---
title: "Adverse reactions to azelastine and levocabastine: descriptive analysis from WHO VigiAccess"
id: "plos-one-7-characterization-of-adverse-reactions-to-two-antihistamine-drugs-a-descriptive"
canonical_url: "https://medichelpline.com/clinical-feed/plos-one-7-characterization-of-adverse-reactions-to-two-antihistamine-drugs-a-descriptive"
content_type: "clinical_feed_article"
specialty: "Pharmacology"
source_name: "PLOS ONE (Medicine)"
source_url: "https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0355852"
published_at: "2026-08-12T14:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Adverse reactions to azelastine and levocabastine: descriptive analysis from WHO VigiAccess
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/plos-one-7-characterization-of-adverse-reactions-to-two-antihistamine-drugs-a-descriptive
- **Specialty:** [Pharmacology](https://medichelpline.com/clinical-feed/pharmacology.md)
- **Primary Source:** PLOS ONE (Medicine)
- **Source URL:** [Original Journal Publication](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0355852)
- **Published At:** 2026-08-12T14:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- This study used the WHO **VigiAccess** spontaneous reporting database to describe adverse drug reactions (ADRs) associated with two intranasal/ocular second‑generation **antihistamines**, **azelastine** and **levocabastine**. - A retrospective descriptive analysis captured global patient demographics and system‑organ class (SOC) level ADR reports for the two drugs from VigiAccess; reporting rates were calculated for comparison. - In total, 11,592 adverse events related to azelastine and levocabastine were reported over the study period. - The most frequently reported SOC categories across both drugs were **General disorders and administration site conditions**, **Nervous system disorders**, **Gastrointestinal disorders**, **Respiratory disorders**, and **Injury, poisoning and procedural complications**. - Absolute counts for the top five SOC categories were reported: General disorders (4,463; 36.7%), Nervous system (3,475; 28.6%), Gastrointestinal (1,558; 12.8%), Respiratory (1,515; 12.5%), and Injury/poisoning (871; 7.2%). - Azelastine had a higher proportion of reports classified as **Nervous system disorders**; levocabastine showed higher proportions in **endocrine disorders**, **injury/poisoning/procedural complications**, and **Nervous system disorders** relative to azelastine. - For SOC‑level ADRs with incidence above 10%, the report notes 2 such SOCs for azelastine and 4 for levocabastine. - The authors note that spontaneous reporting systems have limitations (underreporting, reporting bias, limited clinical detail) and that real‑world pharmacovigilance complements pre‑marketing trials. - The study aims to inform clinicians about common and drug‑specific ADR patterns to support safer, individualized selection between **azelastine** and **levocabastine**. - Full methodological details, individual demographic breakdowns, and complete tables/figures are reported in the original article; data availability is stated as included within the article.
## Clinical Analysis & Structured Key Points
Characterization of adverse reactions to two antihistamine drugs: A descriptive analysis from WHO-VigiAccess | PLOS One Browse Subject Areas ? Click through the PLOS taxonomy to find articles in your field. For more information about PLOS Subject Areas, click here . Article Authors Metrics Comments Media Coverage Peer Review Reader Comments Figures Figures Abstract Introduction Antihistamines like azelastine and levocabastine are key in treating allergies, including allergic rhinitis, conjunctivitis, and urticaria. This study analyzed adverse drug reactions linked to these drugs using data from the WHO VigiAccess database, comparing their adverse drug reaction profiles to help physicians choose lower-risk options for personalized treatment. Methods A retrospective descriptive analysis was used, with data from WHO-VigiAccess on azelastine and levocabastine. Included were global patient demographics (age, gender, location) and details on illness systems/symptoms from direct and annual adverse drug reaction reports. Adverse drug reaction percentages for each drug were calculated for comparison. Results Over the study period, 11,592 adverse events related to both drugs were reported. Both had high rates of General disorders and administration site conditions. Azelastine showed more Nervous system disorders. Levocabastine had higher rates of endocrine disorders, injury/poisoning/procedural complications, and Nervous system disorders. The top five adverse events were: General disorders (4463, 36.7%), Nervous system (3475, 28.6%), Gastrointestinal (1558, 12.8%), Respiratory (1515, 12.5%), and Injury/poisoning (871, 7.2%). For SOC-reported ADRs, > 10% incidence occurred in 2 azelastine cases and 4 levocabastine cases. Conclusion Clinicians should note antihistamine ADRs. This study identifies common and specific reactions reported to the WHO, aiming to guide safer, more judicious use of these drugs. Citation: Li Y, Zhu J, Guo Q, Liao J, Li L, Hu J, et al. (2026) Characterization of adverse reactions to two antihistamine drugs: A descriptive analysis from WHO-VigiAccess. PLoS One 21(8): e0355852. https://doi.org/10.1371/journal.pone.0355852 Editor: Rajeev Singh, Satyawati College, University of Delhi, INDIA Received: August 18, 2025; Accepted: July 27, 2026; Published: August 12, 2026 Copyright: © 2026 Li et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability: The study’s original contributions are included in the article. Funding: This research was partially funded by the National Natural Science Foundation of China (82071023), the Key Project of Medical Science and Technology of Henan Province (SBGJ202102160), and the Scientific Research Project of Colleges and Universities in Henan Province (21A320053). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: The authors have declared that no competing interests exist. Introduction Allergic rhinitis (ARs) is a prevalent chronic inflammatory condition with a global prevalence of up to 40%, exhibiting a rising trend in recent years, making it a significant global public health issue [ 1 – 3 ]. It usually manifests as runny nose, nasal congestion, sneezing, itchy nose, itchy eyes, and itchy throat, and so on [ 3 ]. Clinically, nasal mucosal congestion, increased secretion of nasal contents, as well as pale edema of the turbinates, can be observed [ 4 ]. This condition significantly impacts the patient’s quality of life and physical and mental health [ 5 ]. ARs episodes usually exhibit a seasonal or intermittent pattern and are highly prevalent in seasons when allergens (e.g., pollen, willow, dust mites, molds, and so on) increase. During pathogenesis, allergens entering the nasal cavity stimulate the nasal mucosa, penetrating the epithelial barrier, which are then taken up and processed by antigen-presenting cells [ 5 ]. This leads to the differentiation of naïve T cells into Th2 helper T cells capable of releasing cytokines (e.g., IL-4, IL-5). This results in the generation of B cells with allergen-specific IgE that bind to high-affinity IgE receptors on mast cells, Langerhans cells, monocytes, and basophils. Upon subsequent encounters with the allergen, the associated antigenic determinant cluster (i.e., a 7–8 amino acid peptide) is recognized by the IgE molecule in the region of the specific IgE antigen-binding site (which binds to mast cells and basophils), resulting in mast cell activation and release of biologically active mediators, such as histamine, leukotrienes, and platelet-activating factor. Binding of these mediators to receptors on blood vessels, mucus-secreting glands, and sensory nerves induces physiologic responses associated with ARs symptoms [ 6 – 9 ] ( Fig 1 ). Effective treatment strategies encompass the use of mast cell stabilizers, antihistamines, glucocorticoids (GCS), leukotriene receptor antagonists, and nasal decongestants [ 10 , 11 ]. The combination therapy most frequently employed, involving nasal GCS administration and antihistamines, is currently regarded as the most effective treatment option [12]. Download: PNG larger image TIFF original image Fig 1. Pathogenesis of allergic rhinitis. Allergens penetrating the nasal epithelial barrier are taken up by antigen-presenting cells, which promote the differentiation of naive T cells into Th2 cells. Th2-derived cytokines drive allergen-specific IgE production by B cells. IgE binds to high-affinity receptors on mast cells and basophils. Upon allergen re-exposure, IgE cross-linking triggers mast cell degranulation and the release of mediators such as histamine, leukotrienes, and platelet-activating factor, which act on blood vessels, mucus glands, and sensory nerves to produce AR symptoms. https://doi.org/10.1371/journal.pone.0355852.g001 Histamine exerts a significant role in the pathogenesis of AR. In the early allergic immune response, elevated mast cell activity leads to the release of histamine, that binds to H1 receptors on nasal mucosal epithelial cells, mediating increases in vascular permeability and a lowering of the epithelial barrier, bronchial smooth muscle contraction, and the recruitment of inflammatory factors [ 12 , 13 ]. Antihistamines such as azelastine and levocabastine are capable of inhibiting histamine-mediated allergic reactions through competitive binding to the H1 receptor with histamine, thus achieving therapeutic effects [ 14 ]. Azelastine, a phthalazinone derivative, is a second‑generation antihistamine and a selective H1‑receptor antagonist. It exhibits unique pharmacological properties by inhibiting the synthesis and/or expression of various chemical mediators of allergic reactions [ 15 ], such as leukotrienes, kallikreins, cytokines, chemokines, and superoxide radicals [ 16 , 17 ]. Levocabastine is also a second‑generation antihistamine and a selective, long‑acting H1‑receptor antagonist administered via the nasal and ocular routes. In controlled trials, levocabastine has been shown to be both efficacious and well‑tolerated in the treatment of AR and allergic conjunctivitis [ 18 , 19 ]. Clinically utilized antihistamine nasal sprays have undergone numerous animal and clinical trials leading to their clinical use. While offering therapeutic benefits, side effects are inevitable. Clinical evidence indicates that first-generation antihistamines cross the blood-brain barrier and have sedative and drying effects on patients. Second-generation antihistamines generally exhibit better tolerability and have reduced sedative and drying effects. Intranasal antihistamines may result in hyperemia and desiccation of the nasal mucosa, with epistaxis and, in some cases, headache. Other drugs for ARs, such as leukotriene modulators (e.g., montelukast), have been linked to anxiety, depression, and nightmares in some patients. Cortisol drugs also commonly induce adverse effects such as nosebleeds, and in a few patients, nasal ulcers and septal ulcers [ 20 ]. While all marketed drugs are subject to rigorous clinical trials and long-term adjustments, the sample size in such experiments is inherently limited, and it cannot fully anticipate all the symptoms that may occur when the drug is used in various types of patients, nor predict interactions with other medications in patients with multiple comorbidities [ 21 ]. Thus, more study is warranted on drug safety evaluation based on big, real-world sample data. This study identified two antihistamine nasal sprays approved by the U.S. Food and Drug Administration (FDA) for the treatment of AR, including azelastine and levocabastine. A descriptive analysis of spontaneously reported adverse drug reactions (ADRs) in VigiAccess was carried out, and the reporting rates of adverse responses between the two pharmaceuticals were compared, in an effort to clarify the parallels and differences in adverse reactions between these two medications. In this study, we used disproportionate analyses ADR signals included in the Vigiaccess database.The study aimed to detect new and unexpected ADRs not described in the drug label. Given the paucity of research on the comparison of adverse reactions between these two drugs, this study aims to offer a theoretical basis for clinicians when selecting drugs to treat patients with different ARs. Materials and methods Drug sample Table 1 presents the drug structures, main indications, and targets of action of the two drugs primarily studied in this article. Both azelastine and levocabastine are H1-receptor antagonists, effective in the treatment of ARs and allergic conjunctivitis. Azelastine has been in clinical use since 1986, predating the commercialization of levocabastine. Azelastine is primarily administered as a nasal spray for the treatment of seasonal and perennial ARs and has demonstrated efficacy in managing urticaria. Levocabastine, available in the form of nasal sprays and eye drops, is commonly employed for symptomatic relief of ARs and allergic conjunctivitis. These medications have been in clinical use for over two decades and are accessible in China. Other antihistamines, including loratadine, cetirizine, and olopatadine, are instrumental in the management of ARs. Download: PNG larger image TIFF original image Table 1. General information on two antihistamine agents. https://doi.org/10.1371/journal.pone.0355852.t001 Date sources All data used in the article was obtained from the WHO-VigiAccess website ( https://www.vigiaccess.org ). We obtained all adverse events (AEs) that occurred after using each medication as of August 31, 2024, using the brand and generic names of the medication. The WHO information system gathers information on age group, sex, reporting year, and the world’s major continents. Excel 2016 was used to examine descriptive data. The PIDM database is accessible through the free site WHO-VigiAccess. Users can access drug safety reports that the UMC has received. The definitions are based on the Medical Dictionary of Regulatory Activities (MedDRA) system organ categories (SOCs) and preferred terms (PTs). Therefore, a search was conducted of the records for each antihistamine, and individual AEs were identified employing the MedDRA SOC and PT criteria to examine the range of toxicities. A number of dictionaries, including the World Health Organization Adverse Reaction Terminology (WHO-ART), are the source of words used in MedDRA. According to MedDRA, there are 20 SOCs, and a thorough analysis was conducted of those directly related to disease symptoms. This study concentrated on PTs, which were aggregated data publicly available from the VigiBase database through WHO-VigiAccess. The spontaneous reporting system, introduced in the 1960s, remains the backbone of pharmacovigilance [ 22 ]. The primary goal of spontaneous reporting is the early identification of AEs that were previously undetected. Furthermore, spontaneous reporting facilitates the acquisition of new insights into known drug-adverse reaction associations. Global safety data is compiled by the Uppsala Monitoring Centre (UMC) on behalf of the WHO’s International Drug Monitoring (PIDM). Through VigiBase, the global voluntary reporting program, UMC has gathered and preserved over 20 million ADR reports from over 170 countries by December 2018 [ 23 ]. Since 2015, public access to the data stored in VigiBase has been provided through VigiAccess. VigiAccess databases support searches by the trade name of a drug product, which then identifies the active ingredient(s) contained and displays the ADR report results based on these active ingredient(s). Statistical analysis This study utilized a retrospective quantitative research design. Descriptive analysis using Excel was conducted to analyze the characteristics of ADR profiles for two drugs. The number of ADR symptoms divided by the total number of ADR complaints was used to get the ADR reporting rate for each medication. Based on the top 20 symptoms with the greatest rates of ADR reporting, common ADRs for each medicine were determined. For the purpose of a descriptive comparison, the incidence of ADR symptoms recorded for each drug was computed and examined. Descriptive variables were organized using frequencies and percentages. Adverse event data were retrieved from the WHO-VigiAccess database. Using Python 3.10 with the requests library, the BASENAMEs of all drugs in the WHODRUG dictionary were queried, and the JSON data returned from the front-end pages were collected. The data were then structured and visualized using the Pandas library and exported to Excel spreadsheets. All subsequent disproportionality analyses, including the calculation of ROR, PRR, and their 95% confidence intervals, were performed using SAS 9.4 software. The individual case safety reports (ICSRs) retrieved from VigiAccess were further screened according to the following criteria. Only ICSRs in which azelastine or levocabastine was recorded as a “suspected” drug were included in the analysis. Reports where these antihistamines were coded exclusively as “concomitant” medications were excluded. To ensure data quality, duplicate reports, identified by matching report identifiers, and reports with missing or incomplete adverse event information were excluded. After applying these criteria, all eligible ICSRs were retained for disproportionality analysis. Disproportionality analysis We used the Reporting Odds Ratio (ROR) and the Proportional Reporting Ratio (PRR) as two disproportionality reporting methodologies based on the disproportionality analysis. A common technique in pharmacovigilance, the measure of odds imbalance serves as the foundation for the computation of ROR and PRR. ROR quantifies the odds imbalance of reporting AEs for a specific drug relative to other drugs and is defined by the following equation: where (a) is the number of reports of a specific drug and a specific AE, (b) is the number of reports of the same drug with other AEs, (c) is the number of reports of other drugs with the same AE, and (d)is the number of reports of other drugs with other AEs. The statistical robustness of the ROR calculation is dependent upon the presence of at least 5 cases (a ≥ 5) of a particular drug and adverse event combination. PRR is an additional metric used to quantify the disproportionality of AE reports and is calculated using the following formula: and like ROR, requires at least 5 cases (a ≥ 5) of a specific drug and AE combination to be considered valid. The signal is deemed disproportionate and may raise safety concerns if the ROR value is more than two (ROR > 2) and the lower limit of the 95% confidence interval (CI) for the ROR is greater than one (lower limit of the 95% CI for ROR > 1). By using these criteria, it is ensured that random variation cannot be the cause of the observed disproportionality. The calculation formulas, standard errors, 95% confidence intervals, and signal detection criteria are summarized in Table 2 . Download: PNG larger image TIFF original image Table 2. The principles of disproportionate measurement and the criteria for signal detection. https://doi.org/10.1371/journal.pone.0355852.t002 In our analysis, the application of ROR and PRR permitted a systematic assessment of the disproportionality of adverse reactions reported with antihistamines. The analysis’s findings support efforts in pharmacovigilance that try to improve drug safety. For the targeted analysis of neurological disorders, all AEs coded to PTs belonging to the MedDRA SOC “Nervous system disorders” were included. The specific PTs identified for azelastine and levocabastine in this SOC comprised: burning sensation, hypoaesthesia, ageusia, migraine, paraesthesia, balance disorder, headache, parosmia, tremor, sedation, dysgeusia, dizziness, anosmia, and somnolence. No further restriction at the High-Level Term (HLT) or High-Level Group Term (HLGT) level was applied. In all disproportionality analyses, the reference group for each drug–ADR pair consisted of all other drug–ADR combinations in the WHO-VigiAccess database. Specifically, the 2 × 2 contingency table was constructed with the study drug and target ADR as the index pair (cells *a* and *b*), while all other drugs and all other ADRs in the database served as the background comparator (cells *c* and *d*), as defined in the formulas above. Ethics statement Ethical approval was not required for the study involving humans in accordance with the local legislation and institutional requirements. Written informed consent to participate in this study was not required from the participants or the participants’ legal guardians/next of kin in accordance with the national legislation and the institutional requirements. Results General characteristics of the cases studied Adverse reaction reports for the drugs azelastine and levocabastine were first received in the WHO-VigiAccess database in 1988 and 1992, respectively. As of 2024, the WHO database contained 10, 793 and 799 ADR reports for these two drugs, totaling 11, 592. The numbers of AEs covered in these ADR reports were 15,330 for azelastine and 1,292 for levocabastine. Table 3 displays, among the 11, 592 reports of these two antihistamines, excluding 972 cases of unknown gender, the number of ADRs reported in females (7, 262, 62.65%) was higher than that of males (3, 376, 29.12%), with a male-to-female ratio of 2.15:1 and a gender difference. After exclusion of reports without age information, the most frequently reported age group for AEs was 45–65 years for azelastine, compared to 18–44 years for levocabastine. Over half of the reported cases of azelastine occurred in the Americas, and close to 90% of the cases of levocabastine occurred in Europe. Table 3 also lists the year of reporting for each study drug. Both drugs were documented through 2010. Over the past decade, azelastine exhibited the highest ADR incidence in 2020 and was also higher in 2016 and 2023 than in other years; levocabastine exhibited a higher ADR incidence in 2022 than in other years. ADR incidence rates for both drugs have shown an increasing trend over the past decade, excluding years with significant increases. Download: PNG larger image TIFF original image Table 3. Characteristics of ADR reports of two antihistamines. https://doi.org/10.1371/journal.pone.0355852.t003 Distribution of 27 SOCs for 2 antihistamines Table 4 displays the rate of 27 SOC reports for the 2 antihistamines. The highest rates of adverse reactions observed in both azelastine and levocabastine were General disorders and administration site conditions. Furthermore, azelastine treatment exhibited a higher incidence of adverse reactions for Nervous system disorders. Lev
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