|Year : 2022 | Volume
| Issue : 1 | Page : 28-31
Comparative clinical assessment of updosing of bilastine and combination of levocetirizine and hydroxyzine in chronic spontaneous urticaria
Bela Shah1, Deval Mistry1, Neha Jangid1, Shikha Shah1, Shruti Kamat1, Dhiraj Dhoot2, Gaurav Deshmukh2
1 Department of Dermatology, Venereology and Leprosy, BJ Medical College, Civil Hospital, Ahmedabad, Gujarat, India
2 Global Medical Affairs, Glenmark Pharmaceuticals Limited, Mumbai, Maharashtra, India
|Date of Submission||04-Apr-2021|
|Date of Decision||25-May-2021|
|Date of Acceptance||12-Jul-2021|
|Date of Web Publication||25-Feb-2022|
B D Sawant Marg, Chakala, Andheri (E), Mumbai, Maharashtra
Source of Support: None, Conflict of Interest: None
Background: Second-generation antihistamines (SGAHs) are first-line drugs in management of chronic spontaneous urticaria (CSU). However, almost 50% of the patients do not respond to standard dose of SGAH. Various guidelines recommend either updosing of SGAH or combination of different antihistamines in such patients. However, the studies comparing these treatment regimens are limited. Materials and Methods: In this comparative study, CSU patients were randomized to receive standard dose of either bilastine or levocetirizine for 2 weeks. After 2 weeks of treatment, nonresponders received a double dose of bilastine while hydroxyzine 25 mg once daily was added in the levocetirizine group. Patients were primarily evaluated for improvement in CSU, quality of life (QOL), and somnolence. Results: At the end of 2 weeks, 23/39 and 17/36 achieved well-controlled urticaria, and at the end of 4 weeks, 9/16 and 5/19 patients achieved well-controlled urticaria in the bilastine and levocetirizine groups, respectively. Only one patient in the bilastine group was symptom free and none in levocetirizine at the end of 4 weeks. At week 2, there was no statistical difference in Urticaria Activity Score over 7 days (UAS7) improvement between both the groups, however, at week 4, there was a statistical difference (P < 0.05). Somnolence was significantly lower in the bilastine group (P < 0.05). Bilastine was statistically significant (P < 0.05) in the improvement of QOL by CU-Q2oL as compared to levocetirizine. No major adverse events were reported during study period, however, bilastine was associated with significantly lower Adverse events (AEs) compared to levocetirizine (P < 0.05). Conclusion: Updosing of bilastine improves CSU symptoms without compromising safety as compared to combination of levocetirizine and hydroxyzine.
Keywords: Bilastine, chronic spontaneous urticaria, hydroxyzine, levocetirizine, updosing
|How to cite this article:|
Shah B, Mistry D, Jangid N, Shah S, Kamat S, Dhoot D, Deshmukh G. Comparative clinical assessment of updosing of bilastine and combination of levocetirizine and hydroxyzine in chronic spontaneous urticaria. Clin Dermatol Rev 2022;6:28-31
|How to cite this URL:|
Shah B, Mistry D, Jangid N, Shah S, Kamat S, Dhoot D, Deshmukh G. Comparative clinical assessment of updosing of bilastine and combination of levocetirizine and hydroxyzine in chronic spontaneous urticaria. Clin Dermatol Rev [serial online] 2022 [cited 2022 Sep 25];6:28-31. Available from: https://www.cdriadvlkn.org/text.asp?2022/6/1/28/338592
| Introduction|| |
H1 receptor antagonists (H1-antihistamines) are the mainstay of treatment in chronic spontaneous urticaria (CSU). Modern second-generation antihistamines (SGAHs) are preferred over first-generation antihistamines (FGAHs) as first-line symptomatic treatment for CSU because of their good safety profile. However, treatment with licensed dose of H1-antihistamine leads to the absence of symptoms in <50% of the patients with CSU. In these refractory CSU patients, the European Academy of Allergy and Clinical Immunology/Global Allergy and Asthma European Network/European Dermatology Forum/World Allergy Organization guidelines recommend increasing the dosage up to fourfold. However, apart from updosing, Japanese and American guidelines recommend either switching to other H1-antihistamines or combination of antihistamines. In real-world practice in India, many physicians prescribe SGAH in the morning and FGAH in the evening as a combination of antihistamines. However, no study has provided high-quality evidence about the efficacy of combination of H1-antihistamines in patients with CSU.
This study was designed to mimic the real-life situation in which the antihistamine dose is either increased gradually or combined with FGAH depending on the effectiveness of the previous dose. Levocetirizine dihydrochloride, cetirizine hydrochloride, fexofenadine hydrochloride, hydroxyzine hydrochloride, etc., are available for a long time and are commonly prescribed antihistamine in CSU in India. Recently, bilastine received approval in the management of CSU. We report an open-label, comparative study of the effects of bilastine at 20 mg and levocetirizine 5 mg daily for 2 weeks in CSU patients and then updosing of bilastine to 40 mg/day and combination of levocetirizine 5 mg and hydroxyzine 25 mg for another 2 weeks in nonresponsive patients.
| Materials and Methods|| |
After obtaining ethics committee approval (Om Institutional Ethics Committee; ECR/1168/Inst/GJ/2018), this prospective, comparative study was done in a tertiary care hospital in Ahmedabad during April 2020 to October 2020. Eligible patients within the age group of 18–60 years and with a clinical history of CSU for at least 6 weeks with an identifiable cause and Urticaria Activity Score over 7 days (UAS7) of ≥7 were recruited. A total of 75 patients were included in the study, as shown in [Figure 1].
Following 1-week baseline period, during which only rescue medication of prednisolone 30 mg was allowed, there were two treatment periods each of 2 weeks. During the first treatment period, all 75 patients took either 20 mg bilastine or levocetirizine 5 mg orally every day at night. At the end of this period, all patients with a complete response (UAS7 ≤ 6) were discontinued from further analysis. The remaining 35 patients went on to the second treatment period, during which 16 patients in the bilastine group took 40 mg bilastine daily (20 mg twice a day), whereas 19 patients in the levocetirizine group took levocetirizine 5 mg in the morning and hydroxyzine 25 mg at night. During each period, patients made daily recordings of their Urticaria Activity Score (UAS) and documented any adverse responses. At the end of each period, the patients underwent a physical examination and their UAS7 was calculated for the last 7 days. The primary outcome measures included improvement in urticaria symptoms (UAS7), somnolence Visual analogue scale (VAS), and quality of life (QOL). Study design and baseline demographics are detailed in [Figure 1] and [Table 1], respectively.
| Results|| |
In initial 2-week treatment period, the mean (±SD) UAS7 fell from a baseline value of 17.63 ± 3.99 to 7.85 ± 4.56 in the bilastine group, whereas in the levocetirizine group, it was reduced to 9.47 ± 5.39 from 17.98 ± 5.09. This fall was statistically significant in both the groups (P < 0.05) (paired t-test), but there was no statistical difference between both the groups (P = 0.16). Following first treatment period, 23 patients (59%) in the bilastine group and 17 patients (47.2%) in the levocetirizine group had well-controlled urticaria whereas 14 and 13 patients had mild activity urticaria in the bilastine and levocetirizine groups, respectively. None of the patients was symptom free in any of the groups [Figure 2]. There was no statistical difference (Fisher's exact test, P = 0.8) between the two groups.
|Figure 2: Total number of patients with improvement at weeks 2 and 4 by as per UAS7|
Click here to view
Updosing to 40 mg bilastine produced a further mean UAS7 fall from 12.56 ± 3.08 to 5.25 ± 3.09. This 59% fall was statistically significant (P < 0.001). Similarly, after adding hydroxyzine to levocetirizine, the mean UAS7 fell from 13.68 ± 3.9 to 8.0 ± 3.14 (41% reduction; P < 0.001). On comparison between the two groups, statistical difference was seen (P = 0.013), suggesting superiority of bilastine. Furthermore, 9 patients (56.25%) in the bilastine group and 5 patients (26.3%) in the levocetirizine group had well-controlled urticaria whereas 1 patient became symptom free in the bilastine group and none in the levocetirizine group [Figure 2]. This difference was statistically significant (P = 0.04, Fisher's exact test) between the two groups.
Urticaria-associated discomfort during the preceding week was measured using VAS. In terms of VAS, there was a statistical difference between the bilastine and levocetirizine groups at both visits [Figure 3]. It suggests that bilastine is well accepted as a nonsedating antihistamine as compared to levocetirizine by patients. A major concern with increasing doses of H1-antihistamines is that of somnolence. Sleepiness with the drug was measured by VAS. Levocetirizine had a higher mean VAS score and it increased when hydroxyzine was added. The somnolence score of bilastine did not increase when it was updosed. Bilastine was statistically better (P < 0.05) than levocetirizine as a nonsedating antihistamine.
|Figure 3: Primary outcomes measured during the follow-up visits (2nd and 4th weeks) by VAS|
Click here to view
QOL was assessed by using the Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL), which asked questions about pruritus, swelling, and impact on life activities, sleep problems, looks, and limits to obtain the patient's view of both the overall impact of chronic urticaria and the effectiveness of its treatment. The results showed that bilastine is statistically significant (P < 0.05) in the improvement of QOL by CU2QoL as compared to levocetirizine at both visits [Figure 4].
|Figure 4: Changes in quality of life measured during the follow-up visits (weeks 2 and 4)|
Click here to view
A total of 23 adverse events were reported [Table 2]. These included sedation (14), headache (3), nausea (4), and fatigue (2). In terms of AE, there was a statistical difference between the bilastine and levocetirizine groups (P < 0.05). This could be due to addition of hydroxyzine in levocetirizine arm. No other major adverse events occurred.
| Discussion|| |
The current guidelines recommend increasing the dose of SGAH in CSU patients who do not respond to licensed doses to obtain a better disease control. A number of publications that evaluated different SGAHs in increasing doses have clearly shown that majority of patients with previously uncontrolled CSU exhibit significant improvements of their symptoms after going through this approach.,
In our study, on updosing 56.25% of the patients responded well to bilastine 20 mg twice a day. This is in concordance with other studies done on bilastine., Weller et al. in their study concluded that updosing of bilastine by twofold was an effective approach for the majority of CSU patients.
Since more than 40% of the CSU patients do not respond to standard dose of SGAHs, some guidelines suggest addition of a second antihistamine., Although the use of FGAH is discouraged in the European guideline, as per one report, 15% of the patients were treated with hydroxyzine at some time during their disease. Moreover, after failure of treatment with SGAHs, successful use of FGAH has been described. Furthermore, the US guideline does support the use of FGAH in patients who do not achieve adequate control of their symptoms with higher dose SGAHs.
In our study, we added hydroxyzine in levocetirizine arm to compare the efficacy and safety of this combination with updosing of bilastine. It was found that only 35.7% of the patients were under control of CSU. On comparison, updosing of bilastine was statistically significant than this approach. This was not in accordance with one of the published reports where addition of FGAH leads to sufficient disease control.
It is well known that somnolence is one of the most reported unwanted effects of antihistamines. However, in our study, patients on bilastine did not experience increased somnolence when stepping up their daily dose. Moreover, patients in the bilastine group had lower somnolence than levocetirizine at both visits, days 14 and 28. It could be due to tolerance to somnolence which can develop within 4 days of subsequent use of H1-antihistamines., In a previously conducted study, sedation was significantly lower in the bilastine 20 mg group compared to levocetirizine 5 mg. Hydroxyzine, a first-generation sedating antihistamine, is known to cause drowsiness and similar effects were observed in our study. Somnolence was the highest in the levocetirizine group and further increased when hydroxyzine was added. Sedation-related adverse events were maximum in the levocetirizine and hydroxyzine groups, indicating sedating effects of FGAH. This could be explained by binding of the drug to H1-receptors in the brain leading to sedation.
The relief from urticaria-related discomfort could have led to a better quality of sleep with subsequent prolonged wakefulness during the day. Daytime sedation disrupts a patient's life and it is important to choose nonsedating therapy to improve the QOL. There is clinical evidence that bilastine improved the QOL., Furthermore, our study showed that updosing of bilastine is better than combination of levocetirizine and hydroxyzine in improving QOL.
According to the authors, this is the first kind of the study which concluded that increasing the daily dose of second-generation antihistamine (up to two times) is a better option than the combination of FGAH and SGAH in reducing urticaria symptoms.
| Conclusion|| |
This study provides evidence that in patients with CSU, increasing the daily dose of bilastine (up to two times) is a better option than the combination of levocetirizine and hydroxyzine in reducing urticaria symptoms without compromising patient safety. The limitation of this study is the small sample size. Future studies with a large sample size at multiple sites would provide good quality clinical evidence and support this concept in the management of CSU.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient (s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initial s will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
This clinical study was carried out with unrestricted grant from Glenmark Pharmaceuticals Limited.
Conflicts of interest
Dr. Dhiraj Dhoot and Dr. Gaurav Deshmukh are employees of Glenmark Pharmaceuticals Limited. The rest of authors do not have any conflict of interest.
| References|| |
Church MK, Labeaga L. Bilastine: A new H1 -antihistamine with an optimal profile for up dosing in urticaria. J Eur Acad Dermatol Venereol 2017;31:1447-52.
Zuberbier T, Aberer W, Asero R, Abdul Latiff AH, Baker D, Ballmer-Weber B, et al.
LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria. Allergy 2018;73:1393-414.
Vestergaard C, Toubi E, Maurer M, Triggiani M, Ballmer-Weber B, Marsland A, et al.
Treatment of chronic spontaneous urticaria with an inadequate response to H1-antihistamines: An expert opinion. Eur J Dermatol 2017;27:10-9.
Hiragun T, Hide M. Japanese guidelines for diagnosis and treatment of urticaria. Arerugi 2017;66:23-6.
Bernstein JA, Lang DM, Khan DA, Craig T, Dreyfus D, Hsieh F, et al.
The diagnosis and management of acute and chronic urticaria: 2014 update. J Allergy Clin Immunol 2014;133:1270-7.
Sánchez-Borges M, Caballero-Fonseca F, Capriles-Hulett A. Treatment of recalcitrant chronic urticaria with nonsedating antihistamines: Is there evidence for updosing? J Investig Allergol Clin Immunol 2013;23:141-4.
Sánchez-Borges M, Ansotegui I, Jimenez JM, Rojo MI, Serrano C, Yañez A. Comparative efficacy of non-sedating antihistamine updosing in patients with chronic urticaria. World Allergy Organ J 2014;7:33.
Krause K, Spohr A, Zuberbier T, Church MK, Maurer M. Up-dosing with bilastine results in improved effectiveness in cold contact urticaria. Allergy 2013;68:921-8.
Weller K, Church MK, Hawro T, Altrichter S, Labeaga L, Magerl M, et al.
Updosing of bilastine is effective in moderate to severe chronic spontaneous urticaria: A real-life study. Allergy 2018;73:2073-5.
van den Elzen MT, van Os-Medendorp H, van den Brink I, van den Hurk K, Kouznetsova OI, Lokin AS, et al.
Effectiveness and safety of antihistamines up to fourfold or higher in treatment of chronic spontaneous urticaria. Clin Transl Allergy 2017;7:4.
Kaplan AP. What the first 10,000 patients with chronic urticaria have taught me: A personal journey. J Allergy Clin Immunol 2009;123:713-7.
Richardson GS, Roehrs TA, Rosenthal L, Koshorek G, Roth T. Tolerance to daytime sedative effects of H1 antihistamines. J Clin Psychopharmacol 2002;22:511-5.
Podder I, Das A, Ghosh S, Biswas D, Sengupta S, Chowdhury SN. Effectiveness, safety, and tolerability of bilastine 20mg vs levocetirizine 5 mg for the treatment of chronic spontaneous urticaria: A double-blind, parallel group, randomized controlled trial. Dermatol Ther 2020;33:e13946.
Farré M, Pérez-Mañá C, Papaseit E, Menoyo E, Pérez M, Martin S, et al.
Bilastine vs. hydroxyzine: Occupation of brain histamine H1 -receptors evaluated by positron emission tomography in healthy volunteers. Br J Clin Pharmacol 2014;78:970-80.
Serra E, Campo C, Novák Z, Majorek-Olechowska B, Pulka G, García-Bea A, et al.
Efficacy and safety of bilastine in reducing pruritus in patients with chronic spontaneous urticaria and other skin diseases: An exploratory study. J Dermatolog Treat 2020;31:270-8.
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2]