Maximum dosage of cetirizine for hives?

Q: 

Since hydroxyzine is dosed up to 100 mg at night to treat hives preventively, and since cetirizine 10 mg is the metabolic equivalent of 25 mg dosing of hydroxyzine, wouldn't guidelines suggest a max of 40 mg of cetirizine preventively?

A: 

Unfortunately there is no data available demonstrating the efficacy and/or safety for 40 mg/daily of cetirizine for chronic idiopathic urticaria, and that is why a 40 mg dose in not in any guidelines.

Hydroxyzine is approved in the US by the FDA for use in the management of pruritus due to allergic conditions such as chronic urticaria and atopic and contact dermatoses, and in histamine-mediated pruritus: in adults, 25 mg t.i.d. or q.i.d.; children under 6 years, 50 mg daily in divided doses; and over 6 years, 50 to 100 mg daily in divided doses.

The FDA approves cetirizine for use as 10 mg daily. 

Yes, hydroxyzine is metabolized in the liver to its main metabolite (45%) cetirizine.

As far as safety at a 40 mg daily dose of cetirizine, one needs to consider the possibility of increased drowsiness and/or sedation. Another concern with a much higher than recommended dose of cetirizine is the possible risk of increased QT prolongation, leading to the consequence of severe cardiac arrhythmias.

The below is from the paper by the National Institute for Health and Care Excellence (NICE) in the UK entitled “Chronic urticaria: off label doses of cetirizine,” published July 8, 2014, looking at studies on increased doses of cetirizine and their efficacy in chronic hives.

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 randomized 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 rst treatment period, 22 continued this treatment. In the second treatment period, the severity of wheals 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 rst 1- to 2-week period, urticarial symptom scores were statistically significantly lower than in the screening period in both groups (p<0.01 for wheals, 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 signi cantly 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 randomized to either placebo or cetirizine 20 mg daily for 3 weeks before switching to the alternative treatment. In the 11 people analyzed (2 were excluded because of lack of adherence), a statistically signi cant 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 randomized 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 wheals 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, Zyrtec), 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 randomization 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 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. 

  1. Asero R (2007) Chronic unremitting urticaria: is the use of antihistamines above the licensed dose effective? A preliminary study of cetirizine at licensed and above-licensed doses. Clinical and Experimental Dermatology 32: 34−8 
  2. Kameyoshi Y, Tanaka T, Mihara S et al. (2007) Increasing the dose of cetirizine may lead to better control of chronic idiopathic urticaria: an open study of 21 patients. British Journal of Dermatology 157 (4): 803−4
  3. Okubo Y, Shigoka Y, Yamazaki M et al. (2013) Double dose of cetirizine hydrochloride is effective for patients with urticaria resistant: a prospective, randomized, non-blinded, comparative clinical study and assessment of quality of life. Journal of Dermatological Treatment 24: 153−60
  4. Powell RJ, Du Toit GL, Siddique N et al. (2007) BSACI guidelines for the management of chronic urticaria and angio-oedema. Clinical and Experimental Allergy 37: 631−50
  5. Zuberbier T, Aberer W, Burtin B et al. (1995) Efficacy of cetirizine in cholinergic urticaria. Acta Dermato-Venereologica 75: 147−9
  6. Zuberbier T, Asero R, Bindslev-Jensen C et al. (2009) EAACI/GA2LEN/EDF/WAO guideline: management of urticaria. Allergy 64: 1427–43
  7. Zuberbier T, Munzberger C, Haustein U et al. (1996) Double-blind crossover study of high-dose cetirizine in cholinergic urticaria. Dermatology 193: 324−7 

Michael S. Blaiss, MD