Key points from the evidence

The content of this evidence summary was up-to-date in July 2014. See summaries of product characteristics (SPCs), British national formulary (BNF) or the MHRA or NICE websites for up-to-date information.

Summary

Overall, 2 small randomised controlled trials (RCTs) and 2 double-blind crossover studies (total n=76) suggest that cetirizine 20 mg daily may improve weals and itching in adults with severe chronic urticaria refractory to standard doses of antihistamines. However, symptoms remain in a proportion of people and the studies have many limitations. Nevertheless, cetirizine 20 mg appears to be well tolerated and the benefits may outweigh the risks for some people whose quality of life is significantly impaired by the condition. No data are available from high quality studies on the use of cetirizine at doses higher than 20 mg.

Regulatory status: Cetirizine is licensed for the relief of symptoms of chronic idiopathic urticaria at a dose of 10 mg daily in adults. The use of higher doses of cetirizine, as discussed in this evidence summary, is off-label.

Effectiveness

  • Four small studies suggest that cetirizine 20 mg daily may improve symptoms in adults with severe chronic urticaria.

  • In Okubo et al (2013), itching and weals improved in people who took cetirizine 20 mg daily or olopatadine 5 mg twice daily as a dose increase from cetirizine 10 mg. However, improvements were not statistically significant (n=18).

  • In Kameyoshi et al (2007), urticarial symptom scores were statistically significantly improved in people who continued on cetirizine 20 mg daily after a dose increase from 10 mg daily, compared to people who had a dose increase to 20 mg daily for 1−2 weeks and who then were stepped down to 10 mg daily for 1−2 weeks (n = 21; p<0.01).

  • In Zuberbier et al (1996), a double blind crossover study (n=11), a statistically significant reduction was seen in all urticarial symptoms with cetirizine 20 mg compared with placebo (p=0.013).

  • In Zuberbier et al (1995), a double blind crossover study (n=24), the only significant difference between cetirizine 10 mg and 20 mg was in improvement of weals (p=0.04); it is not reported which dose was more effective.

Safety

  • Few adverse effects were reported in the 4 studies in this evidence summary.

  • According to the summaries of product characteristics (for example, Zirtek), cetirizine 10 mg daily has minor central nervous system adverse effects including somnolence, fatigue, dizziness and dry mouth.

Patient factors

  • Chronic urticaria can significantly reduce quality of life and is sometimes refractory to standard treatment. From the limited evidence available, cetirizine 20 mg appears to be well tolerated. Some people may be prepared to risk adverse effects such as drowsiness in order to reduce symptoms.

  • Little information is available on the use of off‑label doses of cetirizine in children and young people under 16 years, or adults over 65 years.

  • No information is available from RCTs on the use of doses above 20 mg cetirizine.

Resource implications

  • According to the Drug Tariff (May 2014), the cost of 30 cetirizine 10 mg tablets is £1.06.

Introduction and current guidance

Urticaria is a superficial swelling of the skin that results in a red, raised, itchy rash (weals). Acute urticaria may be caused by allergy to foods, drugs, irritants, insect bites and stings, physical stimuli and viral infection. It is usually a self-limiting, one-off episode. By contrast, the cause of many cases of chronic urticaria cannot be identified and it may remit and relapse, triggered by, for example, viral illness, stress, or drugs. In chronic urticaria, symptoms last for more than 6 weeks (recurrence of acute symptoms or persistent symptoms) and may last for months or years (NICE Clinical knowledge summary: urticaria).

The underlying cause of urticaria should be identified and managed, if possible. People with urticaria who need treatment should be offered a non‑sedating antihistamine at the standard licensed dose. People with severe urticaria may also be given a short course of oral corticosteroids. If response to treatment is inadequate, it is common practice to increase the dose of non‑sedating antihistamine when the potential benefits are considered to outweigh the risks (British Society for Allergy and Clinical Immunology guidelines for the management of chronic urticaria and angio-oedema, 2007).

Cetirizine is licensed for the relief of symptoms of chronic idiopathic urticaria at a dose of 10 mg daily in adults. This evidence summary looks at the evidence supporting the off-label use of high doses of cetirizine for chronic urticaria.

Full text of Introduction and current guidance.

Product overview

Cetirizine is a non-sedating antihistamine, which is licensed for the relief of symptoms of chronic idiopathic urticaria at a dose of 10 mg daily in adults and young people aged over 12 years. Lower doses are licensed for use in children. Use of higher doses of cetirizine is off‑label.

Full text of Product overview.

Evidence review

This evidence summary is based on 2 small RCTs and 2 double-blind crossover studies that assessed the safety and efficacy of doses of cetirizine higher than 10 mg for treating chronic urticaria in people with symptoms that are unresponsive to standard doses of antihistamines.

  • 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.

Full text of Evidence review.

Context and estimated impact for the NHS

According to the Drug Tariff (May 2014), the cost of 30 cetirizine 10 mg tablets is £1.06.

The NHS prescription cost analysis for England 2012 reported that 4,964,700 prescriptions for cetirizine were dispensed in primary care in England in 2011 at a net cost of £6,266,700 (net cost per item £1.26). It is not known how many of these prescription items were for chronic urticaria, or how many were for off-label doses.

Full text of Context and estimated impact for the NHS.

Information for the public

A plain English summary is available on the NICE website. This sets out the main points from the evidence summary in non-technical language and may be especially helpful for people with chronic urticaria who are thinking about trying off-label doses of cetirizine.

About this evidence summary

'Evidence summaries: unlicensed or off-label medicines' summarise the published evidence for selected unlicensed or off-label medicines that are considered to be of significance to the NHS, where there are no clinically appropriate licensed alternatives. The summaries provide information for clinicians and patients to inform their decision‑making and support the construction and updating of local formularies.

The summaries support decision-making on the use of an unlicensed or off-label medicine for an individual patient, where there are good clinical reasons for its use, usually when there is no licensed medicine for the condition requiring treatment, or the licensed medicine is not appropriate for that individual.

The strengths and weaknesses of the relevant evidence are critically reviewed within this summary, but this summary is not NICE guidance.