, Volume 40, Issue 5, pp 762-781
Date: 17 Nov 2012

Cetirizine

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Summary

Synopsis

Cetirizine, a piperazine derivative and carboxylated metabolite of hydroxyzine, is a potent histamine H1-receptor antagonist with antiallergic properties. It has marked affinity for peripheral histamine H1-receptors and, at the standard dose of 10mg daily, lacks the CNS depressant effects of standard antihistamines. In addition, it inhibits histamine release and eosinophil chemotaxis during the secondary phase of the allergic response. Results from controlled clinical trials indicate that cetirizine is an effective and well tolerated treatment of seasonal and perennial allergic rhinitis and chronic idiopathic urticaria. Cetirizine appears to be as effective as conventional dosages ofterfenadine, chlorpheniramine and hydroxyzine in relieving symptoms associated with these disorders and produces a markedly lower incidence of sedation than chlorpheniramine, hydroxyzine and several other standard antihistamines. Thus, cetirizine appears to provide a useful alternative to other ‘nonsedating’ antihistamines; cetirizine may also have a future role in the treatment of allergic asthma and certain forms of physical urticaria.

Pharmacodynamic Properties

Cetirizine demonstrates similar affinity to terfenadine for in vitro binding to peripheral histamine H1-receptors. However, it is highly selective for histamine H1-receptors, possessing less affinity than terfenadine or hydroxyzine for calcium channel receptors, adrenergic α1-, dopamine D2-, serotonin 5-HT2 receptors and muscarinic receptors. Standard tests of antihistaminic activity in animals have shown cetirizine to have greater potency on a weight-to-weight basis than other antihistamines such as clemastine, mepyramine, terfenadine and hydroxyzine. In human studies, suppression of the weal esponse to intradermally injected histamine was greater with cetirizine 10mg than with placebo, peaking at 4 to 8 hours and lasting up to 24 hours. Cetirizine 10mg had a similar potency to diphenhydramine 50mg, hydroxyzine 25mg and terfenadine 180mg, but was more potent than terfenadine 60mg with a more rapid onset and longer duration of action, more potent than loratadine 10mg, chlorpheniramine 6mg or mequitazine 5mg, and more rapid in onset than astemizole 10mg.

Cetirizine 5 to 20mg also provided a dose-dependent protective effect from bronchospasrn induced by inhaled histamine in asthmatics: a 20mg dose was superior in activity; o hydroxyzine 25mg.

Antiallergic activity has been shown in models using allergens and other inflammatory agents. Cetirizine had little effect on mast cells and the release of mediators of immediate hypersensitivity. However, eosinophil chemotaxis in response to allergens was inhibited in atopic subjects. An inhibitory effect on the responses of neutrophils and platelets in allergy has also been demonstrated in experimental models and human volunteers.

In psychomotor performance studies, cetirizine 10mg did not significantly affect subjective or objective assessments of drowsiness, or objective assessments of cognitive impairment in volunteers.

Pharmacokinetic Properties

Cetirizine is rapidly absorbed, reaching peak plasma concentrations of 257 μg/L within 1 hour of administration of 10mg oral doses to healthy volunteers (980 μg/L in children); AUC was 2.87 mg/L · h with this dose (6.37 mg/L · h in children). Plasma concentrations and AUC increase linearly with dose. Food does not affect the extent of absorption, but may slightly reduce the rate.

The volume of distribution of cetirizine at steady-state is 30 to 40L. Animal studies indicate that peak concentrations in the brain are less than 10% of plasma concentrations.

The terminal phase elimination half-life is 7 to 10 hours. Approximately 70% of a dose of cetirizine is excreted in the urine, mainly as unchanged drug, although small amounts of unidentified metabolites are found. Approximately 10% of the total dose is excreted in the faeces. The apparent total body clearance is 0.04 to 0.05 L/h/kg (0.06 to 0.07 L/h/kg in children).

In patients with even mild impairment of renal function, the terminal elimination half-life of cetirizine is increased to approximately 20 hours. Half-life is also prolonged in elderly volunteers, an effect independent of age per se, but dependent on renal function. The elimination half-life is somewhat shorter in children, being 6 to 7 hours.

Therapeutic Efficacy

A number of randomised double-blind studies, most placebo controlled and many crossover in design, have established the efficacy of cetirizine 5mg to 20mg daily in the treatment of seasonal and perennial allergic rhinitis, and chronic idiopathic urticaria. In addition, several reports suggest a role for cetirizine 15 to 20mg daily, administered in 2 divided doses, in the treatment of pollen-associated asthma in atopic individuals. Comparisons with other histamine H1-receptor antagonists generally indicate similar symptomatic control, as well as patient and investigator acceptance, between cetirizine 5mg to 10mg daily, terfenadine 60mg twice daily and chlorpheniramine 8mg twice daily in seasonal allergic rhinitis; cetirizine 10mg daily and terfenadine 60mg twice daily in perennial allergic rhinitis; and cetirizine 5mg to 20mg daily, terfenadine 60mg twice daily and hydroxyzine 25mg once to 3 times daily in chronic idiopathic urticaria. A single brief report indicated that cetirizine 10mg twice daily alleviated asthmatic symptoms more successfully than did terfenadine 60mg twice daily in patients with pollen-associated asthma.

Adverse Effects

In the comparative studies discussed above, the incidence of sedation and/or somnolence was generally similar between cetirizine and terfenadine, and not significantly different from that reported with placebo. In contrast, the incidence reported with chlorpheniramine 8mg twice daily in patients with seasonal allergic rhinitis, and with hydroxyzine 25mg to 75mg daily in patients with chronic idiopathic urticaria, was significantly greater than that reported with placebo. Collated results from 1502 patients who received cetirizine 10mg in double-blind placebo-controlled clinical trials conducted in Europe indicate an incidence of sedation similar to that of other ‘nonsedating’ antihistamines, such as astemizole and terfenadine, and substantially less than that with ketotifen, clemastine, chlorpheniramine or mequitazine. In these collated results, there was no significant difference between cetirizine and placebo treatment in the incidence of headache, gastrointestinal disturbance, anticholinergic effects, dizziness or cardiovascular effects.

Dosage and Administration

The recommended dosage of cetirizine in adults and children over the age of 12 is one 10mg tablet daily (Europe) or one 5 or 10mg tablet daily, up to a maximum of 20mg once daily (USA and Canada). In the elderly and in patients with even a mild degree of renal impairment dosage should be reduced.

Various sections of the manuscript reviewed by: J. Bergman, Division of Behavioral Biology, New England Regional Primate Research Center, Harvard Medical School, Southborough, Massachusetts, USA; M.L. Brandon, Allergy Medical Group of San Diego, Inc., San Diego, California, USA; R.H. Champion, Department of Dermatology, Addenbrooke’s Hospital, Cambridge, England; G.M. Cochrane, Department of Thoracic Medicine, Guy’s Hospital, London, England; C. Grangette, Centre D’Immunologie et de Biologie Parasitaire, Institut Pasteur, Lille, France; S.T. Holgate, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, England; F. Horak, Vienna Hospital, Vienna, Austria; R.T. Jackson, Section of Otolaryngology, The Emory Clinic, Atlanta, Georgia, USA; K. Kontou-Fili, Section of Allergy and Clinical Immunology, Laikon General Hospital, Athens, Greece; C. Leprevost, Centre D’Immunologie et de Biologie Parasitaire, Institut Pasteur, Lille, France; S. Makino, Department of Medicine and Clinical Immunology, Dokkyo University School of Medicine, Mibu, Japan; D.W. Moote, Allergy and Clinical Immunology, Victoria Hospital, London, Ontario, Canada; M.D. Rawlins, Department of Pharmacological Sciences, University of Newcastle upon Tyne, Newcastle upon Tyne, England; N. W. Todd, Section of Otolaryngology, The Emory Clinic, Atlanta, Georgia, USA; J.S. Turner, Division of Otolaryngology, Emory University School of Medicine, Atlanta, Georgia, USA; R. Wood-Baker, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, England.