Effect of budesonide aqueous nasal spray on hypothalamic-pituitary-adrenal axis function in children with allergic rhinitis

Effect of budesonide aqueous nasal spray on hypothalamic-pituitary-adrenal axis function in children with allergic rhinitis Kenneth T. Kim, MD*; Nathan Rabinovitch, MD ; Thomas Uryniak, MS ; Brandon Simpson, BS ; Liza O Dowd, MD ; and Frank Casty, MD Background: Intranasal corticosteroids are safe and effective for treating allergic rhinitis in adults. Since children may receive more systemic corticosteroid on a dose-per-weight basis than adults, the safety of corticosteroid therapy in pediatric patients is an important issue. Objective: To determine the effects of treatment with budesonide aqueous nasal spray using the recommended once-daily dose for adults and children 6 years and older on hypothalamic-pituitary-adrenal (HPA) axis function in pediatric patients with allergic rhinitis. Methods: In a 6-week, multicenter, double-blind, placebo-controlled study, 78 patients aged 2 to 5 years with allergic rhinitis were treated with budesonide aqueous nasal spray (64 g/d) or placebo. Mean change in morning plasma cortisol levels from baseline to study end 0, 30, and 60 minutes after low-dose (10- g) cosyntropin stimulation and mean change in the difference from 0 to 30 minutes and from 0 to 60 minutes after cosyntropin stimulation were used to evaluate HPA axis function. Results: Mean change from baseline to study end in plasma cortisol levels 0, 30, and 60 minutes after cosyntropin stimulation and the difference from 0 to 30 minutes and from 0 to 60 minutes were not significantly different between the treatment and placebo groups (P.05 for all). At the end of the study, 3 budesonide aqueous nasal spray and 6 placebo patients were classified as having subnormal HPA axis function. The safety and tolerability profile of budesonide aqueous nasal spray was comparable to that of placebo. Conclusions: Administration of budesonide aqueous nasal spray for 6 weeks was well tolerated and safe and had no measurable suppressive effects on HPA axis function in patients aged 2 to 5 years with allergic rhinitis. Ann Allergy Asthma Immunol. 2004;93:61 67. INTRODUCTION Allergic rhinitis is a common chronic medical condition that affects an estimated 40% of children 1 and 10% to 30% of adults in the United States. 2 Intranasal corticosteroids (INSs) are highly efficacious in reducing the symptoms of allergic rhinitis, including rhinorrhea, sneezing, nasal congestion, and itching, without causing significant systemic adverse effects in adult patients. 3 Data also suggest that INSs are more effective than oral antihistamines 4,5 and leukotriene receptor antagonists. 6 As a result, recent guidelines have stated that INSs are the most effective treatment for controlling the symptoms of allergic rhinitis 2 and should be used as a firstline treatment 3 for patients with more than mild intermittent symptoms. Children and adults experience the same allergic rhinitis symptoms, which often produce irritability and sleep disorders and can even affect learning. 3,7 Since children may receive more * Allergy, Asthma & Respiratory Care Medical Center, Long Beach, California. National Jewish Medical and Research Center, Denver, Colorado. AstraZeneca LP, Wilmington, Delaware. This study was supported by a financial grant provided by AstraZeneca LP. Received for publication July 31, 2003. Accepted for publication in revised form December 22, 2003. systemic corticosteroid exposure on a microgram-per-kilogram basis than adults, 8 the safety and tolerability of corticosteroid therapy in pediatric patients are important issues. Dose-dependent hypothalamic-pituitary-adrenal (HPA) axis suppression can occur with systemic administration of corticosteroids and, to a lesser extent, is possible with inhaled administration of corticosteroids. Although plasma levels of corticosteroids are low after intranasal delivery, it is important to evaluate HPA axis function after INS administration because it is a sensitive indicator of the systemic activity of corticosteroids. Reports showing the lack of effect of INSs on HPA axis function in patients 6 years and older, 9 11 3to11yearsold, 12 and 4 to 10.5 years old 13 exist in the literature, including a study demonstrating that budesonide aqueous nasal spray at doses up to 256 g/d does not affect HPA axis function in patients 6 years and older with allergic rhinitis. 14 16 However, there have been no reports of the effects of budesonide aqueous nasal spray (Rhinocort Aqua, AstraZeneca LP, Wilmington, DE) on HPA axis function in patients younger than 6 years. Because budesonide aqueous nasal spray used at the recommended once-daily dose (64 g) has been shown to be highly effective and well tolerated, it is possible that patients younger than 6 years may be prescribed this medication even though it is only indicated for children older than 6 years. Therefore, safety studies that evaluate HPA axis function in VOLUME 93, JULY, 2004 61

patients younger than 6 years should be conducted. The objective of the present study was to evaluate the effect of the recommended once-daily dose of budesonide aqueous nasal spray (64 g), compared with placebo, on HPA axis function in patients aged 2 to 5 years with allergic rhinitis. MATERIALS AND METHODS Patient Population Patients enrolled were of either sex, were aged 2 and 5 years, and had a documented history of allergic rhinitis, which included either a positive response to a skin prick test or at least a 4-week history of continuous chronic symptoms of allergic rhinitis and nasal secretions positive for eosinophils. Patients were permitted to take rescue medication for their allergic rhinitis symptoms but were excluded from the study if they met any of the following criteria: use of systemic corticosteroids within 90 days of the screening visit; use of inhaled glucocorticoids, INSs, moderate- or high-potency topical corticosteroids (topical steroid potency class II or greater), or an investigational drug or device within 30 days of the screening visit; a clinically relevant deviation from normal in physical examination results or the presence of a significant chronic disease; asthma requiring treatment with ongoing oral or inhaled glucocorticoids or leukotriene modifiers; a history of hypersensitivity or intolerance to glucocorticoid therapy; use of concomitant medications that may interfere with the interpretations of the data in the study; evidence of nasal polyps, candidiasis, short- or long-term sinusitis, or structural abnormalities of the nose; or previous randomization into a study using budesonide aqueous nasal spray. Study Design This was a 6-week, randomized, double-blind, placebo-controlled study conducted at 11 centers in the United States (AstraZeneca study SD-005 to 0697) to examine the effects of the recommended once-daily dose of budesonide aqueous nasal spray (32- g spray per nostril; 64- g total dose) compared with matching placebo on HPA axis function. Patients were screened between day 30 and day 4 before randomization and treatment. At screening, patients underwent a physical examination that included measurement of vital signs, body weight, and height; visual examination of the nasal cavity; and a skin prick test for perennial and seasonal allergies present in the patient s environment at the time of the study if one had not been performed within the previous year. Eligible pediatric patients were issued a daily log, and instructions for completion were reviewed with both the patient and a parent or guardian. The daily log contained information pertaining to adverse events (AEs), concomitant medication use, and study and rescue medication use. At the second study visit, patients were randomized to a treatment group stratified by age ( 2 to 3 years, 3 to 4 years, 4 to 5 years, and 5 to 6 years).a5-mlplasma sample was obtained for determination of baseline cortisol levels (assayed by Quest Diagnostics, formerly SmithKline Beecham Clinical Laboratories, Van Nuys, CA), followed immediately by an injection of 10 g of cosyntropin via intravenous catheter. Additional plasma cortisol samples were obtained 30 and 60 minutes after intravenous cosyntropin stimulation, and at each point, pediatric patients or their parents or guardians were interviewed to determine the occurrence of any AEs. At the end of the visit, study medication was provided in identical bottles containing either budesonide aqueous nasal spray or placebo. To ensure proper dosing technique, the first dose was administered at the study site. Patients returned to the study site for an interim visit 3 weeks after treatment initiation. Daily logs were reviewed for completeness and accuracy, study medication containers were collected, and new patient daily logs and study medication were dispensed. At week 6 of treatment, patients returned to the study site, and the patient daily log and used study medication containers were collected. Next, the investigator and the parents or legal guardians completed a 5-point global evaluation of efficacy, and patients underwent a physical examination identical to the one that took place at screening. The 1-hour cosyntropin stimulation test was repeated in the same manner as on the first day of the study. Two weeks later, the parents or legal guardians were contacted via telephone regarding the patient s AEs and concomitant medication use since the previous visit. Investigational site personnel evaluated study drug compliance at the interim visit (3 weeks after treatment initiation) and at the end of the study treatment period (6 weeks) by collecting study drug bottles and reviewing patient daily logs. Investigators at each center received approval from an independent ethics committee or institutional review board (IRB) (The Copernicus Group IRB [Cary, NC], Eastern Virginia Medical School IRB [Norfolk, VA], or National Jewish Medical & Research Center IRB [Denver, CO]) and obtained written informed consent from the legal guardians of each patient before enrollment. Assessments The primary objective of this study was to determine the effect of budesonide aqueous nasal spray compared with placebo on HPA axis function from baseline (day 1) to the end of the study (week 6). We evaluated HPA axis function by analyzing the mean change from baseline to the end of the study in morning plasma cortisol levels 0, 30, and 60 minutes after low-dose (10- g) cosyntropin stimulation and the mean change from baseline to the end of the study in the difference from 0 to 30 minutes and from 0 to 60 minutes after cosyntropin stimulation. Normal HPA axis function was identified by a morning basal plasma cortisol level of at least 148 nmol/l and a 30- or 60-minute postcosyntropin stimulation plasma cortisol level of at least 498 nmol/l. These cutoff values are consistent with those described for normal 17 and stimulated cortisol levels (reviewed by Dorin et al 18 ). Subnormal HPA axis function was defined as a morning basal plasma cortisol level less than 148 nmol/l or a 30- or 60- minute postcosyntropin stimulation plasma cortisol level less than 498 nmol/l. Negative HPA axis function was identified when both the morning plasma cortisol level and the 30- and 62 ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY

60-minute postcosyntropin stimulation values were below these levels. In such cases, a diagnosis of adrenocortical insufficiency was established. Although this study was not designed to evaluate efficacy, symptom control was examined by a subjective global evaluation of the control of the patient s allergic rhinitis symptoms by the investigators and the parents or guardians at the end of the 6-week study treatment schedule only. Investigators and parents or guardians completed the global evaluation of efficacy using a 5-point scale (0 indicates more aggravated symptoms [became worse] and 4 indicates total symptom control) in response to the question, How do you feel the test drug has controlled the patient s allergic rhinitis symptoms since he or she started taking the study medication? Statistical Analyses For the primary study variable (HPA axis function), the intent-to-treat principle was used, and differences between the 2 treatment groups were evaluated using an analysis of covariance with terms for treatment, baseline plasma cortisol value, center, and age strata. The global assessments of allergic rhinitis symptom control data were analyzed using the Cochran-Mantel-Haenszel test. Changes from baseline to the end of the study in vital signs, body weight, and laboratory variables were summarized by treatment group using descriptive statistics. Safety Safety was evaluated in each patient who received at least 1 treatment spray (intent-to-treat principle). In addition to the evaluation of HPA axis function, safety was also evaluated by the study investigators using clinical evaluations, laboratory parameters, and vital signs and by monitoring AEs. RESULTS Patients A total of 78 patients were randomized and received treatment in this study. Thirty-nine patients received budesonide aqueous nasal spray (22 boys and 17 girls) and 39 received placebo (29 boys and 10 girls) once daily for 6 weeks. More patients assigned to the budesonide aqueous nasal spray group completed the study (92% [36/39]) compared with the placebo group (85% [33/39]). Two patients in the budesonide aqueous nasal spray group and 3 in the placebo group were withdrawn from the study after randomization but before study completion because of inadequate baseline cortisol measurements. An additional patient in the budesonide aqueous nasal spray group was withdrawn prematurely because intravenous access for blood sampling could not be established. Three patients in the placebo group were discontinued before completion of the study: 1 because the baseline sample for clinical laboratory tests was hemolyzed, 1 for a protocol violation, and 1 after consent was withdrawn. Demographic characteristics were well matched with respect to patient age between the 2 randomized groups. A higher proportion of boys and white patients were enrolled in the placebo group (74% and 72%, respectively) than in the budesonide aqueous nasal spray group (56% and 49%, respectively), but these differences were not thought to be clinically meaningful. Demographic characteristics are listed in Table 1. HPA Axis Function There were no differences in plasma cortisol levels between age groups (data not shown) or in either treatment group regarding unstimulated cortisol values or in response to cosyntropin stimulation at baseline or at the end of the study (Fig 1). No significant differences were detected in the mean change from baseline to the end of the study in plasma cortisol levels at the time of cosyntropin stimulation and 30 and 60 minutes after cosyntropin stimulation between budesonide aqueous nasal spray and placebo treatments (Fig 2; Table 2; P.05 for all). In addition, there were no significant differences in the mean change in plasma cortisol levels from baseline to the end of the study in the difference from 0 to 30 minutes and from 0 to 60 minutes between budesonide aqueous nasal spray and placebo treatments (Fig 2; Table 2; P.05 for both). At the end of the study, 3 patients (9%) in the budesonide aqueous nasal spray group and 6 (18%) in the placebo group met the criteria for subnormal HPA axis function (Table 3). Of the 9 patients who had subnormal HPA axis function at the end of the study, all but 1 had normal HPA axis function at baseline. This 1 patient (placebo group) had subnormal 30- and 60-minute stimulated cortisol values (397 and 466 nmol/l, respectively) at baseline with the first plasma sample evaluated (all patients had plasma samples split into 2 samples); however, following reanalysis of the second sample (if the first split sample was abnormal, then the second split sample was evaluated), the 30-minute stimulated cortisol value was close to the 498-nmol/L cutoff value (495 nmol/l) and the 60-minute stimulated value was within the reference range (578 nmol/l). The patient also had no evidence of primary or secondary adrenal insufficiency, and no other risk factors were revealed during the investigator evaluation of Table 1. Demographic Characteristics BANS Placebo Total patients (N 78) Sex, No. (%) Female 17 (43.6) 10 (25.6) 27 (34.6) Male 22 (56.4) 29 (74.4) 51 (65.4) Age stratum, No. (%)* 2to 3 y 8 (20.5) 12 (30.8) 20 (25.6) 3to 4 y 11 (28.2) 9 (23.1) 20 (25.6) 4to 5 y 11 (28.2) 9 (23.1) 20 (25.6) 5to 6 y 9 (23.1) 9 (23.1) 18 (23.1) Age, y Mean (SE) 3.5 (0.17) 3.4 (0.19) 3.5 (0.13) Median (range) 4 (2 5) 3 (2 5) 3 (2 5) Abbreviation: BANS, budesonide aqueous nasal spray. * Randomization was stratified by age using the 4 strata defined in the table. VOLUME 93, JULY, 2004 63

Figure 1. Mean SE plasma cortisol levels before and after cosyntropin stimulation at baseline and at the end of the study for budesonide aqueous nasal spray and placebo. There was no indication of differences in morning plasma cortisol values 0, 30, and 60 minutes after cosyntropin stimulation between the budesonide aqueous nasal spray and placebo groups. Note the increase in plasma cortisol levels in both treatment groups and after cosyntropin stimulation at baseline and at end of study. Figure 2. Mean SE change in the difference in morning plasma cortisol values from baseline to the end of the study. The mean change from baseline to the end of the study in morning plasma cortisol levels 0, 30, and 60 minutes after cosyntropin stimulation were not significantly different between the budesonide aqueous nasal spray and placebo groups. There were also no significant differences in the mean change in morning plasma cortisol levels from baseline to the end of the study in the difference from 0 to 30 minutes and from 0 to 60 minutes after cosyntropin stimulation between the budesonide aqueous nasal spray and placebo groups. patient history, physical examination, laboratory values, or medical review. Thus, the patient was allowed into the study. Treatment Compliance Mean compliance with study treatment was 97% for the budesonide aqueous nasal spray group and 98% for the placebo group. The median compliance with study treatment was 100% in both groups, and only 1 patient in each group had less than 80% compliance. Global Symptom Assessment At the end of the study, the proportions of patients rated as having substantial to total control of their allergic rhinitis symptoms with use of the study medication were 52% and 55% in the budesonide aqueous nasal spray and placebo groups, respectively, based on investigator ratings and 54% and 58% based on parent or guardian ratings. These responses made by the investigator or the parent or guardian did not differ significantly between the 2 treatment groups. Concomitant Therapies and Rescue Medication At least 1 medication was received concomitantly with study medication by each of the 39 patients (100%) in the budesonide aqueous nasal spray group and by 36 (92%) of the 39 patients in the placebo group during the 6-week study treatment period, including concomitant medications for AEs or intercurrent illness or a change in dose or frequency of a drug that was begun before study medication. The most frequent concomitant medications ( 10%) were eutectic mixture of local anesthetics, diphenhydramine hydrochloride, salbutamol, paracetamol, cetirizine hydrochloride, ibuprofen, and Triaminic. Eutectic mixture of local anesthetics cream was the most commonly used concomitant medication during this study in both treatment groups. This topical analgesic was allowed by the protocol before the venipuncture procedure and was applied under an occlusive dressing for at least 1 hour. Except for salbutamol, which was used by a higher proportion of pediatric patients in the budesonide aqueous nasal spray group (33%) compared with the placebo group (13%), the frequencies of specific concomitant medication use did not differ between the 2 treatment groups. Patients were permitted to take rescue medication for their allergic rhinitis symptoms, except those listed in the exclusionary criteria. Rescue medication for allergic rhinitis symptoms was taken by 17 patients (44%) in the budesonide aqueous nasal spray group and 9 (23%) in the placebo group. Adverse Events Safety was evaluated in all patients who received at least 1 dose of study spray. At least 1 AE was reported during study treatment by 23 patients (59%) in the budesonide aqueous nasal spray group and by 14 (36%) in the placebo group. A listing of the most common AEs ( 5%) is provided in Table 4. Although there was a higher incidence of patients who reported an AE in the budesonide aqueous nasal spray group compared with the placebo group, there were no clinically relevant differences in the type of AEs between treatment 64 ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY

Table 2. Changes in Plasma Cortisol Levels from Baseline to the End of the Study Variable Treatment group N Baseline mean (SE), nmol/l Change from baseline, mean (SE), nmol/l P value* Baseline to week 6 Placebo 33 248.0 (17.3) 1.87 (14.56).32 BANS 33 259.6 (16.4) 22.35 (16.02) Baseline to week 6 30 minutes postcosyntropin stimulation Placebo 30 583.5 (18.4) 27.81 (19.72).68 BANS 35 567.1 (17.7) 17.58 (18.72) Baseline to week 6 60 minutes postcosyntropin stimulation Placebo 32 644.5 (18.9) 48.89 (21.78).54 BANS 34 664.9 (16.3) 32.54 (21.62) Baseline to week 6 Placebo 30 331.3 (18.9) 17.51 (20.32).48 Difference from 0 to 30 minutes postcosyntropin stimulation BANS 33 311.8 (18.0) 2.32 (21.13) Baseline to week 6 Placebo 32 396.0 (18.7) 33.6 (21.4).17 Difference from 0 to 60 minutes postcosyntropin stimulation BANS 32 409.1 (19.5) 8.45 (23.57) Abbreviation: BANS, budesonide aqueous nasal spray. * P value associated with analysis of covariance that included terms for treatment, baseline plasma cortisol value, center, and age strata. Table 3. Number of Patients with Normal and Subnormal HPA Axis Function Visit Classification* BANS (n 35) Placebo (n 33) Total patients (N 68) Baseline Normal HPA axis function 32 31 63 Subnormal HPA axis function 3 2 5 Missing 0 0 0 End of study Normal HPA axis function 30 26 56 Subnormal HPA axis function 3 6 9 Missing 2 1 3 Abbreviations: BANS, budesonide aqueous nasal spray; HPA, hypothalamic-pituitary-adrenal. * Normal HPA axis function is defined as a basal plasma cortisol level of 148 nmol/l or greater and a 30- or 60-minute postcosyntropin stimulation value of 498 nmol/l or greater. Table 4. Most Frequent Adverse Events ( 5%) during Treatment* Adverse event BANS Placebo Total patients (N 78) Patients with adverse events 23 (59.0) 14 (35.9) 37 (47.4) Respiratory infection 2 (5.1) 4 (10.3) 6 (7.7) Otitis media 3 (7.7) 2 (5.1) 5 (6.4) Accident and/or injury 4 (10.3) 0 (0) 4 (5.1) Fever 3 (7.7) 1 (2.6) 4 (5.1) Gastroenteritis 2 (5.1) 2 (5.1) 4 (5.1) Headache 1 (2.6) 3 (7.7) 4 (5.1) Insect bite/scratch 1 (2.6) 2 (5.1) 3 (3.8) Parasitosis 2 (5.1) 1 (2.6) 3 (3.8) Rash 1 (2.6) 2 (5.1) 3 (3.8) Coughing 2 (5.1) 0 (0) 2 (2.6) Abbreviation: BANS, budesonide aqueous nasal spray. * Data are given as number (percentage). groups. Many of the AEs reported during the study treatment period were those common in children, such as fever, otitis media, and accident or injury. Only 3 AEs, reported by 2 patients, were considered by the investigators to be treatment related: nasal irritation (n 1) and nervousness and increased appetite (n 1) reported in the budesonide aqueous nasal spray group. Both study treatments were well tolerated, and no patient withdrew from the study prematurely because of an AE. Although most AEs reported during the treatment period were rated by the investigator as mild or moderate in intensity, 1 serious AE (thrombocytopenia) occurred in a placebotreated patient. The types and reporting frequencies of AEs reported during the treatment period did not seem to differ appreciably as a function of sex, age strata, or race. Mean changes from baseline in hematologic and clinical chemistry parameters, as well as mean changes in vital sign measurements and body weight, were small and comparable in the budesonide aqueous nasal spray and placebo groups. DISCUSSION The results of this study show that once-daily administration of budesonide aqueous nasal spray (64 g) for 6 consecutive weeks has no measurable suppressive effects on HPA axis function in patients aged 2 to 5 years with allergic rhinitis. Furthermore, compliance with study treatment was very high and similar between groups, suggesting that the lack of significant effects of budesonide aqueous nasal spray on HPA axis function was not due to patients failing to adhere to their treatment. The possibility exists that patients may have entered false log entries or that they might have dumped their medications; these scenarios were not controlled for in this study. VOLUME 93, JULY, 2004 65

The cosyntropin stimulation method is a sensitive and standard adrenal stimulation test used to monitor the reserve function of the adrenal glands in response to potential systemic exposure to corticosteroids. This test has been used previously in pediatric and adult patients to determine the effects of budesonide aqueous nasal spray and other INSs on HPA axis function. 11,12,14,19,20 The standard dose of cosyntropin used to stimulate adrenocortical function is 250 g, whereas in this study a lower dose of cosyntropin (10 g) was used. Previous reports have suggested that lower concentrations of cosyntropin are as sensitive 18 or more sensitive of adrenocortical function than the 250- g dose. 9,21 Dorin et al 18 found that the operating characteristics of the 250- g cosyntropin dose were similar to those of the 1- g dose. In contrast, in the study by Broide et al, 21 a low dose of cosyntropin (0.5 g) was suggested to be fairly similar to physiologic levels of adrenocorticotropic hormone (corticotropin) compared with the higher, more supraphysiologic cosyntropin dose (250 g). The authors 21 also reported that the 0.5- g dose could reveal patients with mild adrenal insufficiency that was not detected by the standard high dose (250 g) of cosyntropin. The safety and tolerability profile of budesonide aqueous nasal spray in the present study was similar to that of placebo when characterized by the rates and types of AEs, discontinuations because of AEs, concomitant therapies, and rescue medications. Similar results have been reported with budesonide aqueous nasal spray in patients 6 years and older. 14 Overall, the present results in this younger pediatric patient population are similar to those found in older pediatric populations using budesonide aqueous nasal spray. 14,15 The absence of cortisol suppression in the budesonide aqueous nasal spray group in this study is an important safety finding in this younger pediatric population. Although most of the new-generation corticosteroids, including budesonide aqueous nasal spray, have a low potential for systemic exposure and effect on HPA axis function (owing to their high first-pass metabolism and formation of minimally active metabolites), the chronic and persistent nature of allergic rhinitis symptoms may necessitate the long-term continual use of corticosteroids. Taken together, the results of this study evaluating the adrenal-stimulated cortisol values, combined with HPA axis function measurements from previous studies, indicate that budesonide aqueous nasal spray had little effect on adrenal function at the doses studied. The present study did not include examinations of bone growth, bone composition, or histologic changes in nasal mucosa; therefore, future studies need to be conducted to supplement the excellent safety profile reported herein for budesonide aqueous nasal spray in this young pediatric population. The current study was not designed to evaluate the relative efficacy of budesonide aqueous nasal spray and placebo in treating allergic rhinitis symptoms in pediatric patients. The only efficacy measures of study drug effectiveness collected during the treatment period were subjective measures of global efficacy made by the investigators and the parents or guardians at the end of the study. Both sets of assessors indicated that approximately one half of the pediatric patients had substantial or total symptom control with either budesonide aqueous nasal spray or placebo, and there was no statistically significant difference in global assessments between the 2 treatment groups. However, children were not required to demonstrate a certain level of symptoms before randomization, rescue medication use was allowed throughout the study, and only a single evaluation of efficacy at the end of 6 weeks of treatment was measured (vs evaluation of daily signs and symptoms). The budesonide aqueous nasal spray treated group showed an increase in the use of rescue medication, which may indicate that these patients had more severe allergic rhinitis than the placebo-treated group. The efficacy of budesonide aqueous nasal spray in treating allergic rhinitis in children is well established using objective measures of efficacy. Creticos et al 14 reported that 4 weeks of treatment with budesonide aqueous nasal spray (64 g) administered once daily to adults and children with seasonal allergic rhinitis resulted in significantly reduced individual symptoms of runny nose and sneezing using a nasal index score. Furthermore, Meltzer 15 reported that 6 weeks of treatment with 64 g of budesonide aqueous nasal spray once daily not only significantly decreased nasal index scores from baseline but also significantly decreased eosinophil and basophil counts in both children and adults with perennial allergic rhinitis compared with the placebo group. In conclusion, the results of this study with 64 g of budesonide aqueous nasal spray administered as 1 (32- g) spray per nostril daily for 6 weeks in patients aged 2 to 5 years with allergic rhinitis showed an absence of measurable suppressive effects on HPA axis function, and budesonide aqueous nasal spray was well tolerated based on the favorable AE profile. ACKNOWLEDGMENTS Christopher Tobias, PhD, and Stella Chow, PhD (Tri-Med Communications, Media, PA), contributed to the preparation of the manuscript. REFERENCES 1. Galant SP, Wilkinson R. Clinical prescribing of allergic rhinitis medication in the preschool and young school-age child: what are the options? BioDrugs. 2001;15:453 463. 2. Dykewicz MS, Fineman S. Executive Summary of Joint Task Force Practice Parameters on Diagnosis and Management of Rhinitis. Ann Allergy Asthma Immunol. 1998;81:463 468. 3. Bousquet J, Van Cauwenberge P, Khaltaev N. Allergic rhinitis and its impact on asthma. J Allergy Clin Immunol. 2001;108: S147 S334. 4. Yanez A, Rodrigo GJ. Intranasal corticosteroids versus topical H 1 receptor antagonists for the treatment of allergic rhinitis: a systematic review with meta-analysis. Ann Allergy Asthma Immunol. 2002;89:479 484. 5. Weiner JM, Abramson MJ, Puy RM. 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6. Nathan RA. Pharmacotherapy for allergic rhinitis: a critical review of leukotriene receptor antagonists compared with other treatments. Ann Allergy Asthma Immunol. 2003;90:182 190. 7. van Cauwenberge P, Bachert C, Passalacqua G, et al. Consensus statement on the treatment of allergic rhinitis: European Academy of Allergology and Clinical Immunology. Allergy. 2000; 55:116 134. 8. Kamada AK, Parks DP, Szefler SJ. Inhaled glucocorticoid therapy in children: how much is safe? Pediatr Pulmonol. 1992;12: 71 72. 9. Boner AL. Effects of intranasal corticosteroids on the hypothalamic-pituitary-adrenal axis in children. J Allergy Clin Immunol. 2001;108:S32 S39. 10. Allen DB. Systemic effects of intranasal steroids: an endocrinologist s perspective. J Allergy Clin Immunol. 2000;106: S179 S190. 11. Meltzer EO, Berger WE, Berkowitz RB, et al. A dose-ranging study of mometasone furoate aqueous nasal spray in children with seasonal allergic rhinitis. J Allergy Clin Immunol. 1999; 104:107 114. 12. Nayak AS, Ellis MH, Gross GN, et al. The effects of triamcinolone acetonide aqueous nasal spray on adrenocortical function in children with allergic rhinitis. J Allergy Clin Immunol. 1998; 101:157 162. 13. Skoner DP, Gentile D, Angelini B, Kane R, Birdsall D, Banerji D. The effects of intranasal triamcinolone acetonide and intranasal fluticasone propionate on short-term bone growth and HPA axis in children with allergic rhinitis. Ann Allergy Asthma Immunol. 2003;90:56 62. 14. Creticos P, Fireman P, Settipane G, Bernstein D, Casale T, Schwartz H. Intranasal budesonide aqueous pump spray (Rhinocort Aqua) for the treatment of seasonal allergic rhinitis: Rhinocort Aqua Study Group. Allergy Asthma Proc. 1998;19: 285 294. 15. Meltzer EO. Clinical and antiinflammatory effects of intranasal budesonide aqueous pump spray in the treatment of perennial allergic rhinitis. Ann Allergy Asthma Immunol. 1998;81: 128 134. 16. Day JH, Briscoe MP, Rafeiro E, Ellis AK, Pettersson E, Akerlund A. Onset of action of intranasal budesonide (Rhinocort aqua) in seasonal allergic rhinitis studied in a controlled exposure model. J Allergy Clin Immunol. 2000;105:489 494. 17. Schmidt IL, Lahner H, Mann K, Petersenn S. Diagnosis of adrenal insufficiency: evaluation of the corticotropin-releasing hormone test and basal serum cortisol in comparison to the insulin tolerance test in patients with hypothalamic-pituitaryadrenal disease. J Clin Endocrinol Metab. 2003;88:4193 4198. 18. Dorin RI, Qualls CR, Crapo LM. Diagnosis of adrenal insufficiency. Ann Intern Med. 2003;139:194 204. 19. Schenkel EJ, Skoner DP, Bronsky EA, et al. Absence of growth retardation in children with perennial allergic rhinitis after one year of treatment with mometasone furoate aqueous nasal spray. Pediatrics. 2000;105:E22. 20. Vargas R, Dockhorn RJ, Findlay SR, Korenblat PE, Field EA, Kral KM. Effect of fluticasone propionate aqueous nasal spray versus oral prednisone on the hypothalamic-pituitary-adrenal axis. J Allergy Clin Immunol. 1998;102:191 197. 21. Broide J, Soferman R, Kivity S, et al. Low-dose adrenocorticotropin test reveals impaired adrenal function in patients taking inhaled corticosteroids. J Clin Endocrinol Metab. 1995;80: 1243 1246. Requests for reprints should be addressed to: Kenneth T. Kim, MD Allergy, Asthma & Respiratory Care Medical Center 2600 Redondo Ave Suite 400 Long Beach, CA 90806 E-mail: drkkim@wcctrials.com VOLUME 93, JULY, 2004 67