open-label study by Lieberman P et al. sought to examine Azelastine nasal spray's effectiveness to relieve symptoms of nonallergic vasomotor rhinitis, seasonal allergic rhinitis, and seasonal allergic rhinitis with nonallergic triggers (mixed rhinitis). Regardless of rhinitis diagnosis during the 2-week trial period, the second-generation antihistamine Azelastine aided to manage all rhinitis symptoms, including nasal congestion. [9]

A randomized, double-blind, parallel-group clinical investigation showed that 0.15% Azelastine nasal spray at 2 sprays/nostril twice a day was well-tolerated and remarkably reduced the nasal symptoms associated with seasonal allergic rhinitis. [10]

Azelastine vs. Desloratadine in people with allergen-induced seasonal allergic rhinitis

Azelastine nasal spray illustrated superior efficacy than Desloratadine tablets and placebo in a randomized, double-blind experiment carried out by Horak F et al. The decline in Total Nasal Symptom Score (TNSS) and Major Nasal Symptom Score (MNSS) was fastest following Azelastine therapy. For all nasal symptoms, including nasal congestion, Azelastine therapy resulted in a significant reduction in symptom severity. [11]

Azelastine vs. Mometasone furoate in seasonal allergic rhinitis patients

A research compared the onset of action and efficacy of Azelastine hydrochloride nasal spray to those of placebo and Mometasone furoate (an intranasal steroid) in individuals diagnosed with seasonal allergic rhinitis. Azelastine nasal spray demonstrated marked improvement in TNSS at 15 minutes when compared to placebo. Azelastine was found to be superior to both placebo and Mometasone nasal spray in minimizing nasal symptoms occurring within eight hours following allergen challenge. [12]

1. Azelastine. Drug Bank. Accession Number DB00972. Available online from: https://go.drugbank.com/drugs/DB00972 [Last accessed on: 24 June 2022]
2. Lieberman PL, Settipane RA. Azelastine nasal spray: a review of pharmacology and clinical efficacy in allergic and nonallergic rhinitis. Allergy and Asthma Proceedings. 2003 Mar-Apr;24(2):95-105
3. Zheng Q, Ma D, Zhu Q, Tang S, Chen C. Effect of azelastine hydrochloride combined with montelukast sodium in the treatment of patients with allergic rhinitis. American Journal of Translational Research. 2021 Aug 15;13(8):9570-9577.
4. Horak F. Effectiveness of twice daily azelastine nasal spray in patients with seasonal allergic rhinitis. Ther Clin Risk Manag. 2008 Oct;4(5):1009-22.
5. Azelastine. FDA LABEL. Available online from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/020114s026lbl.pdf [Last accessed on: 24 June 2022]
6. Lee TA, Pickard AS. Meta-analysis of azelastine nasal spray for the treatment of allergic rhinitis. Pharmacotherapy. 2007 Jun;27(6):852-9.
7. Howland WC, Amar NJ, Wheeler W, Sacks H. Efficacy and safety of azelastine 0.15% nasal spray administered once daily in patients with allergy to Texas mountain cedar pollen. International Forum of Allergy & Rhinology. 2011 Jul-Aug;1(4):275-9.
8. LaForce CF, Corren J, Wheeler WJ, Berger WE; Rhinitis Study Group. Efficacy of azelastine nasal spray in seasonal allergic rhinitis patients who remain symptomatic after treatment with fexofenadine. Annals of Allergy, Asthma & Immunology. 2004 Aug;93(2):154-9.
9. Lieberman P, Kaliner MA, Wheeler WJ. Open-label evaluation of azelastine nasal spray in patients with seasonal allergic rhinitis and nonallergic vasomotor rhinitis. Current Medical Research and Opinion. 2005 Apr;21(4):611-8.
10. Shah S, Berger W, Lumry W, La Force C, Wheeler W, Sacks H. Efficacy and safety of azelastine 0.15% nasal spray and azelastine 0.10% nasal spray in patients with seasonal allergic rhinitis. Allergy & Rhinology (Providence). 2010 Jan 1;1(1):7.
11. Horak F, Zieglmayer UP, Zieglmayer R, Kavina A, Marschall K, Munzel U et al. Azelastine nasal spray and desloratadine tablets in pollen-induced seasonal allergic rhinitis: a pharmacodynamic study of onset of action and efficacy. Curr Med Res Opin. 2006 Jan;22(1):151-7.
12. Patel P, D'Andrea C, Sacks HJ. Onset of action of azelastine nasal spray compared with mometasone nasal spray and placebo in subjects with seasonal allergic rhinitis evaluated in an environmental exposure chamber. American Journal of Rhinology. 2007 Jul-Aug;21(4):499-503.