Cetirizine, the carboxylated metabolite of hydroxyzine, is a specific and long-acting histamine H1-receptor antagonist. It has marked antiallergic properties and inhibits eosinophil chemotaxis during the allergic response. Clinical trial results indicate that cetirizine is an effective and well tolerated treatment for seasonal/perennial allergic rhinitis and chronic idiopathic urticaria in adults, and for seasonal/perennial allergic rhinitis in children. Cetirizine 10 mg/day appears to be as effective as conventional dosages of other established antihistamines such as astemizole, hydroxyzine, ketotifen, loratadine or terfenadine in relieving symptoms of these disorders, and is associated with a significantly lower incidence of sedation than hydroxyzine. However, when sedation was subjectively assessed, cetirizine appeared to be more sedating than placebo, loratadine or terfenadine in some clinical trials. This difference was not observed in several other double-blind studies. In contrast, when assessed objectively in pharmacodynamic comparisons, cetirizine was rarely more sedating than placebo or other second generation histamine H1-receptor antagonists. Cetirizine may also have a role in the treatment of certain forms of physical urticaria, atopic dermatitis and reactions to mosquito bites. In addition, it is being studied for the treatment of allergic asthma in adults and children. The pharmacokinetic profile and predominantly renal excretion of cetirizine suggest that this agent may have a reduced potential for adverse drug interactions involving hepatic enzyme systems compared with other histamine H1-receptor antagonists which are extensively metabolised. Thus, cetirizine, with its rapid onset and long duration of action, appears to provide a useful alternative to the antihistamine agents in clinical use.
Overview of Pharmacology
Cetirizine is a specific histamine H1-receptor antagonist which has greater antihistaminic activity than clemastine, hydroxyzine, mepyramine and terfenadine in animal models. In atopic and nonatopic volunteers, cetirizine 10mg, administered as a single dose or daily for 2 to 28 days, significantly suppressed histamine-, allergen- and antigen-induced weal and flare response compared with placebo. Following histamine challenge, this effect peaked 4 to 8 hours after administration of cetirizine and lasted up to 24 hours after a single dose. Against histamine-induced weal and flare, cetirizine 10mg had similar activity to diphenhydramine 50mg or hydroxyzine 25mg, and was at least as effective as standard doses of astemizole, azelastine, brompheniramine, chlorphenamine (chlorpheniramine), clemastine, cyproheptadine, ebastine, ketotifen, loratadine, mequitazine, oxatomide or terfenadine. In addition, it had a significantly more rapid onset of action than astemizole 10mg against histamine-induced weal and flare. In antiallergic assessments of weal and flare response, cetirizine 10mg was as active as astemizole 10mg, ketotifen 1mg or terfenadine 120mg, and was significantly more active than chlorphenamine 8mg or loratadine 10mg. A 20mg dose of cetirizine was also superior to clemastine 2mg in antiallergic studies.
Cetirizine 5 to 20mg provided dose-dependent protection against inhaled histamine-induced bronchospasm in patients with asthma, and protected some patients from allergen-induced bron-chospasm. The immediate and late responses to allergen challenge in patients with allergic rhinitis were also attenuated by cetirizine 10 mg/day. The effect of cetirizine 10mg on histamine-induced bronchial response was significantly greater than that of astemizole 10mg, brompheniramine 4mg, chlorphenamine 4mg, clemastine lmg, cyproheptadine 4mg or terfenadine 60mg, while cetirizine 20mg was superior to hydroxyzine 25mg.
Most in vitro investigations and studies in atopic or healthy volunteers showed that cetirizine had no effect on mast cells, but inhibited neutrophil and platelet responses following allergen challenge. Eosinophil chemotaxis following challenge with allergen, platelet activating factor or compound 48/80, but not histamine, was inhibited by cetirizine in a dose-dependent fashion. In addition, intercellular adhesion molecule-1 expression on epithelial cells was inhibited by cetirizine in vitro and in vivo, suggesting that cetirizine also has activity other than antagonism of histamine H1-receptors.
In pharmacodynamic studies, subjective and objective measurements of drowsiness and cognitive performance were not usually significantly altered by cetirizine in single doses of ≤ 20mg. The incidence of sedation with cetirizine 10mg was similar to that of placebo, loratadine 10mg, or terfenadine 120mg, but was significantly less than that of oxatomide 30mg or ketotifen 1mg in pharmacodynamic studies conducted in nonatopic volunteers. In most assessments of psychomotor performance, cetirizine 5 to 20mg in single or repeated doses caused no impairment, whereas a single 10mg dose caused significant impairment of driving performance in 1 trial.
Mean peak plasma concentrations (Cmax) of 257 and 580 μg/L were reached within 1 hour of the oral administration of cetirizine 10 and 20mg, respectively, to healthy adult volunteers. Food may delay the rate, but does not affect the extent, of cetirizine absorption. In adults, the terminal elimination half-life (t½β) is 6.5 to 10 hours. Over a 5-day period, about 70% of cetirizine 10mg is excreted in the urine (60% over 24 hours), predominantly as unchanged drug, and about 10% is excreted in the faeces. Cmax and t½β of cetirizine on a mg/kg basis are lower in very young children with symptoms of allergy than in adults, suggesting more rapid elimination in the former. In patients with renal impairment, the t½β of cetirizine is increased reflecting a reduction in renal and total body clearance. These parameters are similarly altered in the elderly, an effect that appears to be dependent on renal function rather than age per se.
The efficacy of cetirizine 5 to 20 mg/day in the treatment of seasonal and perennial allergic rhinitis, and chronic idiopathic urticaria has been established in a number of randomised blinded clinical studies. In addition, higher dosages of cetirizine tended to reduce some symptoms of mild allergic asthma (10 to 30 mg/day), were effective in the treatment of some physical urticarias (10 to 30 mg/day), and reduced symptoms in patients with moderate to severe atopic dermatitis (10 to 40 mg/day). Local reactions to mosquito bites have also been attenuated by treatment with cetirizine 10 mg/day.
In comparisons with other antihistamines, cetirizine 5, 10 or 20 mg/day produced at least similar symptomatic control to astemizole 10 mg/day, loratadine 10 mg/day, or terfenadine 60mg twice daily or 120 mg/day in patients with seasonal allergic rhinitis; astemizole 10 mg/day, ketotifen 2 mg/day or terfenadine 120 mg/day in patients with perennial allergic rhinitis; astemizole 10 mg/day, hydroxyzine 25 to 75 mg/day or terfenadine 120 mg/day in those with chronic idiopathic urticaria; and terfenadine 60mg twice daily in patients with mild allergic asthma or atopic dermatitis. Cetirizine 5 or 10 mg/day was also effective in children (aged ≤ 12 years) with seasonal or perennial allergic rhinitis, while dosages of 5 to 15mg twice daily reduced the incidence of mild asthma in children and adolescents.
In a summary of placebo-controlled clinical trials, the most commonly reported adverse effects during cetirizine therapy were sedation, headache, dry mouth, fatigue and nausea. Comparative trials which included small numbers of patients and the results of earlier trials suggested that the incidence of sedation seen with cetirizine was similar to that of placebo, astemizole, loratadine or terfenadine. However, in some more recent comparisons cetirizine 10 mg/day tended to produce more sedation than loratadine 10 mg/day, terfenadine 120 mg/day or placebo. In contrast, cetirizine 5 to 20 mg/day produced significantly less sedation than hydroxyzine 25 to 75 mg/day. Spontaneously resolving liver function test abnormalities have been infrequently reported during cetirizine therapy.
Dosage and Administration
In adults and children aged > 12 years, the recommended initial cetirizine dosage is 10 mg/day (Europe) or 5 to 10 mg/day, up to a maximum of 20 mg/day (US and Canada). The recommended dosage for children aged 2 to 6 years is 5 mg/day, and for those aged up to 11 years it is 10 mg/day. In patients with moderate or severe renal impairment, the dosage of cetirizine should be reduced.