Effectiveness of as-needed antihistamines in chronic spontaneous urticaria patients under omalizumab treatment.

The question how second-generation antihistamines (sgAHs) should be used when chronic spontaneous urticaria (CSU) is under control with omalizumab is still unanswered. This study aimed to investigate the effectiveness of as-needed sgAHs in patients with well-controlled urticaria under omalizumab treatment. Patients from four different urticaria centers who were treated with omalizumab 300 mg/4 weeks for at least 3 months, had well-controlled urticaria (Urticaria Control Test: 16 > UCT≥12) and were using sgAHs only if needed, were included in this study. In order to assess effectiveness of sgAHs, change in the itch, hives, and total itch-hives scores before and after sgAHs were evaluated using modified urticaria activity score-twice daily. Fifty-three patients [38 female (71.7%)] with mean age 41.1 ± 11.4 years were included in this study. Median sgAH intake per patient throughout the 4 week-intervals was 3 (2-5) tablets. sgAH intake decreased itch, hives and total itch-hives scores 45.7% ± 52.9, 42.4% ± 39.1, and 50.2% ± 51.1, respectively (P < .001 for all). This decrease was similar in both isolated-urticaria and urticaria-and-angioedema phenotypes. Baseline IgE levels were positively correlated with the decrease of three symptom scores (r = 0.31, P = .05; r = 0.375, P = .017; r = 0.31, P = .05, respectively) that showed in patients with higher baseline total IgE levels, as needed sgAH intake decreased the symptom scores less. Our study showed that sgAHs may still be an effective option for the treatment of the intermittent symptoms in patients with well-controlled urticaria under omalizumab treatment. Baseline total IgE levels may be used as a potential biomarker for sgAH effectiveness in these patients.

Cardiac safety of second-generation H1 -antihistamines when updosed in chronic spontaneous urticaria.

The symptoms of chronic urticaria, be it chronic spontaneous urticaria (CSU) or chronic inducible urticaria (CindU), are mediated primarily by the actions of histamine on H1 receptors located on endothelial cells (the weal) and on sensory nerves (neurogenic flare and pruritus). Thus, second-generation H1 antihistamines (sgAHs) are the primary treatment of these conditions. However, many patients are poorly responsive to licensed doses of antihistamines. In these patients, the current EAACI/GA2 LEN/EDF/WAO guideline for urticaria suggests updosing of sgAHs up to fourfold. However, such updosing is off-label and the responsibility resides with the prescribing physician. Therefore, the safety of the drug when used above its licensed dose is of paramount importance. An important aspect of safety is potential cardiotoxicity. This problem was initially identified some 20 years ago with cardiotoxic deaths occurring with astemizole and terfenadine, two early sgAHs. In this review, we discuss the mechanisms and assessments of potential cardiotoxicity of H1 antihistamines when updosed to four times their licensed dose. In particular, we have focused on the potential of H1 antihistamines to block hERG (human Ether-a-go-go-Related Gene) voltage-gated K+ channels, also known as Kv11.1 channels according to the IUPHAR classification. Blockade of these channels causes QT prolongation leading to torsade de pointes that may possibly degenerate into ventricular fibrillation and sudden death. We considered in detail bilastine, cetirizine, levocetirizine, ebastine, fexofenadine, loratadine, desloratadine, mizolastine and rupatadine and concluded that all these drugs have an excellent safety profile with no evidence of cardiotoxicity even when updosed up to four times their standard licensed dose, provided that the prescribers carefully consider and rule out potential risk factors for cardiotoxicity, such as the presence of inherited long QT syndrome, older age, cardiovascular disorders, hypokalemia and hypomagnesemia, or the use of drugs that either have direct QT prolonging effects or inhibit sgAH metabolism.

Antihistamines: Recommended Dosage - Divergence between Clinical Practice and Guideline Recommendations.

The updosing of second-generation antihistamines for chronic urticaria is based on inconsistent findings. Herein, we report data on the treatment of children with chronic spontaneous urticaria (CSU) unresponsive to single doses of second-generation H(1)-antihistamines in whom an increase in antihistamine was performed without improvement and with a high prevalence of adverse events. Thus, it appears that well-controlled, well-designed clinical trials are needed to clarify which nonsedating antihistamines should be used, in what dose, and for how long in patients not responding to the standard treatment, despite the improvement in health care that guidelines help to incorporate. Furthermore, a critical use of such guidelines should be done to improve the knowledge in CSU, especially in the pediatric population.

Urticaria in children and adolescents: An updated review of the pathogenesis and management.

The present survey represents the latest data on diagnosis and management of childhood urticaria. It has been observed that urticaria occurs less often in children than adults, with symptoms rarely lasting for over 6 weeks. Triggers or aggravating factors can be found only in 21%-55% of cases. Finding autoantibodies in children does not impact a disease prognosis, unlike in adult patients, where the presence of autoantibodies is associated with a more prolonged run of the disease, a more severe prognosis and more intensive treatment methods. The incidence of food allergy equals to 8%-10% of cases. The incidence of Helicobacter Pylori infection in children is lower than that in adults and comes to 10%-18%. Medical experts recommend using the same treatment schemes for adults and children. This survey describes different urticaria management patterns suggested by experts from Europe, America, and Russia in their recent guidelines. It has been noted that unlike the guidelines from 2014, the 2018 clinical practice guidelines for the diagnosis and management of urticarial once again suggest a four-step treatment scheme with assigning omalizumab for Step 3 and cyclosporine A for Step 4 in the event of low therapeutic efficacy of the previous step or its impossibility. Leukotriene antagonists (LTRAs) are currently removed from basic management to alternative programs.

Intranasal corticosteroids reduced acute rhinosinusitis in children with allergic rhinitis: A nested case-control study.

BACKGROUND: Children with allergic rhinitis (AR) have substantially more acute rhinosinusitis than children without AR. We evaluated whether intranasal corticosteroids (INCS), second-generation antihistamines (SGH), and/or intranasal antihistamines (INH) for AR affect acute rhinosinusitis in children with AR aged 2-18 years. METHODS: By using the National Health Research Institutes Database 2005 of Taiwan, a cohort of patients with AR aged 2-18 years treated with AR medications between 2002 and 2018 was made, within which a nested case-control study was performed. Risk settings for acute rhinosinusitis cases matched controls for age, sex, and comorbidities. Current users of INCS, INH, and/or SGH were compared with remote and recent users of any AR medications and current users of INCS with and without SGH were compared with current users of SGH. RESULTS: Current users of SGH and/or INCS had a higher risk of acute rhinosinusitis than remote users of AR drugs, and current users of SGH had a higher risk of acute rhinosinusitis than recent users; however, no difference in the risk of acute rhinosinusitis was found between current users of INCS and recent users of AR drugs. Current users of INCS with and without SGH had a lower risk of acute rhinosinusitis than current users of SGH alone. CONCLUSIONS: Treatment of INCS with and without SGH diminished the risk of acute rhinosinusitis compared with treatment using SGH alone. Adequate INCS treatment for patients with AR is important to reduce the incidence of acute rhinosinusitis.

Potential risk of driving performance under combined conditions of taking second-generation antihistamines and attending calls using a hands-free function.

OBJECTIVE: Although second-generation antihistamines have reduced sedation-related side effects compared to first-generation antihistamines, sedation may still impair motor vehicle driving performance. Moreover, receiving/making phone calls using a hands-free function can negatively affect driving performance. Therefore, herein, driving performance was evaluated using a driving simulator to gain insights into the hazards of driving by combining second-generation antihistamines and a calling task, i.e., simulated calls using a hands-free function. METHODS: In this study, 20 subjects drove in a driving simulator in the absence or presence of a calling task while taking or not taking second-generation antihistamines. Driving performances for nonemergency and emergency events were determined, and a comparative analysis of intra-individual variability when taking and not taking second-generation antihistamines was conducted. RESULTS: First, when nonemergency and emergency were examined in the absence of a calling task, no significant difference in driving performance was observed between taking and not taking second-generation antihistamines. Next, when the nonemergency event was examined in the presence of a calling task, no significant difference in driving performance was observed between taking and not taking second-generation antihistamines. However, when the emergency event was examined in the presence of a calling task, a significant difference in driving performance was observed between taking and not taking second-generation antihistamines, thus resulting in reduced driving performance. CONCLUSIONS: The new system with added calling tasks allowed the extraction of the potential risks of driving performance of second-generation antihistamines that may have been previously overlooked. This study suggests that pharmacists and other healthcare professionals may need to instruct people taking any second-generation antihistamine to focus on driving and not on subtasks that require cognitive load such as talking while driving.

Efficacy and Safety of Up-dosed Second-generation Antihistamines in Uncontrolled Chronic Spontaneous Urticaria: A Review.

Background: Oral second-generation antihistamines (sgAH) constitute the first-line treatment for chronic spontaneous urticaria (CSU), a debilitating dermatological condition. However, many patients respond incompletely, and up-dosing sgAHs up to four-fold their conventional dose is recommended for disease control. Many physicians refrain from up-dosing due to a paucity of efficacy and safety data, instead adding a second antihistamine or an immunomodulator. Objective: With the aim of addressing this knowledge gap, we conducted a literature review to highlight efficacy and safety data on up-dosed sgAHs. Methods: We conducted a comprehensive search of the literature across multiple databases (PubMed, EMBASE, MEDLINE and Google scholar) using the keywords (alone and in combination) and MeSH items as well as non-MeSH terms such as "chronic spontaneous urticaria", "chronic idiopathic urticaria", AND "updosing", "second-generation anti-histamines", "cetirizine", "fexofenadine", "levocetirizine", "desloratadine", "ebastine", "bilastine", and "rupatadine". Results: Our review suggests bilastine, fexofenadine, levocetirizine, and cetirizine are recommended for up-dosing in non-responsive patients with CSU (Grade A recommendation), while desloratadine and ebastine can be recommended (Grade B recommendation). Among those with Grade A recommendation, bilastine and levocetirizine may be up-dosed safely to four times, while fexofenadine has been studied at three times the conventional dose. None of the drugs showed any dose-dependent increase of adverse effects; however, cetirizine up-dosing may increase the risk of dose-related sedation. There were no reports of systemic complications, including cardiotoxicity, at higher than licensed doses of these drugs. Only cetirizine and rupatadine up-dosing have been documented to be effective and safe in children, while there is lack of data on geriatric patients and pregnant or lactating females.

Insights into urticaria in pediatric and adult populations and its management with fexofenadine hydrochloride.

OBJECTIVE: The present narrative review provides a comprehensive update of the current knowledge on urticaria, both in adult and pediatric populations, and on the safety and efficacy of fexofenadine hydrochloride (HCl) as a treatment option. DATA SOURCE: A literature search was conducted on Embase and Medline. STUDY SELECTION: Clinical studies published in English and published between 1999 and 2020 were selected. RESULTS: Although the exact pathogenesis of urticaria is not fully understood, multiple pathways of mast cell activation are discussed to explain the existence of phenotypically different clinical manifestations of urticaria. An overview of the worldwide prevalence of chronic urticaria, including disease burden and patient's quality of life is provided. The impact of urticaria on patient's life differs on the basis of whether its form is acute or chronic, but pharmacological approaches are most often needed to control the disabling symptoms. A summary of the current management of urticaria recommended by different guidelines across countries (Global; European; American; Australian; Asian; Japanese) is presented. Non-sedating, second-generation H1-antihistamines are the preferred choice of treatment across several guidelines worldwide. Herein, the efficacy and safety of fexofenadine HCl, a representative second-generation H1-antihistamine approved for the treatment of urticaria, is discussed. The occurrence of urticaria manifestations in COVID-19 patients is also briefly presented. CONCLUSION: The burden of acute and chronic urticaria is high for patients. Second generation anti-histamines such as fexofenadine HCl can help managing the symptoms.

How bilastine is used to treat allergic rhinitis and urticaria in children.

Management guidelines for allergic rhinitis and urticaria recommend oral second-generation antihistamines as first-line treatment. The efficacy and safety of bilastine, the newest nonsedating second-generation antihistamine, are well established in adolescents/adults with these allergic conditions. The bilastine development program for pediatric use (2-<12 years) followed EMA-authorized processes. Pharmacokinetic/pharmacodynamic simulation and modeling and a pharmacokinetic study were conducted to identify and confirm the pediatric dose (10 mg/day). A Phase III, multicenter, double-blind, randomized, placebo-controlled, parallel-group study was performed to confirm the safety of bilastine 10 mg/day in children. In this article, evidence is reviewed for use of bilastine in children with allergic rhinoconjunctivitis or urticaria. Several cases are presented which demonstrate its role in routine clinical practice.

Fexofenadine: review of safety, efficacy and unmet needs in children with allergic rhinitis.

Allergic rhinitis (AR) is the most common undiagnosed chronic condition in children. Moderate/severe AR symptoms significantly impair quality of life, and cause sleep disruption, absenteeism and decreased productivity. Additionally, untreated AR predisposes children to asthma and other chronic conditions. Although intranasal corticosteroids are the most effective pharmacologic treatment for AR, oral antihistamines are often preferred. First-generation antihistamines may be chosen to relieve AR symptoms as they are inexpensive and widely available; however, they cause sedative and cardiovascular negative effects due to poor receptor selectivity. Therefore, second-generation antihistamines were developed to reduce adverse effects while retaining efficacy. There are fewer clinical trials in children than adults, therefore, efficacy and safety data is limited, particularly in children under 6 years, highlighting the need to generate these data in young children with AR. Fexofenadine, a highly selective second-generation antihistamine, effectively alleviates symptoms of AR, is non-sedating due to decreased blood-brain barrier permeability, and is devoid of cardiovascular side effects. Importantly, fexofenadine relieves the ocular symptoms of allergic conjunctivitis, which occur concomitantly with AR, improving quality of life. Overall, fexofenadine displays a favorable safety profile and results in greater treatment satisfaction in children compared with other second-generation antihistamines. This review aimed to evaluate and compare the safety and efficacy of fexofenadine with other available first- and second-generation antihistamines in children with AR.

Comparative Efficacy and Acceptability of Licensed Dose Second-Generation Antihistamines in Chronic Spontaneous Urticaria: A Network Meta-Analysis.

BACKGROUND: Licensed dose second-generation H1-antihistamines (sgAHs) are the first-line treatment in chronic spontaneous urticaria (CSU). However, the available evidence up to the present is insufficient to rank sgAHs in terms of their efficacy. OBJECTIVES: To study the comparative efficacy and acceptability of all licensed dose sgAHs in CSU treatment. METHODS: We searched PubMed, Scopus, the Cochrane Central Register of Controlled Trials, and Web of Science for randomized controlled trials (RCTs) that included licensed dose sgAHs in CSU treatment up until March 2020. A network meta-analysis was performed to estimate the standardized mean difference (SMD) and 95% confidence interval (CI) from both direct and indirect evidence for efficacy outcomes. The primary outcome was the total symptom score (TSS) changes from baseline. Secondary outcomes were changes in pruritus score and wheal score from baseline. The acceptability was estimated using odds ratios. RESULTS: We identified and included 22 RCTs with 3943 patients for evidence synthesis. Olopatadine, fexofenadine, bilastine, rupatadine, and levocetirizine were more efficacious than placebo in TSS. Olopatadine was ranked first for all efficacy outcomes (TSS: SMD -1.26 [95% CI: -1.94 to -0.58], pruritus score: SMD -0.82 [95% CI: -1.30 to -0.35], and wheal score: SMD -0.65 [95% CI: -1.10 to -0.55]). The acceptability of all included sgAHs was not inferior to the placebo. CONCLUSIONS: Olopatadine, fexofenadine, bilastine, rupatadine, and levocetirizine demonstrate superior therapeutic efficacy to placebo for the treatment of patients with CSU. Because of the low to very low quality of almost all studies included in this study, rigorous head-to-head trials are needed to confirm our findings.

Clinical characteristics and management of chronic spontaneous urticaria in patients refractory to H1-Antihistamines in Asia, Middle-East and Africa: Results from the AWARE-AMAC study.

BACKGROUND: Chronic urticaria (CU) is a condition characterized by recurrent itchy hives and/or angioedema for ≥6 weeks. Most of the data about CU come from western countries with very little information available about CU in Asia, Africa, and the Middle East. METHODS: AWARE-AMAC is a 24-month prospective, observational, real-world, non-interventional study in patients aged ≥18 years from Asia, the Middle East, and Africa (AMAC) with CU refractory to H1-antihistamines (H1-AH). The main objective was to describe the real-world experience with CU, including clinical characteristics, presence of angioedema, treatment patterns (shifts between treatment classes and changes within a treatment class), investigator-assessed disease control, and the impact on quality of life. Subgroups of interest were type of CU at Baseline and treatment class (based on 2013 urticaria guidelines). There were no mandatory visits and diagnostic/monitoring procedures additional to routine practice, except the patient diary (7-day Urticaria Activity Score) and patient reported outcome assessments. RESULTS: The focus of the current manuscript is on patients with chronic spontaneous urticaria (CSU), who formed 98% of the sample. Patients were predominantly female (69.6% female, mean age ± SD 39.8 ± 13.29 years). Time since current diagnosis (Mean ± SD) was 28.6 ± 49.06 months. Amongst patients with CSU, 31.0% had comorbid chronic inducible urticaria (CINDU) and 46.4% had a history of angioedema. 91.9% received H1-AH therapy (±other treatments). The most frequently prescribed treatment classes at Baseline were any/combination of medications, not classified under the other 7 treatment classes, named "Others" (30.5%) followed by, omalizumab (OMA; 23.6%) and second-generation H1-AH monotherapy (sgAH; 15.1%). At Month 12, the most prescribed treatment classes (>15%) for patients were OMA (23.5%) and "Other" (21.3%); 19.7% received "No drug". At Month 24, OMA (22.5%), and "Other" (17.9%) were most frequently prescribed; 28.6% received "No drug". Overall, 79.5% of patients had some type of change in treatment. Over the study period, improvement in self-reported QoL increased, which was mirrored by better disease control. CONCLUSION: In AMAC countries, the non-recommended "Other" treatment class played a major role in the initial management of CU patients. High usage of H1-AH (±other treatments) and OMA was observed. Treatment changes were observed in a majority of patients. Treatment escalation from sgAH was mostly via OMA. Improvement of disease control and QoL was achieved during the study period. TRIAL REGISTRATION: Observational study (NA).

Management of urticarial vasculitis: A worldwide physician perspective.

BACKGROUND: Urticarial vasculitis (UV) is a rare type of leukocytoclastic vasculitis characterized by long lasting urticarial skin lesions and poor response to treatment. As of yet, no clinical guidelines, diagnostic criteria, or treatment algorithms exist, and the approaches to the diagnostic workup and treatment of UV patients may differ globally. We conducted an online survey to examine how UV patients are diagnosed and treated by international specialists and to reveal the greatest challenges in managing UV patients worldwide. METHODS: Distribution of the questionnaire included an email to individuals in the World Allergy Organization (WAO) database, with no restrictions applied to the specialty, affiliation, or nationality of the participants (November 2018). The email contained a link (Internet address) to the online questionnaire. Responses were anonymous. The link to the questionnaire was further sent to the network of Urticaria Centers of Reference and Excellence (UCARE) in the Global Allergy and Asthma European Network (GA2LEN) as well as to the Turkish Dermatology Society and the Japanese Society of Allergology, who distributed the link to their members. In addition, the survey link was posted online in the group of the Russian Society of Allergologists and Immunologists. RESULTS: We received 883 completed surveys from physicians in 92 countries. UV was reported to be rare in clinical practice, with an average of 5 patients per physician per year. More than two-thirds of physicians reported wheals, burning of the skin, and residual hyperpigmentation in 60-100% of UV patients. The most frequently reported reason for receiving referrals of patients with UV was to establish the diagnosis. The most important features for establishing the diagnosis of UV were wheals of longer than 24 hours duration (72%), the results of skin biopsy (63%), and post-inflammatory hyperpigmentation (46%). The most common tests ordered in UV patients were complete blood count, erythrocyte sedimentation rate, C-reactive protein, complement components, antinuclear antibodies, and skin biopsy. Physicians considered UV to be of unknown cause in most patients, and drugs and systemic lupus erythematosus to be the most common identifiable causes. Two of 3 physicians reported that they use second-generation antihistamines in standard dose as the first-line therapy in patients with UV. The greatest perceived challenges in the management of UV were the limited efficacy of drugs and the absence of clinical guidelines and treatment algorithms. CONCLUSIONS: UV is a challenging disease. Skin biopsy, a gold standard for UV diagnosis, is not performed by many physicians. This may lead to misdiagnosis of UV, for example, as chronic spontaneous urticaria, and to inadequate treatment. International consensus-based recommendations for the classification of UV and the diagnostic workup and treatment, as well as prospective studies evaluating potentially safe and effective drugs for the treatment of UV, are necessary.

Treatment of allergic rhinitis and urticaria: a review of the newest antihistamine drug bilastine.

Allergic rhinitis and urticaria are common allergic diseases that may have a major negative impact on patients' quality of life. Bilastine, a novel new-generation antihistamine that is highly selective for the H1 histamine receptor, has a rapid onset and prolonged duration of action. This agent does not interact with the cytochrome P450 system and does not undergo significant metabolism in humans, suggesting that it has very low potential for drug-drug interactions, and does not require dose adjustment in renal impairment. As bilastine is not metabolized and is excreted largely unchanged, hepatic impairment is not expected to increase systemic exposure above the drug's safety margin. Bilastine has demonstrated similar efficacy to cetirizine and desloratadine in patients with seasonal allergic rhinitis and, in a Vienna Chamber study, a potentially longer duration of action than fexofenadine in patients with asymptomatic seasonal allergic rhinitis. It has also shown significant efficacy (similar to that of cetirizine) and safety in the long-term treatment of perennial allergic rhinitis. Bilastine showed similar efficacy to levocetirizine in patients with chronic spontaneous urticaria and can be safely used at doses of up to fourfold higher than standard dosage (80 mg once daily). The fourfold higher than standard dose is specified as an acceptable second-line treatment option for urticaria in international guidelines. Bilastine is generally well tolerated, both at standard and at supratherapeutic doses, appears to have less sedative potential than other second-generation antihistamines, and has no cardiotoxicity. Based on its pharmacokinetic properties, efficacy, and tolerability profile, bilastine will be valuable in the management of allergic rhinitis and urticaria.

[Antihistamines for the treatment of urticaria in Mexico]. / Antihistamínicos en el tratamiento de la urticaria en México.

There are four types of histamine receptors. Allergic symptoms, especially those in rhinoconjunctivitis and urticaria, are mainly caused by activation of histamine receptor 1 (H1). Consequently, oral H1-antihistamines form and integral part of the treatment of these diseases. Antihistamines are inverse agonists that stabilize the non-active configuration of the histamine receptor. First generation H1-antihistamines cause a variety of adverse effects via several mechanisms: sedation (accumulation in the central nervous system), dry mouth, urinary retention, weight gain (low selectivity: stimulation of serotonin/muscarinic/alpha-adrenergic receptors) and drug interactions (substrate of CYP450-3A4). Generally second generation H1-antihistamines have a better safety profile. New guidelines on allergic rhinitis and urticaria recommend second generation H1-antihistamines as first line drugs, with -if necessary- four-times updosing to obtain control in urticaria. The enhanced efficacy of quadruple doses in urticaria, while maintaining a good safety profile, has been shown for bilastine, desloratadine and levocetirizine (rupatadine). For ebastine and fexofenadine only the safety of quadruple doses has been shown till now. Extreme precaution should be taken with astemizol and terfenadine that never should be up-dosed, as high serum concentrations can cause potentially fatal ventricular tachycardia. First generation antihistamines are not recommended as first line treatment and updosing is not safe.

Existen cuatro tipos de receptores histaminérgicos. Los síntomas de alergia, especialmente rinoconjuntivitis alérgica y urticaria, son principalmente causados por activación del receptor H1; por ende, los antihistamínicos H1 orales (anti-H1) forman parte integral del tratamiento de estas enfermedades. Los antihistamínicos son agonistas inversos, porque estabilizan la forma inactiva del receptor. Los antihistamínicos H1 de primera generación producen efectos adversos por varios mecanismos: sedación (fijación a receptores H1 cerebrales), boca seca, retención urinaria, aumento de peso (baja selectividad: estimulación de los receptores de serotonina, muscarina y alfa-adrenérgicos) e interacciones medicamentosas (con sustrato de citocromo P450-3A4). Los antihistamínicos H1 de segunda generación son generalmente más seguros. Las nuevas guías de tratamiento de la rinitis alérgica y urticaria recomiendan como manejo de primera intención a los antihistamínicos H1 de segunda generación. En urticaria se recomienda hasta cuadruplicar su dosis en caso necesario. El aumento de la eficacia en el control de la urticaria con cuádruple dosis, sin que se afecte la seguridad, se ha documentado para bilastina, desloratadina y levocetirizina (rupatadina). Respecto de ebastina y fexofenadina, hasta ahora, sólo se comprobó la seguridad de cuádruple dosis. Una rigurosa excepción son astemizol y terfenadina, que a concentraciones séricas elevadas pueden causar taquicardia ventricular. No se recomiendan los antihistamínicos H1 de primera generación y aumentar su dosis no es seguro.