Drugs

, Volume 59, Issue 4, pp 981–1006 | Cite as

Ebastine

An Update of its Use in Allergic Disorders
Adis Drug Evaluation

Summary

Abstract

Ebastine is a second-generation antihistamine which undergoes transformation to its active metabolite, carebastine. Its antihistaminic and antiallergic effects have been demonstrated in in vitro and in vivo studies, in addition to data obtained from clinical trials.

Patients with allergic rhinitis or chronic idiopathic urticaria experienced significant improvement in their symptoms with ebastine 10 or 20mg once daily. Some studies in patients with seasonal allergic rhinitis (SAR) have indicated trends towards greater efficacy with the 20mg than the 10mg dose, although only 1 study has shown statistically significant benefits. In comparative trials in patients with SAR, ebastine 10mg was as effective as most other second-generation antihistamines, including astemizole, azelastine, cetirizine, loratadine and terfenadine. Ebastine 20 mg/day was significantly superior to loratadine 10 mg/day in patients with SAR according to effects on secondary efficacy variables in comparative studies; 1 study found significantly greater changes from baseline in mean total symptom score with ebastine 20mg (−43 vs −36% with loratadine, p = 0.045). In patients with perennial allergic rhinitis, ebastine 10 or 20mg daily was significantly more effective than loratadine in reducing total symptom scores from baseline in 1 comparative study.

There have been no reports of serious adverse cardiac effects during ebastine therapy. Increases in corrected QT interval have been observed during clinical trials; however, these have not been considered clinically significant and were generally of similar magnitude to those seen with loratadine.The normal diurnal variation in QTc interval and the problems associated in correcting for changes in heart rate also complicate assessment of this issue. The incidence of adverse events during ebastine treatment is not significantly greater than that observed with placebo or other second-generation antihistamines.

Conclusions: Ebastine 10mg daily is a well tolerated and effective treatment for allergic rhinitis and chronic idiopathic urticaria. At this dosage, it is as effective as the other second-generation antihistamines against which it has been compared. Ebastine 20mg has similar tolerability to the 10mg dose, and trends towards greater efficacy with the higher dose have been shown in some studies. Ebastine does not appear to be associated with any significant cardiac adverse events. Ebastine is a useful treatment option for patients with allergic rhinitis or chronic idiopathic urticaria.

Pharmacodynamics

Single doses of ebastine (10mg or more) are significantly better than placebo in inhibiting histamine-induced wheal and flare. After a week of treatment, 1 study found that ebastine 10 mg/day was as active in inhibiting wheal and flare response as terfenadine 60mg twice daily and loratadine 10 mg/day. A number of trials found cetirizine 10 mg/day superior in activity to ebastine 10 mg/day at assessments performed 2 to 3 hours after drug administration; however, these differences were not detected at 24 hours. In addition, ebastine 20 mg/day was superior in activity to loratadine 10 mg/day; ebastine 20 mg/day was also more active than fexofenadine 120 mg/day at tests performed 24 hours after drug administration, although both agents were similar in effect at 4 hours.

There were no significant differences between placebo and ebastine recipients in wheal or flare responses to histamine challenge 5 days after stopping treatment (7 days of either placebo or ebastine 20 mg/day).

The antiallergic effects of ebastine have been demonstrated in in vitro and in vivo studies; assessment has included nasal challenge tests, skinprick testing, and measurement of the levels of allergic mediators in adults and children with allergies.

Single and multiple therapeutic doses of ebastine did not impair psychomotor performance or driving ability in volunteers. In addition, treatment with ebastine 20mg daily for 1 week did not potentiate the depressant effects of ethanol or the psychomotor performance impairing effects of diazepam.

Concerns regarding possible adverse cardiac effects of second-generation antihistamines have been complicated by contradicting results from in vivo and in vitro models. In clinical studies, difficulties have arisen because of diurnal variation in the QT interval and the use of differing heart rate correction formulae that may provide misleading results. However, most studies in animal in vivo or in vitro models have found that any changes in QTc interval associated with ebastine are noticeably less than those seen with similar concentrations of terfenadine and are not considered to be clinically significant. No clinically relevant abnormalities were found on 24-hour Holter monitoring of healthy elderly and young volunteers who received 10 days of treatment with ebastine 10 mg/day or placebo. Data obtained from >1000 patients enrolled in controlled trials also indicate that ebastine 10 or 20 mg/day is not associated with clinically significant changes in corrected QT (QTc) interval.

Although increased plasma levels of ebastine have been observed during coadministration with ketoconazole or erythromycin, any associated changes in QTc interval have been small and not clinically significant.

Pharmacokinetics

Plasma levels of ebastine are low or undetectable after oral administration; therefore, pharmacokinetic studies generally measure the concentrations of the active metabolite, carebastine. In vitro studies using human liver microsomes indicate that, although the metabolism of ebastine does involve the cytochrome P450 (CYP) CYP3A4 enzyme, the conversion of ebastine to carebastine appears to be mediated by other unidentified enzymes. The pharmacokinetics of carebastine are linear.

After oral administration of ebastine 10mg to healthy volunteers, peak plasma concentrations (Cmax) of carebastine ranged from 0.09 to 0.12 mg/L, with a time to reach Cmax of 2.6 to 5.7 hours. Values for the area under the plasma concentration-time curve (AUC) ranged from 1.75 to 2.94 mg/L·h. Results from 2 studies found the volume of distribution of carebastine to be 89.5 and 123L. The elimination half-life (t1/2β) of carebastine ranged from 10.3 to 19.3 hours, with the main route of excretion being the kidneys.

Pharmacokinetic parameters in children and elderly volunteers were generally similar to those seen in healthy adults, although values for Cmax and AUC were higher in children than in adults. Patients with hepatic or severe renal impairment (creatinine clearance <1.8 L/h/1.73m2) had significantly increased values for t1/2β compared with those obtained from healthy volunteers.

The metabolism of single doses of ebastine 20mg was significantly impaired in healthy volunteers receiving multiple doses of either ketoconazole or erythromycin (drugs that inhibit CYP metabolism). In contrast, cimetidine had no significant effects on the metabolism of a single dose of ebastine 20mg.

Therapeutic Use

In clinical trials, ebastine 10 to 20mg once daily for 1 to 12 weeks was effective in the treatment of adults with allergic rhinitis. Although there is a lack of statistical data, studies in patients with seasonal allergic rhinitis (SAR) indicate a trend towards greater efficacy with ebastine 20mg than with 10mg, with 1 study showing significantly greater reductions in total symptom score with the higher dose (13.7 vs 11.8 with 10 mg, p = 0.027) in the subgroup of patients with more severe symptoms (defined as those with a baseline total symptom score greater than the mean for the study population).

In patients with SAR, comparative trials have shown ebastine 10 mg/day to be as effective at relieving symptoms as total daily doses of astemizole 10mg, azelastine 0.56mg (as an intranasal spray), cetirizine 10mg, loratadine 10mg and terfenadine 120mg. In 1 of 3 similarly designed trials (all unpublished, double-blind and placebo-controlled), ebastine 20 mg/day produced significantly greater percentage reductions from baseline in mean total symptom score than those seen with loratadine 10 mg/day (−43 vs −36%, p = 0.045). Although changes in mean total symptom score did not differ significantly between treatments in other studies, all found ebastine 20mg to be significantly superior to loratadine according to some or most of the secondary efficacy variables. Ebastine 20mg daily was also significantly superior to cetirizine 10mg daily in some of the variables assessed after 1 week in a double-blind study in 343 patients with SAR; however, at the end of the 2-week study, cetirizine had reached a similar level of efficacy.

Once-daily doses of ebastine 10mg and astemizole 10mg were similarly effective when used as prophylaxis against the onset of SAR symptoms in a non-blind randomised study in 217 patients with a history of SAR.

Data on efficacy of ebastine in children are limited; however, 1 double-blind study in 173 children with SAR found that ebastine 5 mg/day for 3 weeks significantly improved overall symptom scores compared with placebo.

Ebastine 10 and 20 mg/day are significantly more effective than placebo for improving symptoms of perennial allergic rhinitis (PAR). No significant differences have been found between the 2 doses. In 1 large comparative randomised double-blind trial in patients with PAR, ebastine 10 and 20mg were significantly more effective than loratadine 10mg at reducing total symptom scores from baseline. Ebastine 10mg daily was also as effective as cetirizine 10 mg/day in improving total PAR symptom scores from baseline during a 4-week trial; however, improvement was significantly faster with cetirizine, and significantly more cetirizine recipients were symptom-free by the end of the trial (17.8 vs 6.9% with ebastine, p = 0.02).

Ebastine 5 to 20mg daily is as effective in the treatment of chronic idiopathic urticaria as terfenadine 60mg twice daily, ketotifen 2mg once daily and astemizole 10mg once daily. Preliminary findings from studies also indicate benefits in the treatment of pruritic dermatoses, and significant improvements in morning peak expiratory flow rates in 20 patients with asthma were seen during treatment with ebastine.

Tolerability

Ebastine was well tolerated in clinical trials, with a similar incidence of adverse events to that observed with placebo. In comparative trials with other second-generation antihistamines, ebastine was at least as well tolerated as astemizole, cetirizine, loratadine and azelastine. There have been no significant differences in tolerability reported between ebastine 10 and 20mg.

The adverse events most commonly reported during treatment with ebastine 10 or 20mg were headache (≈6 to 13% of patients in individual trials), somnolence (1.4 to 9%) and dry mouth (4 to 7%). Less frequently occurring adverse events (<5% of patients) included asthenia, nausea, abdominal pain, gastrointestinal upset, altered appetite and insomnia.

Although both terfenadine and astemizole have been associated with serious cardiac abnormalities — in particular, ventricular arrhythmias — no such events have been reported during treatment with ebastine. Some studies have found small statistically significant increases in QTc interval (compared with baseline or placebo values) during treatment with ebastine 20mg daily; however, these differences were not considered clinically significant and were not sustained throughout the studies. Normal diurnal variation and the use of heart rate correction formulae also complicate the assessment of the significance of these changes. Comparative studies found similar percentages of patients with QTc intervals >0.444 seconds with ebastine (10 or 20mg) and loratadine 10mg. Analysis of pooled ECG data from a number of large clinical trials did not find any patients treated with ebastine who had QTc intervals of >0.5 seconds.

Laboratory tests failed to find any clinically significant differences between patients who received ebastine and those who received placebo or other second-generation antihistamines.

Dosage and Administration

Single daily oral doses of ebastine 10mg are effective in the treatment of adults with allergic rhinitis or chronic idiopathic urticaria; increasing the dose to 20mg daily does not significantly affect tolerability and may be of use in some patients. A dose of 5mg daily is recommended in children. Ebastine, like other antihistamines, should be used with caution in patients with known QTc prolongation.

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© Adis International Limited 2000

Authors and Affiliations

  1. 1.Adis International LimitedMairangi Bay, AucklandNew Zealand

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