Background Antihistamines are used for the treatment of allergic rhinitis, allergic conjunctivitis, chronic spontaneous urticaria and atopic eczema.
Objective To study the reports of adverse drug reactions (ADRs) in children using antihistamines to provide prescribers with an overview of the possible toxicity.
Design We studied ADRs in children reported to the Netherlands Pharmacovigilance Centre Lareb in the years 1991–2014, assessed the Naranjo score and, when possible, computed the reporting OR.
Results Serious ADRs included one death (malignant neuroleptic syndrome), cardiac arrhythmia (one case) and convulsions (three cases). Skin eruptions, headache and somnolence were the most frequently reported ADRs. Aggression and agitation were also reported.
Conclusions Toxicity can occur with second-generation antihistamines. The main toxicity relates to skin eruptions and central nervous system problems.
- adverse drug reaction
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What is already known on this topic
The older, first-generation antihistamines cause somnolence in a large proportion of patients.
Second-generation antihistamines are thought to have fewer side effects based on pharmaceutical company studies.
What this study adds
Skin eruptions and headache were the most frequently reported adverse drug reactions (ADRs) to antihistamines.
Somnolence, aggression, agitation, hyperactivity and seizures can occur with second-generation antihistamines.
ADRs to antihistamines are more common than suggested by pharmaceutical company studies.
Systemic antihistamines are prescribed to many children. Indications for use are allergic diseases.1 In an overview published in 2001, the authors stated that second-generation H1-antihistamines had few side effects.2 We decided to study the safety profile of systemic antihistamines in children to provide prescribing physicians with an overview of relevant adverse drug reactions (ADRs). We therefore studied the reports of ADRs in children after taking antihistamines in the Dutch spontaneous reporting database of the Netherlands Pharmacovigilance Centre Lareb.
We retrospectively studied all reported ADRs on systemic antihistamines (Anatomical and Therapeutic Chemical classification (ATC) code R06A) in children aged 0–18 years reported to the Netherlands Pharmacovigilance Centre Lareb in the years 1991–2014. All these reports were assessed for causality by trained assessors.
Data including suspect drug, co-medication, age and sex of the patient, and the suspected ADR were extracted from the database. Reported ADRs were classified in the database and divided into the categories non-serious and serious. The latter includes fatal outcome, life-threatening, requiring (prolongation of) hospitalisation, resulting in significant disability/incapacity and other medically important conditions. All other ADRs were classified as non-serious.3
We excluded promethazine (ATC code DO4AA10) and deptropine (ATC code R06AX16) because prescribing promethazine for children was discouraged after multiple reports of serious ADRs,4 and deptropine was marketed only in the Netherlands and withdrawn for the same reason.5
We describe the serious and most often reported ADRs. In selected cases, we reassessed the causality of the reported drug reactions based on the Naranjo score and the reporting OR (ROR). The Naranjo score is a quantitative method of assessing the connection between a drug and an adverse effect.6 The ROR compares the rate of reporting a specific adverse effect in a drug with the rate of reporting the same adverse effect in all other drugs. The ROR is calculated by a division: the numerator is the number of cases in which an antihistamine was used and a specific ADR was reported divided by the number of cases using antihistamines in which this ADR was not reported; the denominator is the number of paediatric cases using other suspected drugs reporting a specific ADR divided by the number of paediatric cases using other suspected drugs without reporting that specific ADR. It is expressed as a point estimate with corresponding 95% CIs. At least three reports have to be present in the database to compute a reliable ROR.7 The ROR offers insight into disproportionality of an association, not into causality.
We found 291 reports on ADRs and excluded 63 (22%) because they were associated with the use of promethazine (16) or deptropine (47), leaving 228 reports.
In 148 (65%) reports, boys were involved with mean and median ages of 9.6 years and 10.0 years (range 1–18 years). The drugs most often mentioned were desloratadine (16%), loratadine (15%) and ketotifen (13%).
There were five serious ADRs (table 1). A four-year-old girl developed a malignant neuroleptic syndrome after the use of alimemazine. Her case has been described elsewhere.8 The second concerns a report about a boy aged 14 with atrioventricular re-entry tachycardia after administration of azithromycin for respiratory tract infection and fexofenadine for allergy with a latency period of 8 days (6 days after withdrawal of the azithromycin). Concomitant drugs were nasal fluticasone and inhaled fluticasone/salmeterol 100/50 μg twice daily. The relationship between cause and drug was deemed probable.
Three reports involved convulsions. The first concerned an 11-year-old girl who had a convulsion lasting for 10 min after using loratadine. She also used cromoglicic acid and salbutamol. The EEG was normal. In this case, the relation was deemed possible.
The second case was a girl, aged 2 years who had convulsions after administration of loratadine, with a latency of 3 days after starting the medication. She also had fever and used no other drugs. The correlation was deemed possible.
The third report concerned a 16-year-old boy with tonic-clonic seizures following administration of desloratadine for an allergy to grass pollen, with a latency of 8 days after starting the medication. He was admitted to hospital for one night. Concomitant medication was not reported and had an unremarkable history. Consequently, the relationship between the drug and adverse effect was deemed probable.
Somnolence was reported 12 times after using newer antihistamines, including levocetirizine (two reports), cetirizine (two) and dimetindene (two). Aggression was reported after ketotifen (n=3; ROR=27.9; 95% CI 8.1 to 96) and desloratadine (n=3; ROR=9.6; 95% CI 3.0 to 31).
Aggression, hyperactivity, or agitation were also reported after cetirizine, ketotifen, levocetirizine, loratadine, astemizole, dimetindene, and cyproheptadine. Lareb received 16 reports of headache including terfenadine (n=4; ROR=5.3; 95% CI 1.7 to 16), fexofenadine, loratadine (n=3; ROR=2.9; 95% CI 0.9 to 9.8), levocetirizine (n=5; ROR=3.3; 95% CI 1.3 to 8.7), desloratadine (n=2), and cetirizine. Skin eruptions, rashes, and exanthemas were reported after nearly all antihistamines (n=33).
In this study, we found a relation between systemic antihistamines, convulsions and disturbed behavior, such as hyperactivity and aggression. We also found an association with somnolence, headaches and skin eruptions.
One death occurred in a girl who had received alimemazine as a sedative, which caused the malignant neuroleptic syndrome.8 For the relief of allergic symptoms, the dose is lower than for sedation (0.25 vs 2 mg/kg, respectively).9
One teenage boy had cardiac arrhythmia after taking fexofenadine. As far as we know, this is the first report of cardiac arrhythmia after fexofenadine in a teenager, although arrhythmias after antihistamines, including fexofenadine, have been reported in adults.10 ,11
Convulsions after desloratadine have been reported previously.12 ,13 Possibly, the central histaminergic system plays a role in the inhibition of convulsions. It has been hypothesised that in some patients, higher drug levels may occur owing to mutation of the efflux transporter enzyme.12 This phenomenon might also play a part in causing somnolence and alterations of behaviour. Overall, the occurrence of ADRs in the central nervous system demonstrates that the blood–brain barrier is passed in some patients.
In 2015, Lareb notified the Dutch Medicines Evaluation Board that behavioural disturbances had been seen in patients using desloratadine, including children.14 In addition, a positive dechallenge was reported several times. The time to onset varied from 1 to 3 days in several reports. Hyperactivity might be a direct effect of the drug on the brain but it might also be that when allergic symptoms are relieved the children have more energy. We found no reports of this association.
Skin eruptions were reported many times—after cetirizine,15 hydroxyzine,16 ,17 loratadine18 and fexofenadine.19 Many drugs are associated with skin eruptions and therefore it is not surprising that antihistamines can also cause skin problems. Many children with allergic diseases already have skin eruptions and it is disturbing when further eruptions arise after antihistamines. If in doubt, antihistamines should be stopped and reintroduced to establish or exclude an association before adding more drugs.
The association of antihistamines with headache has been found previously and summaries of side effects of antihistamines mention headache. We found one case report of an 8-year-old girl in whom levocetirizine appeared to be the cause of severe headache.20
We found several studies on the safety of antihistamines for children. Simons followed up for 18 months a group of 500 young children (12–24 months of age) who were receiving levocetirizine and found none of the ADRs we described.21 Also, Potter found none of these ADRs in a group of 150 older children (6–12 years of age) receiving levocetirizine followed up for 4 weeks.22 In two large trials in almost 400 children, aged 6–24 months, receiving 15 or 30 mg or placebo, no serious ADRs or changes on the electrocardiogram were established.23 Levocetirizine was compared with placebo in a group of 177 children with seasonal allergic rhinitis and the authors found no differences in ADRs between the groups.24 Thus, the ADRs we found were never described in these safety studies, which were all sponsored by the manufacturers.
The strength of this study is that the study material consisted of all paediatric ADR reports on systemic antihistamines located in the database of the Netherlands Pharmacovigilance Centre Lareb. A limitation inherent to using a voluntary spontaneous reporting database is under-reporting,25 and thus the true incidence of ADRs cannot be found. On the other hand, because reporting is voluntary, it will occur only when patients, parents or professionals suspect a correlation. A voluntary reporting system provides early warnings of drug-related harm. Another limitation of voluntary reporting data is that the causality of the reported ADRs is not always certain.
Details of all serious ADRs effects have not been published. However, the published safety studies we found were all sponsored by the manufacturers, which might have led to bias.
When prescribing antihistamines, clinicians should be aware of ADRs such as somnolence, altered behaviour, skin eruptions and headache. Moreover, there is a possible relation between convulsions and (des)loratadine.
Contributors Both authors made substantial contributions to the conception and design of the work, and the acquisition, analysis and interpretation of data. They drafted the paper and revised it critically for important intellectual content. Both approved the final version. They are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.