, Volume 64, Issue 5, pp 523-561
Date: 17 Sep 2012

Cetirizine

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Summary

Abstract

Cetirizine is a selective, second-generation histamine H1 receptor antagonist, with a rapid onset, a long duration of activity and low potential for interaction with drugs metabolised by the hepatic cytochrome P450 system. Cetirizine was generally more effective than other H1 receptor antagonists at inhibiting histamine-induced wheal and flare responses.

Cetirizine is an effective and well tolerated agent for the treatment of symptoms of seasonal allergic rhinitis (SAR), perennial allergic rhinitis (PAR) and chronic idiopathic urticaria (CIU) in adult, adolescent and paediatric patients. In adults with these allergic disorders, cetirizine was as effective as conventional dosages of ebastine (SAR, PAR, CIU), fexofenadine (SAR), loratadine (SAR, CIU) or mizolastine (SAR). This agent was significantly more effective, and with a more rapid onset of action, than loratadine in 2-day studies in environmental exposure units (SAR). In paediatric patients, cetirizine was as at least as effective as chlorphenamine (chlorpheniramine) [SAR], loratadine (SAR, PAR) and oxatomide (CIU) in the short term, and more effective than oxatomide and ketotifen (PAR) in the long term.

Cetirizine was effective in reducing symptoms of allergic asthma in adults and reduced the relative risk of developing asthma in infants with atopic dermatitis sensitised to grass pollen or house dust mite allergens. It had a corticosteroid-sparing effect in infants with severe atopic dermatitis and was effective in ameliorating reactions to mosquito bites in adults.

Cetirizine was well tolerated in adults, adolescents and paediatric patients with allergic disorders. In adult, adolescent and paediatric patients aged 2–11 years, the incidence of somnolence with cetirizine was dose related and was generally similar to that with other second-generation H1 receptor antagonists. Although, its sedative effect was greater than that of fexofenadine in some clinical trials and that of loratadine or fexofenadine in a postmarketing surveillance study. In infants aged 6–24 months, the tolerability profile of cetirizine was similar to that of placebo. Cetirizine did not have any adverse effects on cognitive function in adults, or cognitive function, behaviour or achievement of psychomotor milestones in paediatric patients. Cetirizine was not associated with cardiotoxicity.

Conclusion: Cetirizine is well established in the treatment of symptoms of SAR, PAR or CIU. It demonstrated a corticosteroid-sparing effect and reduced the relative risk of developing asthma in sensitised infants with atopic dermatitis. Cetirizine was effective in the treatment of allergic cough and mosquito bites; however, its precise role in these indications has yet to be clearly established. On the basis of its favourable efficacy and tolerability profile and rapid onset of action, cetirizine provides an important option for the treatment of a wide range of allergic disorders.

Pharmacodynamic Profile

Cetirizine, the carboxylated metabolite of hydroxyzine, exists as a zwitterion, which may partly account for its high hydrogen-binding capacity, limited biotransformation, low-to-moderate lipophilicity and limited ability to cross the blood-brain barrier. It is a highly selective histamine H1 receptor antagonist, with very low affinity for several other types of receptors, including adrenergic and serotoninergic receptors. Single or multiple doses of oral cetirizine 10mg inhibited histamine-induced wheal and flare responses in nonatopic and atopic adults and paediatric patients, and was generally more effective than therapeutic doses of several other antihistamine agents, including ebastine or loratadine. The effect of cetirizine peaked at 4–8 hours and was sustained for at least 24 hours. Cetirizine 5–20mg provided dose-dependent protection against inhaled histamine-induced bronchospasm in patients with asthma. Relative to placebo, nasal airway resistance was reduced in patients with allergic rhinitis and forced expiratory volume in 1 second was increased in patients with asthma.

Cetirizine effectively inhibited allergen-induced wheal and flare responses in atopic and nonatopic volunteers, and at therapeutic doses was at least as effective as standard doses of acrivastine, astemizole, fexofenadine or loratadine. Cetirizine has shown several modulatory effects on the inflammatory response.

Cetirizine 10mg once daily generally did not impair CNS function, although somnolence has been reported in clinical trials. At therapeutic dosages, cetirizine was associated with no or mild impairment of driving and psychometric test performance. Cetirizine did not effect cognitive function in adults, or cognitive function, behaviour or psychomotor milestones in paediatric patients.

Unlike terfenadine or astemizole, cetirizine has not been associated with adverse cardiac effects, either as monotherapy, or when administered in combination with agents that are metabolised by the cytochrome P450 system (e.g. macrolides). In healthy adult volunteers and in paediatric patients, cetirizine had no clinically relevant effect on the QTc interval or ECG parameters. In in vitro studies, cetirizine had no significant effect on cardiac potassium channels.

Pharmacokinetic Profile

Oral cetirizine undergoes rapid, dose-dependent absorption in the gut, with maximum plasma concentrations achieved in approximately 1–2 hours. There was no difference in the bioavailability of the drug with tablet and syrup formulations. Steady-state plasma concentrations are achieved within 2 days and remain stable thereafter, with no clinically relevant accumulation of the drug after 2 weeks’ treatment with oral cetirizine 10mg once daily. Although the presence of food may have some effect on the rate of absorption, there is no difference in the extent of absorption in the fasted and fed states. Approximately 90% of the drug is bound to plasma proteins, mainly albumin.

Cetirizine is extensively distributed throughout the body. Oral cetirizine was rapidly distributed into tear fluid in patients with allergic conjunctivitis and was distributed into breast milk; however, the drug does not readily penetrate the blood-brain barrier.

Cetirizine undergoes minimal metabolism and is predominantly excreted via the urine (70% of the administered dose), with a further 10% of the dose eliminated in the faeces. Small quantities of an O-dealkylation metabolite were excreted in plasma and faeces and two unidentified metabolites have been recovered in the urine. The mean terminal elimination half-life (t1/2β) of cetirizine after a single oral 10mg dose was 6.7–8.6 hours in healthy adult volunteers and the apparent total body clearance (CL) at this dosage was 2.76–5.22 L/h.

The t1/2β in paediatric patients was generally shorter than that in adults; CL values were higher. Although there were significant differences in absorption and elimination values in elderly volunteers relative to younger volunteers, these differences correlated with creatinine clearance rather than with age per se. In patients with mild-to-severe renal impairment, renal clearance and CL are decreased and t1/2β is prolonged relative to individuals with normal renal function, with haemodialysis having no clinically relevant effect on pharmacokinetic parameters. There were significant and clinically relevant changes in absorption and elimination parameters in patients with hepatic impairment relative to those with normal hepatic function.

Cetirizine has a low potential for drug interactions, since it is only minimally metabolised by the liver. Concomitant administration of cetirizine with cimetidine, theophylline or a macrolide (erythromycin or azithromycin) had no clinically relevant effect on the pharmacokinetic profiles of cetirizine or the concomitantly administered agent.

Therapeutic Use

In adult, adolescent and paediatric (aged 2–12 years) patients with seasonal allergic rhinitis (SAR), cetirizine 5 or 10mg once daily was significantly more effective than placebo, according to improvements in total symptom severity (TSS) scores and global assessments of efficacy. Cetirizine was effective in improving multiple domains of health-related quality of life (HR-QOL), assessed according to the Rhinoconjunctivitis Quality of Life Questionnaire (paediatric or adult) and the Activity Impairment-Allergy Specific questionnaire.

In adult and adolescent outpatients with SAR, once-daily doses of cetirizine 5 or 10mg were as effective as standard dosages of ebastine, fexofenadine or mizolastine in the treatment of SAR, according to improvements in TSS score and global assessments of efficacy. However, oral cetirizine 10 mg/day was not as effective as treatment with the corticosteroid fluticasone propionate 200 μg/day administered as a nasal spray. In 2-day studies in an environmental exposure unit, cetirizine 10 mg/day was significantly more effective than loratadine 10 mg/day in treating the symptoms of SAR. The onset of action was more rapid with cetirizine than loratadine (2-day study). In paediatric patients with SAR, cetirizine 10 mg/ day was as effective as chlorphenamine 2mg administered three times daily; cetirizine 10 mg/day, but not loratadine 10 mg/day, was more effective than placebo.

Cetirizine plus montelukast was as effective as topical corticosteroid (budesonide or mometasone) therapy in improving objective and subjective measures of treatment response in SAR, according to data from two small, single-blind, placebo-controlled, crossover studies.

Cetirizine 5 or 10mg once daily was significantly more effective than placebo in adult, adolescent and paediatric patients with perennial allergic rhinitis (PAR). Cetirizine 10 mg/day was as effective as short-term treatment with standard dosages of ebastine, but not long-term treatment (12 months) with budesonide, in adults and adolescents with PAR. Cetirizine significantly improved HR-QOL in adults with PAR (assessed according to the Short-Form 36 Health Survey). Short-term (1–4 weeks) cetirizine was as effective as oxatomide or loratadine in paediatric patients, but long-term treatment (12 weeks) with cetirizine was significantly more effective than oxatomide or ketotifen.

Cetirizine 10mg once daily was significantly more effective than placebo in reducing the symptoms of chronic idiopathic urticaria (CIU), including the number and size of wheals, the number of urticarial episodes and severity of pruritus. Cetirizine 10 mg/day was as effective as standard dosages of hydroxyzine or loratadine. Cetirizine was less effective than montelukast in adults and adolescents with chronic urticaria due to food additives and/or acetylsalicylic acid. The onset of action of cetirizine was faster than that of hydroxyzine. In paediatric patients (aged 2–6 years), cetirizine 5 mg/day was as effective as oxatomide 25 mg/day in reducing symptoms of CIU. Twice-daily administration of cetirizine 0.25 mg/kg was effective in the prevention of acute urticaria in infants aged 12–24 months with atopic dermatitis.

Cetirizine was associated with a reduction in total symptoms of atopic dermatitis in adult, adolescent and paediatric patients, according to data from a limited number of studies. However, at treatment end, its effect was not significantly different from that with placebo, except in recipients of cetirizine 40 mg/day (higher than the recommended dosage). Nevertheless, in infants with severe atopic dermatitis, twice-daily administration of cetirizine 0.25 mg/kg was associated with a significantly greater corticosteroid-sparing effect than placebo.

The symptoms of asthma were relieved to a significantly greater extent with cetirizine 10mg once daily than with placebo in adults with SAR. Cetirizine 0.25 mg/kg twice daily was effective in preventing the development of asthma in infants (aged 10–28 months) with atopic dermatitis who were sensitised to grass pollen or house dust mite.

Data from a limited number of small studies show that cetirizine attenuated local reactions to mosquito bites (initial wheal response and pruritus) and reduced the intensity and frequency of allergic cough in paediatric patients with allergic rhinitis.

Tolerability

In placebo-controlled studies in adults, the most common adverse experiences associated with cetirizine ≤10 mg/day were somnolence (14%), fatigue (6%), dry mouth (5%), pharyngitis (2%) and dizziness (2%). The incidence of these adverse events in placebo recipients was ≤6%. The incidence of discontinuation due to adverse events was similar in patients treated with cetirizine 5 or 10 mg/day or placebo.

In placebo-controlled studies in paediatric patients (aged 6 months to 11 years), cetirizine 5 or 10 mg/day was well tolerated. Headache (11–14%), pharyngitis (3–6%), abdominal pain (4–6%), increased coughing (3–4%), somnolence (2–4%) and epistaxis (2–4%) were commonly reported adverse experiences.

In paediatric patients aged 2–11 years, adverse experiences were more common in cetirizine than placebo recipients. In infants aged 6–24 months, the tolerability profile of cetirizine was similar to that of placebo.

The incidence of somnolence in placebo-controlled studies in adults, adolescents and paediatric patients aged 2–11 years was dose dependent. In infants aged 6–24 months, the incidence of somnolence was similar in cetirizine or placebo recipients.

The incidence of somnolence in adults and adolescents treated with cetirizine was significantly less than that in recipients of hydroxyzine, and was generally similar to that of other second-generation H1 receptor antagonists; although its sedative effect was greater than that of fexofenadine in some clinical studies and that of loratadine or fexofenadine in a postmarketing surveillance study.

Cetirizine administration was not associated with clinically relevant cardiac abnormalities in adults or adolescents (aged ≥12 years) or paediatric patients (aged 6 months to 12 years).

Overdose of cetirizine did not produce clinically significant CNS or cardiovascular toxicity, despite ingestion of a mean dose >4 times the maximum recommended daily dose.

Dosage and Administration

Oral cetirizine, available in a syrup or tablet formulation, is indicated for the relief of symptoms of SAR, PAR and CIU. In the US, cetirizine is approved for use in patients with PAR or CIU (aged ≥6 months) or SAR (aged ≥2 years), whereas in the UK it is approved for use in patients with PAR or CIU (aged ≥6 years) and with SAR (aged ≥2 years). The drug may be taken without regard to food. The recommended dosage varies from country to country, with the dosage adjustments based on age, and the presence of renal and/or hepatic impairment. Cetirizine should be given to pregnant women only if clearly indicated (pregnancy category B rating in the US).

Various sections of the manuscript reviewed by: B.G. Bender, National Jewish Medical and Research Center, Denver, Colorado, USA; J.H. Day, Kingston General Hospital, Kingston, Ontario, Canada; D. Reichmuth, Allergy and Asthma Care of Florida, Ocala, Florida, USA; R.F. Lockey, University of South Florida of Medicine, Tampa, Florida, USA; F.E.R. Simons, Children’s Hospital of Winnipeg, Winnipeg, Manitoba, Canada; G.M. Walsh, University of Aberdeen Medical School, Aberdeen, UK; J.O. Warner, University of Southampton, Southampton, UK.

Data Selection

Sources: Medical literature published in any language since 1980 on cetirizine, identified using Medline and EMBASE, supplemented by AdisBase (a proprietary database of Adis International). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.
Search strategy: Medline search terms were ‘cetirizine’. EMBASE search terms were ‘cetirizine’. AdisBase search terms were ‘cetirizine’. Searches were last updated 1 February 2003.
Selection: Studies in patients with allergic disorders who received cetirizine. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.
Index terms: cetirizine, allergic disorders, allergic rhinitis, asthma, atopic dermatitis, pharmacodynamics, pharmacokinetics, therapeutic use, tolerability, urticaria.