Safety of Desloratadine Syrup in Children*

Key words: Allergic rhinitis – Antihistamine – Children – Chronic idiopathic urticaria – Desloratadine – Safety

SUMMARY

Background: Allergic rhinitis (AR) and acute urticaria are common childhood maladies. Typically, the first-line treatment options for both include non-sedating antihistamines. First-generation antihistamines, such as diphenhydramine and hydroxyzine, although useful, cause sedation. Desloratadine, an oral non-sedating antihistamine, has been shown in multiple studies to be safe and effective in relieving the symptoms of AR and chronic idiopathic urticaria (CIU) in adults and adolescents.

Objective and methods: The current double-blind, placebo- controlled, parallel-group, single-center studies were undertaken to determine the safety and tolerability of desloratadine syrup in children aged 2 years-11 years with AR or CIU. Over 14 days, subjects aged 2years-5 years were randomly assigned to receive once a day either 1.25mg of desloratadine syrup (0.5mg/mL) or matching placebo, and subjects aged 6years-11 years were randomly assigned to receive once a day either 2.5 mg of desloratadine syrup or matching placebo. Safety evaluations included adverse event report collection, monitoring of vital signs, clinical laboratory measurements, and standard 12-lead electrocardiogram (ECG) measurements.

Results: In the study involving subjects aged 2years-5years (n = 111), the incidence of adverse events was 7/55 for the group treated with desloratadine and 6/56 for placebo. In the study involving subjects aged 6years-11 years (n = 120), the incidence of adverse events was 1/60 for the group treated with desloratadine and 6/60 for placebo. No severe or serious adverse events occurred, and no clinically relevant changes were noted in median clinical laboratory test values or mean vital signs in either group. ECG results from both age groups demonstrated no significant changes (p = NS) in mean ventricular rate or PR, QRS, or QT. No subjects had a Fridericia QT^sub c^ interval > 440 ms at day 8 or day 15.

Conclusion: These studies demonstrate the safety of desloratadine syrup in children aged 2years-11 years with AR or CIU.

Introduction

Antihistamines are widely used to treat a variety of conditions in children, including allergic rhinitis (AR) and chronic idiopathic urticaria (CIU)1. AR, which affects up to 40% of the pediatric population, causes symptoms of rhinorrhea, nasal itching, itching of the palate and/or throat, sneezing, and red, watery eyes2. Although these symptoms may seem simply bother-some, AR is a significant cause of lost school and daycare attendance2, and studies have shown that unmedicated AR is associated with sedation and impaired cognitive functioning3,4. These data support reports of impaired learning ability in children with AR5. AR also shares pathologic mechanisms with asthma, and the two disorders commonly coexist6-9. CIU, which is characterized by daily or almost-daily widespread wheals for at least 6 weeks without a known cause10, produces pruritus that can interrupt daily activities and alter sleep11,12. Patients also feel fatigued frequently. Various studies have indicated that approximately 3% of preschool children and 2% of older children may suffer from urticaria. Of the children who develop urticaria, most are classified into an idiopathic grouping13.

Antihistamines, particularly those of a non-sedating nature, are commonly used as first-line therapy to treat AR and CIU in children11,14,15. Clinicians are aware that first-generation antihistamines (e.g., diphenhydramine, hydroxyzine) can cause central nervous system adverse effects, including sedation, which may affect psychomotor performance, especially in children16. In children, as in adults, first-generation antihistamines can also produce significant anticholinergic effects1. Newer antihistamines have been rigorously studied in children because it has been demonstrated that certain second-generation agents (e.g., terfenadine, astemizole) may (1) induce potentially fatal cardiac toxicity when taken in overdose or in combination with other drugs that inhibit their metabolism or (2) produce prolongation of the corrected QT (QT^sub c^) interval17-19.

Desloratadine is a selective H^sub 1^-receptor antagonist. Clinically, desloratadine 5-mg tablets have been shown effective in the treatment of AR and CIU in adults and adolescents 12 years-17 years old. Studies with desloratadine have shown significant relief (p < 0.01 for each) of the reflective morning-evening total nasal and non-nasal symptoms of seasonal AR20, significant improvement in both instantaneous and reflective total nasal symptoms (p < 0.005) and in the morning-evening reflective total non-nasal symptoms (p = 0.023) of perennial AR21, and significant relief of reflective morning-evening pruritus (p < 0.05) and morning instantaneous total symptoms of CIU (p < 0.01)22. Availability of a syrup formulation of desloratadine is desirable because most pediatric patients and some adult patients can find solid oral formulations difficult to swallow; administration of a syrup may eliminate the risk of tablet aspiration.

Two separate studies were undertaken to determine the safety and tolerability of desloratadine syrup in children 2 years-11 years old with AR or CIU. We believe these studies to be the first clinical trials conducted to evaluate the safety of desloratadine in select pediatric age groups (i.e., 2 years-5 years and 6 years-11 years).

Subjects and methods

Study Population

These two randomized, double-blind, placebo-controlled, parallel- group, single-center studies are of identical design. All participants had AR or CIU: one study enrolled children 2 years-5 years of age, and the other enrolled children 6years-11 years of age.

Inclusion/Exclusion Criteria

Subjects were considered for study inclusion if they met the respective age requirements and had a documented history of AR or CIU. Subjects with a diagnosis of AR had either a positive radioallergosorbent test (RAST) or a positive skin test response to an appropriate allergen. Subjects were required to be in general good health, confirmed by physical examination and routine clinical and laboratory testing, and free of clinically significant disease that would interfere with study evaluations.

Subjects were excluded from participation in the study if they had a history of allergies to more than two classes of medications, were allergic to or could not tolerate antihistamines, or had a history of hypersensitivity to the study drug or its excipients. Additionally, subjects were excluded if they had had an upper respiratory tract or sinus infection that required antibiotic therapy within 14 days before the screening visit, or a viral upper respiratory infection within 7 days before the screening visit. Subjects with a history of noncompliance with medications or treatment protocols or with conditions that would interfere with the ability of the parent or guardian to reliably complete a drug diary were also excluded.

In both study groups, subjects were allowed to take any medication that was not restricted by the protocol and that would not be expected to interfere with the study drug. Chronic medication was to be dosed on a stable regimen. Medications prohibited before study enrollment and during the study included corticosteroids; nasal cromolyn sodium or nedocromil; systemic antihistamines; topical, nasal, oral, or ocular decongestants; systemic antibiotics; and immunotherapy (unless a stable maintenance dose was prescribed). Appropriate washout was necessary before study entry.

The study was conducted in accordance with good clinical practice (GCP) guidelines and was approved by the institutional review board of the study center involved (Arkansas Research Human Volunteers Research Committee, Little Rock, Arkansas). All subjects and parents/ guardians provided written informed consent.

Study Design

Subjects treated on an inpatient or outpatient basis from a single private, phase I clinical research unit (Arkansas Research Medical Testing Center, Little Rock, Arkansas) were randomly assigned to once-daily therapy with either desloratadine syrup (0.5 mg/mL) or matching placebo for a total of 15 days. Subjects 2years- 5years of age received either 1.25mg (2.5 mL) of desloratadine or placebo once daily, and subjects 6 years-11 years of age received either 2.5 mg (5 mL) of desloratadine or placebo once daily. Children aged 2 years-5 years were stratified by age into four subgroups: 2 to < 3 years, 3 to < 4 years, 4 to < 5 years, and 5 to < 6 years old. Similarly, children aged 6 years-11 years were stratified by age into six subgroups: 6 to < 7 years, 7 to < 8 years, 8 to < 9 years, 9 to < 10years, 10 to < 11 years, and 11 to < 12 years old.

After a screening visit (visit 1, day -14 to day -1), subjects were randomly assigned; they then received study medication at visit 2, with subsequent visits occurring on day 8 and day 15 (visits 3 and 4, respectively). Subjects (and parents/guardians) were instructed to take the study drug once daily in the morning at approximately the same time each day, without regard for timing of meals or daily activities. At each visit after baseline, subject compliance was evaluated by asking the parent or guardian whether the study drug had been administered to the subject as instructed, by reviewing diary cards, \and by examining the subject’s drug supply.

Safety Evaluations

Efficacy was not assessed in these studies. Safety was the primary objective and was evaluated at each study visit through adverse event reporting and monitoring of vital signs. Adverse events were collected with the use of a diary (recorded by the subject’s parent or guardian); the physician or designee also interviewed the subject and parent or guardian about adverse events and current illnesses. Severity of adverse events was graded as mild (awareness of sign, symptom, or event, but easily tolerated), moderate (uncomfortable, interfering with usual activity, may warrant intervention), or severe (incapacitating, significantly affects clinical status, warrants intervention). A serious adverse event was (1) one that was fatal, life-threatening, or significantly or permanently disabling; (2) required in-patient or prolonged hospitalization; or (3) was a congenital anomaly or birth defect. The physician assessed the relationship of any adverse event to the administration of the study drug and categorized it as unlikely, possible, or probable.

A standard 12-lead electrocardiogram (ECG), which recorded ventricular rate and PR, QRS, QT, and QT^sub c^ intervals, was performed at the screening visit and on days 8 and 15. The Fridericia formula was used to calculate the QT^sub c^ intervals. This formula was selected over the Bazett formula because it is more appropriate for the correction of high heart rates, which are usually found in younger children. Changes from baseline in the QT^sub c^ interval (Fridericia) were categorized based on 30 ms increments (i.e., < 0 ms, 0 ms-30 ms, 31 ms-60 ms, > 60 ms.)

Clinical laboratory measurements, including complete blood count, blood chemistries, and urinalysis, were performed on samples collected at the screening visit (visit 1) and after 15 days of treatment (visit 4). Laboratory test values were evaluated for clinically meaningful change for each treatment group. Clinically meaningful abnormalities were defined as blood value > 2.6 times the upper limit of normal, a hemoglobin concentration < 9.4 g/dL, a platelet count ≤ 74 000/L, or a white blood cell count < 2 900/ μL. Vital signs, including blood pressure, heart rate, respiratory rate, body weight, and height, were also evaluated at each study visit. Mean changes from baseline for each vital sign were evaluated by age, sex, and race.

Statistical Analysis

Adverse events, clinical laboratory measurements, and vital signs were summarized using descriptive statistics. ECG parameters were analyzed by an analysis of variance (ANOVA), which controlled for variance due to treatment. The treatment comparison was based on least squares means from the ANOVA, using a 5% (2-sided) significance level.

Results

Baseline Characteristics and Subject Disposition

A total of 111 subjects aged 2 years-5 years and 120 subjects aged 6 years-11 years were enrolled and received at least one dose of study drug. There were no major deviations from subject compliance during either study. Baseline characteristics for age, sex, and race were similar between groups. The proportions of children in the various age categories were similar between treatment groups, except in the age groups 4 to < 5 years, 9 to < 10 years, 10 to < 11 years, and 11 to < 12 years, where more children were enrolled in the placebo group than in the desloratadine group; in the age groups 5 to < 6 years, 7 to < 8 years, and 8 to < 9 years, more subjects were assigned to the desloratadine group (Table 1). Proportions of sex and race were similar between the groups, except that among the 6-year-11-year-old subjects, more girls than boys enrolled in the placebo group. Overall, the number of African American subjects was greater than that of any other race. The differences between the treatment groups in age and race have not influenced the outcomes of the study. No subjects discontinued from either study.

Safety Analysis

Adverse Events

In the study involving subjects aged 2 years-5 years, the incidence of adverse events was 7/55 in the desloratadine group and 6/56 in the placebo group, with no severe or serious events or deaths (Table 2). One event (an ear infection in the placebo group) was considered moderate in severity; the other events were considered mild. In the desloratadine group, two events – mild rash in one subject with a history of eczema and headache in another subject – were considered possibly related to treatment. The subject experiencing the rash interrupted therapy for 4 days, but subsequently completed the full course of study medication. No events in the placebo group were considered treatment related. No appreciable differences were noted between the two treatment groups.

In the study involving subjects aged 6 years-11 years, the incidence of adverse events was 1/60 in the desloratadine group and 6/60 in the placebo group, with no severe or serious events or deaths (Table 2). All events were mild in nature, and none was considered to be related to treatment. There was no appreciable difference in the incidence of adverse events when results were stratified by subject age.

Table 1. Baseline characteristics

Clinical Laboratory Measurements and Vital Signs

Overall, no clinically relevant changes were noted in median clinical laboratory test values or mean vital signs. A number of subjects in both studies had laboratory values that were outside the normal range, but no consistent changes were observed in any group. Increase in heart rate was observed in the study of subjects aged 2 years-5 years, but the incidence was similar in the desloratadine and placebo groups. At visits 3 and 4, respectively, four and two subjects in the desloratadine group (range: 30.6%-60.3%) and six and five subjects in the placebo group (range: 31.0%-44.2%) had heart rate increases ≥ 30% of baseline. In subjects aged 6 years-11 years, an increase in heart rate (30.3%) was observed at a single visit (visit 4) in one subject treated with desloratadine. These changes were not considered treatment related.

ECG Parameters

In the study involving subjects aged 2 years-5 years, no significant differences (p = NS) were noted in mean ventricular rate or PR, QRS, QT, or QT^sub c^ interval (Fridericia formula) at baseline. The Fridericia QT^sub c^ was calculated as the QT interval/ (60/ventricular rate]^sup 1/3^. In general, ECG parameters were similar between groups on days 8 and 15. Statistically significant differences in mean ventricular rate were observed on day 8 (p = 0.039) and day 15 (p = 0.010), and a statistically significant increase (p = 0.046) in mean QT interval was observed on day 15 in the placebo group (Table 3). These changes were not determined to be clinically significant. Changes from baseline in the QT^sub c^ interval (Fridericia) were summarized based on 30-ms increments (< 0 ms, 0 ms-30 ms, 31 ms-60 ms, and >60ms). Five subjects (9%) in the desloratadine-treated group and four subjects (7%) in the placebo group had a QT^sub c^ change from baseline of between 31 ms and 60 ms. No subject had a QT^sub c^ change > 60 ms on day 8 or day 15. Similar results were observed across all age subgroups.

Table 2. Adverse events, n (%)

Table 3. ECG parameters: mean change from baseline for children aged 2 years-5 years

In the study involving subjects aged 6 years-11 years, no significant differences (p = NS) in mean ventricular rate or PR, QRS, QT, or QT^sub c^ interval at baseline and no significant differences between groups on day 8 (p = NS) or day 15 (p = NS) were noted (Table 4). Similar to subjects in the 2 years-5 years group, nearly all subjects 6 years-11 years of age had a < 30-ms change from baseline for the QT^sub c^ interval (Fridericia). Five subjects (8%) in the desloratadine-treated group and two subjects (3%) in the placebo group had a change from baseline of 31 ms-60 ms. No subjects had a QT^sub c^ change > 60 ms at day 8 or day 15. Similar results were observed across all age subgroups. One male subject in the placebo group had a prolonged QT^sub c^ interval on day 15 (445 ms, marginally above the upper limit of the normal reference range [440 ms]).

Discussion

These two studies assessed the safety of desloratadine in children 2 years-11 years of age. Separate open-label, single-dose trials were previously conducted in healthy boys and girls to evaluate the pharmacokinetic profile of desloratadine syrup (0.5 mg/ mL) and to determine standard doses for the pediatric population23. Once-daily doses of 1.25 mg and 2.5 mg of desloratadine syrup (0.5 mg/mL) in subjects aged 2 years-5 years and 6 years-11 years, respectively, produced desloratadine maximum concentration (C^sub max^) and area under the curve (AUC) values that were similar to those observed in adults administered a standard 5-mg desloratadine tablet, which is the approved dose. Similar results were observed for 3-hydroxydesloratadine, the main active metabolite of desloratadine.

In these studies in children, desloratadine was well tolerated with no unusual, serious, or unexpected adverse events occurring during the study period. No clinically meaningful differences from baseline or between treatment groups were noted in ventricular rate or in PR, QRS, QT, or QT^sub c^ interval; no clinically relevant changes in clinical laboratory values or vital signs were reported.

Table 4. ECG parameters: mean change from baseline for children aged 6 years-11 years

The cardiac safety of desloratadine is supported by ECG data obtained from more than 2400 individuals during the drug’s development (data on file, Schering-Plough, Kenilworth, NJ, USA). These data demonstrate that desloratadine produced no clinically significant changes in any ECG parameter compared with placebo. Banfield et al. reported that co-administration of desloratadine 7.5 mg with ketoconazole or placebo in healthy adults showed no statistical\ly or clinically significant changes in QT, PR, QRS, or QT^sub c^ interval24.

The current studies demonstrate the safety of desloratadine in the pediatric population. Although efficacy studies have not yet been completed in children younger than 12 years of age, knowledge of the pathophysiology and treatment of AR and CIU in adults may provide insight into the efficacy of desloratadine in the pediatric population. AR and CIU in adults and children have similar pathophysiologies and symptomatologies. As has been noted earlier, desloratadine 5 mg has been shown to be effective in adults in relieving the symptoms of AR and CIU20-22. In addition, pharmacokinetic data discussed in this report demonstrate that pediatric doses of desloratadine syrup and the 5-mg adult dose of desloratadine provide a comparable degree of exposure to desloratadine and its metabolite23. This evidence suggests that desloratadine syrup could be effective in the treatment of AR and CIU in the pediatric population and warrants further study.

Conclusion

These studies demonstrate that desloratadine syrup is safe and well tolerated in children aged 2 years-11 years.

Acknowledgment

This study was funded by Schering-Plough Research Institute, Kenilworth, NJ, USA.

* A preliminary report of these data was delivered in Orlando, Florida, at the Annual Meeting of the American College of Asthma, Allergy, and Immunology on 16-20 November 2001

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CrossRef links are available in the online published version of this paper: http://www.cmrojournal.com

Paper CMRO-2540-3, Accepted for publication: 21 October 2004

Published Online: 22 November 2004

doi: 10.1185/030079904X14148

Melvyn Bloom1, Heribert Staudinger1 and Jerry Herron2

1 Schering-Plough Research Institute, Kenilworth, New Jersey, USA

2 Arkansas Research Medical Testing Center, Little Rock, Arkansas, USA

Address for correspondence: Dr Melvyn Bloom, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. Tel: +1 908 740 7618; Fax: +1 908 740 2145; email: melvyn.bloom@spcorp.com

Copyright Librapharm Dec 2004