Introduction
Histamine is a biogenic amine that, by acting through its receptors, contributes to the development of allergic diseases such as allergic rhinitis and urticaria. Four types of histamine receptors have been identified: H1, H2, H3, and H4. When histamine binds to the H1 receptor, it promotes the release of mediators involved in allergic reactions from mast cells and basophils, activates antigen-presenting cells, stimulates the activation and proliferation of T helper 1 (Th1) cells, enhances interferon production and cell adhesion molecule synthesis, and promotes eosinophil and neutrophil chemotaxis [1]. H1 receptors are expressed not only on eosinophils, neutrophils, monocytes, dendritic cells, T and B lymphocytes, epithelial cells, endothelial cells, hepatocytes, and respiratory and vascular smooth muscle cells, but also in the central nervous system (CNS), where histamine functions as a neurotransmitter [2]. Antihistamines are inverse agonists of H1 histamine receptors and are classified as either first-generation (older) or second-generation (newer) antihistamines [3].
This article reviews the safety profile of bilastine, the newest second-generation antihistamine, and discusses the impact of bilastine treatment on patients' quality of life.
First- and Second-Generation Antihistamines
Most first-generation antihistamines have been used in clinical practice since the 1940s and 1950s. They are chemically related to anticholinergic agents, tranquilizers, antipsychotics, and antihypertensive drugs, resulting in relatively low receptor selectivity. Consequently, first-generation antihistamines frequently interact with receptors for other biogenic amines, producing undesirable anticholinergic, anti-α-adrenergic, and antiserotonergic effects. In addition, they readily cross the blood-brain barrier and bind to H1 histamine receptors located on histaminergic neurons throughout the CNS.
As a result, they commonly cause drowsiness, sedation, fatigue, cognitive impairment, psychomotor dysfunction, and memory disturbances. Owing to their central nervous system effects, overdose with first-generation antihistamines may be life-threatening [4]. These agents are lipophilic, rapidly absorbed, and extensively metabolized by the hepatic cytochrome P450 enzyme system. Consequently, they are typically administered three to four times daily and may interact with other medications metabolized through the cytochrome P450 pathway [2]. Although first-generation antihistamines effectively reduce the symptoms of allergic diseases, their sedative and anticholinergic adverse effects impair daily functioning and increase the risk of accidents during activities requiring alertness, such as driving or operating machinery. Furthermore, the weakness, dizziness, and fatigue commonly associated with these medications may reduce patient adherence to treatment recommendations. For all of these reasons, particularly because of their CNS effects, first-generation antihistamines are not recommended for the long-term treatment of allergic diseases [3,4].
Second-generation antihistamines have been available since the 1980s and are characterized by more favorable pharmacokinetic properties and minimal or no sedative effects. Compared with first-generation antihistamines, they are less lipophilic and are good substrates for P-glycoprotein, which effectively limits their passage across the blood-brain barrier and minimizes CNS depression.
Second-generation antihistamines are highly selective for H1 histamine receptors and therefore produce virtually no clinically relevant effects on other biogenic amine receptors. Interactions with other medications, foods, or herbal products are absent or clinically insignificant [2,5]. This group includes loratadine, desloratadine, fexofenadine, cetirizine, levocetirizine, and bilastine.
Bilastine Pharmacology
Bilastine is a novel antihistamine with a unique chemical structure that differs from all other currently available antihistamines. It is neither an active metabolite nor an enantiomer of another antihistamine. Animal studies have demonstrated that bilastine has moderate to high affinity for H1 histamine receptors—approximately three times greater than cetirizine and five times greater than fexofenadine. Bilastine binds specifically and selectively to H1 histamine receptors and, even at high concentrations, does not bind to 30 other tested receptors, including muscarinic M3 receptors, serotonin receptors, α1-adrenoceptors, β2-adrenoceptors, bradykinin receptors, leukotriene D4 receptors, calcium receptors, or other histamine receptor subtypes (H2, H3, and H4) [6,7].
Following oral administration, bilastine is rapidly absorbed, reaching peak plasma concentrations approximately one hour after dosing. The mean oral bioavailability is 61%. Repeated administration at therapeutic doses does not result in drug accumulation. At therapeutic doses, 84–90% of bilastine is bound to plasma proteins [8,9].
Bilastine undergoes minimal metabolism in humans and neither induces nor inhibits the cytochrome P450 enzyme system. Following administration of a 20 mg dose to healthy volunteers, approximately 95% of the unchanged drug was excreted, with 28.3% eliminated in urine and 66.5% in feces. In healthy volunteers, the mean elimination half-life was 14.5 hours, and total plasma clearance was 18.1 L/h [8].
The efficacy of bilastine in the treatment of allergic rhinitis and urticaria has been demonstrated in clinical trials involving more than 4,600 patients. In these studies, bilastine was compared with placebo and other second-generation antihistamines.
No statistically significant differences in treatment efficacy were observed between bilastine and other second-generation antihistamines, including cetirizine, levocetirizine, and desloratadine [10]. Clinical studies have shown that 20 mg of bilastine is as effective as 10 mg of cetirizine in the treatment of seasonal allergic rhinitis, while its duration of action exceeds that of 120 mg of fexofenadine [11].
Bilastine Safety Data
The safety, tolerability, and adverse effect profile of bilastine have been extensively evaluated in clinical trials. The drug has been shown to be well tolerated in patients with intermittent and persistent allergic rhinitis as well as chronic urticaria. Adverse events occurred at frequencies comparable to those observed in the placebo group, with no reports of serious adverse events or deaths. The most commonly reported adverse effects were headache, dizziness, fatigue, and somnolence [12–15].
Bilastine does not cross the blood-brain barrier and therefore does not exert central nervous system (CNS) depressant effects. In a double-blind, placebo-controlled study, bilastine was administered at doses of 20 mg, 40 mg, and 80 mg once daily for seven days. Objective assessments included motor function, cognition, attention, psychomotor performance, and information-processing abilities, as well as subjective mood changes.
The effects of the 20 mg dose, the standard therapeutic dose used in clinical practice, did not differ significantly from those of placebo. Although the 40 mg dose produced a subjective sensation of drowsiness, objective psychomotor performance remained unchanged. Only the 80 mg dose—four times the standard therapeutic dose—resulted in measurable impairment in selected psychomotor performance tests [16,17].
Furthermore, because bilastine does not affect the CNS, it does not impair driving ability. Neither single nor repeated doses of 20 mg or 40 mg negatively affected driving performance, indicating that bilastine may be safely used by individuals who drive [18,19].
Alcohol is known to potentiate the sedative and psychomotor-impairing effects of first-generation antihistamines. A double-blind, placebo-controlled clinical study evaluated the interaction between bilastine (20 mg and 80 mg) and alcohol (0.8 g/kg), comparing its effects with cetirizine 10 mg and hydroxyzine 25 mg. The combination of bilastine 20 mg with alcohol produced effects comparable to those observed with alcohol plus placebo, whereas cetirizine 10 mg and hydroxyzine 25 mg significantly enhanced alcohol-induced CNS impairment.
In contrast, the 80 mg dose of bilastine significantly potentiated the effects of alcohol to a degree similar to that observed with cetirizine 10 mg and hydroxyzine 25 mg [20]. First-generation antihistamines are also known to interact with benzodiazepines, enhancing their sedative effects.
Second-generation antihistamines do not exhibit this interaction. A 20 mg dose of bilastine did not increase the CNS-depressant effects of lorazepam 3 mg, whether administered as a single dose or concomitantly over an eight-day period [21].
Cardiovascular safety is another critical consideration when evaluating antihistamines. Bilastine was assessed according to the International Council for Harmonisation (ICH) E14 guidelines. Healthy volunteers received bilastine 20 mg, bilastine 100 mg, bilastine 20 mg combined with ketoconazole 400 mg, or moxifloxacin 400 mg as a positive control.
Bilastine monotherapy, administered at both therapeutic and supratherapeutic doses, had no effect on T-wave morphology or corrected QT (QTc) interval on electrocardiography. QTc prolongation was observed when bilastine was administered together with ketoconazole; however, investigators concluded that this effect was primarily attributable to ketoconazole-induced alterations in cardiac repolarization rather than to bilastine itself [22,23].
Because bilastine undergoes minimal metabolism in humans, is not a substrate of the cytochrome P450 enzyme system, and is excreted largely unchanged, dose adjustment is not required in patients with hepatic impairment. Likewise, clinically relevant interactions with drugs metabolized by cytochrome P450 are not expected.
Dose adjustment is also unnecessary in patients with renal impairment. However, in individuals with moderate to severe renal dysfunction, concomitant use of strong P-glycoprotein inhibitors—including ketoconazole, erythromycin, cyclosporine, diltiazem, and grapefruit juice—should be avoided because bilastine is a substrate of P-glycoprotein [24].
Evaluation of Quality of Life in Patients With Allergic Rhinitis and Urticaria
Health-related quality of life (HRQoL) measures describe disease burden and treatment outcomes from the patient's perspective. Although subjective, these measures are important for assessing the social and economic impact of disease. Most allergic diseases, particularly allergic rhinitis and urticaria, are not life-threatening but are highly prevalent and substantially impair patients' daily quality of life. Clinical studies have shown that, in patients with intermittent or persistent allergic rhinitis, only a moderate correlation exists between symptom severity and quality of life, confirming that symptom intensity does not fully reflect patients' subjective experience of disease burden. Patients with chronic urticaria generally report poorer quality of life than those with rhinitis and/or asthma because of the disease's effects on sleep, eating habits, work performance, and overall physical and psychological well-being [25].
Quality of life is evaluated using standardized questionnaires. These are broadly divided into two categories: (a) generic questionnaires, which assess general aspects of health-related quality of life across different diseases and populations, enabling comparisons between conditions; and (b) disease-specific questionnaires, which focus on issues particularly relevant to a given disease within a specific patient population. Disease-specific instruments are more sensitive and better suited for comparing treatments for the same condition but do not allow comparisons across different diseases.
Both types of questionnaires are used in patients with allergic diseases. In addition, the Visual Analogue Scale (VAS) has been validated as a tool for assessing disease severity in allergic rhinitis, urticaria, and other allergic disorders, particularly in children. In clinical practice, HRQoL questionnaires and the VAS complement one another. Quality-of-life assessments are widely used to monitor disease progression in clinical and pharmacoeconomic studies. Their use is particularly important when evaluating new antihistamines, as these agents remain the cornerstone of treatment for allergic diseases [26].
The Impact of Bilastine on Quality of Life in Patients With Allergic Rhinitis
Allergic rhinitis negatively affects patients' social functioning and contributes to daytime sleepiness [27], impaired learning [28], and reduced work productivity [29]. Based on its impact on quality of life—including sleep, work or school performance, leisure activities, and symptom burden—allergic rhinitis is classified as either mild or moderate-to-severe. Current treatment guidelines recommend second-generation, non-sedating antihistamines as first-line therapy for allergic rhinitis [30]. These medications have been shown to improve patients' quality of life. Comparative studies evaluating different second-generation antihistamines have found no statistically significant differences in either clinical efficacy or improvements in health-related quality of life.
Most clinical trials have demonstrated a substantial placebo effect, reflecting the natural course of the disease, fluctuations in symptom severity, and other contributing factors [26]. In patients with allergic rhinitis treated for 14 days with bilastine 20 mg/day, desloratadine 5 mg/day, or placebo, both antihistamine groups showed significantly greater reductions in symptom severity than the placebo group, with no statistically significant difference between bilastine and desloratadine.
Assessment of health-related quality of life likewise demonstrated significant improvement in both active treatment groups compared with placebo. The correlation between changes in symptom severity and improvements in quality of life was moderate. Visual Analogue Scale scores also showed clear improvement in both treatment groups [14].
Similarly, in patients treated for 14 days with bilastine 20 mg/day, cetirizine 10 mg/day, or placebo, symptom severity decreased significantly in both antihistamine groups compared with placebo, with no statistically significant difference between bilastine and cetirizine. Quality of life, assessed by disease-related discomfort using the Visual Analogue Scale, improved equally in both treatment groups (54.6%) and significantly more than in the placebo group [13].
The Impact of Bilastine on Quality of Life in Patients With Chronic Urticaria
Chronic urticaria impairs health-related quality of life to a degree comparable with atopic dermatitis and to a greater extent than psoriasis, acne vulgaris, vitiligo, or Behçet's disease [31]. When assessed using generic quality-of-life questionnaires, patients with chronic urticaria experience impairment comparable to that observed in patients with severe ischemic heart disease or those awaiting coronary artery bypass surgery [32].
Second-generation antihistamines are recommended as first-line therapy for chronic urticaria. Comparative studies have found no statistically significant differences between these agents regarding symptom control or improvements in quality of life [33]. The effects of bilastine on quality of life in patients with chronic urticaria have been directly compared with those of levocetirizine.
Bilastine was significantly more effective than placebo and equally effective as levocetirizine in reducing pruritus and the number and size of wheals. Quality-of-life assessments demonstrated improvement in both treatment groups, with no statistically significant difference between bilastine and levocetirizine. Overall discomfort, assessed using the Visual Analogue Scale, also decreased significantly and to a similar extent with both medications [15]. These findings indicate that bilastine effectively improves the quality of life of patients with chronic urticaria.
Summary
Bilastine is a second-generation antihistamine with a unique chemical structure that is not related to any other currently available antihistamine. It is neither an active metabolite nor an enantiomer of another antihistamine. Its efficacy has been well established in the treatment of allergic rhinitis and chronic urticaria.
Because bilastine does not cross the blood-brain barrier, it does not produce central nervous system depression. Furthermore, it does not potentiate the sedative effects of alcohol or benzodiazepines and has no clinically significant interactions with other medications. Bilastine does not prolong the QT interval and does not require dose adjustment in patients with hepatic or renal impairment.
Quality of life is substantially impaired in patients with allergic diseases. Treatment with antihistamines, including bilastine, significantly improves health-related quality of life in patients with allergic rhinitis and chronic urticaria.
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Author Neringa Buterlevičiūtė, Laura Malinauskienė,
Vilnius University Hospital Santaros Clinic, Center for Pulmonology and Allergology
Article from the journal "Internistas"
LT/Ope/2014/09
