Clinical and antiinflammatory effects of intranasal budesonide aqueous pump spray in the treatment of perennial allergic rhinitis Eli O Meltzer, MD

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1 Clinical and antiinflammatory effects of intranasal budesonide aqueous pump spray in the treatment of perennial allergic rhinitis Eli O Meltzer, MD Background: Intranasal corticosteroids are among the most effective treatments for perennial allergic rhinitis (PAR). Some individuals unable to tolerate aerosols may prefer an aqueous nasal spray. Objective: To determine the efficacy, safety, and antiinflammatory effects of an intranasal aqueous pump spray formulation of budesonide. Methods: Four hundred seventy-eight patients [257 adults, 221 children (6 to 17 years)] with PAR were randomized to budesonide aqueous pump spray (Rhinocort Aqua) 32, 64, 128, or, or placebo once daily for 6 weeks. Patients recorded nasal/ocular symptom severity daily. Nasal cytology was evaluated at baseline and end of treatment. The study was powered only to evaluate the overall population for significance. Results: Following 6 weeks of treatment, significant differences from baseline in nasal index score (NIS) sum of blocked nose, runny nose, and sneezing scores were observed in the 32-, 64-, and 256- g aqueous budesonide groups compared with placebo (P.031). No dose response was found for changes in NIS. Significant reductions from baseline NIS were observed with 256- g aqueous budesonide compared with placebo in the first 24 hours following treatment (P.004). Aqueous budesonide also significantly reduced individual nasal symptoms in two or more of the active treatment groups (P.035). Patients overall treatment efficacy assessments showed significantly greater symptom control with aqueous budesonide (P.006), and overall quality of life improved. Significantly greater decreases in eosinophils and basophils were found in aqueous budesonide-treated groups (P.007). The frequency of adverse events was similar among all treatments. Conclusions: Once daily aqueous budesonide is well tolerated and effective in relieving nasal symptoms and inflammation associated with PAR. Ann Allergy Asthma Immunol 1998;81: INTRODUCTION Allergic rhinitis, including both perennial (PAR) and seasonal (SAR) rhinitis, affects 10% to 30% of adults and children. 1,2 The most common symptoms associated with PAR and SAR are runny nose, sneezing, and nasal congestion (blocked nose), the latter being especially problematic in patients with PAR. 3 Intranasal corticosteroids have proven to be one of the most effective and well-tolerated treatments for PAR and SAR. 2,4 6 They provide This study was supported by Astra USA, Inc. Received for publication March 10, Accepted for publication in revised form June 18, relief of allergy-related symptoms without the systemic side effects associated with many oral antihistamines, eliminate the need for concomitant decongestants to relieve nasal congestion, provide direct delivery to the target organ (nasal mucosa), reduce the inflammation recognized as a prominent feature of allergic rhinitis, and are safe and well tolerated when long-term therapyisrequiredasinpar. 4,7 9 Uncovering the pathophysiology of allergic rhinitis has led to an increased understanding of how and why topical corticosteroids effectively and safely reduce the symptoms of PAR and SAR. The allergic response is comprised of two components that involve inflammatory mediators and cells (eg, mast cells, basophils, and eosinophils), an early phase that occurs within 1 hour of exposure to allergens, and a late phase occurring approximately 3 to 10 hours after initial exposure. Topical corticosteroids markedly decrease the number of basophils, eosinophils, and mast cells found in the nasal mucosa, leading to reductions in blocked nose, runny nose, and sneezing. 4 This decrease can be used as a morphologic marker to evaluate the efficacy of intranasal corticosteroid therapy. 4 6,10,11 Several studies in adults and children have documented the effectiveness and safety of pressurized aerosol metered-dose inhaler (pmdi) and dry powder formulations of the intranasal glucocorticosteroid budesonide in reducing the symptoms of PAR 9,12 17 and SAR, but did not study a range of doses or examine antiinflammatory properties of budesonide. An aqueous nasal spray may be a personal choice for some individuals and preferable for patients unable to tolerate aerosols, especially those with dry, crusting nasal mucosa. The aqueous, benzalkonium chloride-free, intranasal formulation of budesonide (intranasal budesonide aqueous spray, Rhinocort Aqua) has been shown to be at least as effective and well tolerated as the pmdi and dry powder formulations in both PAR and SAR patients. 3,29,30 In addition, the budesonide aqueous formulation is thixotropic 31 ; when applied to the nasal mucosa, the liquid formulation becomes a higher viscosity liquid. The objective of the current study was to evaluate the safety and efficacy of once-daily budesonide aqueous spray (32, 64, 128, and 256 g) versus placebo for 6 weeks in re- 128 ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY

2 lieving nasal symptoms and inflammation in adults and children with PAR. In addition, the study also was designed to determine if a dose-response relationship was present. METHODS Subjects Males and females, 6 years of age or older, with a 2-year history of PAR requiring treatment with medication other than decongestants only, and a positive skin prick test ( 3 mm) for perennial allergens were enrolled in the study. Patients were required to have at least two of the following nasal symptoms blocked nose, runny nose, and sneezing during 4 of 7 days of the baseline period with a nasal symptom score 2 (on a scale of 0 to 3). Patients were excluded if they had other significant medical diseases, structural abnormalities of the nose symptomatic enough to cause nasal obstruction, or recent or active sinusitis, rhinitis medicamentosa, or atrophic rhinitis. Patients with coexisting seasonal rhinitis also were excluded, unless the specific allergen was not in season, as were patients receiving immunotherapy for perennial allergens for less than 6 months or patients who were not on stable maintenance doses. Patients who used medications possibly influencing symptoms (eg, nasal cromolyn sodium or nedocromil within 2 weeks, topical nasal or systemic glucocorticosteroids within 1 month, or antihistamines, topical or oral decongestants, or other medications that could mask rhinitis symptoms within 3 days of enrollment) also were excluded. Pregnant or nursing women were not entered. The study protocol was approved by an Institutional Review Board, all patients/legal guardians provided written informed consent, and the study was performed according to the Declaration of Helsinki. Study Design This was a double-blind, randomized, placebo-controlled, parallel-group study conducted in 20 centers geographically distributed throughout the United States. Each center was to enroll 24 patients after the end of the fall pollen season (approximately the second week of November 1994) and to enroll equal numbers of children (ages 6 to 17) and adults (age 18). Following a 1-week baseline period, patients were randomized to budesonide aqueous spray (Rhinocort Aqua, Astra),,, or, or placebo once daily for 6 weeks. Patients were required to visit the clinic five times: at enrollment, at randomization, and after 2, 4, and 6 weeks of treatment. At enrollment, a physical examination, nasal examination, medical history, and skin prick test for both seasonal and perennial allergens were performed. Blood and urine samples also were collected for clinical laboratory evaluations. Patients were given a diary card to record the severity of nasal symptoms (blocked nose, runny nose, sneezing, and nasal itching) and ocular symptoms (itching, redness, and tearing) according to the following 4-point scale: 0 no symptoms; 1 mild symptoms, present but not troublesome; 2 moderate symptoms, frequently troublesome, but not sufficient to interfere with normal daily activity or nighttime sleep; and 3 severe symptoms, sufficiently troublesome to interfere with normal daily activity or nighttime sleep. Diary cards were to be completed each morning and reflected the previous 24 hours throughout the study period. Patients returned to their respective study centers at the end of the 1-week baseline period and eligible patients were randomized to treatment. During this visit, a nasal examination was performed, a Rhinoprobe sample was obtained from one nostril to evaluate nasal cytology, and a Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) 32,33 was completed. After obtaining the Rhinoprobe sample, investigators used the following 5-point rating scale to evaluate separately basophils, eosinophils, and neutrophils: 0 none, 1 a few scattered cells of small clumps, 2 a moderate number of cells and larger clumps, 3 still larger clumps but do not cover the entire field, and 4 large clumps which cover the entire field. Patients rated items within each quality-of-life domain (practical problems, non-hay fever symptoms, nasal symptoms, ocular symptoms, activities, emotional symptoms, and sleep) according to the following scale: 1 not troubled, 2 hardly troubled at all, 3 somewhat troubled, 4 moderately troubled, 5 quite a bit troubled, 6 very troubled, and 7 extremely troubled. Patients were issued study medication and given a new diary card to record symptom severity. During visits 2 and 4 weeks after initiation of treatment, patients had nasal examinations and were asked to evaluate the control of nasal symptoms (overall treatment efficacy) using the following 5-point scale: 0 symptoms were aggravated, 1 no control over symptoms, 2 minor control over symptoms, 3 substantial control over symptoms, and 4 total control over symptoms. At the final study visit, the physical examination, nasal examination, and laboratory tests were repeated, and a final Rhinoprobe sample was obtained. Patients again evaluated overall treatment efficacy and completed a final quality-of-life questionnaire. The primary efficacy variable was the NIS, calculated as the sum of individual scores for three nasal symptoms: blocked nose, runny nose, and sneezing. Secondary efficacy variables included individual nasal symptoms (blocked nose, runny nose, and sneezing, as well as nasal itching), ocular symptoms (itching, redness, and tearing), patients overall assessments of treatment efficacy, nasal cytology, and quality-of-life evaluations. Quality-oflife was assessed using the average response to items within each domain and the average response to all items for an overall quality-of-life score. Information regarding adverse events (AEs) was recorded at all visits after randomization and included dates of onset and resolution, seriousness, maximum intensity, outcome, causality, and action taken. VOLUME 81, AUGUST,

3 Statistical Analyses The study was powered only to evaluate the overall study population for statistical significance. Baseline NIS was calculated as the average NIS over the 7 days prior to randomization/treatment. All budesonide aqueous spray treatment groups were compared with placebo with respect to change in NIS from baseline to the NIS averaged over the 6-week treatment period. Baseline individual symptom scores were calculated as the average of individual symptom scores over the 7 days prior to randomization/treatment. Budesonide aqueous spray treatment groups were compared with placebo with respect to the change in individual symptom scores from baseline to individual symptom scores averaged over the 6-week treatment period. Changes in NIS and changes in individual scores from baseline were analyzed using analysis of variance (ANOVA) that included terms for treatment and center by treatment interaction. To determine if a dose-response relationship existed, the change in NIS for the highest dose group was compared with that for the lowest dose group and a regression model was used to discern the slope of the dose-response line. Changes in NIS at 24, 48, and 72 hours were evaluated following the first dose of budesonide aqueous spray and compared with placebo. An ANOVA was used to compare budesonide aqueous spray (average of the response scores over the entire treatment period) with placebo for overall assessment of treatment efficacy. Changes in quality-of-life scores from baseline to end of treatment were analyzed using an ANOVA method, and pairwise comparisons were made to compare each active treatment to placebo in terms of average scores within each domain, and in terms of overall scores. Changes in nasal cytology scores from baseline to the end of treatment also were analyzed via ANOVA. An 0.05 level was set for statistical significance for treatment effects, and an 0.10 level was used to assess interaction effects. All statistical comparisons were performed as two-sided tests. Table 1. Demographic and Baseline Characteristics Characteristic RESULTS Patient Disposition Four hundred seventy-eight patients (245 males and 233 females) were randomized into the five treatment groups. Baseline demographics were comparable between all treatment groups as shown in Table 1. Seventythree percent of patients reported previous nasal preparation use, 59% reported antihistamine use, 15% unspecified use, 10% analgesic use, and 9% reported allergen or immunotherapy use in the treatment of their rhinitis. Rates of prior rhinitis medication use were similar across treatment groups. Analgesics, antiasthmatics, and antiinflammatory/antirheumatic products were the most commonly used nonrhinitis medications prior to the study. Of the 478 patients randomized, 447 (94%) completed the study and 31 (6%) patients discontinued prior to study completion. Eleven patients withdrew because of AEs, one because of disease deterioration/not improved, and 19 for other reasons. Discontinuation rates were comparable across treatment groups. Efficacy Nasal Index Score. The NIS scores at baseline were comparable for all treatment groups, with mean scores ranging from 6.0 to 6.3 indicating moderate rhinitis symptoms (Table 2). Following 6 weeks of treatment, NIS de- Budesonide Aqueous Spray Treatment Group (n 98) (n 93) (n 98) Total (n 478) Gender Male Female Race Caucasian Black Oriental Other Mean age, yr Range Mean duration of rhinitis, yr Table 2. Mean Change from Baseline in Nasal Index Scores* (n 96) Budesonide Aqueous Spray Treatment Group Baseline NIS Mean NIS (weeks 1 6) Mean change from baseline Difference from placebo % CI 1.20, , , , 0.29 P value versus placebo *CI confidence interval and NIS nasal index score (sum of symptom scores for blocked nose, runny nose, and sneezing). Mean change from baseline adjusted for center effect and baseline NIS. Difference from placebo. 130 ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY

4 creased significantly from baseline for the 32-, 64-, and 256- g treatment groups compared with placebo (P.031). There was borderline significance for the mean decrease in NIS from baseline in the budesonide aqueous spray 128- g group (P.051), with the magnitude of change similar to the decreases observed for the other budesonide aqueous spray groups. No dose-response relationship was found. Significant reductions in NIS scores from baseline were observed with 256 g budesonide aqueous spray compared with placebo at 24 hours following the first dose of study medication (P.004). This effect was maintained after 48 (P.046) and 72 (P.025) hours following the first dose of 256 g budesonide aqueous spray. Individual Symptom Scores. Mean scores for individual nasal symptoms indicated moderately severe rhinitis at baseline (Table 3). Blocked nose was significantly reduced in all budesonide aqueous spray groups compared with placebo (P.035), and runny nose and sneezing were also less in all budesonide groups compared with placebo and significantly reduced in the 32- g and 256- g groups (P.017). Analyses of secondary symptoms (nasal itching, eye itching, eye redness, and tearing) showed no consistent differences between the budesonide aqueous spray and placebo groups. Overall Evaluation of Efficacy. Patients reported that budesonide aqueous spray, at all dosage levels, resulted in significantly greater control of rhinitis symptoms than placebo (P.006). Mean overall treatment efficacy scores ranged from 2.27 to 2.33 for the budesonide aqueous spray groups compared with 1.98 for the placebo group (Table 4). Nasal Cytology. Overall, decreases in eosinophils and basophils were significantly greater for all four budesonide aqueous spray groups compared with placebo (P.007). Mean scores for eosinophils decreased for all budesonide aqueous spray groups with adjusted mean changes ranging from 0.42 to 0.62, although there was no change for the placebo group. Basophil Table 3. Mean Change from Baseline in Individual Symptoms Scores (n 96) scores decreased with budesonide aqueous spray treatment, with adjusted mean changes ranging from 0.17 to 0.39, while the adjusted mean change for placebo was No significant decreases in neutrophil scores were observed. Figure 1 shows the percentage of patients with decreases and increases from baseline in eosinophils, basophils, and neutrophils. Overall in the budesonide aqueous spray groups, but not in the placebo group, a greater proportion of patients had decreases in eosinophils and basophils, while approximately equal proportions of patients showed increases and decreases in neutrophils. Budesonide Aqueous Spray Treatment Group Blocked nose Baseline score Mean score (weeks 1 6) Mean change from baseline* Difference from placebo P value versus placebo Runny nose Baseline score Mean score (weeks 1 6) Mean change from baseline* Difference from placebo P value versus placebo Sneezing Baseline score Mean score (weeks 1 6) Mean change from baseline* Difference from placebo P value versus placebo * Mean change from baseline adjusted for center effect and baseline score. Table 4. Patient Overall Evaluation of Treatment Efficacy Budesonide Aqueous Spray Treatment Group (n 95) (n 93) (n 98) Average score Adjusted average score* Difference from placebo % Confidence interval 0.12, , , , 0.56 P value versus placebo * Adjusted average score is mean assessment over all treatment visits after randomization, adjusted for center effect. Difference from placebo. Quality-of-Life. Quality-of-life, assessed using the RQLQ, demonstrated improvements in nasal symptoms, activities, and practical problems in most budesonide aqueous spray groups. For adults ( 18 years), all budesonide aqueous spray treatment groups reported significant improvements in practical problems compared with placebo (P.038), scores for activities and overall scores improved (decreased) significantly compared with placebo for the 32- g and 256- g groups (P.036), while the 256- g group reported significant improvement in sleep and non-hay fever symptoms compared with placebo (P.042). VOLUME 81, AUGUST,

5 respiratory infection (2% budesonide aqueous spray versus 3% placebo) were the two most common AEs rated as probably or possibly related to study drug administration. No clinically significant trends or shifts were observed over the course of the study in laboratory parameters or vital signs. Twelve patients developed clinically relevant worsenings in nasal examinations; however, these changes were equivalent across all treatment groups and none were judged to be related to study medication. Discontinuations due to AEs. Eleven (2%) patients, 10 (3%) treated with budesonide aqueous spray, and one (1%) in the placebo group discontinued because of an AE. No apparent differences in rates of discontinuations were observed across treatment groups. Among budesonide aqueous spray patients, four patients in the 32- g group, one in the 64- g group, and five in the 128- g group discontinued, with bronchospasm being the most common reason for discontinuation (2 patients, 1%). Figure 1. Change in basophils, eosinophils, and neutrophils from baseline to end of treatment. In addition, significant improvements in nasal symptoms occurred for the 32- g and 128- g groups. Improvements for each of the abovementioned parameters and overall improvement were not significantly greater for any of the active treatment groups compared with placebo for children and adolescents (6 to 17 years); sample sizes for children were smaller than for adults. Adjusted mean changes, although not statistically significant for children, changed consistently in the direction of improvement in qualityof-life with budesonide treatment. Safety Adverse Events. The majority of AEs were mild or moderate in intensity, no serious AEs were reported, and no apparent differences were observed in the distribution of AEs across treatment groups. Overall, a total of 236 patients reported one or more AEs, 186 (49%) in the budesonide aqueous spray groups and 50 (52%) in the placebo group. The most commonly reported AEs were respiratory infection (12% budesonide aqueous spray versus 16% placebo), pharyngitis (7% budesonide aqueous spray versus 4% placebo), epistaxis/blood-tinged mucus (8% budesonide aqueous spray versus 2% placebo), and headache (7% budesonide aqueous spray versus 11% placebo). Thirty-two (8%) AEs in the budesonide aqueous spray groups and 7 (7%) AEs in the placebo group were reported as being severe by patients, but none of these were judged by investigators to be related to administration of study drug. A total of 63 patients (14% budesonide aqueous spray versus 10% placebo) were judged by investigators as having AEs that were probably or possibly related to study drug. Epistaxis/ blood-tinged mucus (6% budesonide aqueous spray versus 1% placebo) and DISCUSSION The current study demonstrated that budesonide aqueous pump spray effectively and safely relieved the symptoms of PAR in adults and children when administered once daily in doses of 32, 64, 128, and per day for 6 weeks. By the end of the 6-week treatment period, greater improvements from baseline in NIS scores occurred in all the budesonide aqueous spray groups compared with placebo, although no dose-response relationship was observed. Significant reductions in NIS (sum of scores for blocked nose, runny nose, and sneezing) were observed within 24 hours following the first dose of budesonide aqueous spray. When individual symptom scores were analyzed separately, blocked nose was significantly reduced compared with placebo in all groups of patients receiving budesonide aqueous spray. Runny nose and sneezing were significantly reduced in the 32- g and 256- g budesonide aqueous spray groups. In addition, budesonide aque- 132 ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY

6 ous spray patients reported a significantly greater overall control of rhinitis symptoms than patients given placebo. This study confirms the effectiveness of intranasal budesonide aqueous spray in relieving nasal symptoms that have been reported in other intranasal budesonide studies with PAR patients. 3,9,12 17 For example, in one 6-week, crossover study comparing the efficacy of budesonide aqueous spray (200 g twice daily) with beclomethasone dipropionate (BDP) aqueous nasal spray (100 g four times daily), the total nasal symptom score was significantly lower after budesonide aqueous spray treatment than with BDP, with significantly fewer reports of blocked nose, runny nose, and sore eyes. A greater proportion of patients also stated a preference for budesonide aqueous spray over BDP aqueous on the basis of effect, side effects, and overall satisfaction with treatment. 3 The antiinflammatory effects of budesonide appear to be responsible for its efficacy in relieving nasal symptoms and have been confirmed in our study. Nasal cytology analyses demonstrated significant reductions from baseline in eosinophils and basophils in all budesonide aqueous spray groups compared with placebo. These results are consistent with other studies in which treatment with budesonide significantly reduced the number of eosinophils. 34,35 When asked to evaluate overall treatment efficacy, budesonide aqueous spray patients reported significantly greater control of rhinitis symptoms than did patients treated with placebo. Budesonide aqueous spray patients also reported an improvement in overall quality-of-life, as well as improvements in nasal symptoms, practical problems, non-hay fever symptoms, eye symptoms, activities, emotional symptoms, and sleep. These improvements were significant for adult patients ( 18 years), but not for younger patients. Factors such as different interpretation of words related to the quality-of-life scale and the influence of a parent s opinion may have affected the outcome in pediatric and adolescent patients. Budesonide aqueous spray was well tolerated during the course of this study. The numbers and types of AEs were comparable for all budesonide aqueous spray groups and placebo. The most frequently reported AEs across all treatment groups were respiratory infection, pharyngitis, epistaxis, and headache. These findings are consistent with other placebo-controlled studies of intranasal budesonide. 12,22 24,28 In conclusion, this study demonstrates that once-daily intranasal budesonide aqueous spray provides effective relief of the symptoms and inflammation associated with PAR and is well tolerated in both adults and children. ACKNOWLEDGMENTS This study was supported by Astra USA, Inc. The Rhinocort Aqua Study Group includes: Jeffrey Adelglass, Dallas, TX; Charles Banov, North Charleston, SC; Edwin Bronsky, Salt Lake City, UT; William Busse, Madison, WI; Paul Chervinsky, North Dartmouth, MA; Joseph Diaz, San Antonio, TX; Jordan Fink, Milwaukee, WI; Stanley Galant, Orange, CA; Jay Grossman, Tucson, AZ; Craig LaForce, Raleigh, NC; H. Terry Levine, Overland Park, KS; Richard Lockey, Tampa, FL; Eli Meltzer, San Diego, CA; Louis Mendelson, West Hartford, CT; Zev Munk, Houston, TX; Juan C. Nadal, Westborough, MA; David Pearlman, Aurora, CO; Bruce Prenner, San Diego, CA; Ross Rocklin, Westborough, MA; Gail Shapiro, Seattle, WA; David Tinkelman, Atlanta, GA; and Allan Weinstein, Washington, DC. REFERENCES 1. Corey JP. Advances in the pharmacotherapy of allergic rhinitis: secondgeneration H 1 -receptor antagonists. Otolaryngol Head Neck Surg 1993; 109: Pedinoff AJ. Approaches to the treatment of seasonal allergic rhinitis. South Med J 1996;89: Adamopoulos G, Manolopoulos L, Giotakis I. A comparison of the efficacy and patient acceptability of budesonide and beclomethasone dipropionate aqueous nasal sprays in patients with perennial rhinitis. Clin Otolaryngol 1995;20: Mygind N, Dahl R. The rationale for use of topical corticosteroids in allergic rhinitis. Clin Exp Allergy 1996; 26(suppl 3): Suonpää J. Treatment of allergic rhinitis. Ann Med 1996;28: Tan RA, Siegel SC. Diagnosis and management of seasonal and perennial allergic rhinitis. Compr Ther 1996;22: Mabry RL. 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