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Data mining in FAERS: association of newer-generation H1-antihistamines with nervous system disorders

BMC Pharmacology and Toxicology volume 25, Article number: 95 (2024) Cite this article

Abstract

Background

H1-antihistamines are widely used to treat symptoms depending on histamine release in a variety of conditions. However, neurological adverse events have been reported in post-marketing surveillance studies and there are limited literatures comparing the neurological disorders associated with newer-generation H1-antihistamines from real-world datasets.

Aims

We performed a comparative analysis of nervous system disorders and several newer-generation H1-antihistamines including: cetirizine, loratadine, levocetirizine, desloratadine and fexofenadine.

Methods

Disproportionality analysis was used to identify the suspected drug neurological adverse events associated with H1-antihistamines of interest via the Food and Drug Administration Adverse Event Reporting System. The proportional reporting ratio (PRR), χ2 (chi-square) and the reporting odds ratio (ROR) with 95% confidence interval (CI) were used to estimate the association.

Results

AE reports of 43,815 cases from 2017 to 2021 were extracted from FAERS. The H1-antihistamines included in our study were associated with various neurological adverse events that could be classified into 12 aspects, containing 42 preferred terms. The majority of adverse event reports were concentrated at somnolence: cetirizine [N = 1342, ROR (95%CI) = 11.8 (11.2–12.5), PRR = 10.8, χ2 = 11755.4], levocetirizine [N = 1276, ROR(95%CI) = 28.5 (26.7–30.3), PRR = 22.7, χ2 = 26218.4], loratadine[N = 516, ROR(95%CI) = 4.6 (4.2-5.0), PRR = 4.4, χ2 = 1378.1], desloratadine [N = 33, ROR(95%CI) = 6.1 (4.3–8.6), PRR = 5.8, χ2 = 131.9], fexofenadine [N = 498, ROR(95%CI) = 5.0 (4.6–5.5), PRR = 4.8, χ2 = 1519.0].

Conclusion

Neurological AEs associated with individual newer generation H1-antihistamines of interest varies a lot, whereas somnolence was the most common AE reports. Fexofenadine was highly associated with headaches. Sedative effects associated with levocetirizine and cetirizine should arouse more concern. Seizures significantly associated with levocetirizine and desloratadine were infrequently reported, further research is needed to avoid possible serious outcomes. Patients taking cetirizine probably have higher risk of dystonia and anticholinergic syndrome.

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Introduction

The newer-generation H1-antihistamines constitute the first-line treatment for urticarial and allergic rhinitis with a better safety profile [1, 2]. Neurological side effects, such as sedation, are most frequently associated with H1-antihistamines, which might lead to life-threatening outcomes for patients [3]. A recent cohort study conducted in 63 Chinese pediatric patients showed that no adverse event was induced by cetirizine either in the recommended dosage group or the overdose group [4]. A human lactation study incuding 32 women indicated that the transfer of cetirizine and levocetirizine into breast milk is low [5] and it is safe in the breastfed infant [5, 6]. Fexofenadine, levocetirizine, and cetirizine are recommended for up-dosing with chronic spontaneous urticaria (Grade A recommendation) [1]. Overall objective tests have not shown clinically relevant differences in the central nervous system effects of levocetirizine, cetirizine and loratadine [2]. Conversely, neurological adverse effects, such as sedation and impaired psychomotor function, had been documented in literatures [2, 7, 8]. Cetirizine probably had higher risk of central nervous system side effects compared to other second generation H1-antihistamines [9]. An animal experiment demonstrated that cetirizine and loratadine at a dose of 50 mg/kg could markedly inhibit memory retrieval of the rats [10]. Cetirizine, levocetirizne, loratadine, desloratadine and fexofenadine are listed in the Anticholinergic Burden Scale as low potency anticholinergics which could deteriorate cognitive impairment, especially for the elderly [11]. Some other studies showed that levocetirizine and desloratadine probably had adverse effects on cognitive and psychomotor performance, whereas cetirizine and loratadine showed dose-ranging impairment [12]. However, fexofenadine was free from these side effects [13, 14], even in a higher dose [14]. Moreover, levocetirizine was more likely to cause drowsiness and sedation than desloratadine and fexofenading [13, 15]. A recent study revealed that cumulative dose of the second generation H1-antihistamine raised elevated dementia risk [16]. Several cases of cetirizine-induced dystonic reactions had been reported, and most of the patients were children [17,18,19,20,21,22]. Additionally, it can cause oculogyric crisis, mainly impacting the pediatric group [21, 23, 24]. An association was found between stabbing headaches and levecetirizine [25]. A relationship was observed between desloratadine and epilepsy in some cases [26]. The nervous system impairment might lead to a poor academic performance [27] and lower work efficiency, as well as decreased quality of life [12].

To the best of our knowledge, limited real-world study has been conducted to evaluate the association between neurological disorders and newer-generation H1-antihistamines. FAERS is the largest post-marketing safety surveillance database for all marketed drug and therapeutic biologic products [28], which could provide the regulatory agencies with more than 80% of potential adverse drug reaction signals [29]. We aimed to raise awareness of the nervous system disorders associated with using newer-generation H1-antihistamines.

Methods

Data source

This was a real-word study based on FDA Adverse Events Reporting System (FAERS). AE reports, medication quality complaints and medication error reports were submitted to FAERS spontaneously by pharmacists, physicians, health professionals, consumers, lawyers and manufacturers [30]. Data sets from FAERS include: demographic and administrative information, report sources, drug information, preferred terms coded for the AEs, patient outcomes, therapy periods, drug administration and deleted cases.

A primary suspected drug coded as “PS” may have one or two more AEs, and it may also include concomitant medications. Each AE might be submitted more than once by different reporters, thus duplicated reports were removed by case ID. A total of 6,900,469 cases from 2017 to 2021 were retrieved. We searched the generic and brand names of each drug identified as “PS” in the data processing. Dmographic characteristics such as sex, age, reactions and reporters’ type were collected. Finally, 43,815 cases were included: cetirizine (n = 13,560), levocetirizne (n = 6111), loratadine (n = 12,479), desloratadine (n = 609), fexofenadine (n = 11,056). Duplicated AE reports and the records with incorrect or erred inputs were excluded. 10,663 neurological AE reports associated with drugs of interest were selected for further study. Data management were performed using My SQL5·7.

Definition of neurological AEs

Terminology is stratified into five levels in the Medical Dictionary for Regulatory Activities (MedDRA): system organ class (SOC), high level group terms (HLGT), high level terms (HLT), preferred terms (PT), and low level terms (LLT). AEs are coded by PT in the MedDRA (version-25·0) vocabulary in FAERS [28]. Neurological AEs were identified by using SOC “Nervous System Disorders (MedDRA code: 10029205)”.

Statistical analysis

Disproportionality analysis was used to identify statistical associations between drugs and AEs. These methods have been frequently used to detect risk signals with high sensitivity and reliability, reducing biases [31, 32]. The proportional reporting ratio (PRR), χ2 (chi-square) and the reporting odds ratio (ROR) with 95% confidence interval (CI) were calculated to report the signal strength (Tables 1 and 2). In each case, a particular adverse event that is more likely to be induced by a particular drug will typically get a higher score [33]. A positive signal of disproportionality was defined as ROR at least one, PRR at least two, χ2 at least four, and three or more cases [34]. Data management was performed using MySQL 5.7 and statistical analysis was conducted using Microsoft Excel 2016.

Table 1 Fourfold table of measures of PRR and χ2
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Table 2 Major algorithms of disproportional analysis
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Results

Summary characteristics of all AE reports submitted to FAERS

The number of neurological AE reports is of concern. Olopatadine was excluded from the study as the neurological AE reports number was zero (Fig. 1).

Fig. 1
figure 1

Summary characteristics of all AE reports identified by SOC submitted to FAERS (x-axis: types of SOC associated with drugs of interest, y-axis: the number of AE reports)

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Basic characteristics

A total of 43,815 cases were obtained during the study period. Majority of the cases were reported by comsumers for cetirizine, levocetirizine, loratadine and fexofenadine. Most cases were reported by physician for desloratadine (n = 178; 29·2%) (Table 3).

Table 3 Demographic characteristics of AE reports submitted for H1-antihistamines of interest in FAERS
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The newer-generation H1-antihistamines were associated with a series of neurological AEs defined by 42 PTs, which could be classified into 12 aspects: central nervous system vascular disorders, cranial nerve disorders (excl neoplasms), demyelinating disorders, headache, movement disorders (incl parkinsonism), mental impairment disorders, neurological disorders NEC, neurological disorders of the eye, neuromuscular disorders, peripheral neuropathies, seizures (incl subtypes), sleep disturbances (incl subtypes).There is variation in types and severity of neurological AEs across individual H1-antihistamines (Table 4).

Table 4 Nervous system disorders associated with individual H1-antihistamines. (HLGT: high level group term, PT: preferred term,–: not a positive signal, n: total number of AE reports for individual drug)
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Central nervous system vascular disorders, cranial nerve disorders (excl neoplasms), demyelinating disorders, neurological disorders of the eye, neuromuscular disorders, peripheral neuropathies in individual H1-antihistamines

Compared to other H1-antihistamines of interest, cetirizine was more likely to result in the emergency of positive signals in these aspects. Mild positive signals emerged in the context of lacunar infarction and transient ischaemic attack for levocetirizine and desloratadine respectively (Table 4).

Headache

Desloratadine tended to exhibit positive signals that emerged in migraine with aura, while others were more likely to result in sinus headache (Table 4).

Movement disorders (incl parkinsonism)

It was worth noting that significant positive signals emerged in the context of parkinsonism for desloratadine. Cetirizine tended to exhibit positive signals that emerged in psychomotor hyperactivity and dystonia. Positive signals were observed in the context of psychomotor hyperactivity for both loratadine and fexofenadine (Table 4).

Mental impairment disorders

Only desloratadine exhibited positive signals from this aspect (Table 4).

Neurological disorders NEC

Notably, strong positive signals were observed in the context of somnolence for all H1-anthistamines of interest, and the percentage of reports number is higher than 80% for individual H1-antihistamine. The calculations of PRR and χ2 are higher than 10 and 100,000 respectively for both levcetirizine and cetirizine (Table 4).

Positive signals were observed in the context of consciousness related AEs for levocetirizine and desloratadine. Significant positive signals were observed in regard to hyperpathia, hypercapnic coma and hyporesponsive to stimuli for cetirizine. Positive signals emerged in the coma, syncope, speech disorder and balance disorder for desloratadine (Table 4).

Seizures (incl subtypes)

Significant positive signals emerged in regard to febrile convulsion for levocetirizine and clonic convulsion for fexofenadine. Desloratadine tended to exhibit positive signals that emerged in epilepsy and seizure (Table 4).

Sleep disturbances (incl subtypes)

Levocetirizine is more likely to result in the emergency of positive signals in this aspect. Positive signals also emerged in the context of hypersomnia for cetirizine (Table 4).

Discussion

The newer second-generation antihistamines can still cross the blood-brain barrier especially when taken in excess, though moderately, compared to the first-generation agents [35]. Neurological AEs associated with newer generation H1-antihistamines have been studied for long time. However, most of the literatures were limited by small samples or insufficient evidence. We performed a systematic and comprehensive analysis to detect signals of neurological AEs related to suspected H1-antihistamines of interest via the largest spontaneously AE reporting system, FAERS. We aimed to support the post-marketing safety surveillance. Due to the limitations of this database, such as “self-reporting” pattern that information in reports has not been verified. Thereby, some potential confounders could not be avoided. Moreover, the imperfection of disproportional analysis might lead to false positive signals. Thus, more studies should be provided to evaluate the association in further researches.

Cetirizine and the central nervous system vascular disorders

More significant signals were found in this aspect for cetirizine. Notably, reversible cerebral vasoconstriction syndrome (RCVS) and subarachnoid haemorrhage (SAH) had greater number of AE reports. RCVS is one of the main causes of severe and sudden-onset headaches [36, 37]. As one of the adverse reactions induced by cetirizine [38, 39], headaches are prone to impact children [20, 39]. SAH is a fatal cerebrovascular disease characterized by high mortality and very poor prognosis [40]. However, very few studies had been conducted to describe the association. This novel finding might provide physicians with significant insights.

Fexofenadine/levocetirizine and headache

Significant positive signals emerged in the context of sinus headache for fexofenadine and levocetirizine. In addition, fexofenadine was also associated with head discomfort in this study. Headache has wide range of clinical presentations and different etiologies [41]. A recent review demonstrated that headache is the most common AE associated with fexofenadine, while sinus headache was rarely reported [42]. Actually, most cases of sinus headache were misdiagnosed as either primary headaches or migraines in clinical practice [41], and migraine headache is a common clinical symptom of allergic rhinitis [43]. Our results might provide evidence for deeper research.

Levocetirzine induced headaches were infrequently reported [44]. One case report offered an unusual conclusion that a pediatric patient suffered possibly levocetirizine-induced stabbing headaches [25]. Given the limited evidence and lower number of AE reports, this result should be evaluated more elaborately.

Cetirizine and anticholinergic syndrome

One study showed that there was no significant difference between second generation H1-antihistamine treatments for anticholinergic side effects [9]. However, as they can moderately pass through the blood-brain barrier [35], some of them, such as cetirizine, levocetirizne, loratadine, desloratadine and fexofenadine, are listed in the Anticholinergic Burden Scale as low potency anticholinergics which could deteriorate cognitive impairment [11]. Our results suggested that cetirizine had higher correlation with anticholinergic syndrome. Though, AEs of anticholinergic syndrome induced by second generation antihistamines are infrequently reported, the toxicity is possible for cetirizine when taken an over dosage [45]. Our advice is that a conservative dose of cetirizine might be necessary to avoid anticholinergic adverse effect.

Levocetirizine/cetirizine and sedation/somnolence/hypersomnia

In our study, all H1-antihistamines were highly associated with somnolence, compared with other neurological AEs. Notably, levocetirizine and cetirizine ranked top two, which is consistent with previous study [20]. Meanwhile, significant positive signals were also emeged in the context of sedation and hypersomnia for both of them, suggesting a high-risk of sedative effect for (levo)cetirizine. Moreover, levocetirizine was associated with sleep paralysis. Coincidence with our results, some literatures showed that levocetirizine was more likely to cause somnolence and sedation, compared to desloratadine and fexofenadine [15, 42, 44, 46]. Another literature indicated that in comparison with loratadine and fexofenadine, cetirizine was associated with increased somnolence and less motivation [7]. Moreover, compared to other second generation H1-antihistamines, sedative effects impacted slightest on subjects taking fexofenadine according to some currently available evidence [42]. Conversely, a review demonstrated that sedative effects of levocetirizine had no difference with other second-generation antihistamines [47]. The reason might be related to different administration time, as morning administration of levocetirizine was probably associated with greater risk of heightened somnolence [48].

Though most of the newer-generation H1-antihistamines have moderate sedative effects, physicians should be warned to consider more when prescribing (levo)cetirizine that might lead to serious adverse outcomes for patients [3].

Levocetirizine and the consciousness

In our study, another noteworthy finding was that loss of consciousness and altered state of consciousness were both associated with levocetirizine. To the best of our knowledge, very few evidence could be provided to explain the association. Over doses of sedative medication can cause loss of consciousness [49, 50]. Though, levocetirizine has moderate sedative effects, it does not produce deleterious effect on psychometric and cognitive functions [51]. Nevertheness, according to our results, levocetirizine was highly associated with sedative effects, such as somnolence, hyposomia, sleep paralysis and sedation. This study might initiate a brand new perspective on the sedative effect associated with levocetirizne.

Cetirizine and movement disorders

A novel finding was that the association between cetirizine and psychomotor hyperactivity was highly significant. Psychomotor hyperactivity is mostly found among people with ADHD (attention deficit hyperactivity disorder) [52]. Allergic rhinitis and ADHD might have joint mechanism and represent a comorbidity which connects the nervous system to the immune system [53]. Therefore, we presumed that some of these patients taking cetirizine probably had ADHD. Further researches are needed to analysis the association.

Hyporesponsive to stimuli and psychomotor skills impaired were both associated with cetirizine in our study. Consistent with this result, one study showed that cetirizine had slight negative impact on psychomotor performance and memory scanning speed, inducing marginal effect on cognition [54]. And available evidence on psychomotor function favors fexofenadine [42].

Dystonia associated with using cetirizine has been frequently reported [17,18,19,20,21,22,23,24]. The mechanisms are probably that cetirizine has weak dopamine receptor (D2 receptor) blockade property in the striatum of the basal ganglia and causes interference with postsynaptic dopamine release, thus may inhibit striatal γ-amino butyric acid (GABA) output and causes excitation in the primary motor cortex [55].

Desloratadine and mental impairement disorder

Our results indicated that desloratadine was associated with amnestic disorder and amnesia. Memory deficits associated with desloratadine had been reported but rarely [56]. The impact of H1-antihistamines on memory impairement remains unclear. We hope more elaborate studies should be conducted to examine the results.

Desloratadine/Levocetirizine and seizures

In our study, very strong positive signals were observed in the context of febrile convulsion for levocetirizine, and the reports number was 17. An animal experiment demonstrated that toxic dosage of antihistamines could result in generalized seizure [57]. The possibility of febrile seizures in infants received levocetirizine treatment was of concern [58]. Epidemiological studies have linked prolonged febrile seizures with the development of epilepsy [59]. Nocturnal frontal lobe epilepsy is related to the impaired function of cholinergic receptors [60]. Mechanisms of drug induced febrile seizures are associated with anticholinergic medication [59]. We hope more studies should be conducted to explain this association in more detail.

Our results suggested that desloratadine was associated with seizure and epilepsy. Seizures associated with using desloratadine had been reported [26, 56]. A cohort study found a greater incidence rate of seizure during desloratadine exposed periods when compared to unexposed periods among individuals younger than 20, but no difference was observed in adults [61].

Physicians should be concerned regarding seizures in patients using levocetirizine or desloratadine, especially when treating patients with epilepsy.

Conclusion

Neurological AEs associated with individual newer generation H1-antihistamines of interest varies a lot, whereas somnolence was the most common AE reports. Fexofenadine was highly associated with headaches. Sedative effects associated with levocetirizine and cetirizine should arouse more concern. Seizures significantly associated with levocetirizine and desloratadine were infrequently reported, further research is needed to avoid possible serious outcomes. Patients taking cetirizine probably have higher risk of dystonia and anticholinergic syndrome.

Limitations

Continuous maintenance is necessary for the PT update of MedDRA. The ROR, PRR and χ2 can only reflect the results of data obtained from self-reported AEs, as well as physician-reported AEs, which would be influenced by underreporting and reporting biases. The association between a drug and an AE in FAERS could not prove causality, and more typical clinical cases were needed to confirm the correlation [62]. The spontaneous reporting of AEs from FAERS is not valid, only reports from health providers are assured [63], which is another potential confounder. Most of our conclusions were assumptions, and resources of relevant ADR case reports and studies were limited to prove some of them from existing literatures of high quality. As ROR and PRR have the ability of high sensitivity, false positive errors might occur. However, this study might provide evidence for deeper research in the precise medicine approach.

Data availability

The data analyzed in the current study is publicly available, and supplementary information could be required from contacting with Li Chen (Email: chenl_hxey@scu.edu.cn).

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Acknowledgements

We thank Zhenyan Bo and Kai Tao for providing English language editing help.

Funding

This study was supported by the National Natural Science Foundation of China (No. 82071686). The funding was used for data analysis.

Author information

Authors and Affiliations

  1. Department of Pharmacy, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, 610041, China

    Weiping Hu, Hailong Li, Linan Zeng, Chenghong Feng, Li Chen & Lingli Zhang

  2. Evidence-Based Pharmacy Center, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, 610041, China

    Weiping Hu, Hailong Li, Linan Zeng, Chenghong Feng, Li Chen & Lingli Zhang

  3. Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, Sichuan, 610041, China

    Weiping Hu, Hailong Li, Linan Zeng, Jing Gan, Chenghong Feng, Li Chen & Lingli Zhang

  4. NMPA Key Laboratory for Technical Research on Drug Products In Vitro and In Vivo Correlation, Chengdu, Sichuan, 610041, China

    Hailong Li, Linan Zeng & Lingli Zhang

  5. Chinese Evidence-based Medicine Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China

    Lingli Zhang

  6. Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, 610041, China

    Jing Gan

  7. Key Laboratory of Development and Maternal and Child Diseases of Sichuan Province, Chengdu, Sichuan, 610041, China

    Jing Gan

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  1. Weiping Hu
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  2. Hailong Li
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  5. Chenghong Feng
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  6. Li Chen
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  7. Lingli Zhang
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Contributions

L.L.Z. and W.P.H. contributed to the study conception and design. L.C. and W.P.H. analyzed the data and drafted the manuscript. L.H.L. and Z.L.N. critically revised the manuscript. G.J. and F.C.H. were involved in interpretation of data, and approved the final manuscript.

Corresponding authors

Correspondence to Li Chen or Lingli Zhang.

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Hu, W., Li, H., Zeng, L. et al. Data mining in FAERS: association of newer-generation H1-antihistamines with nervous system disorders. BMC Pharmacol Toxicol 25, 95 (2024). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s40360-024-00822-x

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Keywords

BMC Pharmacology and Toxicology

ISSN: 2050-6511

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