Safety and Tolerability of Montelukast in Placebo-Controlled Pediatric Studies and Their Open-Label Extensions

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1 44: (2009) Safety and Tolerability of Montelukast in -Controlled Pediatric Studies and Their Open-Label Extensions Hans Bisgaard, MD, DMSci, 1 * David Skoner, MD, 2 Maria L. Boza, MD, 3 Carol A. Tozzi, PhD, 4 Kathleen Newcomb, 4 Theodore F. Reiss, MD, 4 Barbara Knorr, MD, 4 and Gertrude Noonan, BA 4 Summary. Background: Montelukast is a potent leukotriene-receptor antagonist administered once daily that provides clinical benefit in the treatment of asthma and allergic rhinitis in children and adults. Because of its wide use as a pediatric controller, there is a need for a further review of the safety and tolerability of montelukast in children. Objective: To summarize safety and tolerability data for montelukast from previously reported as well as from unpublished placebo-controlled, double-blind, pediatric studies and their active-controlled open-label extension/extended studies. Methods: These studies evaluated 2,751 pediatric patients 6 months to 14 years of age with persistent asthma, intermittent asthma associated with upper respiratory infection, or allergic rhinitis. These patients were enrolled in seven randomized, placebo-controlled, double-blind registration and post-registration studies and three active-controlled open-label extension/ extended studies conducted by Merck Research Laboratories between 1995 and Results: Montelukast was well tolerated in all studies. Clinical and laboratory adverse for patients treated with montelukast were generally mild and transient. The most frequent clinical adverse events for all treatments (placebo, montelukast, active control/usual care) in virtually all studies were upper respiratory infection, worsening asthma, pharyngitis, and fever. Conclusion: The clinical and laboratory safety profile for montelukast was similar to that observed for placebo or active control/usual care therapies. The safety profile of montelukast did not change with long-term use. Pediatr Pulmonol. 2009; 44: ß 2009 Wiley-Liss, Inc. Key words: asthma; leukotriene-receptor antagonist. INTRODUCTION Asthma is the most common chronic disease of childhood. Some asthma therapies that are effective in adolescents or school-age children may not be appropriate in younger children because of a narrow therapeutic index or because of the difficulties in assessing new therapies in this age group. 1 Montelukast is a cysteinyl leukotrienereceptor antagonist that provides clinical benefit in the treatment of asthma and allergic rhinitis both in adults and children (as young as 6 months of age for perennial allergic rhinitis in the United States and for asthma in Europe). 1 4 Efficacy and outcome data on montelukast from several pediatric studies have been published, 1 17 including an earlier review of safety data from 1 pediatric and 10 adult studies. 5 This manuscript is one of a series of manuscripts planned on the safety of montelukast. The purpose of this manuscript is to review the safety results (particularly, the most common adverse ) from seven registration and post-registration, placebo-controlled, double-blind studies of montelukast in asthma or allergic rhinitis. In addition, safety results from three activecontrol, open-label extensions or extended studies ß 2009 Wiley-Liss, Inc. (referred to as extension studies) are summarized in this review. This manuscript is not intended to be a comprehensive review of safety data from all studies of montelukast across all age groups. 1 Danish Pediatric Asthma Center, Copenhagen University Hospital, Gentofte, Copenhagen, Denmark. 2 Drexel University, Philadelphia, PA & Allegheny General Hospital, Pittsburgh, Pennsylvania. 3 University of Chile, Santiago, Chile. 4 Merck Research Laboratories, Merck & Co., Inc., Rahway, New Jersey. *Correspondence to: Prof. Hans Bisgaard, Danish Pediatric Asthma Center, Copenhagen University Hospital, Niels Andersensvej 65, DK-2900 Gentofte, Copenhagen, Denmark. bisgaard@copsac.dk Received 10 February 2008; Revised 2 October 2008; Accepted 1 December DOI /ppul Published online 14 May 2009 in Wiley InterScience (

2 Safety of Montelukast in Pediatric Studies 569 METHODS Patients were 2,751 children 6 months to 14 years of age in five short-term and two long-term multicenter, randomized, double-blind, placebo-controlled studies and from open-label, active-controlled extensions to three of these studies. These studies were conducted by Merck Research Laboratories between 1995 and 2004 to evaluate efficacy, safety, and/or tolerability of montelukast compared with placebo or usual care (defined as inhaled/ nebulized cromolyn or nedocromil or inhaled/nebulized corticosteroids [ICS], according to the practitioner s usual practice) in patients with asthma or allergic rhinitis without clinically significant comorbidities (Table 1). Short-acting b-agonists could be used as needed for asthma in all studies. All protocols were approved by the appropriate review boards at each site, and the studies were conducted in conformance with applicable country or local requirements regarding ethical committee review, informed consent, and patient rights and welfare. Informed consent was obtained from each patient s representative prior to the studies, and each patient 6 years of age or older provided written informed assent before any study procedure was performed. Five Short-Term Double-Blind Studies Safety and efficacy data from four multicenter, shortterm placebo-controlled, double-blind studies in children with asthma have been previously published. 1,5,12 14 Briefly, one double-blind study (referred to as the 6- to 24-month-old study) enrolled 256 children 6 24 months of age with persistent asthma for evaluations of safety and tolerability and exploratory efficacy of montelukast (4-mg oral granules) compared with matching-image placebo given once daily for 6 weeks (Table 1). 12 The second double-blind study (referred to as the 2- to 5-year-old study) enrolled 689 children 2 5 years of age with persistent asthma for evaluations of safety with exploratory efficacy end points for montelukast (4-mg chewable tablet) or matching-image placebo given once daily for 12 weeks (Table 1). 1 The third short-term double-blind study (referred to as the knemometry study) was a two-active treatment period, parallel two-arm, 2 2 crossover study that enrolled 71 patients 6 11 years of age with persistent asthma for evaluation of the effect of montelukast (5-mg chewable tablet once daily) on short-term lower leg growth rate (LLGR); placebo and budesonide (200 mg, twice daily) were used as controls. 13 The study consisted of four treatment TABLE 1 Study Designs and Selected Demographics of Pediatric Patients in 9 Asthma Studies and 1 Seasonal Allergic Rhinitis Study Study design/patients Age range Duration No. of patients randomized (M/F) Montelukast 1 control Usual care 2 /active Daily dose and montelukast formulation Reference Short-term double blind Persistent asthma 6 24 months 6 weeks 175 (116/59) 81 (59/22) NA 4-mg OG 12 Persistent asthma 2 5 years 12 weeks 461 (272/189) 228 (131/97) NA 4-mg CT 1 Persistent asthma (knemometry) 6 11 years 3 weeks 13 Montelukast/placebo arm 35 (20/15) 3 37 (22/15) 3 NA 5-mg CT Budesonide/placebo arm NA 33 (19/14) 3 33 (19/14) 3 Persistent asthma 6 14 years 8 weeks 201 (134/67) 135 (83/52) NA 5-mg CT 5,14 Allergic rhinitis 2 14 years 2 weeks 280 (157/123) 133 (77/56) NA 4-mg/5-mg CT 4 Long-term double-blind Intermittent asthma (PREVIA) 2 5 years 12 months 278 (173/105) 271 (177/94) NA 4-mg/5-mg CT 5 6 Persistent asthma (linear growth) 6 9 years 56 weeks 120 (73/47) 121 (79/42) 119 (80/39) 5-mg CT 17 Long-term open-label Persistent asthma 6 24 months 1.2 years 158 (113/45) NA 32 (21/11) 4-mg OG Persistent asthma 2 5 years 2.8 years 364 (212/152) NA 157 (95/62) 4-mg/5-mg CT 5 Persistent asthma 6 14 years 2.8 years 207 (135/72) NA 38 (26/12) 5-mg CT/10-mg FCT 6 5 CT, chewable tablet; FCT, film-coated tablet; M/F, males/females; NA, not applicable; OG, oral granules. 1 Patients in the double-blind studies received matching-image placebo. 2 Usual care ¼ inhaled/nebulized cromolyn/nedocromil or inhaled/nebulized corticosteroids according to the usual practice of the investigator. 3 Thirty-seven patients were randomized to the montelukast/placebo crossover arm and 34 patients were randomized to the budesonide/placebo crossover arm. Each crossover arm consisted of two 3-week active-treatment periods, with a 3-week placebo washout between treatments. Patient numbers above reflect actual exposure to treatment. 4 Patients 5 years old received the 4-mg chewable tablet of montelukast and patients 6 years old received the 5-mg chewable tablet of montelukast. 5 Patients were switched to the 5-mg chewable tablet of montelukast after turning 6 years old. 6 Patients were switched to the 10-mg film-coated tablet of montelukast after turning 15 years old.

3 570 Bisgaard et al. periods, including a 1-week, single-blind, placebo run-in period; two 3-week, double-blind active treatment periods; and a 3-week single-blind, wash-out period between the two active treatment periods (Table 1). The fourth short-term double-blind study (referred to as the 6- to 14-year-old study) enrolled 336 patients 6 14 years of age with persistent asthma for evaluations of asthma control and safety of montelukast (5-mg chewable tablet) or a matching-image placebo given once daily for 8 weeks (Table 1). 5,14 The fifth short-term double-blind study (referred to as the allergic rhinitis study) was a multicenter (31 sites in the United States), randomized, double-blind, placebocontrolled study conducted over a 2-week period during spring pollen season in 413 children 2 14 years of age with seasonal allergic rhinitis. The safety profile of montelukast, along with exploratory evaluations of allergic rhinitis efficacy end points and validation of measurement characteristics of new allergic rhinitis symptom scales, was assessed in this study (Table 1). Patients enrolled in the study demonstrated a positive skin test (wheal diameter at least 3 mm greater than saline control to one of the allergens active during the study season) and a Daytime Rhinitis Symptom Score >2 each day during the 3- to 5-day placebo run-in period. Patients 2 5 years of age received a 4-mg chewable tablet of montelukast or matching-image placebo, and patients 6 14 years of age received a 5-mg chewable tablet or matching-image placebo (Table 1). Two Long-Term Double-Blind Studies Safety data from two multicenter, long-term double-blind studies in children with asthma have been previously reported. 6,17 The PREvention of Viral Induced Asthma (PREVIA) study enrolled 549 children 2 5 years of age with intermittent asthma to evaluate montelukast (4- or 5-mg chewable tablet [depending on age]) or placebo in the prevention of asthma exacerbations over 12 months (Table 1). 6 The second long-term double-blind study (referred to as the linear growth study) enrolled 360 children 6 9 years of age to evaluate the effect of montelukast (5-mg chewable tablet), inhaled beclomethasone (200 mg twice daily), or matching-image placebo on linear growth in prepubertal children over 56 weeks (Table 1). Unique to this study, patients who were discontinued from blinded study drug for reasons other than withdrawal of consent or lost to follow-up were allowed to continue in the study on investigator-prescribed asthma treatment. This design allowed for the continued collection of height data after discontinuation of blinded study drug. 17 Three Open-Label Extension Studies Three of the five short-term double-blind studies described above had active-controlled open-label extensions or an extended safety study in which patients who completed the double-blind period could participate and receive either montelukast or usual care. Usual care in these studies was ICS or inhaled/nebulized cromolyn or nedocromil. 1,5,12,14 For two of the three extension studies, patients entered their respective open-label extension study directly from the double-blind study, without a washout or run-in period. Patients already using concomitant ICS or inhaled/nebulized cromolyn or nedocromil during the double-blind studies were allowed to continue their use, and the dose was not modified if they were allocated to the usual care group in the open-label extension study. For other patients allocated to usual care, once therapy was initiated, the dose was maintained throughout the study. In the third extension study (in patients 6 31 months of age), dosage adjustment of ICS or inhaled/nebulized cromolyn or nedocromil was allowed after 3 months of usual care. The first study was an open-label extended safety study that enrolled 190 patients 6 31 months of age with asthma, including 113 who had completed the 6- to 24-month-old study 12 plus 77 new patients 6 11 months of age (Table 1). This 52-week randomized extension study compared safety and tolerability of montelukast 4- mg oral granules with usual care. Of the 158 patients allocated to treatment with montelukast in this study, 62 had previously received montelukast in the doubleblind study, 32 had previously received placebo, and 64 patients were newly allocated to montelukast. Of the 32 patients in the usual care group, 10 had previously received montelukast in the double-blind study, 9 had previously received placebo, and 13 patients were newly allocated to usual care. The second study was an open-label extension study that enrolled 521 patients with persistent asthma who had completed the 2- to 5-year-old study (Table 1) 1 ; outcome data from this study have been reported. 15 Patients allocated to montelukast received a 4-mg chewable tablet once daily at bedtime; patients were switched to the 5-mg chewable tablet at the first visit after turning 6 years old. Of the 364 patients allocated to treatment with montelukast in this study, 239 had previously received montelukast in the double-blind study and 125 had received placebo. Of the 157 patients in the usual care group, 113 had previously received montelukast and 44 had received placebo in the double-blind study. The third study was an open-label extension that enrolled 245 patients who had completed the 6- to 14- year-old study. 5,14 Preliminary safety data (duration of exposure 1.8 years) from this open-label extension study have been reported. 5 The present analysis includes final safety and tolerability data collected for up to 2.8 years (Table 1). Patients allocated to montelukast in this extension study received a 5-mg chewable tablet once daily at bedtime; patients were switched to a 10-mg

4 Safety of Montelukast in Pediatric Studies 571 film-coated tablet at the first visit after turning 15 years old. Of the 207 patients allocated to treatment with montelukast in this study, 137 had previously received montelukast in the double-blind study and 70 had received placebo. Of the 38 patients in the usual care group, 10 had previously received montelukast and 28 had received placebo in the double-blind study. Reporting of Experiences For all patients, safety evaluations were performed at the time of entry into the study, at visits during the study, and at the last scheduled visit or at the time of discontinuation. Reports of study drug overdosage were recorded. were monitored and reported by investigators according to international regulatory guidelines. 18 The incidences of clinical and laboratory adverse were summarized and compared between treatment groups within each study. An adverse experience was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of any study drug or placebo, whether or not considered related to the use of the drug or placebo. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition temporally associated with the use of a study drug or placebo (including asthma) also was an adverse experience. The investigator judged the seriousness (from a regulatory perspective) of the event and reported its intensity, whether the event resulted in discontinuation of therapy, and its relationship to the drug. 18 An adverse experience was considered serious, from a regulatory perspective, if it resulted in death, was life threatening, resulted in or prolonged an existing inpatient hospitalization, resulted in a persistent or significant disability/ incapacity, or was a congenital anomaly/birth defect (in offspring of subjects taking study drug). Intensity of an adverse experience was rated as mild (awareness of sign or symptom but easily tolerated), moderate (discomfort that caused interference in activity), or severe (incapacitating). The five possible ratings for assessing relationship of the drug to the event were as follows: definitely not, probably not, possibly, probably, or definitely related to study drug. Standard laboratory tests included hematology and blood chemistry parameters. Predefined limits of change from baseline were established for certain laboratory parameters, including alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Normal laboratory ranges for these chemistry parameters, based on the patient s age at randomization, were used for the analysis. The number of patients exceeding predefined limits of change at least once during the study was determined and compared between treatment groups. Statistical Analysis Frequencies of individual adverse (clinical and laboratory) were summarized by treatment group within study. Ninety-five percent confidence intervals (CIs) were computed for pairwise differences in nine studies; in one study, Fisher s exact test was used to screen for significant differences between treatment groups. Summary statistics were computed for montelukast and usual care treatment groups in all open-label studies. Percentages of patients with values outside the predefined limits of change for selected laboratory safety tests were analyzed similarly. Summary statistics for laboratory safety parameters were calculated. All patients who received at least one dose of study drug were included in the safety analyses. In these studies, 95% CIs, or a significant Fisher s exact test, were used as a screening tool to identify potential differences between treatment groups in the incidence of adverse ; this analysis was, therefore, a datadriven post hoc exercise. The term notable difference was used when the 95% CI did not contain zero or the Fisher s exact test had a P-value This rule was applied before rounding of the limits of the 95% CI. As a consequence, the upper or lower limit of a 95% CI that defines a notable difference might be reported as 0.0 after rounding. The findings should be interpreted with care because approximately 5% of these CIs will not contain zero by chance alone, even when there is no treatment difference in occurrence of adverse. RESULTS Patients A total of 2,751 pediatric patients participated in the 10 clinical studies. In the seven double-blind studies, 1,550 patients were treated with montelukast, 1,039 were treated with placebo, and 152 were treated with ICS (counting patients in each treatment that were crossed over in the knemometry study). In the three open-label studies, 729 patients were treated with montelukast and 227 were treated with usual care therapies. Distribution of patients by study, treatment, and gender is shown in Table 1. Duration of Exposure in Open-Label Extension Studies In children 6 24 months of age, 69% of the 158 patients in the montelukast treatment group were treated with montelukast for at least 9 months, 27% for at least 12 months, and the longest duration of montelukast treatment was 1.2 years. For children 2 5 years of age, 75% of the 364 patients were treated with montelukast for more than 1 year, and the longest duration of montelukast treatment was 2.8 years. In children 6 14 years of age, 50% of the 207 patients received montelukast for

5 572 Bisgaard et al. 18 months or longer, and the longest duration of montelukast treatment was 2.8 years. Clinical Experiences Short-Term Double-Blind Studies The five most common adverse reported in the montelukast group within each of the short-term doubleblind studies are shown in Table 2a. In these studies, the most frequent clinical adverse included upper respiratory infection, worsening asthma, and fever. Among the five most frequently reported clinical adverse in patients 6 24 months of age, no clinically meaningful differences were observed between the montelukast and placebo groups (Table 2a). 11 Although it was not among the five most common clinical adverse, influenza-like disease was observed notably more frequently in the placebo group (3.7%) than in the montelukast group (0.0%) (Table 2b). Serious clinical adverse were reported in seven patients in the montelukast group (4.0%) and one in the placebo group (1.2%); none was considered drug related. There was one serious adverse experience of study drug overdose (overdose of 8 mg due to caregiver error) with no associated adverse ; the patient fully recovered. In 2- to 5-year-old patients, worsening asthma was reported as a clinical adverse experience notably more frequently in the placebo group (37.7%) than in the montelukast group (29.7%) (Table 2a). 1 Serious clinical adverse were reported for 17 patients in the montelukast group (3.7%) and nine patients in the placebo group (3.9%), including four patients who had drug overdoses of montelukast (overdoses of 8 72 mg). All patients with serious adverse of study drug overdose fully recovered. As previously reported, three of the four patients had adverse associated with overdoses of montelukast. Serious drug-related adverse were thirst in 1 patient (overdose of 64 mg) and thirst and mydriasis in 1 patient (overdose of 52 mg). One patient had a serious adverse experience of somnolence (overdose of 72 mg) that was not considered drug related by the investigator. Additionally, four patients had drug overdoses of placebo (5 13 tablets) without associated adverse. 1 In the knemometry study, there were no clinically important differences between treatments in the incidence of clinical adverse. Clinical adverse were reported for three patients treated with montelukast (8.6%); none was considered serious (Table 2a). 13 Clinical adverse reported for two patients treated with placebo (oral candidiasis and worsening asthma) and one patient treated with budesonide (worsening asthma) were considered drug related. No clinically meaningful differences were observed between the montelukast and placebo groups in the five most frequently reported clinical adverse TABLE 2a Common Experiences 1 Reported in Short-Term Double-Blind Studies in Children 6 Months to 14 Years of Age 2 14 years old, allergic rhinitis (2 weeks) 6 14 years old, persistent asthma (8 weeks) 2 5 years old, persistent asthma (12 weeks) 6 11 years old, persistent asthma knemometry (10 weeks) 6 24 months old, persistent asthma (6 weeks) (N ¼ 133) (N ¼ 280) (N ¼ 135) (N ¼ 201) (N ¼ 33) BUD (N ¼ 33) (N ¼ 37) (N ¼ 35) (N ¼ 228) (N ¼ 461) (N ¼ 81) (N ¼ 175) Overall (75.4) 62 (76.5) Overall (88.1) 202 (88.6) Overall 2,4 3 (8.6) 7 (18.9) 6 (18.2) 6 (18.2) Overall (75.1) 102 (75.6) Overall 2 73 (26.1) 35 (26.3) URI 56 (32.0) 17 (21.0) Asthma (29.7) 86 (37.7) Nasopharyngitis 1 (2.9) 0 (0.0) 1 (3.0) 2 (6.1) URI 48 (23.9) 40 (29.6) Headache 9 (3.2) 2 (1.5) Asthma 33 (18.9) 18 (22.2) Fever 125 (27.1) 61 (26.8) Asthma 1 (2.9) 2 (5.4) 1 (3.0) 1 (3.0) Headache 38 (18.9) 29 (21.5) Pharyngitis 9 (3.2) 2 (1.5) Fever 23 (13.1) 11 (13.6) URI 123 (26.7) 63 (27.6) Cough 1 (2.9) 2 (5.4) 1 (3.0) 0 (0.0) Asthma 33 (16.4) 31 (23.0) Fever 7 (2.5) 4 (3.0) Diarrhea 19 (10.9) 10 (12.3) Vomiting 75 (16.3) 45 (19.7) Pharyngitis 28 (13.9) 17 (12.6) URI 6 (2.1) 2 (1.5) Vomiting 15 (8.6) 9 (11.1) Cough 58 (12.6) 26 (11.4) Influenza 17 (8.5) 6 (4.4) Otitis media 6 (2.1) 2 (1.5) Otitis media 15 (8.6) 5 (6.2) BUD, budesonide;, montelukast; URI, upper respiratory infection. 1 The five most frequent adverse reported in the montelukast group, listed in descending order for each study. 2 Number (%) of children who reported one or more adverse during the study regardless of causality. 3 Notable difference: estimated difference between montelukast and placebo (95% CI): 8.0% ( 0.18, 16.36). 4 Only three different clinical adverse were reported in patients treated with montelukast.

6 Safety of Montelukast in Pediatric Studies 573 TABLE 2b Experiences With Notable Differences Not Reported in Table of Common Experiences in Short-Term Double-Blind Studies in Children 6 Months to 14 Years of Age 6 24 months old, persistent asthma (6 weeks) 6 14 years old, persistent asthma (8 weeks) 2 14 years old, allergic rhinitis (2 weeks) (N ¼ 175) (N ¼ 81) (N ¼ 201) (N ¼ 135) (N ¼ 280) (N ¼ 133) Influenza-like 0 (0.0) 3 (3.7) Allergic 0 (0.0) 5 (3.7) Sunburn 3 0 (0.0) 3 (2.3) disease 1 rhinitis 2, montelukast. 1 Estimated difference between montelukast and placebo (95% CI): 3.7% ( 10.3, 0.5). 2 Fisher s exact test (P ¼ 0.010). 3 Estimated difference between montelukast and placebo (95% CI): 2.3% ( 6.4, 0.2). in 6- to 14-year-old patients (Table 2a). 5,14 Although it was not among the five most common clinical adverse, allergic rhinitis occurred notably more frequently in the placebo group (3.7%) than in the montelukast group (0.0%; P ¼ 0.01) (Table 2b). Serious clinical adverse were reported for four patients in the montelukast group (2.0%); none was considered drug related. There were no serious clinical adverse reported in the placebo group. Among the five most frequently reported clinical adverse in the allergic rhinitis study, no clinically meaningful differences were observed between the montelukast and placebo groups (Table 2a). Although it was not among the five most common clinical adverse, sunburn was reported notably more frequently in the placebo group (2.3%) than in the montelukast group (0.0%) (Table 2b). One serious clinical adverse experience occurred in the study in the montelukast group; it was not considered drug related. In the short-term double-blind studies, the most commonly reported serious clinical adverse experience, regardless of causality, was worsening asthma, occurring in 15 of 1,152 patients treated with montelukast (1.3%) and 5 of 647 patients treated with placebo (0.8%). No suicidality-related adverse (completed suicide, suicide attempts, suicide ideation) were reported by investigators in the short-term double-blind studies. Clinical Experiences Long-Term Double-Blind Studies The five most common adverse reported in the montelukast group within each of the long-term double-blind studies are shown in Table 3a. The most frequent clinical adverse in patients treated with montelukast were upper respiratory infection, worsening asthma, and fever. No clinically meaningful differences were observed between montelukast and placebo groups in the frequency of the five most common clinical adverse in the PREVIA study (Table 3a). 6 Although not among the five most common clinical adverse, notable differences were detected for purulent rhinitis (montelukast 0.7% vs. placebo 3.7%); dyspnea (montelukast 0.4% vs. placebo 2.6%); and urticaria (montelukast 4.0% vs. placebo 1.1%) (Table 3b). Serious clinical adverse were reported in 24 patients in the montelukast TABLE 3a Common Experiences 1 Reported in Long-Term Double-Blind Studies in Children 2 14 Years of Age 2 5 years old, intermittent asthma PREVIA (12 months) 6 9 years old, persistent asthma linear growth (56 weeks) experience (N ¼ 278) (N ¼ 271) experience (N ¼ 120) BEC (N ¼ 119) (N ¼ 121) Overall (92.4) 240 (88.6) Overall (91.7) 107 (89.9) 110 (90.9) Asthma 134 (48.2) 145 (53.5) Asthma 3 44 (36.7) 51 (42.9) 61 (50.4) URI 105 (37.8) 96 (35.4) Nasopharyngitis 28 (23.3) 28 (23.5) 29 (24.0) Fever 55 (19.8) 47 (17.3) Pharyngitis 16 (13.3) 18 (15.1) 20 (16.5) Cough 52 (18.7) 45 (16.6) URI 14 (11.7) 21 (17.6) 23 (19.0) Rhinitis 41 (14.7) 32 (11.8) Fever 14 (11.7) 15 (12.6) 9 (7.4) BEC, beclomethasone;, montelukast; URI, Upper respiratory infection. 1 The five most frequent adverse reported in the montelukast group, listed, in descending order for each study. 2 Number (%) of children who reported one or more adverse during the study regardless of causality. 3 Estimated difference between montelukast and placebo (95% CI): 13.7% ( 25.7, 1.2).

7 574 Bisgaard et al. TABLE 3b Experiences With Notable Differences Not Reported in Table of Common Experiences in Long-Term Double-Blind Studies in Children 2 14 Years of Age years old, intermittent asthma PREVIA (12 months) (N ¼ 278) (N ¼ 271) Rhinitis purulent 2 2 (0.7) 10 (3.7) Dyspnea 3 1 (0.4) 7 (2.6) Urticaria 4 11 (4.0) 3 (1.1), montelukast. 1 No additional notable differences were reported in the linear growth study. 2 Estimated difference between montelukast and placebo (95% CI): 3.0% ( 6.0, 0.5). 3 Estimated difference between montelukast and placebo (95% CI): 2.2% ( 4.9, 0.1). 4 Estimated difference between montelukast and placebo (95% CI): 2.8% (0.1, 5.9). group (8.6%) and 34 patients in the placebo group (12.5%). One patient in each treatment group had serious clinical adverse that were considered drug related. One patient had an accidental drug overdose of montelukast (overdose of 72 mg) with spontaneous vomiting; the patient fully recovered. One patient in the placebo group had mood swings. Of the five most frequently reported clinical adverse in patients in the linear growth study, worsening asthma was reported notably more frequently in the placebo group (50.4%) than in the montelukast group (36.7%) (Table 3a). 17 Serious clinical adverse were reported for seven patients in the montelukast group (5.8%), five patients in the beclomethasone group (4.2%), and five patients in the placebo group (4.1%). None was considered drug related. Overdoses of study drug were reported in one patient in each treatment group (montelukast 10 mg; beclomethasone 2 placebo tablets; placebo 13 extra tablets over 1.7 months); all patients fully recovered. In the long-term double-blind studies, the most commonly reported serious clinical adverse experience, regardless of causality, was worsening asthma, occurring in 9 of 398 patients treated with montelukast (2.3%), 2 of 119 patients treated with beclomethasone (1.7%), and 17 of 392 patients treated with placebo (4.3%). No suicidality-related adverse (completed suicide, suicide attempts, suicide ideation) were reported by investigators in the long-term double-blind studies. Clinical Experiences Open-Label Extension Studies The overall incidence of clinical adverse in the open-label studies was similar between montelukast and usual care groups and generally reflected what was observed in double-blind studies in terms of reported and their relative frequency (Table 4a). Upper respiratory infection, worsening asthma, and pharyngitis were the most consistently reported clinical adverse in these studies. The five most common clinical adverse in patients 6 24 months of age enrolled in the extended study were upper respiratory infection, worsening asthma, pharyngitis, otitis media, and diarrhea. The incidence of these adverse was similar between the two treatment groups (Table 4a). Although not among the five most common adverse, there was a notably higher incidence of viral infection in patients 6 24 months of age treated with usual care (28.1%) than in those treated with montelukast (10.8%) (Table 4b). The usual care group also had a notably higher incidence of otitis and contact dermatitis than did the montelukast group; TABLE 4a Common Experiences 1 Reported in Long-Term Open-Label Studies in Children 6 Months to 14 Years of Age 6 24 months old, persistent asthma (1.2 years) 2 5 years old, persistent asthma (2.8 years) 6 14 years old, persistent asthma (2.8 years) (N ¼ 158) Usual care (N ¼ 32) (N ¼ 364) Usual care (N ¼ 157) (N ¼ 207) ICS (N ¼ 38) Overall (98.7) 31 (96.9) Overall (97.0) 149 (94.9) Overall (94.7) 33 (86.8) URI 82 (51.9) 15 (46.9) Asthma 218 (59.9) 97 (61.8) URI 125 (60.4) 20 (52.6) Asthma 78 (49.4) 18 (56.2) URI 192 (52.7) 81 (51.6) Asthma 91 (44.0) 16 (42.1) Pharyngitis 58 (36.7) 14 (43.8) Fever 164 (45.1) 60 (38.2) Headache 74 (35.7) 10 (26.3) Otitis media 39 (24.7) 7 (21.9) Pharyngitis 120 (33.3) 50 (31.8) Pharyngitis 67 (32.4) 12 (31.6) Diarrhea 30 (19.0) 8 (25.0) Cough 3 97 (26.6) 24 (15.3) Sinusitis 47 (22.7) 6 (15.8) ICS, inhaled corticosteroids;, montelukast. 1 The five most frequent adverse reported in the montelukast group, listed in descending order for each study. 2 Number (%) of children who reported one or more adverse during the study regardless of causality. 3 Notable difference: estimated difference between montelukast and usual care (95% CI): 11.3% (3.62, 18.12).

8 Safety of Montelukast in Pediatric Studies 575 TABLE 4b Experiences With Notable Differences Not Reported in Table of Common Experiences in Long-Term Open-Label Studies in Children 6 Months to 14 Years of Age months old, persistent asthma (1.2 years) 2 5 years old, persistent asthma (2.8 years) (N ¼ 158) Usual care (N ¼ 32) (N ¼ 364) Usual care (N ¼ 157) Viral infection 2 17 (10.8) 9 (28.1) Bronchitis 5 58 (15.9) 38 (24.2) Otitis 3 1 (0.6) 3 (9.4) Sinus disorder 6 16 (4.4) 15 (9.6) Contact dermatitis 4 1 (0.6) 2 (6.3), montelukast. 1 No notable differences reported in the long-term study in children 6 14 years old. 2 Estimated difference between montelukast and usual care (95% CI): 17.4% ( 35.1, 3.5). 3 Estimated difference between montelukast and usual care (95% CI): 8.7% ( 23.6, 2.0). 4 Estimated difference between montelukast and usual care (95% CI): 5.6% ( 19.5, 0.3). 5 Estimated difference between montelukast and usual care (95% CI): 8.3% ( 16.29, 0.97). 6 Estimated difference between montelukast and usual care (95% CI): 5.2% ( 11.01, 0.64). however, the actual incidence of these adverse was small in both treatment groups (Table 4b). Serious clinical adverse were reported in 15 patients in the montelukast group (9.5%) and 1 patient in the usual care group (3.1%). None of the adverse was considered drug related. Worsening asthma, upper respiratory infection, fever, pharyngitis, and cough were common adverse in children 2 5 years of age enrolled in the open-label extension study (Table 4a). The incidence of cough in the montelukast group (26.6%) was notably higher than in the usual care group (15.3%). In both groups, cough lasted a median of 5 days and resolved while patients continued study therapy. Although not among the five most common adverse, there was a notably higher incidence of bronchitis in the usual care group (24.2%) than in the montelukast group (15.9%), and sinus disorder was reported notably more frequently in the usual care group (9.6%) than in the montelukast group (4.4%) (Table 4b). Serious clinical adverse were reported for 38 patients in the montelukast group (10.4%) and 15 patients in the usual care group (9.6%), including nine patients who had drug overdoses of montelukast (overdoses of 5 92 mg). Four patients in the montelukast group had drug-related serious clinical adverse (all were overdoses of study drug or adverse associated with the overdose). The following serious clinical adverse were considered drug related: study drug overdose (four patients), hypersomnia (one patient), thirst (two patients), and somnolence (one patient). All patients with overdoses of montelukast fully recovered. No serious drug-related adverse were reported in the usual care group. In addition to the serious clinical adverse reported, one patient in the montelukast group had a serious laboratory adverse experience (increased alkaline phosphatase) that was considered drug related. The five most common adverse reported in 6- to 14-year-old patients were upper respiratory infection, worsening asthma, headache, pharyngitis, and sinusitis. The incidence of individual adverse was similar between the two treatment groups in this study (Table 4a). Serious clinical adverse were reported in 16 patients in the montelukast group (7.7%) and 1 patient in the ICS group (2.6%). None was considered to be drug related. Of note, a 12-year-old patient with a history of attention deficit disorder and depression was hospitalized for depression and suicidal ideation while receiving open-label montelukast (1.8 years). Therapy with montelukast was interrupted and treatment with buproprion 75 mg BID was initiated. After recovery from the depression and suicidal ideation, the patient was discharged from the hospital and therapy with montelukast was resumed. The depression and suicidal ideation were not considered to be drug related. The patient was later discontinued from the study due to an asthma exacerbation. In addition to the serious clinical adverse reported, one patient in the montelukast group had a serious laboratory adverse experience (hypokalemia) that was not considered drug related. In the open-label extension studies, the most commonly reported serious clinical adverse experience, regardless ofcausality,wasworseningasthma,occurringin26of 729 patients treated with montelukast (3.6%) and 9 of 227 patients treated with usual care (4.0%). Other than the one serious adverse experience of suicide ideation (described above), there were no suicidality-related adverse (completed suicide, suicide attempts, suicide ideation) reported by investigators in the open-label extension studies. Discontinuations due to Experiences Short-Term Double-Blind Studies In children 6 24 months of age, three patients in each treatment group discontinued due to a clinical adverse experience (Table 5). 12 Patients in the montelukast group discontinued due to rash, vomiting, or worsening asthma;

9 TABLE 5 Number (%) of Patients Who Discontinued From the Study Due to an Experience in Double-Blind and Open-Label Pediatric Studies Short-term double-blind studies 6 24 months old, persistent asthma (6 weeks) 2 5 years old, persistent asthma (12 weeks) 6 11 years old, persistent asthma knemometry (10 weeks) 6 14 years old, persistent asthma (8 weeks) 2 14 years old, allergic rhinitis (2 weeks) experience (N ¼ 175) (N ¼ 81) (N ¼ 461) (N ¼ 228) (N ¼ 35) (N ¼ 37) BUD (N ¼ 33) (N ¼ 33) (N ¼ 201) (N ¼ 135) (N ¼ 280) (N ¼ 133) Clinical 3/175 (1.7) 3/81 (3.7) 16/461 (3.5) 7/228 (3.1) 0/35 (0.0) 1/37 (2.7) 1/33 (3.0) 1/33 (3.0) 8/201 (4.0) 3/135 (2.2) 5/280 (1.8) 1/133 (0.8) Laboratory 0/170 (0.0) 0/79 (0.0) 0/451 (0.0) 1/224 (0.4) 0/35 (0.0) 0/37 (0.0) 0/33 (0.0) 0/33 (0.0) 2/200 (1.0) 0/135 (0.0) 0/272 (0.0) 0/129 (0.0) Long-term double-blind studies 2 5 years old, intermittent asthma PREVIA (12 months) 6 9 years old, persistent asthma linear growth (56 weeks) experience (N ¼ 278) (N ¼ 271) (N ¼ 120) BEC (N ¼ 119) (N ¼ 121) Clinical 1/278 1 (0.4) 10/271 (3.7) 0/120 (0.0) 0/119 (0.0) 0/121 (0.0) Laboratory 0/261 (0.0) 0/251 (0.0) 0/116 (0.0) 0/117 (0.0) 0/117 (0.0) Long-term open-label studies 6 24 months old, persistent asthma (1.2 years) 2 5 years old, persistent asthma (2.8 years) 6 14 years old, persistent asthma (2.8 years) experience (N ¼ 158) Usual care (N ¼ 32) (N ¼ 364) Usual care (N ¼ 157) (N ¼ 207) ICS (N ¼ 38) Clinical 6/158 (3.8) 0/32 (0.0) 18/364 (4.9) 5/157 (3.2) 13/207 (6.3) 0/38 (0.0) Laboratory 0/155 (0.0) 0/31 (0.0) 4/357 (1.1) 0/154 (0.0) 5/207 (2.4) 0/37 (0.0) BEC, beclomethasone; BUD, budesonide; ICS, inhaled corticosteroids;, montelukast. 1 Fisher s exact test (P ¼ 0.005).

10 Safety of Montelukast in Pediatric Studies 577 patients in the placebo group discontinued due to bronchitis, lethargy, or sleep disorder. All events resolved after discontinuation. There were no discontinuations attributed to laboratory adverse in either group. In children 2 5 years of age, 23 patients (16 in the montelukast group and 7 in the placebo group) were discontinued from treatment because of a clinical adverse experience (Table 5). Worsening asthma was the most common adverse experience that resulted in discontinuation of study therapy. 1 One patient in the placebo group discontinued therapy because of a laboratory adverse experience (increased alkaline phosphatase at 6 weeks, which was elevated for this patient at baseline and at 2 weeks after discontinuation as well). Three children in the knemometry study were discontinued from treatment because of a clinical adverse experience (worsening asthma in each case) 13 : one while receiving placebo in the montelukast/placebo arm; one while receiving budesonide; and one while receiving placebo in the budesonide/placebo arm. In 6- to 14-year-old children, eight patients in the montelukast group and three in the placebo group discontinued due to a clinical adverse experience (Table 5). Worsening asthma (five patients in the montelukast group and two patients in the placebo group) was the most common adverse experience that resulted in discontinuation of study therapy. 5,14 Two patients in the montelukast group discontinued therapy due to a laboratory adverse experience: one for increased ALT and one for decreased neutrophils. Both conditions were present at randomization. In 2- to 14-year-old children with allergic rhinitis, five patients (1.8%) treated with montelukast and one patient treated with placebo (0.8%) discontinued due to an adverse experience (Table 5). Two of these discontinuations (one in each treatment group) were due to worsening asthma; others included upper respiratory infection, viral infection, otitis media, and ophthalmic infection. Discontinuations due to Experiences Long-Term Double-Blind Studies In the PREVIA study, 11 patients (1 in the montelukast treatment group [0.4%] and 10 in the placebo group [3.7%]) discontinued treatment due to a clinical adverse experience (P ¼ 0.005) (Table 5). 6 Discontinuation in the montelukast group was due to epilepsy. Discontinuations in the placebo group were due to respiratory tract infection, worsening asthma, pneumonia, decreased peak expiratory flow, cough, abdominal pain, mood swings, abnormal behavior, petecchiae, and hypersensitivity (allergic reaction). There were no discontinuations due to laboratory adverse in the PREVIA study. There were no discontinuations from the study due to adverse in the linear growth study, 17 although one patient in the montelukast group (epilepsy), two in the beclomethasone group (worsening asthma, wheezing), and two in the placebo group (hematuria, worsening asthma) discontinued from blinded study therapy following an adverse clinical experience. All five patients initially remained in the study after discontinuation from blinded study therapy; however, one patient in the beclomethasone group withdrew consent and discontinued approximately 2 weeks later. There were no discontinuations from the study or blinded study therapy due to laboratory adverse in any of the groups in the linear growth study (Table 5). Discontinuations due to Experiences Open-Label Extension Studies In 6- to 24-month-old patients with persistent asthma, six patients (all in the montelukast group) discontinued treatment due to worsening asthma, sinusitis, seizure, or a sleep disorder (trouble staying asleep) (Table 5). The patient with the sleep disorder had two episodes of otitis media concurrent with the sleep disorder. All patients recovered after discontinuation of therapy. There were no discontinuations due to clinical adverse in the usual care group, and there were no discontinuations due to laboratory adverse in either treatment group (Table 5). In 2- to 5-year-old patients with persistent asthma, 23 patients discontinued study drug due to a clinical adverse experience, including 18 in the montelukast group (4.9%) and 5 in the usual care group (3.2%) (Table 5). Worsening asthma was the most frequent clinical adverse experience resulting in discontinuation in both groups. Four patients, all in the montelukast group, discontinued study drug due to a laboratory adverse experience (decreased leukocytes, decreased hemoglobin, increased AST, and increased alkaline phosphatase). In 6- to 14-year-old patients with persistent asthma, 13 patients treated with montelukast (6.3%) discontinued study therapy because of a clinical adverse experience and 5 patients discontinued due to a laboratory adverse experience (2.4%); there were no discontinuations because of an adverse experience in the usual care group (Table 5). Worsening asthma was the most frequent clinical adverse experience resulting in discontinuation (three patients). Reasons for discontinuations due to a laboratory adverse experience included increased AST, increased ALT, decreased neutrophils, and increased total serum bilirubin. Serum Transaminase Values There were no significant differences in the incidence of serum transaminase values exceeding the predefined

11 578 Bisgaard et al. limits of change within all double-blind and open-label studies that included laboratory testing after initiation of treatment (Table 6). 1,12,13 Laboratory tests were not routinely performed after baseline measurements were performed in the PREVIA and knemometry studies. DISCUSSION This article summarizes safety data from seven placebo-controlled, double-blind and three active-controlled, open-label extension studies in 2,751 children 6 months to 14 years of age. The studies included children of different age groups and included patients with viral-induced intermittent asthma, persistent asthma, and seasonal allergic rhinitis. Our review shows that oral montelukast is generally well tolerated, with a safety profile similar to that observed for placebo or usual care therapies. These results are in line with those reported in several pediatric studies of montelukast. 2 4,7,10,11,16 There were few notable differences for individual adverse between treatments in any of the studies described. The most common clinical adverse were upper respiratory infection, worsening asthma, pharyngitis, and fever, reported for all treatments (placebo, usual care, montelukast) and in virtually all studies. Of the five most commonly reported adverse reported within each of these 10 studies, there were seldom any differences in their incidence between treatment groups. In open-label studies, cough was reported notably more frequently in the montelukast group than in the usual care treatment group in 2- to 5-year-old patients; however, cough resolved while patients continued in the study, suggesting this adverse experience presented no clinically important safety concerns. Overall, there were no clinically meaningful differences between treatments in laboratory safety parameters in any of the present studies, and analysis of predefined limits of change for selected parameters showed no tolerability concerns with montelukast therapy. Serum transaminase values that fell outside the predefined limit of change occurred at a low frequency in all groups and were of similar magnitude between/ among treatments. Examination of laboratory adverse TABLE 6 Incidence of Serum Transaminase Levels Outside Predefined Limits of Change 1 in Double-Blind and Open-Label Pediatric Studies 2 Short-term double-blind studies 6 24 months old, persistent asthma (6 weeks) 2 5 years old, persistent asthma (12 weeks) 6 14 years old, persistent asthma (8 weeks) 2 14 years old, allergic rhinitis (2 weeks) Enzyme (N ¼ 175) (N ¼ 81) (N ¼ 461) (N ¼ 228) (N ¼ 201) (N ¼ 135) (N ¼ 280) (N ¼ 133) Alanine aminotransferase 6/164 (3.7) 1/75 (1.3) 1/445 (0.2) 2/223 (0.9) 5/200 (2.5) 1/135 (0.7) 2/271 (0.7) 2/127 (1.6) Aspartate aminotransferase 3/165 (1.8) 1/75 (1.3) 1/447 (0.2) 2/223 (0.9) 3/200 (1.5) 1/135 (0.7) 3/271 (1.1) 0/127 (0.0) Long-term double-blind studies 6 9 years old, persistent asthma linear growth (56 weeks) Enzyme (N ¼ 120) BEC (N ¼ 119) (N ¼ 121) Alanine aminotransferase 1/115 (0.9) 3/115 (2.6) 5/112 (4.5) Aspartate aminotransferase 0/115 (0.0) 0/115 (0.0) 4/112 (3.6) Long-term open-label studies 6 24 months old, persistent asthma (1.2 years) 2 5 years old, persistent asthma (2.8 years) 6 14 years old, persistent asthma (2.8 years) Enzyme (N ¼ 158) Usual care (N ¼ 32) (N ¼ 364) Usual care (N ¼ 157) (N ¼ 207) ICS (N ¼ 38) Alanine aminotransferase 4/153 (2.6) 3/31 (9.7) 9/354 (2.5) 6/153 (3.9) 15/207 (7.2) 6/37 (16.2) Aspartate aminotransferase 0/150 (0.0) 2/31 (6.5) 7/355 (2.0) 8/153 (5.2) 10/207 (4.8) 4/37 (10.8) n/m, number of patients who met criteria/total number of patients with valid measurements; BEC, beclomethasone; ICS, inhaled corticosteroids;, montelukast. 1 Predefined limit of change ¼ increase from baseline 100% and greater than the upper limit of normal. 2 No protocol-specified laboratory safety tests were required after randomization for the PREVIA and knemometry studies; therefore, no analyses of predefined limits of change were performed.

12 Safety of Montelukast in Pediatric Studies 579 experience data from adult and pediatric patients in an earlier report 5 found no important differences between treatments (i.e., montelukast vs. placebo or montelukast vs. inhaled beclomethasone) in the frequency of serum transaminase values greater than the upper limit of normal. The results of safety assessments from these seven double-blind and three open-label extension studies demonstrated that montelukast was well tolerated in patients 6 months to 14 years of age with persistent asthma; viral-induced intermittent asthma; or allergic rhinitis, with treatments extending for up to 34 months. Clinical and laboratory adverse for patients treated with montelukast occurred at frequencies similar to those for comparator therapies. The clinical and laboratory safety profiles for montelukast in these studies were similar to those observed for placebo or usual care therapies. The data from these studies are in agreement with previously reported safety data and highlight the positive safety profile of montelukast in children. Moreover, these results should provide useful information to physicians treating pediatric patients with asthma and allergic rhinitis. ACKNOWLEDGMENTS We thank S.B. Dass PhD for critically reviewing the manuscript. REFERENCES 1. Knorr B, Franchi LM, Bisgaard H, Vermeulen JH, LeSouef P, Santanello N, Michele TM, Reiss TF, Nguyen HH, Bratton DL. Montelukast, a leukotriene receptor antagonist, for the treatment of persistent asthma in children aged 2 to 5 years. Pediatrics 2001;108:E Nayak A, Langdon RB. Montelukast in the treatment of allergic rhinitis: an evidence-based review. Drugs 2007;67: Bjermer L. Montelukast in the treatment of asthma as a systemic disease. Expert Rev Clin Immunol 2005;1: Storms W. Update on montelukast and its role in the treatment of asthma, allergic rhinitis and exercise-induced bronchoconstriction. Expert Opin Pharmacother 2007;8: Storms W, Michele TM, Knorr B, Noonan G, Shapiro G, Zhang J, Shingo S, Reiss TF. Clinical safety and tolerability of montelukast, a leukotriene receptor antagonist, in controlled clinical trials in patients aged 6 years. Clin Exp Allergy 2001;31: Bisgaard H, Garcia MLG, Zielen S, Johnston S, Gilles L, Menten J, Tozzi CA, Polos P. Montelukast reduces viral induced asthma exacerbations in 2 to 5 year old children with intermittent asthma. Am J Respir Crit Care Med 2005;171: Reiss TF, Knorr B, Malmstrom K, Noonan G, Lu S. Clinical efficacy of montelukast in adults and children. Clin Exp Allergy Rev 2001;1: Jarvis B, Markham A. Montelukast: a review of its therapeutic potential in persistent asthma. Drugs 2000;59: Pearlman DS, van Adelsberg J, Philip G, Tilles SA, Busse W, Hendeles L, Loeys T, Dass SB, Reiss TF. Onset and duration of protection against exercise-induced bronchoconstriction by a single oral dose of montelukast. Ann Allergy Asthma Immunol 2006;97: Kemp JP, Dockhorn RJ, Shapiro GG, Nguyen HH, Reiss TF, Seidenberg BC, Knorr B. Montelukast once daily inhibits exercise-induced bronchoconstriction in 6- to 14-year-old children with asthma. J Pediatr 1998;133: Bisgaard H, for the Study Group on Montelukast and Respiratory Syncytial Virus. A randomized trial of montelukast in respiratory syncytial virus postbronchiolitis. Am J Respir Crit Care Med 2003; 167: van Adelsberg J, Moy J, Wei LX, Tozzi CA, Knorr B, Reiss T. Safety, tolerability, and exploratory efficacy of montelukast in 6 to 24 month old patients with asthma. Curr Med Res Opin 2005;21: Pedersen S, Agertoft L, Williams-Herman D, Kuznetsova O, Reiss TF, Knorr B, Dass SB, Wolthers OD. -controlled study of montelukast and budesonide on short-term growth in prepubertal asthmatic children. Pediatr Pulmonol 2007;42: Knorr B, Matz J, Bernstein JA, Nguyen H, Seidenberg BC, Reiss TF, Becker A, for the Pediatric Montelukast Study Group. Montelukast for chronic asthma in 6- to 14-year-old children: a randomized double-blind trial. J Am Med Assoc 1998;279: Davies GM, Dasbach EJ, Santanello NC, Knorr BA, Bratton DL. The effect of montelukast versus usual care on health care utilization in children aged 2 to 5 years with asthma. Clin Ther 2004;26: Luz Garcia Garcia M, Wahn U, Gilles L, Swern A, Tozzi CA, Polos P. Montelukast, compared with fluticasone, for control of asthma among 6- to 14-year-old patients with mild asthma: the MOSAIC study. Pediatrics 2005;116: Becker AB, Kuznetsova O, Vermeulen J, Soto-Quiros ME, Young B, Reiss TF, Dass SB, Knorr BA, for the Montelukast Linear Growth Study Group. Linear growth in prepubertal asthmatic children treated with montelukast, beclomethasone, or placebo: a 56-week randomized double-blind study. Ann Allergy Asthma Immunol 2006;96: Center for Drug Evaluation and Research and Center for Biologics Evaluation and Research. Guidance for Industry E6- Good Clinical Practice: Consolidated Guidance. Rockville, Maryland, USA: Department of Health and Human Services Food and Drug Administration; pp gov/cder/guidance/index.htm.