Levocetirizini dihydrochloridum

Pharmacotherapeutic group: Antihistamines for systemic use, piperazine derivatives, ATC code: R06AE09. Mechanism of action Levocetirizine, the (R) enantiomer of cetirizine, is a potent and selective antagonist of peripheral H1 receptors. Binding studies have shown that levocetirizine has a marked affinity for human H1 receptors (Ki = 3.2 nmol/L). Levocetirizine has twice the affinity of cetirizine (Ki = 6.3 nmol/L). Levocetirizine dissociates from H1 receptors with a half-life of 115 ± 38 min. Following a single dose, levocetirizine achieves 90% receptor occupancy at 4 hours and 57% at 24 hours. Pharmacodynamic studies in healthy volunteers have demonstrated that, at half the dose, levocetirizine produces effects on the skin and nose comparable with those of cetirizine. Pharmacodynamic effects The pharmacodynamic activity of levocetirizine has been investigated in the following randomised, controlled trials: In a study comparing the effects of levocetirizine 5 mg, desloratadine 5 mg and placebo on histamine-induced wheal and flare, treatment with levocetirizine produced a statistically significant reduction (p < 0.001) compared with placebo and desloratadine; this effect was greatest within the first 12 hours and was sustained over 24 hours. In placebo-controlled studies using an allergen exposure chamber model, the onset of action of levocetirizine 5 mg against pollen-induced symptoms was observed one hour after dosing. In vitro studies (Boyden chamber and tissue cultures) have shown that levocetirizine inhibits eotaxin-induced transendothelial migration of eosinophils across both dermal and pulmonary cells. An in vivo pharmacodynamic experimental study (skin chamber method) demonstrated, compared with placebo in 14 adult patients, three principal inhibitory mechanisms (inhibition of VCAM-1 release, modulation of vascular permeability and a reduction in eosinophil recruitment) on the pollen-induced reaction during the first 6 hours after administration of levocetirizine 5 mg. Clinical efficacy and safety The efficacy and safety of levocetirizine have been demonstrated in several double-blind, placebo-controlled clinical trials in adult patients with seasonal, perennial and persistent allergic rhinitis. Several studies have shown that levocetirizine significantly improves the symptoms of allergic rhinitis, including nasal obstruction. A six-month clinical trial in 551 adult patients (276 of whom received levocetirizine) with persistent allergic rhinitis (symptoms present 4 days a week for at least four consecutive weeks) and sensitisation to dust mites and grass pollen demonstrated that levocetirizine 5 mg was clinically and statistically significantly more effective than placebo in reducing the overall allergic rhinitis symptom score throughout the study, with no evidence of tachyphylaxis. Throughout the study, levocetirizine significantly improved patients' quality of life. In a placebo-controlled clinical trial involving 166 patients with chronic idiopathic urticaria, 85 patients received placebo and 81 received levocetirizine 5 mg once daily for over 6 weeks. Treatment with levocetirizine resulted in a significant reduction in the severity of pruritus during the first week and throughout the treatment period compared with placebo. Levocetirizine also produced a substantial improvement in health-related quality of life compared with placebo, as assessed by the Dermatology Life Quality Index. Chronic idiopathic urticaria has been studied as a model for urticarial conditions. As histamine release is a causative factor in urticarial diseases, levocetirizine is expected to provide effective symptomatic relief not only in chronic idiopathic urticaria but also in other urticarial conditions. No clinically significant effect on the QT interval has been observed on ECG with levocetirizine. Paediatric population The safety and efficacy of levocetirizine tablets in children have been investigated in two placebo-controlled clinical trials involving patients aged 6 to 12 years with seasonal and perennial allergic rhinitis. In both studies, levocetirizine significantly improved symptoms and enhanced patients' health-related quality of life. In children younger than 6 years, clinical safety has been established from several short- and long-term studies: one clinical study in which 29 children aged 2 to 6 years with allergic rhinitis received levocetirizine 1.25 mg twice daily for 4 weeks; one clinical study in which 114 children aged 1 to 5 years with allergic rhinitis or chronic idiopathic urticaria received levocetirizine 1.25 mg twice daily for 2 weeks; one clinical study in which 45 children aged 6 to 11 months with allergic rhinitis or chronic idiopathic urticaria received levocetirizine 1.25 mg once daily for 2 weeks; one long-term (18-month) clinical study in 255 atopic subjects aged 12 to 24 months at enrolment treated with levocetirizine. The safety profile was similar to that observed in the short-term studies in children aged 1 to 5 years.