Rupatadine does not potentiate the CNS depressant effects of lorazepam: randomized, double‐blind, crossover, repeated dose, placebo‐controlled study

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Although one defining characteristic of second generation H1-antihistamines is their lack of CNS effects, it has been proved that some compounds of this group are not devoid of such effects.• There is evidence that second generation H1-antihistamine compounds without relevant CNS effects at therapeutic doses could increase the behavioural impairment produced by sedating drugs when both are taken concomitantly.• The evaluation of possible drug interactions is crucial, especially when both compounds could have CNS effects, due to the possible consequences at the patient safety level. WHAT THIS STUDY ADDS• The study demonstrates the lack of CNS effects after repeated administration at therapeutic doses of the unique second generation H1-antihistamine with anti-PAF activity.• The study demonstrates the lack of interaction between repeated administration of rupatadine 10 mg and a single oral dose of lorazepam 2 mg.• The study presents a useful design to evaluate the interaction between two compounds saving time and the exposure of the volunteers to medication. AIMThe main objective was to assess whether benzodiazepine intake when rupatadine plasma concentrations were at steady-state would increase the CNS depressant effects. Rupatadine is a new H1-antihistamine which also inhibits platelet activating factor (PAF) release and has been shown to be clinically effective at doses of 10 mg. METHODSSixteen healthy young volunteers took part in a crossover, randomized, double-blind, placebo controlled trial comprising two experimental periods (repeated administration for 7 days of rupatadine 10 mg or placebo as single oral daily doses, separated by a washout of 14 days). On days 5 and 7, according to a fully balanced design, a single oral dose of lorazepam 2 mg or placebo was added. CNS effects were evaluated on these days by seven objective tests of psychomotor performance and eight subjective visual analogue scales (VAS) at pre-dose and several times after drug intake. Four treatment conditions were evaluated: placebo, rupatadine 10 mg, lorazepam 2 mg and rupatadine 10 mg + lorazepam 2 mg. RESULTSSignificant CNS effects, either impairment of psychomotor performance or subjective sedation, were observed when lorazepam was administered, either alone or in combination with steady state concentrations of rupatadine. No significant differences were found between these two conditions. In addition, rupatadine was not different from placebo. All treatments were well tolerated. CONCLUSIONRepeated doses of rupatadine (10 mg orally) did not enhance the CNS depressant effects of lorazepam (2 mg orally, single dose) either in objective psychomotor tasks or in subjective evaluations.

Histamine and H1-antihistamines: Celebrating a century of progress

“…Novel agents, such as rupatadine, an H 1 -antihistamine/anti-platelet-activating factor agent, 23,24,66,71,123,125 might play a unique role. H 3 -antihistamines lead to an increase in norepinephrine and might have an advantageous decongestant effect in patients with allergic rhinitis administered with or without H 1 -antihistamines.…”

“…Second-generation H 1 -antihistamines do not exacerbate the CNS effects of concurrently used ethanol, benzodiazepines, and other CNS-active substances. 1,18,31,33,[96][97][98]123 About 15 years ago, regulatory agencies rescinded their approval for astemizole and terfenadine, the second-generation H 1 -antihistamines initially introduced, because they potentially cause QT interval prolongation and torsade de pointes. Subsequently, regulatory agencies have scrutinized all secondgeneration H 1 -antihistamines for their proarrhythmic potential and required studies of their cardiac safety at standard doses and high off-label doses, as well as drug interaction studies and studies in the elderly and other vulnerable patients.…”

Update on rupatadine in the management of allergic disorders

“…No interaction was observed when rupatadine was coadministered with fluoxetine (a substrate of CYP2D6) or ethanol . In studies performed in healthy volunteers, no clinically meaningful interaction was observed when rupatadine was coadministered with azithromycin [a gastrointestinal P‐glycoprotein (Pgp) substrate] and rupatadine did not potentiate the CNS depressant effects of lorazepam . Nevertheless, as with other antihistamines, interactions with CNS depressants cannot be excluded.…”

Psychomotor and subjective effects of bilastine, hydroxyzine, and cetirizine, in combination with alcohol: a randomized, double-blind, crossover, and positive-controlled and placebo-controlled Phase I clinical trials.

“…We selected the battery of tests based on our previous experience performing similar studies (Barbanoj et al ., , ; García‐Gea et al ., , ). In addition, these tests enable us to evaluate psychomotor performance in standardized conditions with little interference from other factors, such as interindividual or cultural differences.…”