Safety of antihistamines in children: need for approval of new second-generation antihistamines for young children in Japan

Authors


  • Conflicts of interest: The author declares no conflict of interest.

Correspondence: Naoki Shimojo, Department of Pediatrics, Graduate School of Medicine, Chiba University 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.

E-mail: shimojo@faculty.chiba-u.jp

Summary

In Japan, loratadine, fexofenadine, cetirizine and epinastine are currently approved for paediatric use. However, none of these drugs is officially approved for use in children aged under 2 years, and therefore older second-generation antihistamines such as ketotifen and oxatomide are sometimes prescribed for these patients. Because ketotifen and oxatomide have relatively strong sedative effects, one should be cautious when using these antihistamines in young children. In fact, there are reports describing the development of West syndrome, an intractable epilepsy, in 4-month-old infants taking these drugs. Recent clinical trials in Japanese children with allergic rhinitis have shown no serious adverse effects associated with several new second-generation antihistamines, supporting previous overseas reports. New second-generation antihistamines should be approved in the near future for young children in Japan.

Recent prevalence of allergic diseases in Japanese children

The prevalence of childhood allergic diseases has increased over the last few decades, especially in developed countries. In Japan, Kusunoki et al. [1] recently reported the changes in prevalence of allergic diseases in schoolchildren in a large-scale population-based survey in Kyoto and its suburban areas. By using an International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire, they compared the prevalences of allergic diseases in children between 1996 and 2006. They found that the prevalences of all allergic diseases except bronchial asthma increased from 1996 to 2006 (Fig. 1). The increases in prevalence of Japanese cedar pollinosis, allergic rhinitis (AR) and conjunctivitis were remarkable. These data suggest that prescriptions of H1 antihistamines for the treatment of allergic diseases in children have also increased in Japan and appropriate usage of these drugs is mandatory.

Figure 1.

Changes in prevalences of childhood allergic diseases in Kyoto, Japan. The International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire was used in the study. Adapted from Allergol Int 2009; 58:543–8 with permission. AC, allergic conjunctivitis; AD, atopic dermatitis; AR, allergic rhinitis; BA, bronchial asthma; sJCP, suspected Japanese cedar pollinosis.

H1 antihistamines approved for children in Japan

The classification according to function of first-generation H1 antihistamines, which have sedative effects compared with second-generation compounds that are relatively non-sedating, is now more commonly used than before [2]. Table 1 shows the chemical and functional classification of H1 antihistamines. Many of the H1 antihistamines introduced during the past two decades have been identified through screening of existing compounds, and are chemically related to older medications in the class. For example, acrivastine is related to triprolidine, cetirizine is a metabolite of hydroxyzine, levocetirizine is an enantiomer of cetirizine, desloratadine is a metabolite of loratadine and fexofenadine is a metabolite of terfenadine.

Table 1. Chemical and functional classification of H1-antihistamines
Chemical classFunctional class
First-generation drugsSecond-generation drugs
  1. Adapted from N Engl J Med 2004; 351:2203–17 with permission.

AlkylaminesBrompheniramine, chlorpheniramine, dimethindene, pheniramine, triprolidineAcrivastine
PiperazinesBuclizine, cyclizine, hydroxyzine, meclizine, oxatomideCetirizine, levocetirizine
PiperidinesAzatadine, cyproheptadine, diphenylpyraline, ketotifenAstemizole, desloratadine, ebastine, fexofenadine, levocabastine, loratadine, mizolastine, olopatadine, terfenadine
EthanolaminesCarbinoxamine, clemastine, dimenhydrinate, diphenhydramine, doxylamine, phenyltoloxamine
EthylenediaminesAntazoline, pyrilamine, tripelennamine
PhenothiazinesMethdilazine, promethazine
OthersDoxepinAzelastine, emedastine, epinastine

The H1 antihistamines that are approved for childhood use in Japan are shown in Table 2. It should be noted that older second-generation antihistamines such as ketotifen and oxatomide are allowed to be prescribed from 6 months of age while cetirizine, a new second-generation antihistamine, is approved from 3 years of age. In fact, the market share of H1 antihistamines prescribed for children aged less than 6 years in Japan revealed that 6 of the top 10 antihistamines are first-generation or old second-generation antihistamines (data not shown).

Table 2. Approved H1 antihistamines for children in Japan
Generic nameRegistered nameSyrupDry syrupGranulesTablets
  1. +, available; −, unavailable.

KetotifenZaditen++
>6 months old>6 months old  
OxatomideCeltect+
 Not indicated  
MequitazineZesulan/Nipolazin++
>1 year old >1 year old 
FexofenadineAllegra+
   >7 years old
EpinastineAlesion+
 >3 years old  
LoratadineClaritin++
 >3 years old >7 years old
CetirizineZyrtec++
 >2 years old >7 years old

Reports on side-effects of first-generation/old second-generation H1 antihistamines in childhood in Japan

There have been several reports related to presumed side-effects of first-generation/old second-generation H1 antihistamines in children in Japan. Yasuhara et al. [3] reported two cases of 4-month-old boys who developed West syndrome at 8–10 days after ketotifen administration. Yamashita et al. [4] reported a case of a 4-month-old female infant who developed West syndrome at 11 days after administration of oxatomide for atopic dermatitis. Recently, Haruyama et al. [5] studied the relationships between the clinical characteristics of febrile seizures, such as the type and duration of convulsions, and drug treatment in 265 children treated for febrile seizures in the emergency room of their hospital (Fig. 2) [5]. The duration of convulsions was longer among children who took theophylline and H1 antihistamines than among children who did not take these medications, further suggesting the need for caution in the use of H1 antihistamines. The effects of first-generation/old second-generation antihistamines on maximal electroshock seizures in infant rats were reported by Ishikawa et al. [6]. In their study, diphenhydramine, chlorpheniramine, cyproheptadine and ketotifen caused dose-dependent and significant prolongation of seizures induced by maximal electroshock. These data strongly suggest that one should be cautious in using H1 antihistamines, such as oxatomide and ketotifen, in young children.

Figure 2.

Relationships between drug treatments and durations of febrile seizures. Adapted from World J Pediatr 2008; 4: 202–5 with permission.

Safety studies of second-generation H1 antihistamines in childhood in Japan

To date, there are two reports on the safety of second-generation H1 antihistamines in children in Japan. Saito et al. [7] studied the adverse effects of cetirizine in children with perennial AR (PER) in a 2-week randomized, double-blind, parallel-group, placebo-controlled study and found slightly higher laboratory test abnormalities in the cetirizine group than in the placebo group, although most of the abnormalities were transient (Table 3). Suzuki et al. [8] investigated the adverse events related to the use of loratadine in children with PER in a 4-week open-label study (Table 4). In that study, abnormal laboratory tests were mainly found in pre-school children but the relationships between loratadine and these adverse events were not clear. It is noteworthy that both clinical studies reported few central nervous system side-effects such as lethargy, which is frequently found in the use of first-generation/old second-generation antihistamines. Therefore, the short-term use of new second-generation antihistamines is thought to be safe in young Japanese children. The safety of cetirizine for longer use was reported by Saito et al. [9] in a 12-week multicentre, open-label, phase III study. Simons [10] studied the long-term safety of cetirizine in very young children with atopic dermatitis in the Early Treatment of the Atopic Child (ETAC) study and found no significant differences in drop-outs and serious events between children receiving cetirizine and those receiving a placebo. These data indicate that new second-generation H1 antihistamines may be used safely in young children with allergic diseases.

Table 3. Adverse events in the use of cetirizine in a phase III clinical study in children with perennial allergic rhinitis. A randomized, double-blind, parallel-group, placebo-controlled study (2 weeks)
OrgansSymptom/testCetirizine group (n = 122)Placebo group (n = 117)
  1. Adapted from Rinsho-iyaku 2010; 26:141 (in Japanese) with permission.

GastrointestinalVomiting1 (<1%)0
NeurologicalLethargy1 (<1%)0
RespiratoryNosebleed1 (<1%)0
Laboratory

Elevated ALT

(GPT)

7 (5.7%)2 (1.7%)

Elevated AST

(GOT)

2 (1.6%)0

Elevated

bilirubin

1 (<1%)0
Elevated creatinine1 (<1%)0
Neutropenia1 (<1%)0
Total 12 (9.8%)2 (1.7%)
Table 4. Adverse events in the use of loratadine in children with perennial allergic rhinitis. An open-label study (4 weeks)
OrgansSymptom/test3–6 years old (= 53)7–15 years old (= 104)
  1. Adapted from Allergol Immunol 2009; 16:1966 (in Japanese) with permission.

Gastrointestinal 00
NeurologicalLethargy1 (1.9%)0
CutaneousUrticaria1 (1.9%)0
LaboratoryElevated ALT (GPT)01 (1.0%)
Lymphopaenia1 (1.9%)0
Leucocytosis2 (3.8%)0
Proteinuria1 (1.9%)0
Total 5 (9.4%)1 (1.0%)

Conclusions

  1. There have been several reports of serious adverse effects of first-generation and old second-generation H1 antihistamines in young children in Japan.
  2. New second-generation H1 antihistamines may be safe for use in children as young as 6 months of age based on evidence from Japan and overseas.
  3. New second-generation H1 antihistamines should be approved for young children in Japan in the near future.

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