Selecting optimal second-generation antihistamines for allergic rhinitis and urticaria in Asia

Survey results revealed a high awareness of the ARIA and EAACI/GA(2)LEN/EDF/WAO guidelines. Eighty per cent of ENT and allergy specialists generally follow ARIA guidelines but 20% tailor treatment according to their patients. It was highlighted that current ARIA guidelines, however, lack recommendations for severe patient groups such as those with Samter’s triad, and clinicians felt the need for these inclusions in the guidelines. It was also mentioned that 40% of ENT and allergy specialists prefer to follow country-specific guidelines such as the ‘Clinical Practice Guidelines of Allergic Rhinitis of Thailand’ and ‘British Society of Allergy and Clinical Immunology Guidelines’. In contrast, all dermatologists and allergists surveyed tend to follow EAACI/GA(2)LEN/EDF/WAO guidelines for urticaria. However, they indicated that there may be instances of noncompliance where other clinicians in the region lack awareness of dosage adjustments, or have individual preferences for the use of antihistamine combinations.

The surveyed clinicians indicate that they perceived GPs would fully, or partially, adhere to the ARIA and EAACI/GA(2)LEN/EDF/WAO guidelines, although a fraction may not be aware of their existence. The lack of national (local) guidelines and the fear of prescribing or using steroids were cited as potential contributors to nonadherence to guidelines. It was also highlighted that some GPs still use first-generation antihistamines, due to cheaper pricing and patient preferences relating to the perceived advantages of their sedative effects at night, despite being discouraged by both the ARIA and EAACI/GA(2)LEN/EDF/WAO guidelines.

All ENT and allergy specialists surveyed commonly see persistent or intermittent allergies among their patients. Survey results revealed the most common patient profiles, unmet needs, key decision points for treatment, and practical considerations and/or limitations in treatment of patients with allergic rhinitis (Tables 1, 2). Specifically, the most common patient profiles were “young children” and adults with allergic rhinitis, asthma, and other comorbidities. Some of these patients present with accompanying sinusitis, nasal polyps, asthma, food allergies, and eczema. A fraction of these patients also present with Samter’s triad.

Survey results indicate that an inaccessibility to allergy testing due to the lack of allergy specialists and diagnostic tests in many South-East Asian countries, especially in rural areas, led to inadequate diagnosis of allergic diseases. Furthermore, suitable allergen extracts for allergy testing in APAC, such as local grasses or pollen, are lacking and they may differ from those of the Western world. Other unmet needs include the lack of access to immunotherapy and rhinologic examinations for comorbidities such as nasal endoscopy (for the detection of nasal polyps and rhinosinusitis), and the lack of diagnosis of patients with mixed rhinitis and local allergic rhinitis. The need for a long-acting and non-sedative antihistamine, better immunotherapy vaccines, and other biologics (e.g., lysine acetylsalicylate for provocation testing in cases of suspected Samter’s triad) for severe cases, such as patients with nasal polyposis, were also mentioned.

There are several aspects to diagnosis, and therefore treatment decision-making, for patients with allergic rhinitis, including the skin prick test recommended by the ARIA guidelines [5]. Responses from the survey show, however, that the latter may not be consistently applied across clinical practices—some clinicians may only perform it if patients do not respond to specific treatment possibly due to the dearth of allergy specialists in the region. The presence of clinical symptoms (seasonal or due to environmental triggers) and accompanying symptoms (nasal blockage, rhinorrhea, sinusitis, and nasal polyps) also serve as key diagnostic considerations for allergic rhinitis.

Patient profiles such as age, symptoms and severity (intermittent or persistent), presence of hepatic or renal impairment, concomitant disease, pregnancy, and familial history of atopic diseases, such as allergic rhinitis or asthma, influence treatment decisions. For example, EAACI/GA(2)LEN/EDF/WAO guidelines recommend second-generation H1 antihistamines for pregnant patients. The pattern of symptom occurrence is also another consideration—some patients report an inadequate control of bothersome symptoms, while others experience symptoms of allergic rhinitis that occur in the morning and gradually improve by midday. The presence of symptoms often leads to poorer quality of sleep. Treatment is also determined by previous experience with antihistamines and drug allergies (including those to aspirin and nonsteroidal anti-inflammatory drugs). Table 3 describes the criteria for defining responders versus nonresponders to treatment, and controlled versus uncontrolled symptoms, in the context of allergic rhinitis based on visual analog scale scoring or improvement in symptoms and quality of life post-treatment. The survey also highlighted the role of patients in treatment decision-making where they may demand therapies that restore their quality of life, enabling them to perform their daily activities.

Clinicians surveyed indicate that patients with lower compliance may be preferentially given ‘once-daily’ drugs. Patient preference and lifestyle could also impact compliance; those with an active lifestyle may prefer non-sedative once-daily pills with a rapid onset of action, while a minority prefer slightly sedating antihistamines at night.

The results underscored several limitations to the treatment of allergic rhinitis, including financial constraints and misdiagnosis by non-medical professionals—parents of young patients often mistake their upper respiratory tract infections for allergic rhinitis. Other limitations are the shortage of qualified allergologists and of long-term clinical studies investigating allergic rhinitis as a life-long condition.

Sixty per cent of dermatologists and allergologists described acute urticaria as being the ones most commonly reported amongst their patients. The survey results also reveal the common patient profiles, unmet needs, key decision points for treatment, and practical considerations and/or limitations in treatment of patients with urticaria (Tables 1, 2). Specifically, the most common patient profiles are 20‒40-year-old adults, often without concomitant disease, and pregnant/lactating women.

The pattern of symptoms of chronic urticaria (for example, intermittent or continuous wheals, and characteristic signs on wheals and flares that resolve within 24 h without residual hyperpigmentation), clinical history, and trigger factors influence the diagnosis of urticaria and therefore its treatment. Table 3 describes the criteria for defining responders versus nonresponders to treatment, and controlled versus uncontrolled symptoms in the context of urticaria based on the weekly urticaria activity score, and the change in the number and frequency of urticaria lesions. However, 40% of dermatologists and allergologists still highlighted the requirement for additional tools for the diagnosis of specific subtypes of urticaria and a need to further disseminate and implement EAACI/GA(2)LEN/EDF/WAO guidelines.

Results show that the choice of treatment is dependent on the onset of the drug (preferably with extremely fast onset), drug potency (preferably high), and dosing regimen (preferably once-daily use). The patient’s desire to obtain treatment following diagnosis is also important in determining the course of treatment. In addition, other factors that influence treatment decision include patient age, response to treatment, disease severity, and affordability. Furthermore, caution should be employed when prescribing antihistamines to patients with renal or hepatic impairment, and elderly patients should not take sedating antihistamines. According to 60% of of dermatologists and allergologists surveyed in this study, patients should also have no adverse effects (e.g. central nervous system, cardiac) to the drugs prescribed and treatment should preferably not cause sedation. Other factors that may influence treatment decisions include the level of distress experienced due to the condition, the patient’s occupation and pregnancy status, and previous experience with antihistamines.

High drug costs and limited drug availability are some of the challenges identified by 40% of dermatologists and allergologists for the implementation of existing treatment guidelines for urticaria. Financial constrains often pose a challenge, especially in poor Asian countries where patients are unable to afford a regular dose or increased dose of a drug. Furthermore, institutional practices limiting drug prescriptions to specific agents also pose a challenge to the implementation of these guidelines.

In addition, the survey reiterated that patient adherence has an impact on the management of urticaria. Patients are often hesitant to continue treatment should they not experience immediate relief, despite advice that continued treatment with antihistamines for at least 2 weeks would be required for symptom improvements. The need for a completely non-sedating antihistamine and one that would restore the patient’s quality of life was thus highlighted to enhance patient treatment experience, particularly if they have jobs requiring high concentration. The high expense of some antihistamines and drugs such as omalizumab, specialist reluctance to change management styles, and doctor or patient preference for sedating antihistamines owing to a lack of knowledge on the sedative effects of first-generation antihistamines, limit the usefulness and practical applicability of current treatment guidelines.

Apart from these challenges, 20% of dermatologists and allergologists indicated that many patients are still embarrassed by the itch and rash, impacting their quality of life. Therefore, it was highlighted that better treatment strategies for control of symptoms amongst urticaria patients, their symptoms often leading to lack of/disturbance of sleep, are required. A need for more suitable drugs for those with renal impairment was also cited by 20% of these clinicians.

Many considerations come into play when selecting the optimal antihistamine for patients. Ninety per cent of clinicians surveyed cited drug efficacy and safety as the most important consideration. This is followed by drug impact on sedation and psychomotor function (60%), patient lifestyle (50%) and treatment adherence (50%) (Table 4). Other considerations include concomitant disease, cost, pregnancy and breastfeeding, presence of renal or hepatic problems, cardiac disease and side effects, and consumption of other medications.

This survey highlighted that patient lifestyle also influences the selection of antihistamine; sixty per cent of clinicians stated a need to prescribe non-sedating antihistamines for patients who need to stay alert and require excellent psychomotor responses, and those who are active in sports or outdoor activities. Of note was the need to consider patient adherence/compliance as part of treatment decision-making in the management of not just of allergic rhinitis but—importantly—urticaria. Patients generally prefer to take antihistamines once daily, and those with difficulty adhering to treatment could be prescribed longer-acting, non-sedating drugs such as bilastine and fexofenadine [16, 18]. A good balance between drug efficacy and safety, with no cardiac or central nervous system adverse effects or drug interactions, should be considered in selecting the optimal antihistamine. In this study, the consensus among the surveyed clinicians was that bilastine was the first-choice antihistamine for both allergic rhinitis and urticaria, followed by fexofenadine.

Patients must also be clearly willing and able to pay for the antihistamines prescribed. Otherwise, cheaper alternatives need to be offered to these patients.

Considering the factors listed above, an algorithm to triage patients suffering from allergic rhinitis and urticaria to a selection of the optimal antihistamines is suggested in this manuscript based on the ARIA and EAACI/GA(2)LEN/EDF/WAO guidelines for allergic rhinitis and urticaria [6, 19] (Fig. 1a, b). The most versatile antihistamines for adults and the elderly, as shown in Fig. 1, are bilastine and fexofenadine, bearing in mind patients who might already be taking other drugs (drug-to-drug interactions) and suitability for patients with renal and/or hepatic impairment. As second-generation antihistamines are non-sedative, they are all suitable for patients who lead an active lifestyle (Fig. 1). Consensus among the clinicians indicated a preference in prescribing bilastine or fexofenadine to patients who may have had prior experience with other second-generation antihistamines. Further, the survey revealed that bilastine was the preferred antihistamine of choice for all the patient groups discussed here, i.e., patients with either allergic rhinitis or urticaria, those with or without concomitant disease, hepatic or renal impairment, or those requiring a high level of concentration at work or in their daily lives (Fig. 1).

Clinicians surveyed were also asked to indicate their preferences and collective experiences for the treatment of allergic rhinitis and urticaria using the various second-generation antihistamines. While all second-generation antihistamines listed in Table 5 have been indicated for the treatment of both allergic rhinitis and urticaria, with the exceptions of bilastine, cetirizine, levocetirizine, and rupatadine, the remainder are not indicated for the treatment of allergic rhinoconjunctivitis (Table 5). Clinicians also indicated that due to their earlier approval and availability, the most frequently prescribed drugs for allergic rhinitis and urticaria are cetirizine and levocetirizine. However, with the greater availability of more novel second-generation antihistamines such as bilastine, along with comparable efficacy and greater safety, prescription patterns have started to change, particularly for patients described in Fig. 1. They also indicated that desloratadine works well, especially for patients with chronic urticaria. Table 5 summarizes the observations on efficacy, the commonly prescribed daily dose, and duration of treatment, dose adjustments required and contraindications/adverse effects associated with these antihistamines. Treatment duration for allergic rhinitis and urticaria using second-generation antihistamines ranged from 2 weeks to more than a year, depending on the severity of symptoms. All the antihistamines listed in Table 5 are available in the following APAC countries: Hong Kong, the Philippines, Singapore, and Thailand; bilastine is not yet available in Vietnam, and rupatadine is not available in Malaysia and was only recently introduced in the Philippines and Thailand.

Dose adjustments were typically done with increments in the daily dose of up to four-fold for urticaria if there was no improvement of symptoms between 1 and 4 weeks. Additionally, second-generation antihistamines may be switched if patients experienced side effects, due to nonavailability of the drug or upon the patient’s request for a cheaper alternative. In the context of urticaria, using combinations of antihistamines is not usually found to be particularly beneficial in alleviating the patient’s symptoms. Meanwhile, for allergic rhinitis, some clinicians would opt to change the patient’s antihistamine if the patient reports unsatisfactory symptoms after 4‒6 weeks of continuous treatment. Others would change the second-generation antihistamine if there is not at least a 50% improvement in symptoms following 1 week of treatment, or if the patient complains of side effects other than sedation, such as chest pains, dizziness, dry mouth, or palpitations. Additionally, nasal endoscopy may be performed to eliminate the possibility of nasal polyps, sinusitis or deviated nasal septum. If treatment is not effective with a second-generation antihistamine alone, it is often combined with a nasal steroid spray. A skin prick test and/or nasal allergen provocation test may also be necessary at this point (Some of the survey results included off-label use of antihistamine preparations or combinations, which are not discussed in this manuscript).

Seventy per cent of clinicians highlighted that the benefits of second-generation antihistamines were their non-sedating properties, once-daily dosing and quick onset of action compared with nasal sprays. In addition, many of these newer antihistamines led to fewer anticholinergic effects and drug-to-drug interactions, longer duration of action and anti-inflammatory properties when dosage was increased. Nonetheless, drug costs and safety of some of these antihistamines for the hepatic/renal-impaired patients and those taking other drugs was a major consideration.

Of note were the beneficial properties and characteristics of the second-generation antihistamines bilastine and fexofenadine, as specified by all clinicians: non-sedative, once-daily dosing, highly efficacious, lack of cardiac side effects and safe even for the elderly. Additionally, dose adjustments are not required for patient with hepatic or renal impairment and no severe drug-to-drug interactions have been reported.