Background and aims During the last decades, much attention has been paid to off-label and unlicensed prescriptions in paediatrics. However, on-label prescribing can also cause health issues. In this paper, the case of first-generation H1-antihistamines is investigated, notably the range of indications for which products are licensed in different European countries and the evidence base (or lack thereof) for each indication, as well as reported adverse drug reactions.
Methods Review of the Summary of Product Characteristics of first-generation H1-antihistamines with a focus on paediatric use. This is plotted against the evidence available in the literature.
Results This investigation shows a large variability in labelled indications and licensing ages when compared in five different European countries. Moreover, most of the indications are not based on clinical trials evaluating efficacy and safety of these drugs in children.
Conclusions Many of the licensed indications of first-generation antihistamines do not appear to be evidence based.
- Over-the-counter medication
Statistics from Altmetric.com
What is already known on this topic?
Off-label use in children has been associated with an increased risk of adverse drug reactions.
Side effects are common with first-generation—‘sedating’—H1-antihistamines in children.
What this study adds?
There is a large variability in labelled indications and licensed ages for first-generation H1-antihistamines when compared in five different European countries.
Many first-generation H1-antihistamines have not been adequately evaluated in children.
Most of the labelled indications of first-generation H1-antihistamines are not based on clinical trials in children.
Over the past two decades, there has been an increase in attention surrounding drug use in children. Most of the attention is directed towards unlicensed and off-label drug use in this population. Justifiably, as percentages of unlicensed and off-label drug prescriptions reach 66% in the hospital and 39% in the ambulatory setting.1 The paediatric population is a heterogeneous group, ranging from preterm neonates to postpubertal adolescents. They have complex physiological, developmental and psychological characteristics that differ from adults and these features vary across the neonate to adolescent age range. The simple extrapolation of efficacy and safety from adults to children is insufficient for correct pharmacotherapy in children as it can result in suboptimal therapy, unexpected responses and adverse drug reactions (ADRs).2 The development of effective and safe child-specific treatments therefore requires high-quality trials in children.2–4
On-label use of drugs in children might also confront healthcare professionals and consumers with potential risks. Although it is generally assumed that drugs are considered for labelling only if they have been proven efficacious and safe, many medications, in particular those introduced before 1985 have not been optimally studied in randomised, controlled trials.5 In their day, they received authorisation out of lack of regulation of the required specifications and they remain on the market because the pharmacovigilance systems have not detected enough ADRs requiring their withdrawal.6 A good example of this is the case of the first-generation antihistamines such as alimemazine, cyproheptadine, diphenhydramine and dimenhydrinate. There is widespread use of first-generation H1-antihistamines in children; they have been on the market for a long time and many of them have received over-the-counter (OTC) status,6 though these first-generation H1-antihistamines are known to have the most major side effects. They have poor receptor selectivity for the H1 receptor, occupying muscarinic cholinergic, α-adrenergic, serotonin receptors and ion channels.5 Additionally, first-generation H1-antihistamines are lipophilic, facilitating crossing of the blood–brain barrier into the central nervous system with drowsiness, cholinergic effects and impairment as a consequence.5
The aim of this analysis paper is to compare registered indications of marketed first-generation H1-antihistaminic drugs for children in several European countries and to look for the evidence supporting these indications. Additionally, reported ADRs of these drugs involving children will be evaluated.
For this review, we focused on the first-generation H1-antihistamines with WHO Anatomical Therapeutic Chemical (ATC) classification -code R06, which are available in an oral single-drug preparation in five selected European countries (Belgium, France, Germany, the Netherlands and the UK). Country-specific drug databases and national formularies were searched for first-generation antihistamines.7–13 They were listed using their International Nonproprietary Names (INNs). Second, for each formulation, available on the market, the Summary of Product Characteristics (SPCs) was examined in detail. Their licensed indications, the accessibility on the market (OTC or prescription-only medication, POM) and the age limit for paediatric use in the respective countries were listed and compared. Finally, these labelled indications were compared with the available evidence of efficacy and safety of oral first-generation H1-antihistamines in children. A literature review of clinical trials, case series and case reports of first-generation H1-antihistamines involving children was conducted. Four major databases, namely Medline, Embase, PubMed and Web of Science were searched. Medline and Embase were searched electronically via Ovid. Ovid's age group classification was used to limit the results to the paediatric age groups. PubMed and Web of Science were searched via their specific websites. Abstracts were read and evaluated; if relevant, full papers were obtained. Information regarding formulation, route of administration and comparison was gathered. As for safety, we evaluated the reported ADRs in the obtained papers and consulted the database of The Netherlands Pharmacovigilance Centre Lareb, one of the best organised pharmacovigilance offices in Europe, for reports of ADRs of first-generation H1-antihistamines in children.14
Variability in indications
Sixteen different first-generation H1-antihistamines are marketed in single-drug preparation in the five evaluated countries (see online supplementary table A). When comparing the different INNs, the huge variability in registered indications, accessibility (OTC or POM) and licensing ages for paediatric use is striking. To demonstrate this variability and the (lack of) existing evidence more extensively, three examples will be discussed in the following paragraphs: the case of alimemazine, cyproheptadine and dimethindene maleate.
Overview of the first generation H1-antihistamines available in Belgium, France, Germany, the Netherlands and the United Kingdom, in oral single drug formulation, with ATC-code R06. The table shows labeled indications, ages and accessibility on the market.
Case 1: alimemazine
Alimemazine, also known as trimeprazine, is a first-generation H1-antihistamine in the phenothiazine chemical class. There is a broad range of licensed indications and licensing ages for this drug in the different evaluated countries (table 1). The efficacy of alimemazine for children with sleep problems has been investigated in four small randomised controlled trials (table 2). These trials found conflicting results with some reporting short-term improvement while on alimemazine.15–19 Alimemazine has been shown to have the sedative effect, necessary for the use as a premedicant in children.20 ,21 In addition, in a randomised placebo-controlled trial with 15 children, alimemazine caused relief of retching after Nissen fundoplication.22 In some countries, alimemazine is indicated for itch, allergic diseases, urticaria, cough and asthma bronchiale. However, the clinical trials supporting these specific indications could not be located. Case reports described significant morbidity15 ,23–25 in children of 4 years and younger after alimemazine use and intoxication. All case reports were published more than 10 years ago. Three out of eight ADRs after intake of alimemazine in the Lareb database were in children. Two of them were 2 years or younger.14
Case 2: cyproheptadine
Cyproheptadine is an antihistamine of the piperidine chemical class with antiserotoninergic characteristics. Small prospective studies evaluated cyproheptadine in children with allergic conditions, including primary acquired cold urticaria26 and mite-induced allergic rhinitis.27 In each of these trials, the active comparator (ketotifen and loratadine, respectively) showed similar or better results when compared with cyproheptadine (table 3). The lack of a placebo control group in both above-mentioned studies makes it difficult to determine if cyproheptadine had a positive therapeutic effect. In the UK, cyproheptadine is indicated for prophylaxis of paediatric migraines (table 1). However, clinical data concerning its efficacy were limited to a retrospective chart review in 30 children.28 No trials supporting the use of cyproheptadine in itch (caused by chickenpox) and anaphylaxis could be located. An important side effect of cyproheptadine is increased appetite. This side effect is the reason for the frequent off-label use of cyproheptadine as an appetite stimulant. We could locate two chart reviews evaluating this effect: in children aged 7 months–6 years29 and in children aged 9 months–20 years.30 Reported (side) effects in these chart reviews were—next to increased appetite—somnolence, irritability and abdominal pain. Three out of five side effects of cyproheptadine at Lareb were reported in children; each in a different age group.14
Case 3: dimethindene maleate
The third example is the case of dimethindene maleate, a first-generation antihistamine of the alkylamine chemical class. This drug is indicated for a wide variety of pruritic conditions (table 1). In some countries, it is used in the treatment of itch in the context of a varicella infection. In Belgium, it is available OTC with an approved use in infants 1 month and older. In the neighbouring country The Netherlands, it is a POM, indicated for children aged 1 year and older. Only one trial31 examined the use of this antihistamine in alleviating the pruritus in varicella infection. A randomised placebo-controlled trial in 126 patients showed improvement in severity of itching in the treatment group. However, neither the method of randomisation nor the blinding process was described in this paper (table 4).32 Although there were no published case reports of safety issues in children with this drug, seven out of nine reports of ADRs in the Lareb were in children, all of them <4 years of age.14
Licensed indications may lead to the misconception that these indications are evidence based, even more if they have an OTC status. However, our review shows that the on-label indications for first-generation H1-antihistamines are often not supported by clinical trials in children. The efficacy of orally administered antihistamines in paediatric patients is generally extrapolated from adults or older paediatric patients,6 ,33 which does not match with the current ‘Better Medicines for Children’ policy.34 As stated before, this is clinically relevant because ‘off knowledge’ use of drugs in children might result in underdosing, overdosing and ADRs.
The European Union (EU) Paediatric Regulation, implemented in 2007, created a new type of marketing authorisation to give an incentive for medicinal products that have been on the market in the EU states for some time and therefore are no longer covered by a patent. A successful application results in 10 years of data and market protection.34 This Paediatric Use Marketing Authorisation (PUMA) could be a solution for the lack of knowledge on efficacy and safety of off-patent drugs in children. However, until now, only two drugs received a PUMA.35
Although some first-generation antihistamines may be associated with less sedation than others, sedation associated with this group of antihistamines is so common that these antihistamines have been termed by the US Food and Drug Administration (FDA) as ‘sedating antihistamines’. First-generation antihistamine-induced sedation has been described to occur in more than 50% of patients receiving therapeutic doses, which may adversely affect a child's learning abilities.36–39 Yet, many of the first-generation antihistamines are available to the consumer OTC as sleeping aids underscoring their soporific effects. Moreover, the high accessibility on the market and thus the widespread use of first-generation antihistamines in paediatrics have been accompanied by frequent intoxication. Typically, children ingesting large quantities of first-generation antihistamines experience marked sedation, lethargy and anticholinergic-like symptoms, including dry mouth, tachycardia and hyperactivity, with potential progression to acute psychosis.37 There is probably an under-reporting of these side effects to the pharmacovigilance systems, as most clinicians see these side effects as an already known problem. Paediatric pharmacovigilance will be essential to reduce ADRs with these antihistamines through better detection and prevention of the ADRs.40 ,41 Education of health professionals about the importance of pharmacovigilance has been shown to be effective in increasing reporting of ADRs.41 ,42 Unfortunately, we did not obtain information on the actual use of these antihistamines in the evaluated countries, which would help to assess the possible impact of these ADRs.
Before the treatment with any antihistamine is started, the child and family should be counselled on the appropriate use. That is, age of licensed use, frequency and dosing, clinical effects and possible side effects.43 Moreover, based on the lack of evidence of efficacy and the safety problem of the first-generation H1-antihistamines, Schad and Skoner44 stated that the paediatric use of first-generation antihistamines should even be restricted to two uncommon situations. First, in children with urticaria or dermatitis whose pruritus is so severe that sedation is a benefit rather than a risk and second, if there is anaphylaxis requiring intravenous antihistamine as adjunctive therapy to epinephrine.
In conclusion, this case of first-generation H1-antihistamines demonstrates that on-label prescriptions in children are not free from risks. A broad range of vague indications, as a result of lack of evidence brings a lack of clarity for clinicians, pharmacists and patients. Obviously, this problem is not restricted to the first-generation antihistamines. This article argues for a wider discussion on evaluation of labelled indications for children in general.
Contributors PDB, TC, KB, EM and MVW have expertise in clinical pharmacology and/or pharmaceutical care, including drug evaluation. MVW conceived the idea for this paper. PDB analysed the SPCs and the literature and wrote the first draft of the manuscript. All authors contributed substantially to the interpretation of the data, revised the manuscript, approved the final version and are accountable for it. PDB is the guarantor of the article.
Funding This work was supported by an IWT (Innovation by Science and Technology in Flanders) grant number SB-111279 (recipient: PDB).
Competing interests PDB is the recipient of a doctoral grant for Strategic Basic Research of the Agency for Innovation by Science and Technology (IWT) in Flanders.
Provenance and peer review Not commissioned; externally peer reviewed.
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.