Balanced discussion of second-generation antihistamines’ data

Abstract

Dear editor It is with interest that we read the paper “Treatment of allergic rhinitis and urticaria: a review of the newest antihistamine drug bilastine” by Wang et al,1 in which the authors provide insights into the burden of allergic diseases in the Asia-Pacific region. Unfortunately, we found that the review provides some unsubstantiated information, incorrect statements, and/or data inconsistencies as listed below. The abstract states that bilastine “has very low potential for drug–drug interactions”; however, the drug label lists interactions with ketoconazole, erythromycin, diltiazem, and other intestinal efflux transporters, leading to 2–3-fold increases in drug maximum serum concentration and area under the curve.2 Also, food interactions decrease bilastine’s bioavailability by 30%, and the label recommendation is that it is taken 1 hour before or 2 hours after intake of food or fruit juice.2 Table 2 presents a comparison between widely used antihistamines; however, the +++ score for bilastine’s H1-selectivity is not substantiated by the provided reference.2 Also, the highest Allergic rhinitis and its impact on asthma (ARIA)3 score attributed to bilastine in Table 2 is in contrast to the information provided in Table 1; ie, bilastine does not have higher potency or efficacy than other antihistamines (demonstrated by several studies4–8); has clinically relevant interactions with food;2 has the same indications and is effective on the same symptoms as other antihistamines;2 has only one pediatric study;9 and its side effect profile2 and pharmacodynamic properties are similar to other antihistamines.2 Many papers have reported that it has efficacy and safety similar to cetirizine,4,7,8 desloratadine,5 fexofenadine,8 and levocetirizine.6 Table 2 contains incorrect information about the age groups of the pediatric indications for cetirizine and levocetirizine, both of which are approved by the US Food and Drug Administration for use in children as young as 6 months of age.10,11 Also, Table 2 inaccurately states that bilastine has no contraindications; according to the product label,2 “hypersensitivity to the active substance or to any of the excipients […]” is a contraindication. The section “Bilastine efficacy” states that “the bilastine clinical trial program was designed before the publication of the 2001 ARIA guidelines, so the patient inclusion criteria were based on the former classification of seasonal and perennial allergic rhinitis”; however, this seems to be in contrast to the information on www.ClinicalTrials.gov, where the oldest bilastine study has a start date of April 2003;12 and the other bilastine studies appear with start dates of 2004 through 2016. A 12-month open-label safety analysis7 was described by the authors as “the longest analysis to date with any antihistamine”; however, safety analyses from double-blind randomized trials with cetirizine,13 loratadine,14 and levocetirizine15 over periods of 12–18 months of treatment have already been published. The section “No QTc prolongation” states that “to date, bilastine is the only commercially available anti histamine that has been tested using the stringent ICH E/14 criteria for effects on QT interval”. This is incorrect as a publication in 2007 presented data from an ICH E-14 QT study with levocetirizine.16 The section “Lack of sedation” is misleading, since the bilastine product label2 lists somnolence as a “common” adverse event (ie, occurring in 1%–10% of patients), which is supported by data from several clinical trials reporting somnolence rates with bilastine of 5.8%,6 3.9%,5 3.7%,7 and 1.8%.4 Figure 9 incorrectly presents that updosing with bilastine (80 mg) appears to have 2 to 3 times as many responders as those treated with desloratadine 20 mg or levocetirizine 20 mg. These data come from two clinical trials17,18 with completely different designs, and therefore direct comparison between them is inappropriate. The bilastine data come from a provocation test in subjects without symptoms at the time of study recruitment, whereas the levocetirizine and desloratadine data come from a real clinical trial with difficult-to-treat urticaria patients. Also, the original paper reported 12 patients (~30%) as responders (symptom-free) on levocetirizine 20 mg and 1 responder (<3%) on desloratadine 20 mg. In addition, Figure 9 uses another review article19 as a reference, instead of the primary publications.17,18 As there is an unmet need in the management of allergic rhinitis in the Asia-Pacific region, we welcome novel treatment options. However, based on the available data, there is no evidence to suggest that bilastine provides superior clinical efficacy to other commonly used second-generation antihistamines.4–8