Bilastine Safety in Drivers Treated with Antihistamines
Total Page：16
File Type：pdf, Size：1020Kb
European Review for Medical and Pharmacological Sciences 2018; 22: 820-828 Bilastine safety in drivers who need antihistamines: new evidence from high-speed simulator driving test on allergic patients A. DEMONTE1, M.B. GUANTI1, S. LIBERATI1, A. BIFFI2, F. FERNANDO2, M. FAINELLO3, P. PEPE1 1Department of Surgical, Medical, Dental and Morphological Sciences with Interest in Transplant, Oncological and Regenerative Medicine; Dermatology Unit; University of Modena and Reggio Emilia, Modena, Italy 2Med-Ex Medicine & Exercise srl, Rome Italy 3Addfor Spa, Executive Director Automotive, Turin, Italy Antongiulio Demonte and Mario Bruno Guanti contributed equally to this work Abstract. – OBJECTIVE: Bilastine is a high- ABBREVIATIONS ly selective, non-sedating antihistamine, indicated F1 = Formula One; AR = allergic rhinitis; CU = chro- for the symptomatic treatment of allergic rhinocon- nic urticaria; CNS = central nervous system; BBB = junctivitis and urticaria. Available data suggest that blood-brain barrier; SDLP = Standard Deviation of bilastine interferes neither with driving ability nor Lateral Position; CIs = confidence intervals; TEAE = with flying-related performance. However, no data treatment-emergent adverse event. are available on the effect of bilastine on the driv- ing ability in extreme conditions. Here we analyzed the effect of 7 days treatment with 20 mg bilastine in patients with allergic rhinitis and/or chronic urticar- Introduction ia, on psychophysical performance assessed by the Formula One (F1) high-speed simulator-driving test. Antihistamines are widely used for the treat- PATIENTS AND METHODS: This study is a ment of allergic rhinitis (AR) and/or urticaria1-4. AR phase IV, interventional, prospective, mono-cen- is a heterogeneous disorder characterized by one tric, single arm, open-label trial. Eighteen outpa- tients affected by allergic rhinitis and/or chronic or more symptoms including sneezing, itching, na- urticaria, able to perform a preliminary driving test sal congestion and rhinorrhea as well as non-nasal on F1 simulator were considered (V-1). First, the symptoms such as tearing which can affect driving patients had a screening visit to assess their eligi- performance. Epidemiological studies have indicated bility (V0). Visit 1 (V1), at the end of placebo before that the prevalence of AR has increased progressive- bilastine treatment and Visit 2 (V2), at the end of ly over the last three decades5 and presently affects bilastine treatment. The primary variable parameter 23-30% of the population in Europe6. It is currently was the ability to maintain the vehicle in a central position at different speeds (50, 150, and 250 km/h). estimated that AR has a worldwide prevalence up to RESULTS: Bilastine had a good safety pro- 40%, with significant differences in urban and rural file and was well tolerated in terms of adverse environments7. Chronic urticaria (CU), defined by events, laboratory parameters and vital signs. the presence of urticaria (hives with or without an- Bilastine did not have any negative effect on gioedema) on most days of the week, for a period ≥ of the ability to maintain the requested path, a six weeks, affects up to 1 percent of the general adult constant speed as well as on attention and reac- population in the United States, with similar preva- tivity levels, even in extreme driving conditions. 8-10 CONCLUSIONS: lence in other countries . The clinical admissions This study is the first done in 11 patients with allergic rhinitis and/or chronic ur- for urticaria have increased by 100% since 1990 . ticaria using a F1-high speed simulator-driving The disease is potentially very disabling for the pa- test evaluating subjects’ performance under bi- tients; it is estimated a yearly loss of 5,000 € related lastine treatment. to working and scholastic performance12. Despite the effectiveness of antihistamines in the treatment of Key Words AR and CU, the systemic blocking of H1-receptors, Bilastine, Antihistamine, Driving, Allergic rhinitis, Urticaria, High speed, F1 simulator. including the central nervous system (CNS) ones, is associated with important side effects. 820 Corresponding Author: Patrizia Pepe, MD; e-mail: [email protected] Bilastine safety in drivers treated with antihistamines H1-antihistamines are functionally classified In clinical studies, bilastine has shown to be into two groups. The sedating ones readily cross non-sedating at therapeutic doses; furthermore, the blood-brain barrier (BBB) and occupy H1-re- bilastine does not potentiate the performance im- ceptors located on postsynaptic membranes of his- pairment associated with alcohol consumption20 taminergic neurons throughout the CNS13. For this or with treatment with the benzodiazepine lora- reason, sedating antihistamine have a potentially zepam21. Available data suggest that bilastine at undesired impact on psychophysical performance. the doses of 20 and 40 mg does not impair driving Although this effect per se does not represent a ability22,23 nor psychomotor performance24. The serious health concern, it can lead to diminished flying-related performance, assessed in hypobar- concentration, for example, while driving a car ic conditions simulating an altitude of roughly or operating machinery and interfere with activi- 8000 feet in healthy volunteers gave similar re- ties highly depending on effective psychophysical sults25. On the other hand, no data are available functions with an increased risk of occupational on the effects on driving performance in extreme injuries. Also, patients taking sedating antihista- conditions in patients treated with bilastine. mines are likely to have reduced treatment com- The present study was designed to determine pliance because of excessive fatigue and malaise14. the effects on patients’ attention and reactivity These potential negative effects have been levels of seven consecutive day treatment with mainly overcome by non-sedating antihistamines bilastine 20 mg in subjects with allergic rhinitis which basically do not cross the BBB13. Their use and/or urticaria, both tested with the Formula has reduced the sedative side effects, due to very One (F1) high- speed simulator-driving test. limited diffusion through the BBB13 and as a result of the P-glycoprotein-mediated efflux of the drugs from the CNS15. Moreover, non-sedating antihis- Patients and Methods tamines have less lipid solubility than sedating agents, preventing cellular membranes diffusion16. Study Design Bilastine is a highly selective, non-sedating This was a phase IV, interventional, prospec- second-generation antihistamine, indicated for tive, mono-centric, single arm, open-label trial. the symptomatic treatment of allergic rhinocon- Eligible patients underwent 3 ambulatory visits junctivitis (seasonal and perennial) and urticaria at the hospital site and 3 driving tests at the sim- and generally well-tolerated17-19. ulator center (Figure 1). Figure 1. Study design diagram. 821 A. Demonte, M.B. Guanti, S. Liberati, A. Biffi, F. Fernando, M. Fainello, P. Pepe A screening visit (Visit 1) was performed at contraception from at least 30 days before the both the hospital and the simulator center, during study and up to the end of the study; a valid driv- which patients were evaluated to assess their eli- ing license from more than 3 years; a driving ex- gibility in taking part in the study. The screening perience of at least 5000 km per year. Exclusion visit driving test was intended not only to assess criteria were the presence of autoimmune urti- the ability of the patients to drive without expe- caria, known allergic reactions to antihistamines, riencing signs or symptoms of intolerance (e.g., patients in treatment with diuretics, corticoste- nausea, vomiting or dizziness, etc.), but also to let roids (other than medication applied topically), them familiarize with the driving simulator. Pa- central nervous system drugs, or medication with tients satisfying all inclusion and exclusion criteria sedative effects (sleep-inducing or antidepressant, attended an enrolling visit (Visit 0) at the hospital sedative medications), other drugs that could in- within 2-7 days and started a 7 (+3)-day wash- teract with bilastine. The study was approved by out period with placebo. Then patients repeated the Ethical Local Committee and was performed the F1-high speed simulator test at Visit 1, and in accordance with the ethical standards as laid afterwards initiated the 7 (+3)-day treatment peri- down in the 1964 Declaration of Helsinki and od with bilastine 20 mg. At the end of the bilas- its later amendments. All the patients provided tine-treatment period patients performed the final written informed consent. visit (Visit 2) at the simulator center first, where they performed the final F1-high speed simulator F1-Simulator Driving Test test, and then at the hospital to assess clinical and The F1-simulator driving test lasted approxi- laboratory examination and drug accountability. mately 30 minutes; the maximum speed reached The overall study duration for each patient lasted was 250 km/h. The test was made up of 3 loops: approximately 6 weeks. The study was conducted the first one was used for the familiarization of in compliance with the Declaration of Helsinki, the patient with the test procedures, the second current Good Clinical Practices and applicable one was a linear track with no perturbations, and European and local regulatory requirements. the third one assessed the patient’s reaction to pre-defined stimulation