John N. Kraft HBSc, MD, FRCPC1, Gordon L. Sussman MD, FRCPC, FACP, FAAAAI2,3
1Dermatologist, Lynde Institute for Dermatology, Markham, ON, Canada
2Professor of Medicine, University of Toronto, Toronto, ON, Canada
3Staff Physician Division of Allergy & Immunology, St. Michaels Hospital, Toronto, ON, Canada
In use for more than 75 years, first generation antihistamines (AH) are now widely available over the counter.1 However, first generation AH, including diphenhydramine and hydroxyzine, are associated with significant adverse effects. Given the improved risk/benefit profiles of second generation AH, Global Allergy and Asthma European Network (GA2LEN) has recommended that first generation AH should no longer be available for purchase over the counter. In this article, we examine the safety and efficacy data of the novel, second generation AH bilastine and its role in the treatment of nasal and non-nasal symptoms of seasonal allergic rhinitis and of symptoms associated with chronic spontaneous urticaria (CSU) (e.g. pruritus and hives).
First Generation Antihistamines
- First generation antihistamines (AH), such as diphenhydramine and hydroxyzine, cause significant adverse effects related to their nonselective sedative and anticholinergic activity.2
- These adverse effects include impairment related to reduced rapid eye movement (REM) sleep, which cause hangover or “morning-after” effects, which impair learning, memory and work efficiency.3
- Based on these risks and the availability of newer, second generation AH with improved risk/benefit profiles, GA2LEN now recommends that older, first generation AH should no longer be available for purchase over the counter.4
- Additionally, the Allergic Rhinitis and Its Impact on Asthma (ARIA) Guidelines do not recommend first generation AH for the treatment of allergic rhinitis.2
- Overall, there is very limited use for first generation AH given the availability of newer, more efficacious and much safer, non-sedating, non-impairing AH.
Second Generation Antihistamines
- Second generation AH are available both over-the-counter and by prescription.
- Second generation AH selectively act on histamine 1 receptors, have low penetration of the central nervous system (CNS), and do not interact with adrenergic, muscarinic and dopaminergic receptors.1
- However, while second generation AH have improved side effect profiles, cetirizine causes sedation and most of these agents are metabolized by cytochrome P450, increasing the risk for drug interactions.5
- There is a need for non-sedating second generation AH that do not interact with cytochrome P450, as recommended by the ARIA Guidelines.2
Bilastine (BLEXTEN®): a novel second generation antihistamine
Indications and Use Around the World
- Bilastine (BLEXTEN®) is a novel second generation AH that has been used by more than 71 million patients in 104 countries.
- In December 2016, bilastine became available in Canada with indications for:6
- The symptomatic relief of nasal and non-nasal symptoms of seasonal allergic rhinitis in patients 12 years of age and older.
- The relief of symptoms associated with chronic spontaneous urticaria (CSU) (e.g. pruritus and hives) in patients 18 years of age and older.
- In Europe, bilastine was recently approved for use in children 6 to 11 years of age (>20 kg) for seasonal and perennial allergic rhinoconjunctivitis and urticaria.7
- This approval was based on a pivotal phase 3 trial by Novak et al8 that demonstrated no statistically significant differences between bilastine and placebo with respect to adverse events.
- In Japan, bilastine is also indicated for the treatment of pruritus.
- This approval was based on a 52-week open-label trial that showed a significant improvement in the itch score from 2 weeks to the end of the study.9
Dosage of Bilastine
- In Canada, bilastine is indicated for use at 20 mg, once per day. For maximum absorption, it should be taken 1 hour before eating or 2 hours after.6
- Since bilastine is not metabolized, no dose adjustment is required in patients with hepatic impairment.6
- No dosage adjustments are required in patients with renal impairment; bilastine has not been studied in end stage renal failure.6
- Bilastine has a rapid onset of action of 1 hour after treatment and lasts for 26 hours.6
- Bilastine does not interact with cytochrome P450 and therefore has no metabolic interaction with other drugs metabolized via P450.10
Safety of Bilastine
- At the recommended dose of 20 mg daily, treatment-emergent adverse reactions with bilastine, including somnolence, were equal to placebo.6
- Bilastine does not cross the blood brain barrier11 and therefore, at the 20 mg dose it does not:
- Cause sleepiness or impair performance of tasks related to flying under hypobaric conditions12
- In clinical trials with bilastine administered at doses of up to 40 mg once daily (double the recommended dose), it did not affect psychomotor performance and did not affect the subjects’ driving performance in a standard car driving test.13,14
- Bilastine safety was assessed with no significant concerns in patients older than 65.6,15
At the recommended dose of 20 mg daily, treatment-emergent adverse reactions with bilastine, including somnolence, were equal to placebo.6
Cardiovascular QT Safety Data
- The potential for QT prolongation is considered a class effect for all AH and bilastine, along with other second generation AH, is contraindicated in patients with a history of QT prolongation and/or torsades de pointes including congenital long QT syndromes.6
- Unlike first generation AH, which were introduced decades before clinical pharmacology studies and randomized controlled trials of medication efficacy and safety were required by regulatory agencies5, most second generation AH have been thoroughly evaluated in pharmacology studies and phase 3 trials.
- The cardiac safety of bilastine was assessed in a robust QT study and showed no clinically significant impact on the QTc interval at both therapeutic and supratherapeutic doses.16
- Bilastine, dosed at up to 100 mg, has been shown to have no effect on QT interval.17
- All AH should be avoided in patients with known QT prolongation and used with caution in patients with cardiac arrhythmias.
The Use of Bilastine for the Treatment of Allergic Rhinitis (AR)
- AR occurs after exposure to an air-borne allergen and is characterized by nasal congestion, rhinorrhea, sneezing and nasal itching.
- The prevalence of AR is estimated at 20% of the Canadian population.18
- There are two phase 3 registration studies that support the use of bilastine for the treatment of seasonal AR (SAR).
- The Kuna et al. trial19 was a double-blind, randomized, controlled study performed in patients suffering from SAR to determine the efficacy and safety of bilastine 20 mg, cetirizine 10 mg, and placebo.
- The mean total symptom scores were reduced in the bilastine and cetirizine treated groups to a similar, and significantly greater extent, compared with placebo (Figure 1).
- Bilastine demonstrated a significantly lower incidence of somnolence and fatigue compared to cetirizine (Figure 2):
- Somnolence rate was 1.8% with bilastine vs 7.5% with cetirizine
- Fatigue rate was 0.4% with bilastine vs. 4.8% with cetirizine
- The Bachert et al. trial20 was a double-blind, randomized controlled study performed in patients suffering from SAR which sought to determine the efficacy and safety of bilastine 20 mg, desloratadine 5 mg, and placebo.
- There was no significant difference in change in total symptom score between the bilastine and desloratadine treatment arms and both active arms were significantly better than placebo.20
- Bilastine was equally effective for nasal and non-nasal symptoms.20
- The bilastine and desloratadine safety profiles were comparable to placebo:
- The incidence of somnolence was 3.9% with bilastine, 3.7% with desloratadine and 2.4% with placebo.20
- A phase 3 registration study in a Japanese patient population has also shown bilastine to be effective in the treatment of perennial allergic rhinitis.21
- Since bilastine is not metabolized and does not cause somnolence, it is an excellent fit for the ARIA Guidelines recommendation of a second generation AH that does not cause sedation and does not interact with cytochrome P450.2
The Use of Bilastine for the Treatment of Chronic Spontaneous Urticaria (CSU)
- Spontaneous urticaria results from mast cell activation, with the release of histamine and pro-inflammatory mediators; in the majority of cases no allergy is found.3
- CSU occurs intermittently for at least six weeks, characterized by pruritic wheals, deeper swelling termed angioedema or both.22
- CSU has a prevalence of 0.5-1% of the general population, occurring mostly in women; peak age of onset is 20-40 years, and 10-50% have the disease longer than 5 years.3
- The EAACI/GA2LEN/EDF/WAO 2016 guideline for the treatment of CSU is shown in Figure 3.
- The use of bilastine for CSU is supported by a double-blind, randomized placebo- and active-controlled parallel group study of 516 subjects with chronic spontaneous urticaria.23
- The differences in overall and drug-related incidence of adverse events were not significant between the treatment groups and both agents were well tolerated as compared to placebo.23
- The efficacy and safety of bilastine up-dosing in urticaria has been demonstrated in a 12-week randomized, double-blind, cross-over, placebo-controlled study in adults with cold contact urticaria.24
- 20 patients with cold contact urticaria received each of the following, 20 mg, 40 mg, 80 mg bilastine or placebo for 7 days with 14-day washout periods between treatments.24
- The primary endpoint was the change in critical temperature threshold (CTT) to induce cold urticaria.24
- Key secondary endpoints were changes in pruritus and the safety and tolerability of bilastine.24
- The median CTT was significantly lowered by all doses of bilastine compared to placebo.24
- Bilastine 80 mg was significantly better than the two lower doses.24
- Pro-inflammatory mediators, IL-6 and IL-8 were significantly decreased following up-dosing with 80 mg bilastine, suggesting an anti-inflammatory effect of bilastine at 4 times the therapeutic dose.24
- Pruritus was also significantly lowered by all doses and 13 of the 20 patients reported no itch at a dose of 20 mg daily, demonstrating that bilastine is particularly effective against pruritus.24
This data shows that bilastine is a fast-acting, effective antihistamine for CSU that can be safely up-dosed when needed.
Bilastine has a proven, long-term safety record with use by over 71 million patients in over 104 countries. This novel, second generation antihistamine is non-sedating due to the fact that it does not cross the blood brain barrier. As well, bilastine is not metabolized and does not interact with CYP450.
Bilastine is available by prescription in Canada for the treatment of seasonal allergic rhinitis and chronic spontaneous urticaria. The efficacy data in allergic rhinitis and chronic spontaneous urticaria are comparable to other second generation AHs with a rapid onset of action that lasts for over 24 hours.
Bilastine can be used without dose adjustments in patients with hepatic and renal impairment as well as in elderly patients. At up to double the recommended dose, bilastine did not affect psychomotor performance in clinical trials and did not affect driving performance in a standard car driving test.
Bilastine is available by prescription in Canada for the treatment of seasonal allergic rhinitis and chronic spontaneous urticaria.
Bilastine is not metabolized and does not interact with CYP450.
Bilastine can be used without dose adjustments in patients with hepatic and renal impairment.
Bilastine is non-sedating.
At up to double the recommended dose, bilastine did not affect psychomotor performance and did not affect driving.
- Kuna P, et al. Adv Dermatol Allergol. 2016;33(6):397-410.
- Brozek J, et al. J Allergy Clin Immunol. 2010 Sep;126(3):466-76.
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- Church MK, et al. Allergy. 2010 Apr;65(4):459-66.
- Simons FE, Simons KJ. World Allergy Organ J. 2008 Sep;1(9):145-55.
- BLEXTEN® [Product monograph]. September 6 2017. Aralez Pharmaceuticals Trading DAC. Available from: https://pdf.hres.ca/dpd_pm/00041247.PDF
- Bilastine, SmPC 2017.
- Novak Z, et al. Pediatr Allergy Immunol. 2016 Aug;27(5):493-8.
- Yagami A, et al. J Dermatol. 2017 Apr;44(4):375-385.
- Lucero ML, et al. Drug Chem Toxicol. 2012 Jun;35(S1):18-24.
- Farre M, et al. Br J Clin Pharmacol. 2014 Nov;78(5):970-80.
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- Bachert C, et al. Allergy. 2009 Jan;64(1):158-65.
- Okubo K, et al. Allergol Int. 2017 Jan;66(1):97-105.
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- Krause K, et al. Allergy. 2013 Jul;68(7):921-8.