Comparison of ebastine to cetirizine in seasonal allergic rhinitis in adults
Comparison of ebastine to cetirizine in seasonalallergic rhinitis in adults
Pierre Gehanno, MD*; Clothilde Bremard-Oury, MD†; and Philippe Zeisser, MD†
Background: Second-generation histamine H1-receptor antagonists are accepted
antagonist with no anticholinergic or first-line systemic therapy for seasonal allergic rhinitis. Ebastine is a new histamine sedative effects at therapeutic dosag- H1-receptor blocker that may differ in efficacy from currently used second-gener- es.2–5 Its chemical structure resembles ation agents.
those of terfenadine, the first nonsedat- Objective: To compare the efficacy of daily treatment with ebastine, 10 mg,
ing antihistamine, and diphenylpyra- ebastine, 20 mg, or cetirizine, 10 mg, for relieving symptoms of seasonal allergic line, a classical antihistamine. Ebastine rhinitis in adults.
is metabolized by the liver to the active Methods: In this multicenter, double-blind study, outpatients were randomized to
compound carebastine which has an one of three parallel treatment groups: ebastine, 10 mg, ebastine, 20 mg, or elimination half-life of 10 to 16 hours, cetirizine, 10 mg once daily in the morning for a 2-week period. Patients were thereby facilitating once daily admin- evaluated clinically according to symptoms, discomfort, and a global assessment at istration in the clinical setting.6,7 In baseline and on days 8 and 15 of treatment. The total symptom score, defined as the vitro, ebastine was at least as potent as sum of the total morning score on the day of evaluation and the total evening score terfenadine and astemizole for inhibit- on the preceding day, was the primary efficacy parameter.
ing histamine-induced contractions of Results: Ebastine, 20 mg (n ⫽ 111), ebastine, 10 mg (116), and cetirizine, 10 mg
guinea-pig isolated ileum. In vivo it (116), were all effective for improving nasal and ocular symptoms. There was, was more active than either agent for however, a general trend towards more rapid relief of symptoms with ebastine, 20 protecting against histamine-induced mg, and this reached statistical significance in some efficacy parameters after the first week of treatment. In a subpopulation of 158 patients who presented with more guinea pigs.2,3 In human volunteers, an severe symptoms, statistically significantly greater improvement was seen with oral dose of ebastine, 10 mg, produced ebastine, 20 mg, compared with ebastine, 10 mg, as indicated by the mean change optimal inhibition of histamine-in- from baseline in the total symptom score averaged over the treatment period (⫺13.7 duced skin wheals.6,7 Ebastine, 10 to ⫾ 4.7 vs ⫺11.8 ⫾ 3.8; P ⫽ .027) and in the morning symptom score (⫺6.7 ⫾ 2.7 40 mg/day orally, has been shown to vs ⫺5.7 ⫾ 2.2; P ⫽ .042). All three treatments were well tolerated. Dry mouth, be effective in the treatment of sea- headache, and somnolence were the most common adverse events.
sonal and perennial allergic rhinitis.8–10 Conclusion: Ebastine (10 mg), cetirizine (10 mg), and ebastine (20 mg) admin-
The aim of this study was to evaluate istered orally once daily for 2 weeks all appear to be effective for relieving the the efficacy of ebastine, 10 mg, rela- symptoms of seasonal allergic rhinitis. Ebastine, 20 mg, may have advantages over tive to that of ebastine, 20 mg, once ebastine, 10 mg, and cetirizine, 10 mg, in terms of a reduced time to achieve daily in relieving symptoms of sea- maximal efficacy and a superior level of efficacy in patients with more severe sonal allergic rhinitis in adults, and to compare these dosages directly with Ann Allergy Asthma Immunol 1996;76:507–12.
cetirizine, 10 mg daily, a reference sec- Compared with older compounds of PATIENTS AND METHODS
this class of drugs, the newer, second- In this multicenter, double-blind study, have an established role in the treat- H1-receptor antagonists patients were randomized to one of ment of seasonal allergic rhinitis.1 have a more favorable safety profile, three parallel treatment groups to re- most notably a lack of sedation. They ceive ebastine, 10 mg, ebastine, 20 mg, also appear to have anti-allergy effects or cetirizine, 10 mg, once daily in the * Assistance Publique Hoˆpitaux de Paris, Bi- in addition to histamine blockade.
morning for a 2-week period.
chat-Claude-Bernard, 46 rue Henri-Huchard, These effects may include inhibition of Patients aged 18 to 65 years were 75877 Paris Cedex 18, France.
release of inflammatory mediators, an- † Rhoˆne-Poulenc Rorer, 20, Avenue Ray- recruited by 46 investigators in France.
mond Aron, 92165 Antony Cedex, France.
tagonism of these mediators, and inhi- Inclusion criteria were as follows: di- Rhoˆne-Poulenc Rorer provided sponsorship bition of eosinophil recruitment.
agnosis of seasonal allergic rhinitis of for this study.
at least 1 year's duration, with pollen Received for publication June 16, 1995.
Accepted for publication in revised form sensitization documented by positive October 5, 1995.
is a selective and potent H1-receptor skin prick test and/or RAST class 3– 4; VOLUME 76, JUNE, 1996 a minimum of two nasal symptoms recorded a symptom score for nasal icance. Total morning, total evening, rated as moderate or severe (two or symptoms (nasal discharge, nasal and individual nasal and ocular symp- three respectively on a 4-point severity stuffiness, sneezing, itchy nose) and tom scores were also assessed using scale) at the commencement of the for ocular symptoms (itchy/watery this method. The treatment groups study; and a total symptom score of eyes) twice daily on a diary card using were also compared with respect to ⱖ12 of 20 (sum of the scores of the a 4-point severity scale: 0 (absent) ⫽ patient's discomfort (Student's t test) five nasal and ocular symptoms rated no symptom; 1 (mild) ⫽ symptom is and global assessments of treatment on a 4-point severity scale on the present but not annoying to self; 2 efficacy (Wilcoxon test). Descriptive evening preceding and on the morning (moderate) ⫽ symptom is present and analysis was used for safety data.
of the first consultation). Patients were annoying to self; 3 (severe) ⫽ symp- excluded from the study if they were tom interferes with/or prevents activi- pregnant or lactating, known to have ties of daily living. Baseline scores A total of 343 patients were recruited allergic sinusitis requiring treatment were recorded at entry in the presence for the study, which was conducted with corticosteroids, had a diagnosis of of the investigator.
during the pollinating season (April– acute asthma or nasal polyps, or if they The patient also rated overall dis- June), and were the basis for the intent- had an upper respiratory tract infec- comfort, overall nasal discomfort, and to-treat analysis which included all tion, otitis media, or pharyngitis. Pa- overall eye discomfort using a visual randomized patients. The three treat- tients also excluded from the study analogue scale (0 mm ⫽ no trouble; ment groups were well matched at were those with known hypersensitiv- 100 mm ⫽ trouble maximal) at each baseline in terms of demographic vari- ity to H1-receptor antihistamines, de- visit in the presence of the investigator.
ables and history of seasonal allergic sensitization to pollens during the past In addition, both the patient and the rhinitis (Table 1). Although the ratio of year or anticipated during the study investigator made a global assessment women to men was higher in the ceti- period, or serious concurrent disease of treatment efficacy at the end of rizine group than the ebastine treat- (renal dysfunction, hepatitis, etc), and treatment using a 4-point scale: 0 ⫽ no ment groups, this difference was not those receiving concomitant medica- effect of the medication on allergic statistically significant. Major protocol tion(s) capable of interfering with the rhinitis symptoms or impairment of violations necessitating exclusion from study medication or with evaluations symptoms; 1 ⫽ some allergic symp- the per-protocol analysis occurred in (xanthine derivatives, immunoglobu- toms improved but overall discomfort 42 cases, thus the per-protocol popula- lins, local or systemic corticosteroids, unchanged; 2 ⫽ allergic rhinitis symp- tion consisted of 301 patients. Overall, etc). All patients freely gave their writ- toms and overall discomfort improved; major protocol deviations were distrib- ten informed consent before participat- 3 ⫽ allergic rhinitis symptoms and uted equally among the treatment ing in the study. Recruitment began overall discomfort greatly improved.
groups and were related mainly to non- after the study protocol was formally Patients were followed up 1 week after compliance with the washout period approved by the ethics committee of discontinuation of study medication to for previous treatment, use of prohib- the Versailles Hospital. The study was assess whether their symptoms had ited medication during the treatment conducted between April 20 and July period, and missing diary cards.
After a wash-out period that varied events were recorded and routine lab- from 24 hours to 3 months depending oratory tests were performed at the be- The key results of the analyses per- upon the particular medication a pa- ginning and the end of the study formed on the intent-to-treat popula- tient had been receiving previously, tion are summarized in Table 2. For patients were randomized to receive The primary efficacy criterion was each treatment group, there was im- ebastine, 10 mg, ebastine 20 mg, or the total symptom score, defined as the provement from baseline in the total, cetirizine, 10 mg daily. Placebo tablets sum of the total morning score (sum of morning, and evening symptom scores.
matching ebastine, 10 mg, and placebo the five morning symptoms) on the day Although the decrease in symptom capsules matching cetirizine were ad- of evaluation and of the total evening scores was more marked in the ebas- ministered to ensure double-blinding.
score (sum of the five evening symp- tine, 20-mg group than in the ebastine, Two tablets and one capsule were toms) on the preceding day. For each 10-mg and cetirizine, 10-mg treatment taken as a single dose in the morning treatment group, the mean change groups, the between-group differences on an empty stomach before breakfast from baseline in the total symptom in the mean change in the scores from for 2 weeks.
score averaged over the treatment pe- baseline averaged over the 2-week Patients were assessed at baseline riod was calculated and analyzed on a treatment period were not statistically (day 1) and on day 8 and day 15 of two-by-two basis using the Student's t significant. Fewer patients in the ebas- treatment. Clinical efficacy was evalu- test. All P values reported are two- tine groups than in the cetirizine, ated in three ways: symptoms, discom- tailed and a P value below .05 was 10-mg group discontinued treatment fort, and global assessment. Patients considered to indicate statistical signif- because of lack of efficacy (Table 3).
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY Table 1. Demographic Data and Seasonal Allergic Rhinitis History of 343 Patients in the 'Intent-to-Treat' Population Ebastine, 10 mg
Ebastine, 20 mg
Cetirizine, 10 mg
Duration of seasonal allergic rhinitis,* yr Duration of current episode,* days * Mean ⫾ SD.
Table 2. Patient-Rated Symptom Scores at Baseline and the Mean Change from Baseline (⫾ SD) Averaged Over the 2-Week TreatmentPeriod in the 'Intent-to-Treat' Population Ebastine, 10 mg
Ebastine, 20 mg
Cetirizine, 10 mg
Total score (morning ⫹ evening scores) at baseline Mean change ⫾ SD Morning score* at baseline Mean change ⫾ SD Evening score* at baseline Mean change ⫾ SD * Sum of five individual symptom scores (nasal discharge, nasal stuffiness, sneezing, itchy nose, and itchy/watery eyes).
Table 3. Number of Patients Who Withdrew from Treatment for Seasonal Allergic Rhinitis .048). Overall, the investigators ob- Because of Lack of Efficacy served an improvement in both allergic Ebastine, 10 mg
Ebastine, 20 mg
Cetirizine, 10 mg
rhinitis symptoms and overall discom- fort in 84.6% of patients in the ebas- tine, 20-mg group, compared with 77.8% in the ebastine, 10-mg group, and 72.7% in the cetirizine, 10-mggroup.
A subgroup analysis was performed in patients with more severe symptoms Dropouts due to lack of efficacy gen- 10 mg, in the mean change from base- at baseline. This subgroup was defined erally occurred during the first week of line in the scores for itchy/watery eyes retrospectively as those patients with a treatment. Ebastine, 20 mg appeared to (⫺1.0 vs ⫺0.7; P ⫽ .035).
baseline symptomatic score greater An improvement in patient's dis- quickly than either ebastine, 10 mg, or comfort as assessed by the visual ana- than the mean of the entire patient pop- cetirizine, 10 mg (Fig 1). After 1 week logue scale was observed in all treat- ulation (ie, 18.8). The subpopulation of treatment, the mean change in the ment groups (Fig 2), with ebastine, 20 comprised 158 patients: ebastine, 20 total symptom score from baseline was mg, being significantly more effective mg (n ⫽ 57), ebastine, 10 mg (51), and significantly greater in the ebastine, than cetirizine, 10 mg, after the first cetirizine (50). Ebastine, 20 mg, was 20-mg group than in the ebastine week of treatment (P ⫽ .048). There significantly superior to ebastine, 10 10-mg and cetirizine, 10-mg groups was also greater improvement in pa- mg, as indicated by the mean change (⫺11.9 vs ⫺10.0 [P ⫽ .030] and ⫺9.9 tient's discomfort in the ebastine, from baseline in the total symptom [P ⫽ .027], respectively). The results 10-mg group compared with the ceti- score averaged over the treatment pe- of the per-protocol analysis were sim- rizine group, but the difference did not riod (⫺13.7 ⫾ 4.7 vs ⫺11.8 ⫾ 3.8; ilar to those of the intent-to-treat reach statistical significance.
P ⫽ .027) and in the morning symp- The global assessment of efficacy tom score (⫺6.7 ⫾ 2.7 vs ⫺5.7 ⫾ 2.2; Individual nasal and ocular symp- by both the investigator and the patient P ⫽ .042). There was a similar trend tom scores followed the same trend as at the end of treatment favored ebas- favoring ebastine, 20 mg, over cetiriz- total symptom scores. There was a sta- tine, 20 mg; the difference was statis- ine, 10 mg, for the total symptom score tistically significant difference be- tically significant vs cetirizine, 10 mg, (⫺13.7 ⫾ 4.7 vs ⫺11.8 ⫾ 5.9; P ⫽ tween ebastine, 20 mg, and ebastine, in the investigator's opinion (P ⫽ .07) and morning symptom score VOLUME 76, JUNE, 1996 whom discontinued treatment because of lack of efficacy.
There were no clinically relevant ab- normalities related to drug treatment in routine laboratory tests. One patient in the cetirizine group was withdrawn from the study because of hepatitis A.
DISCUSSION
In earlier studies in patients with sea-
sonal allergic rhinitis, ebastine, 10 mg once daily, was shown to be superior to placebo and equivalent to terfena- dine, 60 mg twice daily, and equivalent to astemizole, 10 mg once daily.12 Figure 1. Mean total symptom scores (intent-to-treat analysis) for 343 patients with seasonal allergic There was no placebo group in the rhinitis treated with ebastine, 10 mg, ebastine, 20 mg, or cetirizine, 10 mg once daily for 2 weeks; *P ⫽ current study; the results demonstrate .03 for ebastine, 20 mg, vs ebastine, 10 mg, and for ebastine, 20 mg, vs cetirizine, 10 mg.
that ebastine, 10 and 20 mg once daily, are at least equivalent in efficacy to cetirizine, 10 mg once daily, for the treatment of seasonal allergic rhinitis (⫺6.7 ⫾ 2.7 vs ⫺5.7 ⫾ 3.4; P ⫽ .09), was unexpected since the incidence of in adults. Cetirizine is a second-gener- but the differences observed were only headache at this dosage was no greater ation antihistamine that has demon- numerical because of the greater stan- than that of placebo in previous clini- strated efficacy at a dosage of 10 mg dard deviation from the mean. All once daily in the treatment of seasonal treatment groups showed similar re- Two patients in the ebastine, 10-mg allergic rhinitis13 and was marketed in sults for the evening symptom scores.
group, and one patient in the cetirizine, Europe at the time the study was con- A total of 302 patients completed 10-mg group, discontinued treatment ducted. There was a general trend to- diary cards for the week following the because of adverse events (hot flushes wards greater efficacy with ebastine, discontinuation of treatment; 35% of and an acute episode of asthma in the 20 mg, although statistical analyses re- these patients were prescribed medica- ebastine group; abdominal pain in the vealed significant differences only for tion to treat recurring symptoms of al- cetirizine group). Somnolence was the reduction in patients' overall dis- lergic rhinitis. This mean percentage is also reported by one patient treated comfort after the first week of treat- difficult to interpret since patients who with ebastine, 10 mg, and by one pa- ment and for the investigators' global finished the study during the pollen tient treated with cetirizine, both of assessment of efficacy. Globally, ebas- season were likely to be more prone to retreatment than those who finished at the end of the season.
SafetyThe pattern and incidence of adverse events was similar in all three treat- ment groups (Table 4). The incidence of dry mouth, asthenia, and somno- lence were lowest in the ebastine, 10-mg group. If asthenia and somno- lence are considered together as repre- senting sedative effects, the differ- ences are more marked, with an incidence of 5.2% for the ebastine, 10-mg group, compared with 13.0% for the cetirizine, 10-mg group, and 9.9% for the ebastine, 20-mg group.
Figure 2. Mean visual analogue scale ratings (intent-to-treat analysis) for overall discomfort in 343 The high incidence of headache re- patients with seasonal allergic rhinitis treated with ebastine, 10 mg, ebastine, 20 mg, or cetirizine, 10 mg ported in the ebastine, 20-mg group, once daily for two week; *P ⬍ .05 for ebastine, 20 mg, vs cetirizine, 10 mg.
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY Table 4. Most Commonly Reported Adverse Events in 343 Patients with Seasonal Allergic Rhinitis Treated with Ebastine, 10 mg, Ebastine,20 mg, or Cetirizine, 10 mg, Once Daily for Two Weeks Ebastine, 10 mg
Ebastine, 20 mg
Cetirizine, 10 mg
n ⴝ 116 (%)
n ⴝ 111 (%)
n ⴝ 116 (%)
tine, 10 mg, and cetirizine, 10 mg, reported differences between ebas- further advantages in the management appeared to possess similar efficacy. In tine and placebo with respect to the of seasonal allergic rhinitis.
addition, maximal efficacy may be incidence of headache.
achieved more quickly with ebastine, The second-generation antihista- 20 mg, than with ebastine, 10 mg, or mines terfenadine and astemizole have We thank the numerous investigators cetirizine, 10 mg. Subgroup analyses the potential to prolong the QT who participated in this study. We also revealed that in patients with more se- val and induce fatal ventricular ar- acknowledge the assistance of Mrs. C.
vere symptoms at baseline, ebastine, rhythmias, although this is generally Vessereau for advice in statistical 20 mg, was significantly more effec- associated with high plasma concentra- tive than ebastine, 10 mg, in improving tions occurring in overdose situations or when terfenadine or astemizole is In this study, both ebastine and coadministered with drugs such as ma- 1. Horak F. Seasonal allergic rhinitis.
cetirizine were well tolerated. The crolide antibacterials, fluoxetine, itra- Newer treatment approaches. Drugs most commonly reported adverse conazole, and ketoconazole that inhibit 1993;45:518 –27.
events were dry mouth, headache, hepatic microsomal enzymes.18,19 To 2. Roberts DJ, Spickett RWJ, Moragues and somnolence. The incidence of J, et al. Ebastine, a new nonsedating date this has not been reported for somnolence and asthenia reported antihistamine. Sydney. Xth Int Cong ebastine. Indeed, pooled electrocardio- with cetirizine was higher than that gram results for 1076 patients enrolled associated with ebastine. The inci- 3. Moragues J, Roberts DJ. Ebastine.
in five multicenter clinical trials re- Drugs Fut 1990;15:674 –9.
dence of somnolence with cetirizine vealed no statistically significant dif- 4. Vincent J, Sumner DJ, Reid JL.
has also been noted to be higher than ferences in maximum observed QT Ebastine: the effect of a new antihista- other second-generation antihista- mine on psychomotor performance intervals during the double-blind pe- 1,14 with the incidence increas- and autonomic responses in healthy ing in frequency at higher dosages as riod for patients who received placebo subjects. Br J Clin Pharmacol 1988;26: shown in the dosage range of cetiriz- (n ⫽ 360) compared with those who ine, 5 to 20 mg, in a placebo-con- received ebastine, 10 mg (272) or 5. Hopes H, Meuret GH, Ungethu¨m W, et trolled trial.15 In addition, a single ebastine 20 mg (444) once daily.20 al. Placebo controlled comparison of 10-mg dose of cetirizine has been None of the patients experienced a QTc acute effects of ebastine and clemas- shown to cause mild impairment of interval greater than 500 msec or a tine on performance and EEG. Eur JClin Pharmacol 1992;42:55–9.
performance, notably during car change from baseline QTc ⬎15%. Fur- 6. Torrent J, Barbanoj MF, Izquierdo I, et driving by healthy volunteers, with thermore, no serious cardiac events al. Ebastine pharmacokinetics and an- alcohol having additive effects to were noted in any of the 226 patients tihistamine effect in man (Abstract).
those of cetirizine.16 In contrast, in a who underwent 24-hour Holter moni- N Engl Reg Allergy Proc 1988;9:474.
similar clinical pharmacology study, 7. Vincent J, Limin˜ana R, Meredith PA, ebastine (20 mg once daily for 1 A characteristic feature of the symp- Reid JL. The pharmacokinetics, anti- week) did not impair skilled perfor- tom complex of seasonal allergic rhi- histamine and concentration-effection mance in objective and subjective nitis is the variability in symptom se- relationship of ebastine in healthy sub- tests, including simulated driving, verity.21 In this context, a second- jects. Br J Clin Pharmacol 1988;26: and there was no clinically notewor- generation antihistamine that could 8. de Molina M, Cadahia A, Cano L, thy interaction between ebastine and offer practitioners the option of modi- Sanz A. Efficacy and tolerability of alcohol.17 The relatively high inci- fying the daily dosage according to ebastine at two dose levels in the treat- dence of headache in the present symptom severity, within a well-toler- ment of seasonal allergic rhinitis. Drug study was probably an artifact of the ated dosage range as is the case for Invest 1989;1:40 – 6.
study since previous studies have not ebastine, 10 to 20 mg, could provide 9. Picado Valle´s C, Cadahia Garcia A, VOLUME 76, JUNE, 1996 Cistero´ Bahima A, et al. Ebastine in 14. Backhouse CI, Renton R, Fidler C, nonsedating antihistamines terfenadine perennial allergic rhinitis. Ann Allergy Rosenberg RM. Multicentre, double- and astemizole. JAMA 1992;268:705.
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20. Connell L, Alderfer V, Garcia J. Elec- against hayfever in general practice 15. Falliers CJ, Brandon ML, Buchman E, trocardiographic evaluation of ebastine patients. J Intern Med 1989;226: et al. Double-blind comparison of ce- in double-blind allergic rhinitis clinical tirizine and placebo in the treatment of trials [poster]. 16th European Congress 11. Luria X, Blakke O, Periz JP. Ebastine: seasonal rhinitis. Ann Allergy 1991; of Allergology and Clinical Immunol- a non sedative antihistamine H ogy, Madrid, 25–30 June, 1995.
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side effect profile similar to that of 16. Ramaekers JG, Uiterwijk MM, 21. Ricketti AJ. Allergic rhinitis. In: placebo. IV World Conference on O'Hanlon JF. Effects of loratadine and Patterson R, eds. Allergic diseases, di- Clinical Pharmacology and Therapeu- cetirizine on actual driving and psy- agnosis and management. 4th edition.
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Request for reprints should be addressed to: Lack of pharmacodynamic and phar- Prof. Pierre Gehanno 13. Spencer CM, Faulds D, Peters DH.
macokinetic interactions of the antihis- Assistance Publique Hoˆpitaux de Paris Cetirizine. A reappraisal of its pharma- tamine ebastine with ethanol in healthy cological properties and therapeutic subjects. Eur J Clin Pharmacol 1992; 46 rue Henri-Huchard use in selected allergic disorders.
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75877 Paris Cedex 18 Drugs 1993;46:1055– 80.
18. Nightingale SL. Warnings issued on ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
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50-54.fm
J. Fd Hyg. Safety Vol. 27, No. 1, pp. 50 54 (2012) Available online at http://www.foodhygiene.or.kr Bactericidal Efficacy of Vital- Oxide , Disinfectant Solution Against Salmonella Typhimurium and Brucella Ovis Chun-Nam Cha , Yeo-Eun Lee , In- Jin Kang , Chang-Yeul Yoo , Sunjeong An , Suk Kim, and Hu- Jang Lee* Research Institute of Live Sciences, College of Veterinary Medicine, Gyeongsang National University,
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Neuroaesthetics: A Coming of Age Story ■ Neuroaesthetics is gaining momentum. At this early junc- gence of experimental neuroaesthetics. I then suggest a few areas ture, it is worth taking stock of where the field is and what lies within neuroaesthetics that might be pursued profitably. Finally, I ahead. Here, I review writings that fall under the rubric of neuro- raise some challenges for the field. These challenges are not