REVIEWS

Ebastine in the Treatment of Allergic Rhinitis

and Urticaria: 30 Years of Clinical Studies
and Real-World Experience
Sastre J
Department of Allergy, Fundación Jimenez Diaz, Madrid. CIBERES, Instituto Carlos III Department of Medicine, Universidad Autónoma de Madrid,
Madrid, Spain

J Investig Allergol Clin Immunol 2020; Vol. 30(3): 156-168

doi: 10.18176/jiaci.0401

Abstract
Histamine, acting predominantly via the H1-receptor, is an important mediator of the symptoms of allergy. H1-antihistamines, which stabilize
the receptor in its inactive form, are the treatment of choice for some chronic allergic conditions. Ebastine is a well-established second-
generation oral H1-antihistamine that is administered once daily at a dose of 10-20 mg and is available both as a standard tablet and
as a fast-dissolving tablet that disintegrates in the mouth. Ebastine has been shown to relieve symptoms in patients with allergic rhinitis
or urticaria in multiple clinical trials. In addition to its antihistamine effects, the drug has modulating effects on the allergic inflammatory
process, thus potentially explaining its beneficial effect on nasal obstruction in some patients. Ebastine is generally well tolerated at
recommended doses and is one of the lowest-risk antihistamines with respect to adverse cognitive/psychomotor effects, as confirmed by
decades of pharmacovigilance. New long-term data confirm its efficacy and tolerability during up to 1 year of treatment in patients with
chronic urticaria.
Key words: Allergic rhinitis. Urticaria. Ebastine. Antihistamines. H1-receptor antagonists.

Resumen
La histamina, que actúa predominantemente a través del receptor H1, es un mediador importante de los síntomas de alergia, y los
antihistamínicos H1, que estabilizan el receptor en su forma inactiva, son el tratamiento de elección para algunas afecciones alérgicas
crónicas. La ebastina es un antihistamínico H1 oral de segunda generación bien establecido. Se administra una vez al día en una dosis de
10 a 20 mg y está disponible como comprimido estándar y también como comprimido de disolución rápida que se desintegra en la boca.
La ebastina ha demostrado en numerosos ensayos clínicos ser eficaz para aliviar los síntomas de pacientes con rinitis alérgica o urticaria.
La ebastina tiene efectos moduladores del proceso inflamatorio alérgico además de sus efectos antihistamínicos, lo que pueden ayudar
a explicar el efecto beneficioso que tiene sobre la obstrucción nasal en algunos pacientes. La ebastina es generalmente bien tolerada a
las dosis recomendadas y es uno de los antihistamínicos de menor riesgo con respecto a los efectos adversos cognitivos/psicomotores,
confirmado después de décadas de farmacovigilancia. Los nuevos datos a largo plazo confirman su eficacia y tolerabilidad hasta un año
de tratamiento en pacientes con urticaria crónica.
Palabras clave: Rinitis alérgica. Urticaria. Ebastina. Antihistamínicos. Antagonistas del receptor H1.

© 2020 Esmon Publicidad J Investig Allergol Clin Immunol 2020; Vol. 30(3): 156-168
doi: 10.18176/jiaci.0401
157 Sastre J

Introduction economic burden for society in terms of work absenteeism

and presenteeism [15,16].
Allergic disorders such as allergic rhinitis and urticaria are Histamine, acting predominantly via the H1-receptor, is an
a common problem worldwide [1,2]. The estimated prevalence important mediator of the symptoms of allergy [17]. It is released
of confirmed allergic rhinitis in Europe ranges from 17% to as a preformed mediator from activated mast cells during the
28.5% [1,3]. The prevalence of the disease is increasing in early phase of the immune response [18]. H1-antihistamines,
other countries with previously low-to-medium prevalence, which stabilize the receptor in its inactive form, are the
such as China, and elsewhere [1,4-6]. The prevalence of treatment of choice for allergic conditions [17] and are included
urticaria is estimated to be 0.5%-5% [2,7-9]. In a cross- in international guidelines for the management of allergic
sectional population survey, lifetime prevalence for all types rhinitis [1,19] and urticaria [20]. Ebastine is a well-established
of urticaria was estimated to be approximately 9%, and this second-generation H1-antihistamine [21] that has been available
was considered to be a lower limit because of the conservative across Europe and worldwide for almost 30 years. The most
prevalence calculations employed [8]. recent comprehensive review of ebastine was published 10
Both allergic rhinitis and urticaria have an adverse years ago [21]. The current review summarizes data on the use
impact on quality of life and daily functioning [7,10-14], of ebastine to treat allergic rhinitis and urticaria and includes
and allergic rhinitis in particular is associated with a high new information that has become available in the last decade.

Table 1. Pharmacodynamic Properties of Ebastine

Antihistamine Activity
Ebastine ≥10 mg reduced histamine-induced cutaneous wheal response vs placebo in healthy adults and adults with allergic rhinitis
(P<.05) [22-29].
After single doses of ebastine 1-30 mg, peak inhibition of wheals occurred 2-12 h after intradermal histamine challenge (dose-dependent
effect); after 24 h, wheals remained reduced by 50% with ebastine 10 mg vs placebo [27,28].
Inhibitory effect of ebastine on wheal/flare responses disappeared by 5 d after stopping administration [30].
Ebastine 10 mg as effective as cetirizine 10 mg, fexofenadine 120 mg, loratadine 10 mg, and mizolastine 10 mg at inhibiting histamine-
induced wheal response [25,29]. Ebastine 20 mg more effective (P<.05) than cetirizine, loratadine, and fexofenadine at 24 h after dosing
[22,25,26]. Results for flare response after cutaneous histamine challenge generally consistent with those for wheal response [22,26,31].
Ebastine fast-dissolving tablet 10 mg and 20 mg more effective than desloratadine 5 mg at inhibiting the histamine-induced wheal
response at 24 h after dosing (P<.001) [23,24].
Ebastine 10 and 30 mg reduced histamine-induced bronchoconstriction vs placebo in patients with asthma; no dose-response
relationship [32].
Antiallergy Effects
In patients with animal/plant allergies, wheal and flare responses to cutaneous allergen challenge reduced significantly (P<.01) by
ebastine 20 mg versus placebo at 6, 24, and 48 h after completing 1 wk of treatment [30].
In patients with grass pollen allergy, ebastine 10 mg reduced pollen-induced wheal diameter significantly vs placebo (P=.013) and to a
similar extent to cetirizine 10 mg, fexofenadine 120 mg, loratadine 10 mg, and mizolastine 10 mg [29]. All antihistamines reduced nasal
blockage and sneezing (but not rhinorrhea) vs placebo at 4 h after nasal provocation with pollen (P<.05) [29].
In patients with grass pollen allergy, mean number of pollen grains needed to induce an allergic response after nasal provocation was
higher in recipients of ebastine 10 or 20 mg vs placebo (P<.05) [33].
Effects on Other Mediators of Inflammation
In nasal polyp cells in vitro, ebastine inhibited anti-IgE-induced release of prostaglandin D2 (PGD2) and leukotrienes C4/D4 (LTC4/D4)
(P<.05). It also inhibited granulocyte-macrophage colony-stimulating factor (GM-CSF), tumour necrosis factor-α and interleukin 8
release [33]. Carebastine had a smaller effect than ebastine.
In patients with grass pollen allergy, ebastine 10 and 20 mg reduced the release of GM-CSF (but not PGD2, LTC4/D4 or other cytokines)
in nasal secretions in a dose-dependent manner [33].
In patients with grass pollen allergy, a smaller increase in nasal eosinophilia was seen after treatment with ebastine 10 mg vs placebo
(P=.004); effect was similar to that seen with cetirizine, fexofenadine, loratadine, and mizolastine [29].
In patients with bronchial asthma, ebastine 10 mg reduced peripheral blood eosinophil count (P<.0253) and serum eosinophil cationic
protein level (P<.0014) in atopic but not nonatopic patients [34].
In patients with persistent allergic rhinitis, ebastine increased production of interferon γ by peripheral blood mononuclear cells in
response to stimulation by grasses (P<.0001) or house dust mite Dermatophagoides farinae (P=.0015) [35].
Ebastine demonstrated potent antiangiogenic activity in in vitro assays (human umbilical vein endothelial cell and human pulmonary
artery cell) (P≤.03) and in an in vivo assay (chick embryo chorioallantoic membrane) (P<.001) [36].

J Investig Allergol Clin Immunol 2020; Vol. 30(3): 156-168 © 2020 Esmon Publicidad
doi: 10.18176/jiaci.0401
 Ebastine in Allergic Rhinitis and Urticaria 158

Pharmacological Properties are often deficient in interferon γ, and it has been shown that
ebastine increases production of interferon γ by peripheral
Ebastine is a second-generation H 1-antihistamine. It blood mononuclear cells in response to stimulation by grasses
has an oxypiperidine-based structure and is metabolized to (P<.0001) or the house-dust mite Dermatophagoides farinae
carebastine, its active metabolite, after oral administration. (P=.0015) in patients with persistent allergic rhinitis [35].
This effect was significantly associated with an improvement
Pharmacodynamic Profile in allergy symptoms, as measured by the total nasal symptom
score (P=.0038) and patient-reported overall symptoms
Since ebastine was introduced 30 years ago, its
in a visual analog scale (P=.004). Angiogenesis, which is
pharmacodynamic activity has been extensively demonstrated
associated with increased expression of vascular endothelial
using cutaneous histamine challenge tests, histamine-induced
growth factor (VEGF), is implicated in airway inflammation
bronchoconstriction tests, cutaneous and nasal allergen
and remodelling in allergic rhinitis and asthma, and ebastine
challenge tests, and measurement of inflammatory mediators.
was found to have potent antiangiogenic activity in in vitro
The findings are summarized in Table 1 [22-36]. The key
and in vivo assays [36]. Carebastine, the active metabolite of
points are as follows: ebastine inhibited cutaneous reaction to
ebastine, inhibited the VEGF-induced angiogenic response
histamine in a dose-dependent manner; and ebastine 20 mg
in a chick embryo chorioallantoic membrane assay (P<.001),
reduced histamine-induced wheals to a greater extent than
with the effect mediated predominantly by an H1-receptor–
cetirizine 10 mg, fexofenadine 120 mg, and loratadine 10 mg.
dependent mechanism and, albeit to a lesser extent, by an
In addition, the quantity of pollen needed to induce a nasal
H1-receptor–independent mechanism [36].
allergic response was greater with ebastine, and the effects of
the drug lasted for at least 48 hours (Table 1).
Pharmacokinetic Profile
Ebastine also has effects on nonhistamine mediators
of inflammation (Table 1). Two relevant studies have been The pharmacokinetic profile of ebastine/carebastine
published since the last review [21]. People with allergies is summarized in Table 2 [21,28,37-52]. Ebastine is

Table 2. Pharmacokinetic Properties of Carebastine [21,28,37-52]a

Parameter Finding
Maximum plasma concentration Single dose: 10 mg, 80-115 ng/mL; 20 mg, 157-243 ng/mL
Multiple doses: 10 mg, 130-162 ng/mL; 20 mg, 273-396 ng/mL
Time to maximum plasma concentration Single dose: 10 mg, 2.6-5.7 h; 20 mg, 1-5 h
Multiple doses: 10 mg, 5.1 h; 20 mg, 4.5-5 h
Area under the plasma-concentration Single dose: 10 mg, 1755-3189 ng/mL/h; 20 mg, 5721 ng/mL/h
time curve Multiple doses: 10 mg, 2742 ng/mL/h; 20 mg, 4200-5608 ng/mL/h
Time to steady-state concentration Approximately 4 days
Effect of food Ebastine can be administered with or without food
Plasma protein binding >95%
Apparent volume of distribution 90-143 L (single 10 mg dose)
Metabolism Via cytochrome P450 enzymes, including CYP3A4, CYP2J2, CYP4F
Urinary excretion Accounts for 66% of administered dosage; mainly in form of conjugated metabolites
Clearance 4.8 L/h (single 10 mg dose)
Elimination half-life Single dose: 10 mg, 10.3-19 h; 20 mg, 15 h
Multiple doses: 10 mg, 19 h; 20 mg, 15-24.5 h
Effect of age and gender Age has no clinically relevant effect on carebastine pharmacokinetics, and dose
modifications are not needed in elderly patients
Hepatic and renal impairment Hepatic and renal impairment have no clinically relevant effect on carebastine
pharmacokinetics. No dose adjustment needed for renal impairment or for mild or
moderate hepatic impairment. Maximum dose in severe hepatic impairment is 10 mg,
as this was the highest dose evaluated in this subgroup
Drug interactions Pharmacokinetic interaction with drugs metabolized by CYP3A4, eg, coadministration
with ketoconazole, itraconazole or erythromycin leads to increased plasma concentrations
of ebastine/carebastine
Pharmacokinetic interaction with rifampin (rifampicin), leading to reduced plasma
concentration of carebastine
No significant interactions with cimetidine, diazepam, or alcohol
Specific values are for adults taking the standard tablet formulation of ebastine.
a

© 2020 Esmon Publicidad J Investig Allergol Clin Immunol 2020; Vol. 30(3): 156-168
doi: 10.18176/jiaci.0401
159 Sastre J

Table 3. Randomized, Double-Blind, Controlled Trials Evaluating the Efficacy of Ebastine in Adults and Adolescents With Seasonal Allergic Rhinitisa

Clinical Trial No. Treatment Results

(Duration)
[54] (4 wk) 40 Ebastine 10-40 mg Ebastine more efficacious than placebo for relief of nasal symptoms (P<.05) but not
(titrated) ocular symptoms.
Placebo Global efficacy rated good/very good by more patients and physicians for
ebastine than placebo (patients 84% vs 40%; physicians: 79% vs 35%; overall P<.01).
[55] (2 wk) 116 Ebastine 10 mg Ebastine 10 mg more efficacious than placebo for relief of nasal symptoms such as
Placebo rhinorrhoea (P=.003) and sneezing (P=.008) (but not nasal obstruction) and ocular
symptoms such as tears and conjunctival irritation (P values not reported).
Ebastine 10 mg more efficacious than placebo based on physician global efficacy rating
of good/excellent (56% vs 46%, P=.008).
[56] (1 wk) 201 Ebastine 10 mg Ebastine 10 and 20 mg more efficacious (P<.05) than placebo for relief of nasal symptoms
Ebastine 20 mg (except obstruction) and ocular symptoms (except watering eyes with ebastine 20 mg).
Placebo Ebastine 10 and 20 mg more efficacious than placebo based on patient (P<.05) and
physician (P<.01) global efficacy rating. More patients and physicians rated ebastine
10 and 20 mg as “efficacious” (i.e. moderate/ good/excellent) than rated placebo as
such (patients 61% vs 66% vs placebo 36%; physicians: 72% vs 64% vs placebo 33%).
No significant differences between ebastine 10 and 20 mg.
[57] (3 wk) 396 Ebastine 10 mg (am) Ebastine 10 mg (am) and 20 mg (am or pm)—but not 10 mg (pm)—more efficacious than
Ebastine 10 mg (pm) placebo at improving total symptom score and relieving individual nasal and ocular
Ebastine 20 mg (am) symptoms (P<.05). Mean change from baseline in total symptom score was –3.5 and
Ebastine 20 mg (pm) –3.2 for ebastine 10 mg (am) and 10 mg (pm) vs –4.0 and –3.6 for ebastine 20 mg (am)
Placebo and 20 mg (pm) vs –2.7 for placebo (estimated from graph).
Ebastine 20 mg (am and pm)—but not ebastine 10 mg (am or pm)—better than
placebo based on patient global efficacy rating (P<.05).
Efficacy was maintained during a 4-month extension period.
[58] (2 wk) 343 Ebastine 10 mg No significant difference in change in total symptom score between groups at study
Ebastine 20 mg end. Greater reduction in total symptom score with ebastine 20 mg vs ebastine 10 mg
Cetirizine 10 mg and cetirizine 10 mg after 1 week (P<.05). In a subgroup with more severe baseline
symptoms (n=158), greater reduction in total symptom score at study end with ebastine
20 mg vs ebastine 10 mg (P=.027) but not vs cetirizine 10 mg.
Physician (but not patient) global efficacy ratings better for ebastine 20 mg (but not
10 mg) vs cetirizine 10 mg (improvement in 85% vs 73%; P=.048).
[59] (4 wk) 749 Ebastine 10 mg Ebastine 10 and 20 mg more efficacious than placebo for all composite scores (P<.01).
Ebastine 20 mg Patient and physician global ratings not significantly different vs placebo for any active treatment.
Loratadine 10 mg Reductions in reflective nasal index scores with/without congestion (but not in reflective
Placebo total symptom score with/without congestion) and in all four snapshot composite scores
were greater with ebastine 20 mg vs loratadine 10 mg (P<.05). No significant differences
between ebastine 10 mg vs loratadine 10 mg for any composite scores.
No significant difference for ebastine 10 or 20 mg vs loratadine for patient or physician
global ratings.
[60] (4 wk) 565 Ebastine 10 mg Ebastine 10 and 20 mg more efficacious than placebo for all composite scores (P<.05);
Ebastine 20 mg loratadine better than placebo for all composite scores except snapshot total symptom
Loratadine 10 mg score and nasal index.
Placebo Patient and physician global ratings better with all active treatments vs placebo (P<.05).
Greater reduction in all four mean daily reflective composite scores (total symptom
score with/without congestion and nasal index with/without congestion), all 4 morning
snapshot composite scores and most individual scores with ebastine 20 mg vs loratadine
10 mg (P<.05). No significant difference between ebastine 10 mg vs loratadine 10 mg.
Patient and physician global ratings did not differ significantly between active treatments.
[61] (2 wk) 703 Ebastine 20 mg Greater reductions in all mean daily reflective and snapshot composite scores (total symptom
Loratadine 10 mg score, nasal index) and individual nasal and ocular scores (except for snapshot nasal congestion)
Placebo with ebastine 20 mg vs placebo (P<.05), but not for loratadine 10 mg vs placebo.
Greater reduction in all mean daily reflective and snapshot composite and individual
nasal and ocular scores with ebastine 20 mg vs loratadine 10 mg (P<.05). Change in
mean daily reflective total symptom score –3.46 (–32.3%) with ebastine 20 mg vs –2.77
(–24.6%) with loratadine 10 mg (P=.0018).
Patient and physician global ratings did not differ significantly between ebastine and loratadine.
a
Efficacy was generally based on evaluation of nasal symptoms (rhinorrhea, sneezing, itching, obstruction) and ocular symptoms (itching, discharge, conjunctivitis).
Symptoms were assessed individually and/or as composite scores, such as total symptom score, nasal index (composite of 4 nasal symptoms) or perennial index (nasal
symptoms excluding obstruction). Symptoms were usually rated on a graded scale (0 = absent, 1 = mild, 2 = moderate, 3 = severe). In some trials, patients recorded
symptom scores twice daily, based on their symptoms over the previous 12 hours (reflective score) and at the time of recording (snapshot score).

J Investig Allergol Clin Immunol 2020; Vol. 30(3): 156-168 © 2020 Esmon Publicidad
doi: 10.18176/jiaci.0401
 Ebastine in Allergic Rhinitis and Urticaria 160

Table 4. Randomized, Double-Blind, Controlled Trials Evaluating the Efficacy of Ebastine in Adults and Adolescents With Perennial Allergic Rhinitisa

Clinical Trial No. Treatment Results

(Duration)
5 [62] (1 wk) 151 Ebastine 10 mg Ebastine 10 mg more efficacious than placebo for relief of all nasal symptoms
Placebo (except obstruction) and ocular symptoms (P<.05).
Efficacy rated as excellent/good/moderate by more patients and physicians for ebastine
10 mg than placebo (54%-55% vs 31%-32%; P<.01).
[63] (12 wk) 290 Ebastine 10 mg Ebastine 20 mg more efficacious than placebo for reduction from baseline in mean daily
Ebastine 20 mg perennial index (–1.9 [–39%] vs –1.2 [–26%], P=.006; estimated from graph), morning
Placebo perennial index (P=.007) and mean daily nasal index (P=.015). Ebastine 10 mg more
effective than placebo for reduction in morning perennial index (P=.047).
More patients and physicians rated condition as somewhat/greatly improved with ebastine
10 mg (72%-80%) and 20 mg (84%) than with placebo (58%) (P<.02).
No significant differences between ebastine 10 and 20 mg.
[64] (4 wk) 214 Ebastine 10 mg No significant difference between ebastine 10 mg and cetirizine 10 mg for mean
Cetirizine 10 mg percentage change in nasal index at study end. Greater mean percentage change in nasal
index with cetirizine 10 mg after 1 week (P<.04).
More cetirizine recipients had reduced nasal congestion (P<.04) and were symptom-free
(P=.02) at study end.
[65] (4 wk) 317 Ebastine 10 mg Ebastine 10 and 20 mg more efficacious than loratadine 10 mg at reducing perennial
Ebastine 20 mg index, nasal index, nasal discharge, and nasal congestion (P<.05). No significant
Loratadine 10 mg differences between ebastine doses.
Condition rated as improved by more patients and physicians for ebastine 10 and 20 mg
(79%-85%) vs loratadine 10 mg (65%-66%) (P<.05).
a
Efficacy was generally based on evaluation of nasal symptoms (rhinorrhea, sneezing, itching, obstruction) and ocular symptoms (itching, discharge, conjunctivitis).
Symptoms were assessed individually and/or as composite scores, such as total symptom score, nasal index (composite of four nasal symptoms) or perennial index (nasal
symptoms excluding obstruction). Symptoms were usually rated on a graded scale (0 = absent, 1 = mild, 2 = moderate, 3 = severe). In some trials, patients recorded
symptom scores twice daily, based on their symptoms over the previous 12 hours (reflective score) and at the time of recording (snapshot score).

administered once daily. After oral administration, ebastine based on intermittent or persistent symptoms and therefore
undergoes rapid and extensive first-pass metabolism to used the earlier terminology of seasonal and perennial allergic
carebastine, its active metabolite [28,48]. Carebastine exhibits rhinitis. Studies generally enrolled adults and adolescents aged
dose-dependent pharmacokinetics [28,48]. Peak plasma ≥12 years, and allergic rhinitis was usually diagnosed based
concentrations of carebastine are reached at 4-6 hours after on the clinical history and a positive skin prick test or IgE test
dosing, and steady-state levels are achieved within 4 days result. The most common primary efficacy parameter was the
(Table 2). Pharmacokinetic bioequivalence between the fast- change from baseline in total symptom score; however, some
dissolving tablet formulation of ebastine (which disintegrates studies used a global evaluation of symptomatic improvement/
in the mouth) and the standard tablet formulation (which is efficacy by the physician or patient.
swallowed) has been established [53]. The results of controlled trials of ebastine in adults/
Coadministration with drugs metabolized by CYP3A4, adolescents with seasonal allergic rhinitis or perennial allergic
such as ketoconazole and erythromycin, leads to increased rhinitis are summarized in Tables 3 [54-61] and 4 [62-65],
plasma concentrations of ebastine/carebastine [37]. Since respectively. Ebastine was significantly more effective than
the previous review, a pharmacokinetic interaction between placebo at relieving the symptoms of seasonal and perennial
rifampicin (rifampin) and ebastine has been reported: allergic rhinitis [54-57,58-63].
coadministration led to reduced oral bioavailability of ebastine, The results of comparisons with other antihistamines
with a 15% decrease in the area under the plasma concentration indicate that ebastine 10 mg was at least as effective as
time curve for carebastine (P<.001) [49]. cetirizine 10 mg and loratadine 10 mg at relieving the
symptoms of allergic rhinitis and that ebastine 20 mg was
generally more effective than loratadine 10 mg [58-61,64,65].
Clinical Efficacy A meta-analysis of 4 studies on seasonal allergic rhinitis
confirmed that ebastine 20 mg was superior to loratadine
Once-daily oral ebastine is indicated for the symptomatic 10 mg, as indicated by the mean change from baseline in the
treatment of allergic rhinitis/rhinoconjunctivitis (adults and overall mean daily reflective total symptom score during the
adolescents aged ≥12 years) and urticaria (adults). first 2 weeks of treatment (–3.61 [–35.4%] vs –3.05 [–29.0%],
P<.001) [66].
Allergic Rhinitis Whereas most nasal symptoms are due primarily to the
Most clinical trials of ebastine in allergic rhinitis were effect of histamine, nasal obstruction is associated with multiple
conducted prior to the introduction of the ARIA classification chemical mediators [67-69], and oral H1-antihistamines tend

© 2020 Esmon Publicidad J Investig Allergol Clin Immunol 2020; Vol. 30(3): 156-168
doi: 10.18176/jiaci.0401
161 Sastre J

to be less effective for nasal congestion than for other nasal prescribed the ebastine fast-dissolving tablet 20 mg within the
symptoms [1]. Three studies that evaluated mean change from previous 2 months (n=461) used the Treatment Satisfaction
baseline in reflective and snapshot nasal congestion symptom Questionnaire for Medication (TSQM). The authors found
scores (total of 6 scores across the 3 studies) found that ebastine that patients rated the ebastine tablet highly for effectiveness
20 mg was more efficacious than placebo for 6 of 6 scores and (TSQM score 74.2 out of a maximum 100), adverse effects
ebastine 10 mg for 4 of 6 scores, whereas loratadine 10 mg (95.3), convenience (87.9), and global satisfaction (78.6) [76].
was more efficacious than placebo for only 1 of 6 scores [70]. Compared with their previous antihistamine therapy, the
A small noncomparative study in patients with persistent ebastine fast-dissolving 20-mg tablet was rated better/much
allergic rhinitis (n=20) that specifically evaluated nasal better by 81% of patients in terms of effectiveness, by 73% for
symptoms found that ebastine 20 mg significantly improved tolerability, 79% for onset of action, and 94% for convenience.
rhinomanometry-assessed nasal airflow by 59% from baseline Overall, 94% of patients indicated they would like to continue
(P=.0001) and modified the response to the nasal decongestion using the ebastine fast-dissolving tablet [76].
test (P=.0003) [71].
Urticaria
Patient Acceptance and Satisfaction
The efficacy of ebastine in the treatment of chronic urticaria
It is important that therapies for allergic rhinitis are was evaluated in adult patients. Ebastine was assessed in
acceptable to patients to ensure that they adhere to long- patients with chronic idiopathic urticaria (which would now
term treatments in the real-world setting. Studies evaluating be designated chronic spontaneous urticaria) in 2 randomized,
patients’ perception of the fast-dissolving tablet formulation double-blind, placebo-controlled trials [77,78], 1 of which also
of ebastine and their willingness to use it have been reviewed included a comparison with terfenadine [78]. Ebastine 10 mg
in detail [21,72]. Patients generally preferred the taste and was significantly more efficacious than placebo at reducing the
texture of the fast-dissolving tablet over the standard ebastine symptoms of urticaria and showed similar efficacy to terfenadine
tablet [73]: they found it convenient and easy to use, perceived (Table 5) [9,77-84]. More recently, a randomized trial with the
it to have a fast onset of action, and reported high levels of primary aim of evaluating a method for predicting response to
satisfaction [73-76]. Most expressed a preference for it over treatment in patients with chronic spontaneous urticaria (n=213)
their previous antihistamine treatment [74-76]. reported that all antihistamines evaluated (ebastine, bilastine,
One of the patient preference studies, which was cetirizine, desloratadine, fexofenadine) provided similar efficacy
available only as a conference abstract for the last full review in terms of symptom relief (assessed using the Urticaria Activity
of ebastine, has since been published in full [76]. This Score) and quality of life (Dermatology Life Quality Index) over
international observational study of patients who had been 8 weeks of treatment (Table 5) [9].

A B
a. Pruritus (P=.0001 baseline to 6 months) a. Pruritus (P=.0001 baseline to 12 months)
Baseline (N=251) 6-Months (N=251) Baseline (N=58) 12-Months (N=58)

None None
Minor Minor
Moderate Moderate
Constant Severe

b. Number of wheals (P=.0001 baseline to 6 months) b. Number of wheals (P=.0001 baseline to 12 months)
Baseline (N=251) 6-Months (N=251) Baseline (N=58) 12-Months (N=58)

0 0
1 to 5 1 to 5
6 to 15 6 to 15
16 or more 16 or more

c. Size of wheals (P=.0001 baseline to 6 months) c. Size of wheals (P=.0001 baseline to 12 months)
Baseline (N=251) 6-Months (N=251) Baseline (N=58) 12-Months (N=58)

0mm 0mm
1-10mm 1-10mm
11-29mm 11-29mm
30mm or more 30mm or more

Figure. Long-term efficacy (A, 6 months; B, 12 months) of ebastine in patients with chronic urticaria: a, pruritus; b, number of wheals; and c, size of
wheals [80].

J Investig Allergol Clin Immunol 2020; Vol. 30(3): 156-168 © 2020 Esmon Publicidad
doi: 10.18176/jiaci.0401
 Ebastine in Allergic Rhinitis and Urticaria 162

In addition, efficacy data from 2 previously unpublished, confirmed the long-term efficacy of ebastine 10 mg in this
long-term, open-label studies of the safety and efficacy patient population.
of ebastine in patients with chronic urticaria have been In the first, 251 adults with chronic urticaria from 11 centers
reported [80,81]. The studies were both multicenter, open- in Spain were enrolled in a 6-month, open-label study
label, noncomparative studies involving adults with chronic evaluating the long-term safety and tolerability of ebastine
urticaria. Efficacy was evaluated through assessments of 10 mg, in which efficacy was assessed as a secondary
symptoms, including pruritus and number and size of wheals, objective [80]. The primary evaluation was performed
and patient and physician global evaluations. Both studies at 6 months. However, a subgroup of patients (n=58) continued

Table 5. Clinical Trials Evaluating the Efficacy of Ebastine in Adults With Urticaria

Clinical Trial No. Treatment Results

(Duration)
Randomized Controlled Clinical Trials in Chronic Spontaneous Urticaria
[77] (2 wk) 204 Ebastine 10 mg Ebastine 10 mg reduced itching and number and size of wheals vs placebo (all P<.001).
Placebo Global efficacy rated by patients and physicians as moderate/good for more ebastine
recipients than placebo recipients (80%-83% vs 51–55%, P<.001).
[78] (12 wk) 211 Ebastine 10 mg Both ebastine 10 mg and terfenadine 120 mg were more efficacious (P<.05) than
Terfenadine 120 mga placebo at reducing severity of itch and number of wheals and lesions as assessed by
Placebo patients (but not physicians). Ebastine was more efficacious than placebo based on
patient/physician global ratings of improvement (73%-75% vs 51%-52%, P≤.004). No
significant differences were found between ebastine and terfenadine for relief of
symptoms, or for global patient/physician ratings.
[9] (8 wk) 180 Ebastine 20 mg 24-h after administration of antihistamine, inhibition of the histamine wheal by >75%
Bilastine 20 mg was significantly associated with better urticaria activity and dermatology life quality
Cetirizine 20 mg index (DLQI) scores. The safety and efficacy of the 5 antihistamines were similar.
Desloratadine 5 mg After updosing, rates of disease control (DLQI score <5) increased from 59% to 77%
Fexofenadine 180 mg with no differences between treatments.
No treatment
Open-Label Clinical Trials in Chronic Urticaria/Chronic Spontaneous Urticaria
[79] (4 wk) 30 Ebastine 10-40 mg Ebastine was safe and effective at higher doses in patients with chronic spontaneous
urticaria, with 17, 8 and 2 patients becoming symptom-free when administered doses of 10, 20, and 40 mg,
respectively.
[80] 251/58 Ebastine 10 mg The percentage of patients with constant pruritus decreased from
(6 mo + 6 mo 23.9% at baseline to 4.8% after 6 months, while the percentage who had ≥16 wheals
follow-up in a decreased from 47% to 13.2% and the percentage who had wheals ≥30 mm in size
subgroup decreased from 28.7% to 7.2% (all P=.0001). At 6 months, more than 70% of patients and
of patients) physicians rated the overall efficacy of ebastine as optimum or good. Significant
differences (P=.0001) were also seen in all symptoms in the subgroup of patients (n=58)
that followed 1 year of treatment.
[81] (12 mo) 192 Ebastine 10 mg Over 12 months there was clear improvement in symptoms, including itching, time
with symptoms, and wheal number/size. The percentage of patients with severe itching
decreased from 22% at baseline to <1% at 12 months, time with symptoms of urticaria
decreased from 38 to 6 hours/week, the percentage of patients with wheals ≥30 mm
decreased from 15% to 3%, and the percentage of patients with ≥16 wheals decreased
from 27% to 6%. The overall evaluation of efficacy indicated that approximately 65% of
patients and physicians considered there had been a major improvement in symptoms.
Longitudinal Study in Acute Urticaria
[82] (4 wk) 150 Ebastine 20 mg After 4 weeks the mean urticaria activity score was 1.08 for ebastine 20 mg, 1.98
Ebastine 10 mg for levocetirizine and 3.98 for ebastine 10 mg. in these 3 groups the percentage of patients
Levocetirizine 5 mg with symptom relief were 80%, 70%, and 50%, respectively.
Double-Blind Crossover Study in Dermographic Urticaria: Pilot Study
[83] 7 Ebastine 20 mg Ebastine prevented signs and symptoms of urticaria resulting from mechanical challenge.
(Single-dose) Placebo Of 7 patients with dermographic urticaria, all continued to experience wheals with
placebo, but only 2 had wheals after ebastine.
Double-Blind Crossover Study in Acquired Cold Urticaria: Pilot Study
[84] 22 Ebastine 20 mg Ebastine was significantly superior to placebo in terms of reducing the number of patients
(Single-dose) Placebo with wheals (P<.001), pruritus (P<.001), and experiencing a burning sensation (P<.05).

Terfenadine administered as 60 mg twice daily. Terfenadine is no longer marketed.

a

© 2020 Esmon Publicidad J Investig Allergol Clin Immunol 2020; Vol. 30(3): 156-168
doi: 10.18176/jiaci.0401
163 Sastre J

Table 6. Long-Term Efficacy of Ebastine in Patients With Chronic Urticaria: from 36 centers across Europe [81]. Some patients entered this
Results From a 12-Month Noncomparative Evaluation of the Safety and open-label study after participating in the trial that compared
Tolerability of Ebastine 10 mg in Europe [81]a ebastine with terfenadine and placebo [78], while others
were enrolled de novo. Statistical comparisons with baseline
Parameter Percentage of Patients
were not performed, although there was a clear improvement
(Unless Otherwise Indicated)
Baseline 6 months 12 months in symptoms (including itching), the number of hours with
symptoms, and wheal number and size during the 12-month
Pruritusb N=192 N=134 N=104 treatment period (Tables 5 and 6). The percentage of patients
None 2.6 50.8 59.6 with severe itching decreased from 22.4% at baseline to <1% at
Minor 27.6 41.8 34.6 12 months, the mean number of hours spent with symptoms of
Moderate 47.4 6.7 4.8 urticaria decreased from 38 to 6 hours per week, the percentage
Severe 22.4 0.8 1.0
of patients with wheals of ≥30 mm in diameter decreased
Mean no. of hours with N=190 N=129 N=103 from 14.6% to 2.8%, and the percentage of patients with ≥16
symptoms/wkb 37.8 h 10.9 h 5.8 h wheals decreased from 27.1% to 5.6%. The overall evaluation
No. of whealsc N=192 N=134 N=107 of efficacy indicated that approximately 65% of both patients
0 30.7 79.1 81.3 and physicians considered there had been a major improvement
1-5 21.9 6.7 10.3 in symptoms during the study (Tables 5 and 6).
6-15 20.3 7.5 1.9 The EAACI/GA2LEN/EDF/WAO guidelines on urticaria
≥16 27.1 5.2 5.6 suggest that in patients with an inadequate response to standard
Not assessed 0.0 1.5 0.9 doses of second-generation H1-antihistamines, the dose can be
Size of whealsc N=192 N=134 N=107 increased by up to 4 times the standard recommended dose [20].
None 30.7 79.1 81.3 The approved dose for ebastine in patients with urticaria is 10
1-10 mm 26.6 7.5 11.2 mg. A small noncomparative study found that ebastine was
11-29 mm 28.1 9.7 3.7 well tolerated and effective at higher doses in patients with
≥30 mm 14.6 2.2 2.8
chronic spontaneous urticaria (Table 5) [79]. Thirty patients
Not assessed 0.0 1.5 0.9
were treated with ebastine for 4 weeks. The initial 10 mg dose
Physician’s global evaluation could be increased after the first and second weeks in those
of efficacy N=192 patients with an inadequate response to 20 mg and then 40 mg
Major improvement - - 65.1
(administered as 10 mg or 20 mg twice daily). At the end of
Minor improvement - - 20.1
No change or worse - - 11.6 the first week, the dose was increased in 10 of 27 patients
Not done/not applicable - - 4.7 (3 patients were lost to follow-up). At the end of the second
week the dose was increased again in 2 of these 10 patients.
Patient’s global evaluation
The overall mean urticaria activity score decreased from 4.6
of efficacy N=192
Major improvement - - 65.6 at baseline to 2.2 after 1 week, 1.1 after 2 weeks, and <1.0 at
Minor improvement - - 16.9 4 weeks. In addition, 17, 8, and 2 patients became symptom-
No change or worse - - 12.7 free on doses of 10, 20, and 40 mg, respectively. One patient
Not done/not applicable - - 6.4 reported mild sedation (at a dose of 40 mg) [79].
Studies of ebastine in types of urticaria other than chronic
a
Multicenter, open-label, non-comparative study at 36 centres across idiopathic/spontaneous urticaria have generally used a dose of
Europe. 20 mg (Table 5). The results of 2 small, double-blind, crossover
b
Patient assessment. studies (n=22 and n=7) suggested that ebastine 20 mg might
c
Physician assessment. be effective at preventing the symptoms of acquired cold
urticaria [84] and dermographic urticaria [82], including
into a second 6-month follow-up phase (ie, total of 12 months). wheals, burning, and itching. Recently, ebastine 20 mg was
All symptoms (pruritus, number and size of wheals) improved found to have similar efficacy to levocetirizine 5 mg and to
significantly (P=.0001) compared with baseline from month 1 be more effective than ebastine 10 mg in the treatment of
(the first postbaseline visit) onwards and remained significantly acute urticaria in patients aged 10-70 years (n=150) [82]. By
improved at 6 months (Figure). The percentage of patients week 4 of the study, complete relief of symptoms was achieved
with constant pruritus decreased from 23.9% at baseline to in 80% of patients taking ebastine 20 mg, 70% of those taking
4.8% after 6 months (Figure, A, a), while the percentage who levocetirizine, and 50% of those taking ebastine 10 mg. The
had ≥16 wheals decreased from 47.0% to 13.2% (Figure, mean Urticaria Activity Scores in these groups at week 4 were
A, b) and the percentage who had wheals ≥30 mm in size 1.08, 1.98, and 3.98, respectively (Table 5).
decreased from 28.7% to 7.2% (Figure, A, c) (all P=.0001).
At 6 months, more than 70% of patients and physicians rated
the overall efficacy of ebastine as optimal or good. Significant
differences (P=.0001) from baseline in all symptoms were
Safety and Tolerability
also seen at 12 months (Figure, B a, b, c) in the subgroup that Ebastine 10-20 mg was generally well tolerated in clinical
continued into the extension period. trials of 1-4 weeks’ duration in patients with allergic rhinitis
The other long-term study evaluated the safety and efficacy or urticaria: the incidence of adverse events with ebastine
of ebastine 10 mg in 192 adults with chronic urticaria enrolled was similar to that for placebo, and most events were mild

J Investig Allergol Clin Immunol 2020; Vol. 30(3): 156-168 © 2020 Esmon Publicidad
doi: 10.18176/jiaci.0401
 Ebastine in Allergic Rhinitis and Urticaria 164

or moderate in severity [54,55,57,59-62,77]. The incidence 12 months), 8.6% reported adverse events beyond 6 months,
of adverse events with ebastine was similar to that for active and 100% of physicians and patients reported overall
comparators such as loratadine and cetirizine [58-60,64,65]. tolerability as “good” at 12 months.
The most common adverse events with ebastine in placebo- The second long-term study in chronic urticaria evaluated
controlled trials were headache (7.9%), drowsiness (3.0%), the safety and tolerability of ebastine in 192 patients over
and dry mouth (2.1%) [21]. a 12-month period [81]. Adverse events were reported for
Ebastine was found to have a favorable risk-benefit ratio with 59.4% of patients during the study period. Most were mild
respect to sedation and had no clinically relevant adverse effects or moderate in severity. The most frequent treatment-related
on cognitive or psychomotor functioning [45,85-90]. A more adverse events were weight gain (7.3%), increased appetite
recent analysis of the central nervous system effects associated (5.2%), headache (4.7%), abdominal pain (4.7%), dry
with second-generation H 1 -antihistamines calculated mouth (2.6%), and nervousness (2.6%). At the end of the
proportional impairment ratios for each drug compared with all study, physicians judged the overall tolerability of ebastine
the others (with higher values indicating greater impairment) as “good” for 87.3% of patients (options: good, fair, poor,
and ranked ebastine as one of the lowest for impairment of not done).
objective measures of cognitive and psychomotor function
(ratio 0, 95%CI, 0-1.91) [91].
Ebastine had no clinically relevant adverse cardiac effects at Conclusion
recommended doses in clinical trials, although small increases
in the QTc interval were seen when ebastine was coadministered Antihistamines are recommended by allergic rhinitis
with ketoconazole or erythromycin [37,92-94]. As a preventive and urticaria guidelines [1,19]. Because of their favorable
measure, caution is recommended for some second- efficacy-to-safety ratio, second-generation H1-antihistamines
generation antihistamines such as ebastine or rupatadine are recommended as first-line therapy for patients with allergic
in patients with known QTc interval prolongation or who rhinitis/rhinoconjunctivitis or urticaria [1,20,94].
use drugs that increase it. A recent case-control analysis of Ebastine is a once-daily, oral, second-generation H1-
antihistamines using 7 population-based healthcare databases antihistamine. The standard starting dose of 10 mg can be
from 5 European countries (ARITMO project) found that increased to 20 mg in patients with more severe or difficult-
ebastine was associated with an increased risk of ventricular to-control symptoms. The availability of 2 formulations in a
tachyarrhythmia in 2 out of the 7 databases, one from Germany number of countries (a standard tablet and a fast-dissolving
(GEPARD, 180 cases and 16 986 controls: adjusted odds ratio tablet that disintegrates in the mouth) provides patients with
[aOR], 3.3, 95%CI, 1.1-10.8 vs no use of any antihistamine) different options to suit their daily lives and preferences.
and the other from The Netherlands (PHARMO, 538 cases Ebastine has been demonstrated to be efficacious and
and 52 890 controls: aOR, 4.6; 95%CI, 1.3-16.2). However, well-tolerated in patients with allergic rhinitis or chronic
no such increased risk was found in the other 5 databases or urticaria in multiple clinical trials. The results of clinical
in the overall pooled analysis involving a much larger number trials published since the last in-depth review of ebastine
of cases/controls (2507/239 523) [95]. Moreover, ebastine support its efficacy and generally good tolerability when
was not prescribed extensively in the countries covered by administered at recommended doses. In particular, new
the study, and only 8 cases and 680 controls were included in long-term data confirm its efficacy and tolerability for up to
total. Pharmacovigilance data collected since ebastine was first 1 year of treatment in patients with chronic urticaria. Recent
introduced in 1989 have not resulted in any relevant change in findings also confirm that ebastine is one of the lowest-
the tolerability and safety texts of the approved summary of risk antihistamines in terms of cognitive and psychomotor
product characteristics after an estimated 65.5 million patients effects. Ebastine was not associated with adverse cardiac
have received the original product. effects in clinical trials. Finally, newer studies support
Studies of 3-4 months’ duration indicated that ebastine 10- previous evidence that in addition to its antihistamine effects,
20 mg was well tolerated in the long term [57,63,78]. Data from ebastine has modulating effects on the nonhistamine allergic
2 previously unpublished, open-label studies in which ebastine inflammatory processes. This may help explain the beneficial
10 mg was administered to patients with chronic urticaria for effect of ebastine on nasal obstruction in some patients.
up to 1 year confirmed that ebastine was well tolerated during No new tolerability or safety signals have emerged from
long-term treatment [80,81]. worldwide use of the drug.
In the first of these studies, in which the main aim was to In conclusion, ebastine is an effective and well-tolerated
evaluate safety and tolerability over a 6-month period (n=251), second-generation H1-antihistamine for the treatment of
the percentage of patients reporting adverse events decreased symptoms in patients with allergic rhinitis or urticaria. Newer
over time, from 17.9% at 1 month to 7.2% at 6 months [80]. data support the findings of earlier clinical trials and further
The most common adverse events reported at 1 month were endorse the usefulness of ebastine in daily clinical practice.
drowsiness (4.6%), headache (3.7%), and gastralgia (2.0%).
The most common adverse events reported at 6 months were
drowsiness (2.0%), gastralgia (1.7%), and increased appetite Acknowledgments
(1.2%). At 6 months, 87.2% of physicians and 84.5% of
patients considered the overall tolerability of ebastine to be Medical writing and editing assistance were provided
“good” (options: good, average, poor, not done). Among 58 by Content Ed Net and funded by Almirall S.A., Barcelona,
patients who continued for an additional 6 months (ie, total of Spain.

© 2020 Esmon Publicidad J Investig Allergol Clin Immunol 2020; Vol. 30(3): 156-168
doi: 10.18176/jiaci.0401
165 Sastre J

Funding 12. Maurer M, Abuzakouk M, Bérard F, Canonica W, Oude Elberink

H, Giménez-Arnau A, et al. The burden of chronic spontaneous
The manuscript was funded by Almirall S.A., Barcelona, urticaria is substantial: Real-world evidence from ASSURE-
Spain. CSU. Allergy. 2017;72:2005-16.
13. Storms W. Allergic rhinitis-induced nasal congestion: its impact
Conflicts of Interest
on sleep quality. Prim Care Respir J. 2008;17:7-18.
The author reports having served as a consultant to FAES 14. Virchow JC, Kay S, Demoly P, Mullol J, Canonica W, Higgins
Farma, GlaxoSmithKline, LETI, Mundipharma, Novartis, V. Impact of ocular symptoms on quality of life (QoL), work
Sanofi, and Thermo Fisher Scientific. He has also been paid productivity and resource utilisation in allergic rhinitis
lecture fees by FAES Farma, GlaxoSmithKline, LETI, Novartis, patients--an observational, cross sectional study in four
Sanofi, and Stallergenes and has received received grant support countries in Europe. J Med Econ. 2011;14:305-14.
for research from ALK, Sanofi, and Thermo Fisher Scientific. 15. Colás C, Brosa M, Antón E, Montoro J, Navarro A, Dordal MT,
et al.; Rhinoconjunctivitis Committee of the Spanish Society of
Allergy and Clinical Immunology. Estimate of the total costs of
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