Chronic urticaria: off-label doses of cetirizine

Drug action

Cetirizine is a second generation, non-sedating antihistamine, which selectively antagonises peripheral H₁-receptors and displays anti-allergic properties. It is a human metabolite of the sedating antihistamine, hydroxyzine (see summaries of product characteristics for cetirizine, for example, Zirtek).

Regulatory status

Cetirizine 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, 5 mg twice daily in children aged 6−12 years, and 2.5 mg twice daily in children aged 2−6 years. It is also licensed at these doses for the relief of nasal and ocular symptoms of seasonal and perennial allergic rhinitis (see summaries of product characteristics for cetirizine, for example, Zirtek).

Use of higher doses of cetirizine is off-label. In line with the guidance from the General Medical Council (GMC), it is the responsibility of the prescriber to determine the clinical need of the patient and the suitability of using cetirizine outside its authorised indications.

Cost

According to the Drug Tariff (May 2014), the cost of:

Clinical effectiveness

Okubo et al (2013)

This Japanese open-label randomised study compared the efficacy and safety of either doubling the dose of cetirizine or replacing cetirizine with olopatadine (an antihistamine which is only available as eye drops in the UK). The study included 51 people aged 16 years or over (mean 39 years) with urticaria (mean duration 7 months). H₁-receptor antagonists and other drugs (not specified) that may have affected the results were stopped at least 3 days before the study started.

All participants received cetirizine 10 mg daily for a mean of 10.1 days. People whose urticaria was refractory to cetirizine 10 mg (n=18: weal or itching graded as 'no change' or 'exacerbated', or treatment reported to be 'relatively unsatisfactory' or worse) were subsequently randomised to receive cetirizine 20 mg daily (n=9) or olopatadine 5 mg twice daily (n=9) for a mean of 13.3 days. Of the 33 people whose symptoms responded to cetirizine 10 mg, 22 continued this treatment (10 stopped treatment because their symptoms resolved and 1 because of drowsiness).

Doctors assessed the severity of weals on a scale of 0−3, where 3 is severe. Participants used a visual analogue scale to record itching. Quality of life was also assessed and an overall evaluation was made. Efficacy was evaluated in only 16 people who changed their treatment (2 people in the olopatadine group dropped out) and 16 people who continued cetirizine 10 mg (6 dropped out).

At the start of the second treatment period, the severity of urticaria varied between the groups, although the statistical significance of differences in baseline characteristics at this stage was not reported. The group that continued to take cetirizine 10 mg had less severe weals and itching than those randomised to cetirizine 20 mg, who had less severe symptoms than those randomised to olopatadine. In this treatment period, the severity of weals improved in all groups: itching improved with cetirizine 20 mg and olopatadine but worsened slightly with cetirizine 10 mg. No change in outcome was statistically significant.

Remission was achieved in 81.3% (13/16) of people in the continued cetirizine 10 mg group, 66.7% (6/9) in the cetirizine 20 mg group and 42.9% (3/7) in the olopatadine group, with no statistically significant differences between the groups. Urticaria worsened in 2 people in each of the cetirizine groups and 3 people in the olopatadine group.

Statistically significant improvements in quality of life scores were seen with continued cetirizine 10 mg (n=16). In the cetirizine 20 mg and olopatadine groups, improvements in quality of life did not reach statistical significance. However, only 5 people were evaluated in each of these groups and they had lower quality of life scores at baseline than those in the continued cetirizine 10 mg group.

Kameyoshi et al (2007)

This open-label randomised study was undertaken in secondary care in Japan. It evaluated the effect of increasing the dose of cetirizine to 20 mg in 21 people (mean age 40 years) with chronic idiopathic urticaria for more than 1 month who had seen only limited benefits (change in total daily urticarial symptom score less than 1 on a scale of 0−9; mean score 4) with the standard 10 mg dose. All participants had previously been unsatisfactorily treated with an average of 3 H₁-receptor antagonists, with or without corticosteroids. These treatments were stopped before the screening period.

Participants were randomised to 2 groups. There were no significant differences between the groups in age or mean urticarial symptom scores at baseline. All participants received cetirizine 10 mg twice daily for 1−2 weeks. Subsequently, 1 group (n=11) continued the 20 mg dosage, whereas the other group (n=10) reverted to the 10 mg dosage for a further 1−2 weeks. People assessed their daily urticarial symptom scores and recorded them in diaries. The number of weals, duration of weals and the severity of itch were each assessed on a scale of 0−3, where 3 is severe, to give a total score of 0−9.

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; mean total scores about 2.5−3). In the group that continued treatment with cetirizine 20 mg, urticarial symptom scores continued to improve (mean total score about 1.5) in the second 1- to 2‑week 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)

This double-blind crossover placebo-controlled study was undertaken in 13 adults (mean age 26.5 years) recruited from 2 dermatology clinics in Germany. It assessed cetirizine 20 mg daily for treating confirmed cholinergic urticaria (generally triggered by physical exercise or a hot shower or bath). For inclusion, participants had attacks of urticaria at least once a week for more than 1 month (mean duration 89 months) and global scores of 3 on provocation of an attack at the time of screening (mean symptoms scores at baseline on a scale of 0−3, where 3 is severe: weals 1.30, erythema 2.00 and itching 2.23). Exclusion criteria included severe chronic disease and use of systemic corticosteroids within 2 months, topical steroids within 2 weeks, other antihistamines within 4 days or anticholinergics within 2 days of study entry.

Participants were randomised to either placebo or cetirizine 20 mg daily. Once they had received a 3-week course of randomised treatment, they were switched to the alternative treatment. Participants recorded trigger factors, symptoms and use of rescue medication (cetirizine 20 mg) in a diary each day. Erythema, weals and itching were assessed on a scale of 0−3. Only the last 2 weeks of the treatment periods were analysed to allow for a washout period. Two people taking placebo were excluded during the first treatment period because of lack of adherence. Only days with trigger factors were included in analyses.

In the 11 people analysed, a statistically significant reduction was seen with cetirizine compared with placebo in weals (mean symptom score 0.23 compared with 0.92 respectively, p=0.015), erythema (mean symptom score 0.29 compared with 0.91 respectively, p=0.033), itching (mean symptom score 0.16 compared with 0.87 respectively, p=0.006) and all symptoms (mean symptom score 0.22 compared with 0.90 respectively, p=0.013). One person taking cetirizine took 1 dose of rescue medication on 1 occasion when 3 trigger factors were present. A second person used 1 dose of rescue medication on day 1 of the cetirizine treatment period and 20 doses throughout the placebo treatment period.

Zuberbier et al (1995)

This study had a similar design to Zuberbier et al (1996). It was a double-blind crossover placebo-controlled study undertaken in 25 adults aged between 18 years and 65 years (mean age 26 years) recruited from 4 dermatology clinics in Germany and Austria. The study assessed cetirizine at doses of 10 mg and 20 mg daily for treating confirmed cholinergic urticaria (triggered by exercise, stress and heat) for more than 1 month (mean duration 5.12 years). Sixteen people had previously tried other antihistamines, usually with unsatisfactory results. Exclusion criteria included liver, cardiac or renal dysfunction and use of corticosteroids within 7 days, antihistamines within 4 days or anticholinergics within 2 days of study entry. Mean baseline scores for weals, erythema and itching were 1.96, 1.96 and 2.12 respectively on a scale of 0−3, where 3 is severe.

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. Participants kept a daily diary of their symptoms (weals, erythema and itching on a scale of 0−3) and trigger factors. One person was excluded because of a major protocol violation (wrong inclusion criteria).

Evaluation of participant diaries showed that cetirizine (both groups combined) statistically significantly improved weals and itching (p=0.01 and p=0.008 respectively) compared with placebo. 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. Mean scores for individual doses were not reported. The average proportion of days with mild or no symptoms was statistically significantly higher with cetirizine compared with placebo (placebo 57%, cetirizine 10 mg 74% and cetirizine 20 mg 81%; cetirizine 20 mg compared with placebo, p=0.01).

Safety and tolerability

Evidence strengths and limitations

Well designed and reported clinical trials comparing the efficacy and safety of off-label doses of cetirizine in chronic urticaria are lacking. The 4 studies outlined in this evidence summary have many limitations that affect their application to clinical practice.

The 4 studies were all small. The numbers of participants randomised ranged from 13 to 25: the total number of people evaluated was only 76. This limits the statistical power of the studies to be able to detect differences between treatment groups. The baseline characteristics of participants were poorly reported and it is generally unclear whether there were any significant differences between treatment groups.

The treatment periods in the studies lasted between 1 and 3 weeks. This limits the studies' ability to assess long-term efficacy and adverse effects. Chronic urticaria fluctuates and any improvements in symptoms may have been due to natural variations in the disease. In addition, urticaria can depend on trigger factors, which may not always be present. Longer studies are needed to identify longer-term adverse effects and eliminate the effects of disease variation.

Although all the studies were randomised and controlled, the method of randomisation is not reported in any of them and it is unlikely that allocation was concealed. This means that researchers (unconsciously or otherwise) could have influenced which intervention group each participant was assigned to. The 2 studies by Zuberbier et al. were placebo-controlled, rather than using an active comparator. The other 2 studies (Okubo et al. 2013 and Kameyoshi et al. 2007) were not blinded. Lack of blinding is another source of bias, which may exacerbated in these studies because participants, aware of which treatment they were taking, also assessed their own symptoms. Analyses were not by intention-to-treat (dropouts were not included), which may also introduce bias.

Symptoms were assessed on severity scales (graded from 0−3) and visual analogue scales. It is not known whether the scales used have been validated in populations with chronic urticaria. In addition, it is unclear whether any statistically significant improvements seen on the symptom scales were clinically important.

Most participants in the studies had chronic urticaria lasting at least 1 month but usually much longer. In the 2 studies by Zuberbier et al., participants had cholinergic urticaria, a specific type of urticaria generally triggered by exercise, heat or stress. Participants' symptoms were generally severe and refractory to treatment with standard doses of antihistamines. None of the studies included children and young people under 16 years: the mean age of participants in 2 of the studies was about 26 years and in the other 2 studies it was about 40 years. This limits their applicability to children and young people, and older adults. Two of the studies (Okubo et al. 2013 and Kameyoshi et al. 2007) were undertaken in Japan, which limits their applicability to the UK population.

Some authors of the Zuberbier et al. studies were employed by UCB Pharma, the manufacturer of a brand of cetirizine (Zirtek).

Overall, these studies suggest that cetirizine 20 mg improves weals and itching in people with severe chronic urticaria refractory to standard doses of antihistamines and is well tolerated. However, symptoms of urticaria remain in a proportion of patients.

The EAACI/GA²LEN/EDF/WAO guideline on the management of urticaria advises that the standard dose of a non-sedating antihistamine may be increased 4-fold if standard doses are ineffective, based on studies using levocetirizine, desloratadine and rupatadine. In the development of this evidence summary, no evidence from RCTs was found supporting the use of doses of cetirizine above 20 mg. An observational study (Asero et al 2007) referenced by the EAACI/GA²LEN/EDF/WAO guideline reported that, of 22 adults with chronic spontaneous urticaria refractory to standard antihistamines, only 1 had satisfactory improvement of symptoms when the dose of cetirizine was increased from 10 mg daily to 10 mg 3 times daily.

Cost effectiveness

No cost-effectiveness studies were identified that compared the use of off-label doses of cetirizine for chronic urticaria with other treatments or placebo.

Table 1 Costs of non-sedating antihistamines licensed for urticaria

Current drug usage

No estimate of the current use of off-label doses of cetirizine for chronic urticaria in UK clinical practice was identified.

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.

Expert advisers

Dr Stephen Kownacki, GP and Executive Chair, Primary Care Dermatology Society

Dr Julian Peace, GP Valley Medical Centre, Stocksbridge and GPSI Dermatology, Barnsley NHSFT

Declarations of interest

No relevant interests declared.

Changes after publication
July 2014: Minor maintenance

Copyright

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ISBN 978-1-4731-0634-5