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Safety and tolerability of montelukast in placebo-controlled pediatric studies and their open-label extensions

Pediatric Pulmonology 44:568–579 (2009) Safety and Tolerability of Montelukast in Hans Bisgaard, MD, DMSci,1* David Skoner, MD,2 Maria L. Boza, MD,3 Carol A. Tozzi, PhD,4 MD,4 Barbara Knorr, MD,4 and Gertrude Noonan, BA Summary. Background: Montelukast is a potent leukotriene-receptor antagonist administeredonce daily that provides clinical benefit in the treatment of asthma and allergic rhinitis in childrenand adults. Because of its wide use as a pediatric controller, there is a need for a further review ofthe safety and tolerability of montelukast in children. Objective: To summarize safety and tolerabilitydata for montelukast from previously reported as well as from unpublished placebo-controlled,double-blind, pediatric studies and their active-controlled open-label extension/extended studies.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 withpersistent asthma, intermittent asthma associated with upper respiratory infection, or allergicrhinitis. These patients were enrolled in seven randomized, placebo-controlled, double-blindregistration and post-registration studies and three active-controlled open-label extension/extended studies conducted by Merck Research Laboratories between 1995 and 2004. Results:Montelukast was well tolerated in all studies. Clinical and laboratory adverse experiences forpatients treated with montelukast were generally mild and transient. The most frequent clinicaladverse events for all treatments (placebo, montelukast, active control/usual care) in virtually allstudies 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 oractive control/usual care therapies. The safety profile of montelukast did not change with long-termuse. Pediatr Pulmonol. 2009; 44:568–579.
Key words: asthma; leukotriene-receptor antagonist.
(referred to as extension studies) are summarized inthis review. This manuscript is not intended to be a Asthma is the most common chronic disease of comprehensive review of safety data from all studies of childhood. Some asthma therapies that are effective in adolescents or school-age children may not be appropriatein younger children because of a narrow therapeutic indexor because of the difficulties in assessing new therapies inthis age group.1 Montelukast is a cysteinyl leukotriene- 1Danish Pediatric Asthma Center, Copenhagen University Hospital, receptor 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 Drexel University, Philadelphia, PA & Allegheny General Hospital, allergic rhinitis in the United States and for asthma inEurope).1–4 3University of Chile, Santiago, Chile.
Efficacy and outcome data on montelukast from several pediatric studies have been published,1–17 including an 4Merck Research Laboratories, Merck & Co., Inc., Rahway, New Jersey.
earlier review of safety data from 1 pediatric and 10 adult *Correspondence to: Prof. Hans Bisgaard, Danish Pediatric Asthma Center, studies.5 This manuscript is one of a series of manuscripts Copenhagen University Hospital, Niels Andersensvej 65, DK-2900 planned on the safety of montelukast. The purpose of Gentofte, Copenhagen, Denmark. E-mail: bisgaard@copsac.dk this manuscript is to review the safety results (particularly,the most common adverse experiences) from seven Received 10 February 2008; Revised 2 October 2008; Accepted 1 December registration and post-registration, placebo-controlled, double-blind studies of montelukast in asthma or allergic rhinitis. In addition, safety results from three active- Published online 14 May 2009 in Wiley InterScience control, open-label extensions or extended studies Safety of Montelukast in Pediatric Studies Patients were 2,751 children 6 months to 14 years of age Safety and efficacy data from four multicenter, short- in five short-term and two long-term multicenter, term placebo-controlled, double-blind studies in children randomized, double-blind, placebo-controlled studies with asthma have been previously published.1,5,12–14 and from open-label, active-controlled extensions to three Briefly, one double-blind study (referred to as the 6- to of these studies. These studies were conducted by Merck 24-month-old study) enrolled 256 children 6–24 months Research Laboratories between 1995 and 2004 to evaluate of age with persistent asthma for evaluations of safety and efficacy, safety, and/or tolerability of montelukast com- tolerability and exploratory efficacy of montelukast (4-mg pared with placebo or usual care (defined as inhaled/ oral granules) compared with matching-image placebo nebulized cromolyn or nedocromil or inhaled/nebulized given once daily for 6 weeks (Table 1).12 corticosteroids [ICS], according to the practitioner’s usual The second double-blind study (referred to as the 2- to practice) in patients with asthma or allergic rhinitis 5-year-old study) enrolled 689 children 2–5 years of age without clinically significant comorbidities (Table 1).
with persistent asthma for evaluations of safety with Short-acting b-agonists could be used as needed for exploratory efficacy end points for montelukast (4-mg chewable tablet) or matching-image placebo given once All protocols were approved by the appropriate review boards at each site, and the studies were conducted in The third short-term double-blind study (referred to as the conformance with applicable country or local require- knemometry study) was a two-active treatment period, ments regarding ethical committee review, informed parallel two-arm, 2 Â 2 crossover study that enrolled consent, and patient rights and welfare. Informed consent 71 patients 6–11 years of age with persistent asthma for was obtained from each patient’s representative prior to evaluation of the effect of montelukast (5-mg chewable the studies, and each patient 6 years of age or older tablet once daily) on short-term lower leg growth rate provided written informed assent before any study (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 AllergicRhinitis Study 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. Patientnumbers 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 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.
periods, including a 1-week, single-blind, placebo run-in sions or an extended safety study in which patients who period; two 3-week, double-blind active treatment periods; completed the double-blind period could participate and and a 3-week single-blind, wash-out period between the two receive either montelukast or usual care. Usual care in these studies was ICS or inhaled/nebulized cromolyn or The fourth short-term double-blind study (referred nedocromil.1,5,12,14 For two of the three extension studies, to as the 6- to 14-year-old study) enrolled 336 patients patients entered their respective open-label extension 6–14 years of age with persistent asthma for evaluations study directly from the double-blind study, without a of asthma control and safety of montelukast (5-mg washout or run-in period. Patients already using con- chewable tablet) or a matching-image placebo given once comitant ICS or inhaled/nebulized cromolyn or nedocro- mil during the double-blind studies were allowed to The fifth short-term double-blind study (referred to as continue their use, and the dose was not modified if they the allergic rhinitis study) was a multicenter (31 sites in were allocated to the usual care group in the open-label the United States), randomized, double-blind, placebo- extension study. For other patients allocated to usual care, controlled study conducted over a 2-week period during once therapy was initiated, the dose was maintained spring pollen season in 413 children 2–14 years of throughout the study. In the third extension study (in age with seasonal allergic rhinitis. The safety profile patients 6–31 months of age), dosage adjustment of ICS or of montelukast, along with exploratory evaluations of inhaled/nebulized cromolyn or nedocromil was allowed allergic rhinitis efficacy end points and validation of measurement characteristics of new allergic rhinitis The first study was an open-label extended safety study symptom scales, was assessed in this study (Table 1).
that enrolled 190 patients 6–31 months of age with Patients enrolled in the study demonstrated a positive skin asthma, including 113 who had completed the 6- to test (wheal diameter at least 3 mm greater than saline 24-month-old study12 plus 77 new patients 6–11 months control to one of the allergens active during the study of age (Table 1). This 52-week randomized extension season) and a Daytime Rhinitis Symptom Score >2 study compared safety and tolerability of montelukast 4- each day during the 3- to 5-day placebo run-in period.
mg oral granules with usual care. Of the 158 patients Patients 2–5 years of age received a 4-mg chewable tablet allocated to treatment with montelukast in this study, of montelukast or matching-image placebo, and patients 62 had previously received montelukast in the double- 6–14 years of age received a 5-mg chewable tablet or blind study, 32 had previously received placebo, and 64 patients were newly allocated to montelukast. Of the32 patients in the usual care group, 10 had previously received montelukast in the double-blind study, 9 hadpreviously received placebo, and 13 patients were newly Safety data from two multicenter, long-term double-blind studies in children with asthma have been previously The second study was an open-label extension study reported.6,17 The PREvention of Viral Induced Asthma that enrolled 521 patients with persistent asthma who had (PREVIA) study enrolled 549 children 2–5 years of age with completed the 2- to 5-year-old study (Table 1)1; outcome intermittent asthma to evaluate montelukast (4- or 5-mg data from this study have been reported.15 Patients chewable tablet [depending on age]) or placebo in the preven- allocated to montelukast received a 4-mg chewable tablet tion of asthma exacerbations over 12 months (Table 1).6 once daily at bedtime; patients were switched to the 5-mg The second long-term double-blind study (referred to as chewable tablet at the first visit after turning 6 years old. Of the linear growth study) enrolled 360 children 6–9 years the 364 patients allocated to treatment with montelukast in of age to evaluate the effect of montelukast (5-mg this study, 239 had previously received montelukast in the chewable tablet), inhaled beclomethasone (200 mg twice double-blind study and 125 had received placebo. Of the daily), or matching-image placebo on linear growth in 157 patients in the usual care group, 113 had previously prepubertal children over 56 weeks (Table 1). Unique to received montelukast and 44 had received placebo in the this study, patients who were discontinued from blinded study drug for reasons other than withdrawal of consent or The third study was an open-label extension that lost to follow-up were allowed to continue in the study on enrolled 245 patients who had completed the 6- to 14- investigator-prescribed asthma treatment. This design year-old study.5,14 Preliminary safety data (duration allowed for the continued collection of height data after of exposure 1.8 years) from this open-label extension study have been reported.5 The present analysis includesfinal safety and tolerability data collected for up to 2.8 years (Table 1). Patients allocated to montelukast Three of the five short-term double-blind studies in this extension study received a 5-mg chewable tablet described above had active-controlled open-label exten- once daily at bedtime; patients were switched to a 10-mg Safety of Montelukast in Pediatric Studies film-coated tablet at the first visit after turning 15 years old. Of the 207 patients allocated to treatment with Frequencies of individual adverse experiences (clinical montelukast in this study, 137 had previously received and laboratory) were summarized by treatment group montelukast in the double-blind study and 70 had received within study. Ninety-five percent confidence intervals placebo. Of the 38 patients in the usual care group, 10 had (CIs) were computed for pairwise differences in nine previously received montelukast and 28 had received studies; in one study, Fisher’s exact test was used to screen for significant differences between treatment groups.
Summary statistics were computed for montelukast andusual care treatment groups in all open-label studies.
For all patients, safety evaluations were performed at Percentages of patients with values outside the predefined the time of entry into the study, at visits during the study, limits of change for selected laboratory safety tests were and at the last scheduled visit or at the time of dis- analyzed similarly. Summary statistics for laboratory continuation. Reports of study drug overdosage were safety parameters were calculated. All patients who received at least one dose of study drug were included in Adverse experiences were monitored and reported by investigators according to international regulatory guide- In these studies, 95% CIs, or a significant Fisher’s exact lines.18 The incidences of clinical and laboratory adverse test, were used as a screening tool to identify potential experiences were summarized and compared between differences between treatment groups in the incidence of adverse experiences; this analysis was, therefore, a ‘‘data- An adverse experience was defined as any unfavorable driven’’ post hoc exercise. The term ‘‘notable difference’’ and unintended change in the structure, function, or was used when the 95% CI did not contain zero or the chemistry of the body temporally associated with the use Fisher’s exact test had a P-value 0.05. This rule was of any study drug or placebo, whether or not considered applied before rounding of the limits of the 95% CI. As a related to the use of the drug or placebo. Any worsening consequence, the upper or lower limit of a 95% CI that (i.e., any clinically significant adverse change in frequency defines a ‘‘notable difference’’ might be reported as 0.0 and/or intensity) of a pre-existing condition temporally after rounding. The findings should be interpreted with associated with the use of a study drug or placebo (including care because approximately 5% of these CIs will not asthma) also was an adverse experience.
contain zero by chance alone, even when there is no The investigator judged the seriousness (from a treatment difference in occurrence of adverse experiences.
regulatory perspective) of the event and reported itsintensity, whether the event resulted in discontinuation of therapy, and its relationship to the drug.18 An adverseexperience was considered serious, from a regulatory perspective, if it resulted in death, was life threatening, A total of 2,751 pediatric patients participated in the resulted in or prolonged an existing inpatient hospital- 10 clinical studies. In the seven double-blind studies, ization, resulted in a persistent or significant disability/ 1,550 patients were treated with montelukast, 1,039 were incapacity, or was a congenital anomaly/birth defect (in treated with placebo, and 152 were treated with ICS offspring of subjects taking study drug). Intensity of an (counting patients in each treatment that were crossed over adverse experience was rated as mild (awareness of sign or in the knemometry study). In the three open-label studies, symptom but easily tolerated), moderate (discomfort that 729 patients were treated with montelukast and 227 were caused interference in activity), or severe (incapacitating).
treated with usual care therapies. Distribution of patients The five possible ratings for assessing relationship of by study, treatment, and gender is shown in Table 1.
the drug to the event were as follows: definitely not,probably not, possibly, probably, or definitely related to Standard laboratory tests included hematology and blood chemistry parameters. Predefined limits of change In children 6–24 months of age, 69% of the 158 patients from baseline were established for certain laboratory in the montelukast treatment group were treated with parameters, including alanine aminotransferase (ALT) montelukast for at least 9 months, 27% for at least and aspartate aminotransferase (AST). Normal laboratory 12 months, and the longest duration of montelukast ranges for these chemistry parameters, based on the treatment was 1.2 years. For children 2–5 years of age, patient’s age at randomization, were used for the analysis.
75% of the 364 patients were treated with montelukast for The number of patients exceeding predefined limits of more than 1 year, and the longest duration of montelukast change at least once during the study was determined and treatment was 2.8 years. In children 6–14 years of age, 50% of the 207 patients received montelukast for 18 months or longer, and the longest duration of montelukast treatment was 2.8 years.
Clinical Adverse Experiences—Short-Term The five most common adverse experiences reported in the montelukast group within each of the short-term double- blind studies are shown in Table 2a. In these studies, the most frequent clinical adverse experiences included upper respiratory infection, worsening asthma, and fever.
Among the five most frequently reported clinical adverse experiences 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 experiences, 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 experiences were reported in seven patients in themontelukast 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 (over- dose of 8 mg due to caregiver error) with no associated adverse experiences; 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 experiences 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 experiences of study drug overdose fully recovered. As previously reported, three of the four patients had adverse experiences associated with overdoses of montelukast. Serious drug-related adverse experiences 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 In the knemometry study, there were no clinically important differences between treatments in the incidence of clinical adverse experiences. Clinical adverse experi- ences were reported for three patients treated with montelukast (8.6%); none was considered serious (Table 2a).13 Clinical adverse experiences reported for two patients treated with placebo (oral candidiasis and worsening asthma) and one patient treated with budeso- nide (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 experiences Safety of Montelukast in Pediatric Studies TABLE 2b— Adverse Experiences With Notable Differences Not Reported in Table of Common Adverse Experiences inShort-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) MNT, montelukast.
1 Estimated difference between montelukast and placebo (95% CI): À3.7% (À10.3, À0.5).
2 Fisher’s exact test (P ¼ 0.010).
3 Estimated difference between montelukast and placebo (95% CI): À2.3% (À6.4, À0.2).
in 6- to 14-year-old patients (Table 2a).5,14 Although it was and 5 of 647 patients treated with placebo (0.8%).
not among the five most common clinical adverse No suicidality-related adverse experiences (completed experiences, allergic rhinitis occurred notably more suicide, suicide attempts, suicide ideation) were reported frequently in the placebo group (3.7%) than in the by investigators in the short-term double-blind studies.
montelukast group (0.0%; P ¼ 0.01) (Table 2b). Serious clinical adverse experiences were reported for four patients in the montelukast group (2.0%); none wasconsidered drug related. There were no serious clinical The five most common adverse experiences reported in adverse experiences reported in the placebo group.
the montelukast group within each of the long-term Among the five most frequently reported clinical double-blind studies are shown in Table 3a. The most adverse experiences in the allergic rhinitis study, no frequent clinical adverse experiences in patients treated clinically meaningful differences were observed between with montelukast were upper respiratory infection, the montelukast and placebo groups (Table 2a). Although it was not among the five most common clinical No clinically meaningful differences were observed adverse experiences, sunburn was reported notably more between montelukast and placebo groups in the frequency frequently in the placebo group (2.3%) than in the of the five most common clinical adverse experiences in montelukast group (0.0%) (Table 2b). One serious the PREVIA study (Table 3a).6 Although not among the clinical adverse experience occurred in the study in the five most common clinical adverse experiences, notable montelukast group; it was not considered drug related.
differences were detected for purulent rhinitis (montelu- In the short-term double-blind studies, the most kast 0.7% vs. placebo 3.7%); dyspnea (montelukast 0.4% commonly reported serious clinical adverse experience, vs. placebo 2.6%); and urticaria (montelukast 4.0% vs.
regardless of causality, was worsening asthma, occurring placebo 1.1%) (Table 3b). Serious clinical adverse ex- in 15 of 1,152 patients treated with montelukast (1.3%) periences were reported in 24 patients in the montelukast TABLE 3a— Common Adverse Experiences1 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) BEC, beclomethasone; MNT, montelukast; URI, Upper respiratory infection.
1 The five most frequent adverse experiences reported in the montelukast group, listed, in descending order for each study.
2 Number (%) of children who reported one or more adverse experiences during the study regardless of causality.
3 Estimated difference between montelukast and placebo (95% CI): À13.7% (À25.7, À1.2).
TABLE 3b— Adverse Experiences With Notable Differences related. Overdoses of study drug were reported in one Not Reported in Table of Common Adverse Experiences in patient in each treatment group (montelukast—10 mg; Long-Term Double-Blind Studies in Children 2–14 Years of 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 suicide, suicide attempts, suicide ideation) were reported by investigators in the long-term double-blind studies.
1 No additional notable differences were reported in the linear growthstudy.
Clinical Adverse Experiences—Open-Label Estimated difference between montelukast and placebo (95% CI):À3.0% (À6.0, À0.5).
3 Estimated difference between montelukast and placebo (95% CI): The overall incidence of clinical adverse experiences in 4 Estimated difference between montelukast and placebo (95% CI): the open-label studies was similar between montelukast and usual care groups and generally reflected what wasobserved in double-blind studies in terms of experiences group (8.6%) and 34 patients in the placebo group reported and their relative frequency (Table 4a). Upper (12.5%). One patient in each treatment group had serious respiratory infection, worsening asthma, and pharyngitis clinical adverse experiences that were considered drug were the most consistently reported clinical adverse related. One patient had an accidental drug overdose of montelukast (overdose of 72 mg) with spontaneous The five most common clinical adverse experiences in vomiting; the patient fully recovered. One patient in the 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 adverse experiences in patients in the linear growth these adverse experiences was similar between the two study, worsening asthma was reported notably more treatment groups (Table 4a). Although not among the five frequently in the placebo group (50.4%) than in the most common adverse experiences, there was a notably montelukast group (36.7%) (Table 3a).17 Serious clinical higher incidence of viral infection in patients 6–24 months adverse experiences were reported for seven patients in of age treated with usual care (28.1%) than in those treated the montelukast group (5.8%), five patients in the with montelukast (10.8%) (Table 4b). The usual care beclomethasone group (4.2%), and five patients in the group also had a notably higher incidence of otitis and placebo group (4.1%). None was considered drug contact dermatitis than did the montelukast group; TABLE 4a— Common Adverse Experiences1 Reported in Long-Term Open-Label Studies in Children 6 Months to 14 Yearsof Age ICS, inhaled corticosteroids; MNT, montelukast.
1 The five most frequent adverse experiences reported in the montelukast group, listed in descending order for each study.
2 Number (%) of children who reported one or more adverse experiences during the study regardless of causality.
3 Notable difference: estimated difference between montelukast and usual care (95% CI): 11.3% (3.62, 18.12).
Safety of Montelukast in Pediatric Studies TABLE 4b— Adverse Experiences With Notable Differences Not Reported in Table of Common Adverse Experiences inLong-Term Open-Label Studies in Children 6 Months to 14 Years of Age1 6–24 months old, persistent asthma ( 1.2 years) 2–5 years old, persistent asthma ( 2.8 years) MNT, 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): À17.4% (À35.1, À3.5).
3 Estimated difference between montelukast and usual care (95% CI): À8.7% (À23.6, À2.0).
4 Estimated difference between montelukast and usual care (95% CI): À5.6% (À19.5, À0.3).
5 Estimated difference between montelukast and usual care (95% CI): À8.3% (À16.29, À0.97).
6 Estimated difference between montelukast and usual care (95% CI): À5.2% (À11.01, À0.64).
however, the actual incidence of these adverse experiences worsening asthma, headache, pharyngitis, and sinusitis.
was small in both treatment groups (Table 4b). Serious The incidence of individual adverse experiences was clinical adverse experiences were reported in 15 patients similar between the two treatment groups in this study in the montelukast group (9.5%) and 1 patient in the usual (Table 4a). Serious clinical adverse experiences were care group (3.1%). None of the adverse experiences was reported in 16 patients in the montelukast group (7.7%) and 1 patient in the ICS group (2.6%). None was considered Worsening asthma, upper respiratory infection, fever, to be drug related. Of note, a 12-year-old patient with a pharyngitis, and cough were common adverse experiences history of attention deficit disorder and depression was in children 2–5 years of age enrolled in the open-label hospitalized for depression and suicidal ideation while extension study (Table 4a). The incidence of cough in the receiving open-label montelukast ($1.8 years). Therapy montelukast group (26.6%) was notably higher than in the with montelukast was interrupted and treatment with usual care group (15.3%). In both groups, cough lasted a buproprion 75 mg BID was initiated. After recovery from median of 5 days and resolved while patients continued the depression and suicidal ideation, the patient was study therapy. Although not among the five most common discharged from the hospital and therapy with montelukast adverse experiences, there was a notably higher incidence was resumed. The depression and suicidal ideation were not of bronchitis in the usual care group (24.2%) than in the considered to be drug related. The patient was later montelukast group (15.9%), and sinus disorder was discontinued from the study due to an asthma exacerbation.
reported notably more frequently in the usual care group In addition to the serious clinical adverse experiences (9.6%) than in the montelukast group (4.4%) (Table 4b).
reported, one patient in the montelukast group had a Serious clinical adverse experiences were reported for 38 serious laboratory adverse experience (hypokalemia) that patients in the montelukast group (10.4%) and 15 patients in the usual care group (9.6%), including nine patients In the open-label extension studies, the most commonly who had drug overdoses of montelukast (overdoses of reported serious clinical adverse experience, regardless 5–92 mg). Four patients in the montelukast group had of causality, was worsening asthma, occurring in 26 of drug-related serious clinical adverse experiences (all were 729 patients treated with montelukast (3.6%) and 9 of overdoses of study drug or adverse experiences associated 227 patients treated with usual care (4.0%). Other than the with the overdose). The following serious clinical adverse one serious adverse experience of suicide ideation (described experiences were considered drug related: study drug above), there were no suicidality-related adverse experiences overdose (four patients), hypersomnia (one patient), thirst (completed suicide, suicide attempts, suicide ideation) (two patients), and somnolence (one patient). All patients reported by investigators in the open-label extension studies.
with overdoses of montelukast fully recovered. No seriousdrug-related adverse experiences were reported in the usual care group. In addition to the serious clinical adverse Experiences—Short-Term Double-Blind Studies experiences reported, one patient in the montelukast grouphad a serious laboratory adverse experience (increased In children 6–24 months of age, three patients in each alkaline phosphatase) that was considered drug related.
treatment group discontinued due to a clinical adverse The five most common adverse experiences reported in experience (Table 5).12 Patients in the montelukast group 6- to 14-year-old patients were upper respiratory infection, discontinued due to rash, vomiting, or worsening asthma; Safety of Montelukast in Pediatric Studies patients in the placebo group discontinued due to There were no discontinuations from the study due to bronchitis, lethargy, or sleep disorder. All events resolved adverse experiences in the linear growth study,17 although after discontinuation. There were no discontinuations one patient in the montelukast group (epilepsy), two in the attributed to laboratory adverse experiences in either beclomethasone group (worsening asthma, wheezing), and two in the placebo group (hematuria, worsening In children 2–5 years of age, 23 patients (16 in the asthma) discontinued from blinded study therapy follow- montelukast group and 7 in the placebo group) were ing an adverse clinical experience. All five patients discontinued from treatment because of a clinical adverse initially remained in the study after discontinuation from experience (Table 5). Worsening asthma was the most blinded study therapy; however, one patient in the common adverse experience that resulted in discontinua- beclomethasone group withdrew consent and discontin- tion of study therapy.1 One patient in the placebo group ued approximately 2 weeks later. There were no discontinued therapy because of a laboratory adverse discontinuations from the study or blinded study therapy experience (increased alkaline phosphatase at 6 weeks, due to laboratory adverse experiences in any of the groups which was elevated for this patient at baseline and at in the linear growth study (Table 5).
2 weeks after discontinuation as well).
Three children in the knemometry study were discon- tinued from treatment because of a clinical adverse Experiences—Open-Label Extension Studies experience (worsening asthma in each case)13: one while In 6- to 24-month-old patients with persistent asthma, receiving placebo in the montelukast/placebo arm; one six patients (all in the montelukast group) discontinued while receiving budesonide; and one while receiving treatment due to worsening asthma, sinusitis, seizure, or a placebo in the budesonide/placebo arm.
sleep disorder (trouble staying asleep) (Table 5). The In 6- to 14-year-old children, eight patients in the patient with the sleep disorder had two episodes of otitis montelukast group and three in the placebo group media concurrent with the sleep disorder. All patients discontinued due to a clinical adverse experience recovered after discontinuation of therapy. There were no (Table 5). Worsening asthma (five patients in the discontinuations due to clinical adverse experiences in the montelukast group and two patients in the placebo group) usual care group, and there were no discontinuations due was the most common adverse experience that resulted in to laboratory adverse experiences in either treatment discontinuation of study therapy.5,14 Two patients in the montelukast group discontinued therapy due to a labo- In 2- to 5-year-old patients with persistent asthma, 23 ratory adverse experience: one for increased ALT and one patients discontinued study drug due to a clinical adverse for decreased neutrophils. Both conditions were present at experience, including 18 in the montelukast group (4.9%) and 5 in the usual care group (3.2%) (Table 5). Worsening In 2- to 14-year-old children with allergic rhinitis, five asthma was the most frequent clinical adverse experience patients (1.8%) treated with montelukast and one patient resulting in discontinuation in both groups. Four patients, treated with placebo (0.8%) discontinued due to an all in the montelukast group, discontinued study drug due adverse experience (Table 5). Two of these discontinua- to a laboratory adverse experience (decreased leukocytes, tions (one in each treatment group) were due to worsening decreased hemoglobin, increased AST, and increased asthma; others included upper respiratory infection, viral infection, otitis media, and ophthalmic infection.
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 Experiences—Long-Term Double-Blind Studies 5 patients discontinued due to a laboratory adverseexperience (2.4%); there were no discontinuations In the PREVIA study, 11 patients (1 in the montelukast because of an adverse experience in the usual care group treatment group [0.4%] and 10 in the placebo group (Table 5). Worsening asthma was the most frequent [3.7%]) discontinued treatment due to a clinical adverse clinical adverse experience resulting in discontinuation experience (P ¼ 0.005) (Table 5).6 Discontinuation in the (three patients). Reasons for discontinuations due to a montelukast group was due to epilepsy. Discontinuations laboratory adverse experience included increased AST, in the placebo group were due to respiratory tract increased ALT, decreased neutrophils, and increased total infection, worsening asthma, pneumonia, decreased peak expiratory flow, cough, abdominal pain, moodswings, abnormal behavior, petecchiae, and hypersensi- tivity (allergic reaction). There were no discontinuationsdue to laboratory adverse experiences in the PREVIA There were no significant differences in the incidence of serum transaminase values exceeding the predefined limits of change within all double-blind and open-label experiences were upper respiratory infection, worsening studies that included laboratory testing after initiation of asthma, pharyngitis, and fever, reported for all treatments treatment (Table 6).1,12,13 Laboratory tests were not (placebo, usual care, montelukast) and in virtually all routinely performed after baseline measurements were performed in the PREVIA and knemometry studies.
Of the five most commonly reported adverse experi- ences reported within each of these 10 studies, there wereseldom any differences in their incidence between treat- ment groups. In open-label studies, cough was reported This article summarizes safety data from seven notably more frequently in the montelukast group than in placebo-controlled, double-blind and three active-con- the usual care treatment group in 2- to 5-year-old patients; trolled, open-label extension studies in 2,751 children however, cough resolved while patients continued in the 6 months to 14 years of age. The studies included children study, suggesting this adverse experience presented no of different age groups and included patients with clinically important safety concerns.
viral-induced intermittent asthma, persistent asthma, and Overall, there were no clinically meaningful differ- seasonal allergic rhinitis. Our review shows that oral ences between treatments in laboratory safety parameters montelukast is generally well tolerated, with a safety in any of the present studies, and analysis of predefined profile similar to that observed for placebo or usual care limits of change for selected parameters showed no therapies. These results are in line with those reported in tolerability concerns with montelukast therapy.
several pediatric studies of montelukast.2–4,7,10,11,16 Serum transaminase values that fell outside the There were few notable differences for individual predefined limit of change occurred at a low frequency adverse experiences between treatments in any of the in all groups and were of similar magnitude between/ studies described. The most common clinical adverse among treatments. Examination of laboratory adverse TABLE 6— Incidence of Serum Transaminase Levels Outside Predefined Limits of Change1 in Double-Blind andOpen-Label Pediatric Studies2 6–9 years old, persistent asthma—linear growth (56 weeks) n/m, number of patients who met criteria/total number of patients with valid measurements; BEC, beclomethasone; ICS, inhaled corticosteroids;MNT, montelukast.
1Predefined limit of change ¼ increase from baseline !100% and greater than the upper limit of normal.
2No protocol-specified laboratory safety tests were required after randomization for the PREVIA and knemometry studies; therefore, no analyses ofpredefined limits of change were performed.
Safety of Montelukast in Pediatric Studies experience data from adult and pediatric patients in an 6. Bisgaard H, Garcia MLG, Zielen S, Johnston S, Gilles L, Menten earlier report5 found no important differences between J, Tozzi CA, Polos P. Montelukast reduces viral induced asthmaexacerbations in 2 to 5 year old children with intermittent asthma.
treatments (i.e., montelukast vs. placebo or montelukast Am J Respir Crit Care Med 2005;171:315–322.
vs. inhaled beclomethasone) in the frequency of serum 7. Reiss TF, Knorr B, Malmstrom K, Noonan G, Lu S. Clinical transaminase values greater than the upper limit of normal.
efficacy of montelukast in adults and children. Clin Exp Allergy The results of safety assessments from these seven double-blind and three open-label extension studies 8. Jarvis B, Markham A. Montelukast: a review of its therapeutic potential in persistent asthma. Drugs 2000;59:891–928.
demonstrated that montelukast was well tolerated in 9. Pearlman DS, van Adelsberg J, Philip G, Tilles SA, Busse W, patients 6 months to 14 years of age with persistent Hendeles L, Loeys T, Dass SB, Reiss TF. Onset and duration of asthma; viral-induced intermittent asthma; or allergic protection against exercise-induced bronchoconstriction by a rhinitis, with treatments extending for up to 34 months.
single oral dose of montelukast. Ann Allergy Asthma Immunol Clinical and laboratory adverse experiences for patients 10. Kemp JP, Dockhorn RJ, Shapiro GG, Nguyen HH, Reiss TF, Seidenberg BC, Knorr B. Montelukast once daily inhibits similar to those for comparator therapies. The clinical exercise-induced bronchoconstriction in 6- to 14-year-old chil- and laboratory safety profiles for montelukast in these dren with asthma. J Pediatr 1998;133:424–428.
studies were similar to those observed for placebo or usual 11. Bisgaard H, for the Study Group on Montelukast and Respiratory Syncytial Virus. A randomized trial of montelukast in respiratorysyncytial virus postbronchiolitis. Am J Respir Crit Care Med The data from these studies are in agreement with previously reported safety data and highlight the positive 12. van Adelsberg J, Moy J, Wei LX, Tozzi CA, Knorr B, Reiss T.
safety profile of montelukast in children. Moreover, these Safety, tolerability, and exploratory efficacy of montelukast in 6 to results should provide useful information to physicians 24 month old patients with asthma. Curr Med Res Opin 2005;21: treating pediatric patients with asthma and allergic 13. Pedersen S, Agertoft L, Williams-Herman D, Kuznetsova O, Reiss TF, Knorr B, Dass SB, Wolthers OD. Placebo-controlled study ofmontelukast and budesonide on short-term growth in prepubertal asthmatic children. Pediatr Pulmonol 2007;42:838–843.
14. Knorr B, Matz J, Bernstein JA, Nguyen H, Seidenberg BC, Reiss TF, We thank S.B. Dass PhD for critically reviewing the Becker A, for the Pediatric Montelukast Study Group. Montelukast for chronic asthma in 6- to 14-year-old children: a randomizeddouble-blind trial. J Am Med Assoc 1998;279:1181–1186.
15. Davies GM, Dasbach EJ, Santanello NC, Knorr BA, Bratton DL.
The effect of montelukast versus usual care on health careutilization in children aged 2 to 5 years with asthma. Clin Ther 1. Knorr B, Franchi LM, Bisgaard H, Vermeulen JH, LeSouef P, Santanello N, Michele TM, Reiss TF, Nguyen HH, Bratton DL.
16. Luz Garcia Garcia M, Wahn U, Gilles L, Swern A, Tozzi CA, Montelukast, a leukotriene receptor antagonist, for the treatment Polos P. Montelukast, compared with fluticasone, for control of of persistent asthma in children aged 2 to 5 years. Pediatrics asthma among 6- to 14-year-old patients with mild asthma: the MOSAIC study. Pediatrics 2005;116:360–369.
2. Nayak A, Langdon RB. Montelukast in the treatment of allergic 17. Becker AB, Kuznetsova O, Vermeulen J, Soto-Quiros ME, Young rhinitis: an evidence-based review. Drugs 2007;67:887–901.
B, Reiss TF, Dass SB, Knorr BA, for the Montelukast Linear 3. Bjermer L. Montelukast in the treatment of asthma as a systemic Growth Study Group. Linear growth in prepubertal asthmatic disease. Expert Rev Clin Immunol 2005;1:325–335.
children treated with montelukast, beclomethasone, or placebo: 4. Storms W. Update on montelukast and its role in the treatment of a 56-week randomized double-blind study. Ann Allergy Asthma asthma, allergic rhinitis and exercise-induced bronchoconstric- tion. Expert Opin Pharmacother 2007;8:2173–2187.
18. Center for Drug Evaluation and Research and Center for 5. Storms W, Michele TM, Knorr B, Noonan G, Shapiro G, Zhang J, Biologics Evaluation and Research. Guidance for Industry E6- Shingo S, Reiss TF. Clinical safety and tolerability of montelu- Good Clinical Practice: Consolidated Guidance. Rockville, kast, a leukotriene receptor antagonist, in controlled clinical Maryland, USA: Department of Health and Human Services trials in patients aged !6 years. Clin Exp Allergy 2001;31: Food and Drug Administration; 1996. pp. 1–58. http://www.fda.

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