Source: Web Search Revision Year: 2007 Publisher: Laboratorios Almirall S.A., Rondo General Mire, 151, 08022 Barcelona, Spain
Ebastine has been shown to produce a rapid and long-lasting inhibition of histamine-induced effect and to have a strong affinity towards H1-receptors.
Following oral administration neither ebastine nor its metabolites cross the blood brain barrier. This characteristic is consistent with the low sedative profile seen in the results of experiments studying the effects of ebastine on the central nervous system.
In vitro and in vivo data demonstrate that ebastine is a potent, long lasting and highly selective histamine H1-receptor antagonist devoid of untoward CNS actions and anticholinergic effects.
Histamine skin wheal studies have shown a statistically and clinically significant anti-histamine effect beginning at 1 hour and lasting in excess of 48 hours. After the discontinuation of the administration of a 5 day-course of treatment with ebastine, the anti-histamine activity remained apparent for more than 72 hours. This activity parallels the plasma levels of the main active acid metabolite, carebastine.
After repeated administration, inhibition of the peripheral receptors remained at a constant level, without tachyphylaxis. These results suggest that ebastine at a dose of at least 10 mg produces a rapid, intense and long-lasting inhibition of peripheral H1-histamine receptors, consistent with a once-a-day administration.
Sedation was studied through pharmaco-EEG, cognitive performance, visual-motor co-ordination tests and subjective estimates. There was no significant increase of sedation at the recommended dose. These results are consistent with those from double-blind clinical trials; the incidence of sedation is comparable between placebo and ebastine.
The actions of ebastine on the heart have been investigated in clinical trials. No influence on the heart, including prolongation of the QT interval, has been observed at the recommended doses. In two studies using repeated doses up to 100 mg per day or 500 mg as a single dose, with a limited number of subjects (n=24 and n=5) small increases in heart rate of a few beats per minute resulted in a shortening of the QT interval with no significant effect of the appropriately corrected QTc.
Ebastine is rapidly absorbed and undergoes extensive first pass metabolism following oral administration. Ebastine is almost totally converted to the pharmacologically active acid metabolite, carebastine. After a single 10 mg oral dose, peak plasma levels of the metabolite occur at 2.6 to 4 hours and achieve levels of 80 to 100 ng/ml.
The half-life of the acid metabolite is between 15 to 19 hours with 66% of the drug being excreted in the urine mainly as conjugated metabolites. Following the repeated administration of 10 mg once-daily, steady state was achieved in 3 to 5 days with peak plasma levels ranging from 130 to 160 ng/ml.
In vitro studies with human liver microsomes show that ebastine is metabolised to carebastine predominantly via the CYP3A4 pathway. Concurrent administration of ebastine with ketaconazole or erythromycin (both CYP3A4 inhibitors) to healthy volunteers was associated with significantly increased plasma concentrations of ebastine and carebastine (see Section 4.5, Interaction with other medicinal products and other forms of interaction).
Both ebastine and carebastine are highly protein bound, >95%.
In elderly subjects, no statistically significant changes were observed in the pharmacokinetics compared to those of young adult volunteers.
In patients with mild, moderate or severe renal insufficiency and in patients with mild to moderate hepatic insufficiency treated with daily doses of 20 mg of ebastine, as well as in patients with severe hepatic insufficiency treated with 10 mg of ebastine, the pharmacokinetic behaviour was not relevantly modified in comparison with healthy subjects. In patients with mild to moderate renal insufficiency, mean carebastine exposure was higher than that observed in healthy volunteers, whereas the plasma concentrations of this metabolite in patients with severe renal failure and in patients with mild, moderate or severe hepatic insufficiency were similar to those observed in healthy subjects. The elimination half-lives of ebastine and carebastine in all groups of patients were in the same range as those of healthy subjects.
Taking into account the high intraindividual variability of both parent drug and metabolite, as well as the wide therapeutic margin, the variations observed in the pharmacokinetic parameters are not likely to be of any clinical significance.
Not applicable.
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