Chronic urticaria: off-label doses of cetirizine

Okubo et al (2013) was an open-label study in which 51 people with chronic urticaria took cetirizine 10 mg daily for a mean of 10.1 days. People whose urticaria was refractory to cetirizine 10 mg (n=18) in the first treatment period were subsequently randomised to receive cetirizine 20 mg daily or olopatadine (an antihistamine which is only available as an eye drop in the UK) 5 mg twice daily in a second treatment period for a mean of 13.3 days. Of the 33 people whose symptoms responded to cetirizine 10 mg in the first treatment period, 22 continued this treatment. In the second treatment period, the severity of weals improved in all groups: itching improved with cetirizine 20 mg and olopatadine but worsened with cetirizine 10 mg. No changes were statistically significant. Remission was achieved in 81.3% of people who continued cetirizine 10 mg, 66.7% of people in the cetirizine 20 mg group and 42.9% of people in the olopatadine group, with no statistically significant differences between the groups.

Kameyoshi et al (2007) was an open-label study in which, following a screening period with cetirizine 10 mg daily, 21 people with chronic idiopathic urticaria who had an inadequate response to the 10 mg dose received cetirizine 10 mg twice daily for 1−2 weeks. Subsequently, 1 group continued the 20 mg dosage, whereas the other group reverted to the 10 mg dosage for a further 1−2 weeks. In the first 1- to 2-week period, urticarial symptom scores were statistically significantly lower than in the screening period in both groups (p<0.01 for weals, duration, itch and total scores). In the group that continued treatment with cetirizine 20 mg, urticarial symptom scores continued to improve in the second treatment period. By contrast, in the group that reverted to 10 mg, the weal, itch and total scores began to increase again, and by the end of the study the weal and itch scores were not significantly different from those seen in the screening period.

Zuberbier et al (1996) was a double-blind crossover study in 13 adults with confirmed cholinergic urticaria (generally triggered by physical exercise or a hot shower or bath). People were randomised to either placebo or cetirizine 20 mg daily for 3 weeks before switching to the alternative treatment. In the 11 people analysed (2 were excluded because of lack of adherence), a statistically significant reduction was seen with cetirizine compared with placebo for weals (p=0.015), erythema (p=0.033), itching (p=0.006) and all symptoms (p=0.013).

Zuberbier et al (1995) was a double-blind crossover study in 25 adults with confirmed cholinergic urticaria (triggered by exercise, stress and heat). People were randomised to receive cetirizine 10 mg or 20 mg daily for 3 weeks (double blind), followed by a 3-week washout period on placebo (single blind) and another 3-week period with the alternative dose of cetirizine. One person was excluded because of incorrect inclusion criteria. The difference between the 2 doses of cetirizine was significant for weals only (p=0.04); it is not reported which dose was more effective. The average proportion of days with mild or no symptoms was statistically significantly higher with cetirizine than placebo (placebo 57%, cetirizine 10 mg 74% and cetirizine 20 mg 81%; cetirizine 20 mg compared with placebo, p=0.01).

Few adverse effects were reported in the studies. According to the summaries of product characteristics for cetirizine (for example, Zirtek), adverse reactions at rates of 1% or more for cetirizine 10 mg daily in placebo-controlled clinical trials include minor central nervous system adverse effects such as somnolence, fatigue, dizziness and dry mouth.

The 4 studies outlined in this evidence summary have many limitations that affect their application to clinical practice. For example, they were small (limiting their statistical power) and of short duration (limiting their ability to assess long-term efficacy and adverse effects, particularly because urticaria fluctuates and depends on the presence of trigger factors). In addition, the method of randomisation is not reported in any of the studies and it is unlikely that allocation was concealed. Two studies were placebo-controlled, rather than using an active comparator, and the other 2 studies were not blinded. None of the study analyses were by intention-to-treat. All of these factors may introduce bias.

The studies generally included adults aged 16−65 years, which limits their applicability to children and young people under 16 years, and adults over 65 years. Two of the studies were undertaken in Japan, which may limit their applicability to the UK population.

The European Academy of Allergology and Clinical Immunology, Global Allergy and Asthma European Network, European Dermatology Forum and World Allergy Organisation guideline on the management of urticaria (EAACI/GA²LEN/EDF/WAO guideline) advises that the standard dose of a non-sedating antihistamine may be increased 4-fold if standard doses are ineffective. In the development of this evidence summary, no evidence from high quality studies was found to support the use of doses of cetirizine higher than 20 mg.