, Volume 51, Issue 2, pp 260-277
Date: 31 Oct 2012

Ebastine

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Abstract

Synopsis

Ebastine is a long-acting nonsedating second generation histamine H1 receptor antagonist which binds preferentially to peripheral H1 receptors in vivo. It has shown antihistamine and antiallergic activity in healthy volunteers and patients with allergies, and protected against histamine-induced bronchoconstriction in patients with asthma.

Significant symptom improvement is observed in patients with seasonal or perennial allergic rhinitis or chronic idiopathic urticaria following administration of ebastine 10 mg/day, or 20 mg/day in severe rhinitis. In clinical trials, the efficacy of ebastine 10 or 20 mg/day was generally similar to standard dosages of terfenadine, cetirizine, astemizole and loratadine in patients with seasonal allergic rhinitis, astemizole, terfenadine and ketotifen in patients with chronic idiopathic urticaria, and ketotifen, terfenadine, chlorpheniramine and mequita-zine in patients with perennial allergic rhinitis.

The most frequent adverse events reported during ebastine therapy are drowsiness, headache and dry mouth, the incidence being similar to that reported in placebo recipients. Serious adverse cardiac events, observed on rare occasions with some other histamine H receptor antagonists, have not been reported with ebastine, and there has been no evidence of QTc interval prolongation related to ebastine therapy.

Thus, once-daily ebastine offers an effective and well-tolerated alternative to other second generation antihistamines in current use for the first-line treatment of seasonal and perennial allergic rhinitis and chronic idiopathic urticaria.

Pharmacodynamic Properties

Ebastine significantly inhibited histamine-induced wheal and flare compared with placebo. The extent of inhibition was dose-dependent with single doses of ebastine between 1 and 30mg. Onset of antihistaminic action was evident within 1 to 3 hours of ebastine administration, peaked between 3 and 12 hours, and was sustained for at least 24 hours. In a comparative study of antihistaminic activity (inhibition of wheal and flare reactions) in patients with allergic rhinitis ebastine 10mg was similar to terfenadine 60mg, superior to loratidine 10mg and less active than terfenadine 120mg or cetirizine 10mg 3 hours after drug administration. 24 hours after administration the antihistaminic activity of ebastine 10mg was similar to that of astemizole 10mg and greater than that of loratadine 10mg and terfenadine 120mg in one study. The activity of ebastine was similar to or greater than that of cetirizine.

Dose-dependent protection against histamine-induced bronchoconstriction in patients with asthma has been demonstrated after administration of ebastine 10 or 30 mg/day for 3 days.

Ebastine showed significant antiallergic activity (determined by allergen skin prick tests and nasal challenge) compared with placebo in adults and children with allergies to pollen.

Ebastine does not readily cross the blood-brain barrier and in murine studies the concentration of the drug required to inhibit [3H]mepyramine binding to cerebral H1 receptors in vitro was about 5-fold higher than that of terfenadine, and 1500-fold higher than that of chlorpheniramine. No significant effects on the CNS have been observed in healthy volunteers given doses of ebastine 10 to 30mg, and the drug did not potentiate the depressant effects of alcohol or diazepam-induced impairment of psychomotor performance.

Preclinical findings suggest that ebastine may have less potential to induce cardiovascular adverse events than terfenadine. Phase I/II clinical studies in healthy elderly and young adult volunteers found no effect of ebastine on cardiac parameters including the QTc interval. In addition, no effect on the QTc interval was observed when plasma concentrations of ebastine were increased as a result of coadministration of the drug with erythromycin or ketoconazole.

Pharmacokinetic Properties

Ebastine is a prodrug which is extensively metabolised by first-pass metabolism to its active carboxylic acid metabolite carebastine. Peak plasma concentrations (Cmax) of carebastine are reached in about 3 to 6 hours in healthy adult volunteers after administration of single oral doses of ebastine, and steady-state plasma concentrations are reached by day 3 to 5 of multiple-dose administration. Cmax and the area under the plasma concentration-time curve for carebastine increased in a dose-dependent manner following administration of ebastine 10 to 90mg, Cmax being about 0.1 mg/L after a single 10mg dose. The bioavailability of carebastine is increased when ebastine is administered with food. Carebastine is about 98% plasma protein bound and has a large volume of distribution (approximately 90 to 140L). The terminal elimination half-life is between 13 and 16 hours, carebastine being eliminated predominantly in the urine.

The pharmacokinetic properties of carebastine in healthy elderly volunteers and children aged 6 to 12 years appear to be similar to those in healthy adults. Hepatic or severe renal impairment did not affect the bioavailability of carebastine but significantly increased the terminal elimination half-life of the drug.

The metabolism of a single dose of ebastine 20mg was significantly slowed and the elimination half-life significantly prolonged in healthy volunteers when coadministered with multiple doses of ketoconazole or erythromycin.

Clinical Efficacy

Clinical trials have shown that ebastine 5 to 20mg once daily is effective in the treatment of seasonal and perennial allergic rhinitis and chronic idiopathic urticaria.

A dosage of 20 mg/day appeared to be more effective than 10 mg/day in the treatment of severe symptoms of seasonal allergic rhinitis; however, both dosages sustained symptom improvement throughout study periods of up to 4 months. Efficacy has been demonstrated in children (aged 2 to 15 years) with seasonal allergic rhinitis with dosages of ebastine 2.5 to 20 mg/day and in adolescents (aged 12 to 17 years) with perennial allergic rhinitis (5 or 10 mg/day).

In comparative studies with other antihistamines, ebastine 10mg once daily provided similar symptom relief to that achieved with terfenadine 60mg twice daily or cetirizine 10 mg/day in patients with seasonal allergic rhinitis. Ebastine 10 mg/day generally showed similar efficacy to that of astemizole 10 mg/day, although the latter was more effective against nasal blockage. The higher dosage of ebastine 20 mg/day tended to be more effective than either cetirizine or lorata-dine 10 mg/day.

Ebastine 5 mg/day was at least as effective as ketotifen 2 mg/day in improving symptoms in patients with perennial allergic rhinitis, and unpublished findings indicate that ebastine 10mg once daily is as effective as terfenadine 60mg twice daily, chlorpheniramine 6mg twice daily or mequitazine 5mg twice daily in the treatment of this condition.

In patients with chronic idiopathic urticaria, astemizole 10 mg/day initially appeared more effective in providing symptom relief than ebastine 5 or 10 mg/day; however, after 4 week’ treatment, similar efficacy was achieved with both drugs. Ebastine 10 mg/day was at least as effective as terfenadine 120 mg/day, and showed similar efficacy to ketotifen 2 mg/day.

Symptom improvement was sustained for 12 months in patients with chronic idiopathic urticaria treated with ebastine 20 mg/day.

Tolerability

Ebastine 5 to 20 mg/day was well tolerated in clinical trials, the incidence of adverse events being similar to that reported in placebo recipients. The most common adverse events were drowsiness, headache and dry mouth, which were mild to moderate in most affected patients. Other less common adverse events included asthenia, gastrointestinal discomfort, nausea/vomiting, increased appetite, diarrhoea, constipation and agitation. In long term studies (up to 1 year) the most common adverse events were headache and gastrointestinal disturbance.

Comparative studies have found ebastine to be at least as well tolerated as other histamine H1 receptor antagonists including astemizole, terfenadine, cetirizine and loratadine. Analysis of pooled ECG data from large clinical trials did not reveal any adverse cardiovascular effects in over 800 patients with allergic rhinitis treated with ebastine 1 to 30 mg/day.

Further clinical experience is warranted to confirm the apparent lack of cardiac events during therapy with ebastine.

Dosage and Administration

A single daily dose of oral ebastine 10mg is effective for the treatment of adults with allergic rhinitis or chronic idiopathic urticaria. The recommended dosage in children is 5mg once daily. A higher dosage of 20 mg/day may provide additional symptom relief in adults with more severe symptoms, and administration in the morning provides maximal benefit.

Ebastine should be administered with caution in patients with an established prolongation of the QTc interval, or hepatic or renal insufficiency.

Various sections of the manuscript reviewed by: E. Altneda, Allergy Unit, Reina Sofia Hospital, Cordoba, Spain; R.B. Berkowitz, Atlanta Allergy Clinic, Atlanta, Georgia, USA; A.L. Boner, Clinica Pediatrica, Univertiá di Verona, Verona, Italy; J. de la Cuadrà Oyanguren, Dermatology Department, Hospital General Universitario de Valencia, Valencia, Spain; H.B. Kaiser, Allergy and Asthma Specialists, Minneapolis, Minnesota, USA; K. Kontou-Fili, Section of Allergy and Clinical Immunology, Division of Internal Medicine, Athens, Greece; H.F. Krause, Department of Otolaryngology, Pittsburgh, Pennsylvania, USA; S. Lane, Department of Allergy and Respiratory Medicine, Guy’s Hospital, London, England; S. Makino, Department of Medicine and Clinical Immunology, Dokkyo University School of Medicine, Mibu, Tochigi, Japan; M.J. Mattila, Department of Pharmacology and Toxicology, University of Helsinki, Helsinki, Finland; J. Peyri, Servicio de Dermatologia, Institut Català de la Salut, Barcelona, Spain; C. Picado, Servicio de Neumologia, Hospital Clinico y Provincial, Barcelona, Spain; F.E.R. Simons, Section of Allergy and Clinical Immunology, University of Manitoba, Winnipeg, Manitoba, Canada; J. van Rooij, Dunne Bierkade, Den Haag, The Netherlands.