The clinical evidence of second-generation H1-antihistamines in the treatment of allergic rhinitis and urticaria in children over 2 years with a special focus on rupatadine

ABSTRACT

Introduction

Many obstacles limit the development of pharmacologic studies in children, in particular ethical and practical issues. Therefore, although second-generation H1-antihistamines (sgAH) are recommended by international guidelines as first-line therapy in childhood allergies, most data on the efficacy of antihistamines in children has been extrapolated from studies in adult patients.

Areas covered

The current review focuses on rupatadine, a well-studied modern sgAH that has dual affinity for histamine H1-receptors and PAF receptors. In recent years, clinical efficacy and safety controlled-clinical trials on rupatadine were conducted in children and were based on latest current guidelines using validated tools of allergic rhinitis and urticaria.

Expert opinion

Children are not little adults since they present specific physiologic, metabolic, and developmental differences that should be evaluated in specific trials. The clinical evidence with rupatadine in children is the most recent and validated in accordance with current recommendations, with extensive direct data on efficacy and safety in pediatric populations over 2 years old.

KEYWORDS:

• Rupatadine
• allergic rhinitis
• chronic spontaneous urticaria
• childhood allergies
• PAF antagonist

1. Introduction

In past decades, antihistamines have become one of the main treatment options for allergic disorders in pediatric patients. Second-generation H1-antihistamines (sgAH) are among the most frequently prescribed medicines in pediatric population. Most common indications include allergic rhinitis (AR), chronic spontaneous urticaria (CSU), and food allergy [1–3]. However, not all antihistamines are alike. In consequence, it is important to understand the pharmacological properties of new antihistamines and the clinical efficacy and safety data of each individual agent obtained directly from clinical studies in children.

Lack of evidence in pediatric pharmacotherapy is common and has obvious and critical implications. Many reasons limit the development of pharmacologic studies in children, in particular ethical and practical issues in carrying out research on pediatric population. These obstacles also include the different pharmacokinetics at different ages, from the neonatal period to adolescence, so a single study in children is not likely to be enough to cover the entire pediatric age span. Additionally, regulatory agencies ask the pharmaceutical companies to stimulate the development of pediatric medicines and provide more information on their use, as a response to the lack of evidence and approval of medicines for children [3]. Therefore, the correct management of allergies in children according to guidelines is necessary, but it is also essential to have good efficacy, safety, and tolerability data from individual pharmacological agents in pediatric patients.

AR is a very common disease with an increasing incidence, especially in the Western countries, where the actual prevalence in the general population fluctuates between 10% and 40%, according to different studies [4–7]. The classic classification of allergic rhinitis (seasonal vs. perennial) is not interchangeable with the ARIA (Allergic Rhinitis and its Impact on Asthma) classification [6,7]. ARIA classification based on symptom duration (intermittent vs. persistent) and severity (mild vs. moderate/severe) has been validated in children [6,7]. The International Study for Asthma and Allergies in Childhood (ISAAC) found that the prevalence of AR varied between 0.8 and 14.9% in children aged 6–7 years old and 1.4 to 39.7% in 13–14 years old worldwide. The Phase III ISAAC data has shown a worldwide trend for increasing symptoms of AR in childhood and found a 10.1% prevalence of AR symptoms in children [8].

Urticaria is a common condition of the skin characterized by the rapid appearance of pruritus and wheals, with or without angioedema, caused by edema and dilatation of the postcapillary venules and lymphatic vessels. CSU is defined as the daily or almost daily appearance of urticaria symptoms throughout 6 consecutive weeks. In the general population, the prevalence of CSU has been estimated 0.1–3% of the population in developed societies [9,10].

A physician-based online survey was conducted in 5 European countries (United Kingdom, Germany, Italy, France, and Spain) to assess the prevalence and clinical characteristics of CSU in pediatric patients. The one-year diagnosed prevalence of chronic urticaria and CSU in children was 1.38% (95% CI, 0.94–1.86) and 0.75% (95% CI, 0.44–1.08), respectively [11], and CSU accounts for more than 50% of total cases of chronic urticaria in children [10].

Although histamine is the main mediator in the pathophysiology of allergic rhinitis and chronic urticaria, it is clearly not the only mediator involved in these processes. In recent years, the role of platelet activating factor (PAF) as a key mediator involved in the allergic hypersensitivity reaction has gained recognition. PAF is an endogenous phospholipid synthesized in inflammatory cells such as mast cells, eosinophils, basophils, neutrophils, macrophages, and platelets, which is released during allergic or inflammatory reactions. In allergic rhinitis, these reactions are associated with increased vascular permeability, eosinophil chemoattraction, and airway hyperresponsiveness. Increased plasma levels of PAF have been reported in patients with urticaria compared with healthy controls [12–17]. Additionally, recent findings in CSU patients, particularly those with sgAH refractoriness, showed significant increases in serum PAF levels and decreases in PAF-AH. Therapies modulating PAF and PAF-acetylhydrolase (PAF-AH), which is responsible for PAF degradation. PAF-AH levels could be effective in patients with CSU refractory to antihistamines [18].

2. Current management of allergic rhinitis and chronic spontaneous urticaria in children

2.1. Use of guidelines in childhood allergies

There are well-designed guidelines for the management of childhood allergies, but many problems remain within current approaches. For example, antihistamine dosing and efficacy data in children has been taken primarily by extrapolation from studies conducted in adults, and there are scarce clinical studies with data directly obtained from pediatric population. It is well known that researchers face methodological and ethical challenges to carry out studies in children and, consequently, few studies are conducted in pediatric population. Some ethical issues are related to children’s vulnerability, informed consent, and confidentiality, while methodological issues are related to the heterogeneous nature of childhood itself according to different ages. Therefore, only few clinical studies on sgAH have been performed in children based on current guidelines using validated assessment tools for allergic rhinitis and urticaria [11–17,19–25]. As a consequence, an additional ethical problem arises: children (the younger the more) are who do not or later benefit from the medical progress.

The use of guidelines is deeply required due to the increasing prevalence of systemic inflammatory conditions in children and different treatment strategies. Main guidelines centered on disease classification, effectiveness and safety of treatment, and improved quality of Life (QoL). One of these guidelines is ARIA (Allergic Rhinitis and its Impact on Asthma), which consider that appropriate treatment of AR may improve patients’ QoL, learning, and work productivity. However, ARIA is best known in adults and its recommendations should be further disseminated in pediatrics [4,6,7,19,20,26].

As stated by ARIA guidelines, AR may be classified as intermittent or persistent, while severity of disease may be rated as mild, moderate, or severe [6,7].The former classification that included seasonal and perennial AR is no longer recommended [4,6,7,19–22,26]. AR is still a condition where patients do not always seek appropriate treatment, may remain undertreated and do not adhere well to treatment. ARIA guidelines recommend the use of sgAH as first-line therapy for intermittent and persistent allergic rhinitis, regardless of disease severity. Most of the sgAH for adults and children have been studied and approved for seasonal and perennial allergic rhinitis, the former classification before ARIA guidelines recommendations, but only a few antihistamines reported efficacy and safety for the treatment of allergic rhinitis based on current ARIA classification, including desloratadine, for both intermittent and persistent allergic rhinitis, and levocetirizine and rupatadine for persistent allergic rhinitis [23].

In the field of urticaria, a clinically useful set of recommendations is the EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis, and management of urticaria. A recent review of the EAACI/GA²LEN/EDF/WAO guideline embraces the definition and classification of urticaria, considering evidence-based diagnostic and therapeutic approaches for different subtypes of urticaria [9].

EAACI/GA²LEN/EDF/WAO guidelines propose sgAH as first-line treatment. Based on a broad consensus, these guidelines recommend aiming at complete symptom control in urticaria with sgAH, considering not only efficacy but also safety and QoL of patients [9]. Additionally, a Global Allergy and Asthma European Network (GA²LEN) position paper recommends that first-generation H1-antihistamines should no longer be available over-the-counter for self-medication of allergic disorders in developed countries since newer non-sedating sgAH with superior risk/benefit ratios are available [24].

Updated urticaria guidelines suggest up-dosing sgAH up to fourfold in patients with chronic urticaria who do not respond to standard doses of sgAH. The second-line treatment recommendation (an increase in the dose of sgAH to fourfold) is evidence-based and consensus-based. Urticaria guidelines also recommend that the same treatment algorithm can be used in children with chronic urticaria after a careful risk-benefit evaluation [9].

There are very few controlled clinical studies with sgAH evidence directly obtained in children using these new guidelines and recommended clinical assessment tools such as UAS7 (7-day Urticaria Activity Score) and QoL specific questionnaires.

2.2. Use of antihistamines in children

International evidence-based guidelines recommend sgAH as first option in the treatment of intermittent AR, persistent AR and CSU because first-generation H1-antihistamines should no longer be used in children due to their unfavorable therapeutic index and frequent side effects [1–5,20–22].

There are no randomized, clinical trials of first-generation H1-antihistamines in children, since these old drugs were launched when clinical trials were not required for approval. However, evidence shows that they are associated with a variety of side effects. These effects are related to the penetration of antihistamines into the Central Nervous System (CNS) binding to brain H1-receptors, which reduces alertness, cognition, learning, memory and psychomotor performance, and promotes sedation and somnolence. Their interaction with cardiac ion channels increases QT interval and may cause ventricular arrhythmias, and lethal doses have been identified in infants and children. Additionally, since they are nonselective for H1-receptors, they bind to other receptors, like muscarinic, serotoninergic and alpha-adrenergic receptors, triggering many unwanted effects. Furthermore, because their pharmacokinetic characteristics three to four doses per day are required. On the contrary, sgAH demonstrate high H1-receptor specificity, although they are not all the same as there are differences in their pharmacological characteristics, for example, their ability to get into the CNS [1–3,23,24].

Knowledge on drug absorption and pharmacokinetics in the pediatric population has greatly increased over the past two decades. In pediatrics, age is a continuum that adds variability to drug disposition and effect. However, the impact of specific age-related effects on pharmacokinetics, pharmacodynamics, and dose requirements is not completely understood. Children are not little adults, since they present specific physiologic, metabolic, and developmental differences. For example, children show increased gastric emptying time and different intestinal motility. They also have enzyme immaturity, not fully developed renal function, and some faster metabolic rates. Absorption can be affected by the differences in gastric pH and stomach emptying time that have been observed in neonates, infants, and children. In addition, low plasma protein concentrations and a higher body water composition can change drug distribution. Metabolic processes are often immature at birth, which can lead to a reduced clearance and a prolonged half-life for those drugs for which metabolism is an important mechanism for elimination. Renal excretion is also reduced in children due to immature glomerular filtration, tubular secretion, and reabsorption [1–3,23–25].

There are also limited data on the pharmacodynamic behavior of drugs in the pediatric population. In children, gastric pH reaches adult acidity between 2 and 3 years of age and cytochrome P450 (CYP) enzymes reaches adult activity between 1 and 4 years of age. Different factors influence pharmacokinetics and pharmacodynamics until they reach adult function, and therefore, modification of drug dose regimens at different pediatric ages is often required [1–3,21–25].

Anyway, results on efficacy in children should be taken with caution since in clinical trials health care providers commonly gather the clinical information by interposed person (commonly parents or caregivers), and it is probable that the information received does not accurately reflect the actual child’s perceptions, particularly when we ask about subjective symptoms (nasal/ocular itching, nasal obstruction). Then, clinical trials in children tend to underestimate the real effect, and for this reason simple pediatric-specific tools to assess efficacy in clinical trials in children are urgently needed [27–31]. In the meantime, symptoms scores, QoL questionnaires and other control tools should be directly delivered to the patient, especially when he/she is an adolescent.

2.3. Clinical data for second-generation antihistamines in children

Antihistamine dosing and efficacy data in children has been taken primarily by extrapolation from efficacy and safety studies conducted in adults. There are scarce clinical studies with data directly obtained from pediatric population. Some clinical studies assessed efficacy of treatment with cetirizine, levocetirizine, desloratadine, fexofenadine and rupatadine in pediatric patients with allergic rhinitis, mainly between 6 and 11 years old (Table 1).

Table 1. Clinical studies that evaluated efficacy of second generation antihistaminesin pediatric patients with allergic rhinitis

	Cetirizine	Levocetirizine	Desloratadine	Fexofenadine	Rupatadine	Bilastine	Ebastine
Classic classification
Seasonal AR (SAR):
Children 2–5 years	N/A	N/A	N/A	N/A	N = 44 (Santamaria, 2018)	N/A	N/A
Children 6–11 years	N = 209 (Peakman 1997)	N = 177 (De Blic, 2005)	Prospective N = 37 (Dizdar, 2007)	N = 875 (Graft, 2001) N = 935 (Wahn, 2003) N = 1110* (Meltzer, 2004)	N = 11 (Izquierdo, 2009)
ARIA classification
Intermittent AR (IAR)	N/A	N/A	N/A	N/A	N/A	N/A	N/A
Perennial AR (PAR)
Children 2–5 years	N = 60 (Chen ST, 2006)	N/A	N/A	N/A	N/A	N/A	N/A
Children 6–11 years	N = 328 (Jobst S, 1994)	N = 306 (Potter, 2005)	N/A	Mix SAR/PAR (Ngamphaiboon, 2005)	N/A
Persistent AR (PER)
Children 6–11 years	N/A	N = 40 (Marcucci, 2011)	N/A	N/A	N = 360 (Potter, 2013)	N/A	N/A
12–17 years** (adolescents included in adult studies)	N/A	N/A	IAR N = 547 (Bousquet, 2009)	N/A	3 studiesN= 241 (Mion 2009) N=736 (Fantin, 2008) N=324 (Valero, 2009)	SAR/PAR N = 1404 (Bachert 2009)(Kuna 2009)(Sastre 2012)	SAR/PAR (Bousquet, 1999)(De Molina 1989)

*Pooled from three studies: one study included fexofenadine HCI 30 mg b.i.d; two studies included fexofenadine HCI at 15 and 60 mg b.i.d [66].

**N represents total sample size of the study. N of subgroup (adolescent 12-17 years) is not detailed.

SAR, seasonal allergic rhinitis

PAR, perennial allergic rhinitis

N/A, not available

With an exception of a study on rupatadine [32], there are no efficacy studies in children aged 2–5 years with seasonal allergic rhinitis, and there have been no clinical studies in children with intermittent allergic rhinitis according to the ARIA classification. Desloratadine has been widely prescribed and used in children, but surprisingly very scarce data from clinical studies in children with allergic rhinitis have been reported. In contrast, the efficacy of rupatadine has been evaluated in children aged 2–5 years [32].

In addition, rupatadine is the only sgAH with data from a randomized, multicenter, double-blind clinical study using the ARIA classification performed by our team and several worldwide investigators in pediatric patients aged 6–11 years with persistent allergic rhinitis [33].

Regarding the efficacy of antihistamines in the management of CSU in children there are also very limited data (Table 2) [34–50]. It is very noticeable that clinical efficacy studies have not been conducted with ebastine, fexofenadine, levocetirizine, bilastine, or desloratadine in pediatric patients with CSU and only one single study assessed the use of cetirizine in children under the age of 6 [36]. In Italy, La Rosa et al. evaluated the efficacy and tolerability of cetirizine in comparison to a more commonly used antihistamine in pediatrics (oxatomide) in children with idiopathic chronic urticaria. This double-blind multicenter study recruited 62 children with ages ranging from 2 to 6 years (mean 3.85 years). The clinical study and the statistical evaluation were finally conducted on 57 children (28 on cetirizine and 29 on oxatomide). In general, the effectiveness of both drugs in the treatment of erythema, papules, edema, and itching demonstrated comparable therapeutic activity (P < 0.001). None of the medications was associated with significant adverse effects and there was no evidence of changes in hematochemical and urinary values [36].

Table 2. Clinical studies that assessed efficacyof second generation antihistamines in pediatric patients with chronic spontaneous urticaria (CSU)

	Cetirizine	Levocetirizine	Desloratadine	Fexofenadine	Rupatadine	Bilastine	Ebastine
Urticaria (CSU)
Children 2–6 years	N = 57 (La Rosa, 2001)	N/A	N/A	N/A	N = 199 (Potter, 2016)	N/A	N/A
12–17 years (adolescents included in adult studies)	N/A	N/A	N/A	N/A	N = 334 (Giménez-Arnau, 2007)	N/A	N/A
					N = 283 (Dubertret, 2007)

N/A, not available

Concerning the so-called new sgAH, efficacy data were published from adolescents (>12 years old) with allergic rhinitis who were included in adult clinical studies of bilastine [45–47] or ebastine [48,49], but there are no efficacy data for bilastine or ebastine obtained directly from children with allergic rhinitis or urticaria (Tables 1, 2 and 3). A prospective open label trial, conducted by Novak et al., assessed the use of bilastine during 12 weeks in children aged 2–11 years with allergic rhinitis or chronic urticaria, but study evaluations were only limited to safety and tolerability [50].

Table 3. Safety data of second generation antihistamines from clinical studies in newborns and children

	Cetirizine	Levocetirizine	Desloratadine	Fexofenadine	Rupatadine	Bilastine	Ebastine
Newborns 6 m-2 years	Prospective N = 817 (Simons,2002) *	Prospective N = 510 (Simons, 2007)**	N = 131 (Lutsky, 2004)	N/A	N/A	N/A	N/A
Children 2–5 years	N/A	N/A	N = 111 (Bloom, 2004)	N = 50 (Segall, 2008) N=453 (Milgrom, 2007)	N = 660 Pooled analysis 2–11 yrs (on file)	N = 509 Pooled analysis Novak (Z, 2016)	N/A
Children 6–11 years	N/A	N/A	N = 120 (Bloom, 2004)				N/A

*ETAC study: Early Treatment of the Atopic Child 12–24 months (18 months long-term safety) [38].

** EPAAC study: Early Prevention of Asthma in Atopic Children 12–24 months (18 months long-term safety) [39].

N/A, not available

Alternatively, the efficacy of rupatadine has been assessed in a multicenter, double-blind, randomized, placebo controlled study conducted by Potter et al. [37] in 199 children aged 2–11 years with CSU as well as in two studies on adult patients (>18 years) with chronic urticaria in which adolescents (≥12 years) were included [12,14].

There are some published studies that reported safety data of sgAH in pediatric patients treated with cetirizine [38], levocetirizine [39], desloratadine [40,41], fexofenadine [42,43], bilastine [45–47], or ebastine (Table 3) [48–50]. These safety studies in children with allergic rhinitis or urticaria, however, had a noncomparative open label design, or were prospective observational studies, without efficacy comparative evaluations. Although this aspect is accepted by regulatory agencies, it is sometimes not possible to demonstrate the potency of the drug compared to placebo or if the dose adjustment is appropriate in children according to their age or weight.

Additionally, a couple of ambitious trials, as prospective follow-up to know the preventive activity of sgAH have been performed. The ETAC study [38] (Early Treatment of the Atopic Child Study) assessed the long term (18 months) safety of cetirizine in 817 children who were 12–24 months old at study entry, while the EPAAC study [39] (Early Prevention of Asthma in Atopic Children Study) evaluated for 18 months the safety of levocetirizine in 510 children who were age 12–24 months].

3. Rupatadine pharmacological properties

Rupatadine has dual affinity for histamine H1-receptors and PAF receptors. Rupatadine, as a sgAH, has a lower potential for H1-receptor occupancy in the brain compared to first-generation antihistamines and is less likely to produce sedation, somnolence or drowsiness at recommended dosages [13–19,26]. The antiallergic/anti-inflammatory properties of rupatadine as PAF antagonist have been demonstrated in vitro and in a broad spectrum of pharmacological in vivo models in mice, rats, guinea pigs, rabbits, dogs and humans [12,15,16]. In summary, rupatadine inhibited the interaction of PAF with its specific receptors in platelet membranes, and also the PAF-induced platelet aggregation (rabbit and human platelets). Non significant anti-PAF effect was observed with terfenadine, loratadine, and ketotifen in platelet aggregation tests with rabbit and human platelets [12,15,16]. In animal models, rupatadine inhibited PAF- and histamine-induced cutaneous wheal reaction, while loratadine, levocabastine and cetirizine only inhibited the effect induced by histamine. Rupatadine also inhibited PAF-induced neutrophil chemotaxis and was shown to be more effective than other antihistamines, such as mizolastine, fexofenadine, loratadine, and cetirizine [12,15,16].

Rupatadine is rapidly absorbed after oral administration, showing a median Tmax of 0.8 h with a single daily dose, or 0.75–1 h with repeated doses. After absorption, the drug undergoes extensive hepatic metabolism by cytochrome P450 system. In vitro metabolism studies using human liver microsomes demonstrated that the isoenzyme 3A4 (CYP3A4) is the primarily responsible for the biotransformation of rupatadine. Therefore, concomitant administration of rupatadine with known CYP3A4 inhibitors (e.g. grapefruit, ketoconazole, erythromycin) is not recommended [51–61]. In contrast, no clinically relevant changes in plasma levels were observed when rupatadine and azithromycin were coadministered [57]. Similarly, no changes on pharmacokinetic of fluoxetine were documented after the administration of rupatadine 10 mg dose.

Rupatadine has several active metabolites that contribute to the drug’s overall efficacy. The most important route of elimination for the drug is via the bile [15,19]. Systemic exposure to rupatadine after food intake increased by 23% compared with that under fasting conditions and Tmax was delayed by 1 hour, but exposure to its metabolites remained unaffected. These changes did not show clinical consequences, and therefore, rupatadine can be administered with or without food [16,17,51–61].

4. Efficacy and safety profile of rupatadine in pediatric patients

4.1. Efficacy of rupatadine in children with AR

There are very few published researches on children with persistent AR diagnosed according to the new ARIA classification and treated with sgAH. Most of the trials conducted previously with sgAH in children were based in the old classification of AR, either seasonal or perennial AR [27–31,62–68]. A study on levocetirizine was reported by Marcucci et al. in children with persistent AR, but it mainly evaluated the anti-inflammatory efficacy of the drug [62]. Therefore, a study conducted by Potter et al. was the first clinical evidence of the efficacy for a sgAH in children with persistent AR [33].

Potter et al. conducted a multicentre, randomized, double-blind, placebo-controlled study including 360 patients aged between 6 and 11 years, with a diagnosis of persistent AR according to ARIA criteria. The primary efficacy endpoint was the change from baseline in the Total Nasal Symptoms Score (T4SS; nasal congestion; sneezing; rhinorrhea; itchy nose, mouth, throat, and/or ears) after 28 days of therapy. Rupatadine showed statistically significant differences compared with placebo, both at 4 weeks (−3.1 ± 2.1 vs. −2.5 ± 1.9; p = 0.018) and 6 weeks (−3.3 ± 2.1 vs. −2.7 ± 1.9; p = 0.048) in the baseline reduction in T4SS (Figure 1). This study was the first large clinical report on the efficacy of a sgAH in children with persistent AR in both symptoms and quality of life [33].

Figure 1. Change from baseline in the T4SS after 28 and 42 days oftreatment with rupatadine oralsolution or placebo in patients aged between 6 and 11 years, with a diagnosis of persistent AR according to ARIA criteria. Reproduced from [33] with permission of John Wiley & Sons

T4SS, Total 4 Nasal Symptoms ScoreAR, allergic rhinitisARIA, Allergic Rhinitis and its Impact on Asthma

In addition, there are very few clinical studies that assessed the efficacy of sgAH in very young children diagnosed according with ARIA classification. Recently, Santamaría et al. conducted a multicenter open-label study in 2–5-year-old children with AR (N = 40). Evaluations of Total Five Symptoms Score (T5SS), including: nasal congestion; sneezing; rhinorrhea; itchy nose, mouth, throat, and/or ears; and itchy, watery, and red eyes, were evaluated. Symptoms were assessed by parents/legal guardian before and after 4 weeks of rupatadine 1 mg/mL oral solution administration, dosed according to body weight. All individual symptoms of T5SS, including nasal congestion, showed a decrease from baseline at both 14 and 28 day. Only 15 adverse events were reported, all of them were of mild intensity, and were considered not related to the study treatment. No QTc prolongation was observed. Therefore, rupatadine demonstrated an improvement of AR symptoms after a daily dose administration and proved to be safe in 2–5-year-old children, a population in which there is a general lack of clinical evidence [32].

4.2. Efficacy of rupatadine in children with urticaria

Recommendations in current guidelines for the treatment of CSU in children are mostly based on extrapolation of data obtained in adults. Potter et al. conducted a double-blind, randomized, parallel-group, multicenter, comparative with active control and placebo-controlled study to assess the efficacy of rupatadine in children aged 2–11 years with CSU. Randomized patients (N = 206) received either rupatadine oral solution (1 mg/ml), or desloratadine oral solution (0.5 mg/ml) or placebo once daily over 6 weeks [37].

A modified UAS7 was employed as the primary endpoint. The absolute change of UAS7 at 42 days showed statistically significant differences in active treatments vs placebo. As percentage of change of UAS7, there was also a statistically significant difference between active treatments and placebo (p = 0.001), the largest main change observed with rupatadine, followed by desloratadine and placebo. Rupatadine, but not desloratadine, was statistically superior to placebo in reduction of pruritus. Subgroup analysis showed that only rupatadine reduced UAS7 scores statistically significantly better than placebo in children with body weight ≥25 kg (p < 0.001), whereas the difference between desloratadine and placebo was not statistically significant. Additionally, fast onset of action was demonstrated with rupatadine. This trial was the first one to evaluate severity and efficacy outcomes of a sgAH using adapted UAS7 in the treatment of CSU in children between 2 and 11 years of age in a placebo-controlled study [37].

4.3. Rupatadine safety profile in children

The safety and tolerability profile of rupatadine has been well established previously in adults and adolescents > 12 years old. Safety data show that rupatadine does not affect the cardiovascular system, without relevant changes in the corrected QT interval, nor does it significantly affect psychomotor activity at clinical doses [54–61]. Similarly, clinical studies on safety of rupatadine in children and very young children showed that the proportion of adverse effects is very low in the pediatric population [12–14,33,37,44,51–53,69].

To assess the long-term safety and tolerability of rupatadine 10 mg once daily, 324 patients (including adolescents ≥12 years) with persistent allergic rhinitis were enrolled by Valero et al. in a multicentre, open-label study. In this long-term safety evaluation, 90% and 83% of patients completed the 1–6 months and 1–12 months treatment periods, respectively. Overall, 20.4% and 10.8% of the patients reported at least one treatment-related AE during the 1–6 months and 1–12 months treatment periods, respectively, and non-unexpected adverse events were reported. Somnolence, headache and dry mouth were the most commonly reported adverse events. Therefore, this study confirmed the good long-term safety and tolerability of rupatadine in adolescents with persistent allergic rhinitis [70].

A database search was conducted by Gonzalez-Nuñez et al. to obtain preclinical and clinical global safety data from rupatadine studies in patients over 2 years old. The assessment confirmed a safety profile for rupatadine which is similar for sgAH in patients with allergic rhinitis or urticaria. The study confirmed that rupatadine is a safe and well tolerated drug, the same as placebo, in patients over 2 years old, with no CNS or cardiovascular effects [44].

5. Conclusions

Many aspects hinder the conduction of pharmacologic studies in children, due to ethical and methodological issues. Therefore, a small number of clinical studies are designed to assess clinical efficacy but not only safety of the treatments for allergic rhinitis and urticaria in pediatric population. As a result, most of the antihistamines, including the new ones, have performed only safety studies in children and extrapolate the efficacy from their studies conducted in adults or adolescents.

SgAH are recommended by current guidelines as first-line option for the treatment of allergic diseases. However, there are very few sgAH studies that assessed the efficacy use of these drugs in children, mainly under 6 years old. Alternatively, in last years, pediatric well-designed studies confirmed efficacy of rupatadine using efficacy data directly obtained in children over 2 years and using current guidelines of allergic rhinitis and urticaria.

6. Expert opinion

Regulatory agencies suggested stimulating the development of new pediatric medicines or new dosage forms and providing more information on their use, in response to the lack of evidence and approval for children’s medications. There are well-designed guidelines for the management of childhood allergies, but many problems remain within current approaches. For example, sgAH are recommended by international guidelines as first-line therapy in childhood allergies as a whole but most data on the efficacy of antihistamines in children has been extrapolated from studies in adult patients. However, as described above, children are not little adults, since they present specific physiologic, metabolic and developmental differences. Therefore, efficacy and safety of pediatric products should be evaluated in ad-hoc clinical trials as in the case of rupatadine.

Very few sgAH have developed a complete clinical program with clinical trials. On the contrary, rupatadine demonstrated an improvement of AR symptoms after a daily dose administration and proved to be safe in 2–11-year-old children, using the latest current guidelines. In CSU, there are no efficacy controlled data with children. Only the efficacy and safety of rupatadine has been proved in a double-blind, randomized, placebo controlled study on children aged 2–11 years as well as in two trials on adult patients in which adolescents over 12 years were included.

A really critical point is that at younger ages, due to the technical and sometimes ethical difficulties, there are no efficacy studies. In the case of AR or CSU, few children aged less than 5 years have efficacy evaluated as in adults or adolescents following the new international guidelines or recommendations.

Finally, it is important to note that in the future the clinical dosage in children below 5 years of age should be evaluated with special attention, that is, through controlled studies, since it is a more vulnerable group of pediatric patients due to its scarce or incomplete information on both efficacy and safety.

Article highlights

• International evidence-based guidelines recommend second-generation H1-antihistamines (sgAH) as first option in the treatment of intermittent AR, persistent AR and CSU.

• Recommendations in current guidelines for the treatment of AR or CSU in children are based mainly on extrapolation of data obtained in adults, but clinical data obtained directly in pediatric populations are scarce.

• Although histamine is acknowledged as the main mediator in the pathophysiology of AR and CSU, other mediators such as the platelet activating factor (PAF) play a key role in the allergic reactions.

• Rupatadine is a well-studied sgAH that demonstrated dual affinity for histamine H1- and PAF receptors.

• Many clinical studies confirmed efficacy of rupatadine using data directly obtained in children over 2 years according to current guidelines of allergic rhinitis and urticaria.

• In the future, clinical dosing at ages below 5 years should be based on controlled clinical studies, as this is a group of pediatric patients highly vulnerable due to scarce or incomplete information on both efficacy and safety.

This box summarizes key points contained in the article.

Reviewer disclosures

One referee is or has been a member of the national and international scientific advisory boards (consulting), received fees for lectures, and grants for research projects from Allakos, AstraZeneca, Genentech-Roche, Glenmark, GlaxoSmithKline, Menarini, Merck Sharp and Dohme, Mitsubishi Tanabe, Mylan/Meda Pharma, Novartis, Sanofi-Genzyme & Regeneron, UCB, and the Uriach Group. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Declaration of interest

A Nieto and A Marzon have received grants from Uriach for conducting clinical trials. They have both also received fees for lectures. The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This manuscript was funded by Uriach. This manuscript had writing and editorial assistance provided for by Content Ed Net (Madrid, Spain) which was funded by Uriach.